tag:blogger.com,1999:blog-13464831418604571362024-03-13T09:35:05.693-07:00API SYNTHESIS INTERNATIONALAll you want to know about drugs..by Dr Anthony Melvin Crasto, Worlddrugtracker, email me ........... amcrasto@gmail.com, call +91 9323115463 IndiaDRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.comBlogger255125tag:blogger.com,1999:blog-1346483141860457136.post-18759931845697569952023-03-09T18:52:00.000-08:002023-03-09T18:52:01.397-08:00Smartchem by Row2 Technologies<p><br /></p>
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</div><div><br /></div><div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen='allowfullscreen' webkitallowfullscreen='webkitallowfullscreen' mozallowfullscreen='mozallowfullscreen' width='563' height='468' src='https://www.blogger.com/video.g?token=AD6v5dwlhzDZ2EdX7UGZrI2_edQB6kCXIBcglAZaN2eG-JD4ZUASqYxzxZlqVYEFnGz3PGHY4BmYH0gqEGsJzyWnRw' class='b-hbp-video b-uploaded' frameborder='0'></iframe></div><br /><div><br /></div>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-1346483141860457136.post-44888480670145962722020-12-07T18:13:00.006-08:002020-12-07T18:13:55.109-08:00Molnupiravir, EIDD 2801<p> </p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjt5TVuBwfTkQmERNyKY1zjA_j_vvT8LBzcx62kNlpnwvV_GS0MxOokIX0xRs1MQglkqkC2uvbMDox2RGdHDi0X19GwuQgcZCKD6CQBSCqceIPjHIONTBfsApCmAEYQGGU8m1kEjVmAA87Q/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="172" data-original-width="300" height="183" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjt5TVuBwfTkQmERNyKY1zjA_j_vvT8LBzcx62kNlpnwvV_GS0MxOokIX0xRs1MQglkqkC2uvbMDox2RGdHDi0X19GwuQgcZCKD6CQBSCqceIPjHIONTBfsApCmAEYQGGU8m1kEjVmAA87Q/" width="320" /></a></div><br /><p></p><h1 class="title-header" style="background-color: white; clear: both; color: #333333; font-family: Kalam, cursive; font-size: 40px; letter-spacing: -1px; line-height: 1.15; margin: 30px 0px; overflow-wrap: break-word; padding: 0px 230px;">Molnupiravir, EIDD 2801</h1><p><br /></p><p><a href="https://newdrugapprovals.org/2020/03/28/eidd-2801/">https://newdrugapprovals.org/2020/03/28/eidd-2801/</a></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com8tag:blogger.com,1999:blog-1346483141860457136.post-49041068724668833232020-10-25T19:27:00.002-07:002020-10-25T19:27:25.292-07:00Triheptanoin<p> <img alt="Skeletal formula of triheptanoin" scale="0" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/6a/Triheptanoin.png/250px-Triheptanoin.png" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; height: auto; max-width: 100%; vertical-align: middle;" /></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">Triheptanoin</p><p><a href="https://newdrugapprovals.org/2020/10/26/triheptanoin/">https://newdrugapprovals.org/2020/10/26/triheptanoin/</a></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-1346483141860457136.post-35879465945956267452020-10-06T19:29:00.001-07:002020-10-06T19:29:08.729-07:00Enarodustat<p> <img alt="Enarodustat (JAN).png" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?sid=384585499&t=l&version=1&deposited=t" /></p><!-- wp:image -->
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<figure class="wp-block-image"><img alt="Enarodustat Chemical Structure" src="https://file.medchemexpress.com/product_pic/hy-109057.gif" /></figure>
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<p>Enarodustat</p>
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<p>エナロデュスタット</p>
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<p>JTZ 951</p>
<!-- /wp:paragraph --><p><a href="https://newdrugapprovals.org/2020/10/07/enarodustat/">https://newdrugapprovals.org/2020/10/07/enarodustat/</a></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com4tag:blogger.com,1999:blog-1346483141860457136.post-68825728467948128372020-09-30T19:57:00.002-07:002020-09-30T19:57:14.439-07:00Sofpironium bromide<p> <img alt="Sofpironium bromide.png" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=86301316&t=l" /></p><p><img alt="File:Sofpironium bromide.jpg" src="https://upload.wikimedia.org/wikipedia/commons/d/d4/Sofpironium_bromide.jpg" /></p><p>Sofpironium bromide</p><p>ソフピロニウム臭化物</p><p>BBI 4000</p><p>READ AT</p><p><a href="https://newdrugapprovals.org/2020/10/01/sofpironium-bromide/">https://newdrugapprovals.org/2020/10/01/sofpironium-bromide/</a></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-1346483141860457136.post-1820008817758407932020-09-26T19:20:00.003-07:002020-09-26T19:20:19.433-07:00Abametapir アバメタピル , абаметапир , أباميتابير , 阿巴甲吡 ,<p> <img alt="Abametapir skeletal.svg" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a1/Abametapir_skeletal.svg/70px-Abametapir_skeletal.svg.png" /></p><p>Abametapir</p><p>CLICK</p><p><a href="https://newdrugapprovals.org/2020/09/27/abametapir-%e3%82%a2%e3%83%90%e3%83%a1%e3%82%bf%e3%83%94%e3%83%ab-%d0%b0%d0%b1%d0%b0%d0%bc%d0%b5%d1%82%d0%b0%d0%bf%d0%b8%d1%80-%d8%a3%d8%a8%d8%a7%d9%85%d9%8a%d8%aa%d8%a7%d8%a8%d9%8a%d8%b1/">https://newdrugapprovals.org/2020/09/27/abametapir-%e3%82%a2%e3%83%90%e3%83%a1%e3%82%bf%e3%83%94%e3%83%ab-%d0%b0%d0%b1%d0%b0%d0%bc%d0%b5%d1%82%d0%b0%d0%bf%d0%b8%d1%80-%d8%a3%d8%a8%d8%a7%d9%85%d9%8a%d8%aa%d8%a7%d8%a8%d9%8a%d8%b1/</a></p><p><br /></p><p><span style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px;">////////////Abametapir, 2020 APPROVALS, FDA 2020, Xeglyze, アバメタピル , </span><span style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; font-weight: 700;">абаметапир</span><span style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px;"> , </span><span style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; font-weight: 700;">أباميتابير</span><span style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px;"> </span><span class="synonym_language" style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px;">, </span><span style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; font-weight: 700;">阿巴甲吡</span><span style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px;"> , BRN 0123183, HA 44, head lice</span></p><p><br /></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-1346483141860457136.post-14730236898660839672020-09-22T19:38:00.000-07:002020-09-22T19:38:01.290-07:00Nifurtimox<p> </p><p style="color: #222222; font-family: "Open Sans", Tahoma, Verdana, Segoe, sans-serif; font-size: 16px; padding: 0px 0px 1em;"><img alt="Nifurtimox.svg" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a6/Nifurtimox.svg/250px-Nifurtimox.svg.png" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a6/Nifurtimox.svg/250px-Nifurtimox.svg.png" style="height: auto; margin-bottom: 10px; margin-top: 8px; max-width: 100%;" /></p><p style="color: #222222; font-family: "Open Sans", Tahoma, Verdana, Segoe, sans-serif; font-size: 16px; padding: 0px 0px 1em;">Nifurtimox</p><p style="padding: 0px 0px 1em;"><span style="color: #222222; font-family: Open Sans, Tahoma, Verdana, Segoe, sans-serif;"><a href="https://newdrugapprovals.org/2020/09/23/nifurtimox/">https://newdrugapprovals.org/2020/09/23/nifurtimox/</a></span></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-1346483141860457136.post-10141033352932874582020-09-19T22:19:00.000-07:002020-09-19T22:19:00.453-07:00Pralsetinib<p> </p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;"><img alt="ChemSpider 2D Image | trans-N-{(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl}cyclohexanecarboxamide | C27H32FN9O2" scale="0" src="http://www.chemspider.com/ImagesHandler.ashx?id=71060332&w=250&h=250" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">Pralsetinib</p><p><br /></p><p>https://newdrugapprovals.org/2020/09/20/pralsetinib/</p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com5tag:blogger.com,1999:blog-1346483141860457136.post-1231579983582237022020-09-13T19:54:00.001-07:002020-09-13T19:54:17.783-07:00ODEVIXIBAT<p> </p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;"><img alt="Structure of ODEVIXIBAT" scale="0" src="https://drugs.ncats.io/img/4493acce-035a-4828-b4b5-4cb4830024f2.svg?size=400&version=16&stereo=false" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;"><img alt="Odevixibat.png" scale="0" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=10153627&t=l" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">Odevixibat</p><p>https://newdrugapprovals.org/2020/09/14/odevixibat/</p><p><br /></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-1346483141860457136.post-12786010328520120172016-10-13T23:40:00.001-07:002016-10-14T18:42:33.267-07:00Register Today for the ACS Symposium in India on Recent Advances in Drug Development, 11-12 November 2016 in Hyderabad, India<div dir="ltr" style="text-align: left;" trbidi="on">
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<span data-mce-style="color: #ff0000;" style="color: red;">Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India</span></h1>
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<span data-mce-style="color: #008000;" style="color: green;">Recent Advances in Drug Development</span></h1>
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Register Today for the ACS Symposium in India on Recent Advances in Drug Development</div>
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<span style="color: #222222; font-family: open sans, tahoma, verdana, segoe, sans-serif;"><b><a href="http://acssymposium.org.in/">http://acssymposium.org.in/</a></b></span><br />
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The theme of the Symposium is Recent Advances in Drug Development. The event will feature lectures by the world's leading researchers and experts in the pharma industry, including:</div>
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<li style="padding-top: 5px;">Dr. Peter Senter of Seattle Genetics</li>
<li style="padding-top: 5px;">Dr. Jagath Reddy Junutula of Cellerant Therapeutics, Inc.</li>
<li style="padding-top: 5px;">Dr. Ming-Wei Wang of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences</li>
</ul>
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This is an exclusive event being organized in partnership with Dr. Reddy's Laboratories for pharma professionals throughout India. <a data-mce-href="http://click.communications.cas.org/?qs=9287116e433966c8f4d34a8174ad3f7b5c33bd5648fe0f6878a8f7d02c4d79256aaa831e82a4f02b" href="http://click.communications.cas.org/?qs=9287116e433966c8f4d34a8174ad3f7b5c33bd5648fe0f6878a8f7d02c4d79256aaa831e82a4f02b" style="color: #222222;"><strong>Space is limited so register today!</strong></a></div>
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Please <a data-mce-href="http://click.communications.cas.org/?qs=9287116e433966c87669ed8f327dc5412b29d647c3bc9471d8b522eb3812d804056575987315d898" href="http://click.communications.cas.org/?qs=9287116e433966c87669ed8f327dc5412b29d647c3bc9471d8b522eb3812d804056575987315d898" style="color: #222222;">visit our website</a> to learn more about the speakers and the program.</div>
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CAS<br />
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<b style="font-size: medium;"><a href="http://acssymposium.org.in/">http://acssymposium.org.in/</a></b></div>
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/////// ACS Symposium, Recent Advances in Drug Development, 11-12 November 2016, Hyderabad, India, dr reddys, cas</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com19tag:blogger.com,1999:blog-1346483141860457136.post-42303155539949084522016-08-16T01:43:00.002-07:002016-08-16T05:56:19.123-07:00ULIXERTINIB, уликсертиниб , أوليكسيرتينيب , 优立替尼 ,<div dir="ltr" style="text-align: left;" trbidi="on">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-58.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-58.jpg" rel="attachment wp-att-8329" style="background-color: white; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><img alt="STR1" class="alignnone size-full wp-image-8329" data-mce-selected="1" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-58.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-58.jpg" height="374" style="height: auto; max-width: 100%; outline: rgb(119, 119, 119) solid 1px; resize: none;" width="544" /></a><br />
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OR</div>
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<img alt="" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=58641927&t=l" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=58641927&t=l" style="height: auto; max-width: 100%;" /></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">ULIXERTINIB</span></div>
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4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide</div>
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<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Formula:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C21H22Cl2N4O2&sort=mw&sort_dir=asc" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C21H22Cl2N4O2&sort=mw&sort_dir=asc" title="Find all compounds with formula C21H22Cl2N4O2">C<sub>21</sub>H<sub>22</sub>Cl<sub>2</sub>N<sub>4</sub>O<sub>2</sub></a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Weight:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">433.33098 g/mol</td></tr>
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BVD-523; BVD-ERK; BVD-ERK/HM; BVD-ERK/ST; VRT-0752271; VRT-752271; VX-271, V</div>
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<strong>уликсертиниб , </strong><strong>أوليكسيرتينيب</strong> , <strong>优立替尼</strong> ,</div>
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<span class="">4-[5-chloro-2-(isopropylamino)-4-pyridyl]-N-[(1S)-1-(3-chlorophenyl)-2-hydroxy-ethyl]-1H-pyrrole-2-carboxamide</span></div>
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<span class="">CAS 869886-67-9</span></div>
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<a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Vertex+Pharmaceuticals,+Incorporated%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Vertex+Pharmaceuticals,+Incorporated%22">Vertex Pharmaceuticals, Incorporated</a> innovators</div>
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<table class="patent-bibdata patent-drawings-missing mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr class="patent-bibdata-list-row "><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-bibdata-value-list"><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Gabriel+Martinez-Botella%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Gabriel+Martinez-Botella%22">Gabriel Martinez-Botella</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Michael+R.+Hale%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Michael+R.+Hale%22">Michael R. Hale</a>,</span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Fran%C3%A7ois+MALTAIS%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Fran%C3%A7ois+MALTAIS%22">François MALTAIS</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Qing+Tang%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Qing+Tang%22">Qing Tang</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Judith+Straub%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Judith+Straub%22">Judith Straub</a></span></span></td></tr>
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<span data-mce-style="color: #ff0000;" style="color: red;">ULIXERTINIB HCl</span></div>
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<img alt="" data-mce-src="https://www.biomol.com/details/CM/gfx/normal/18298.png" src="https://www.biomol.com/details/CM/gfx/normal/18298.png" style="height: auto; max-width: 100%;" /></div>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="100">Molecular Weight</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">469.79</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Formula</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">C21H22Cl2N4O2●HCl</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> CAS</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> 1956366-10-1</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical Name</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1H-Pyrrole-2-carboxamide, 4-[5-chloro-2-[(1-methylethyl)amino]-4-pyridinyl]-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-,hydrochloride(1:1)</td></tr>
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<span data-mce-style="color: #ff0000;" style="color: red;">Ulixertinib malonate</span></div>
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4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide (referred to as ulixertinib malonate)</div>
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<img alt="" data-mce-src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcSBRCS2gVyF3XFlZE1ttZTudzlApgYNnQ2ZOmU1ZfQIe42Nn3ym" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcSBRCS2gVyF3XFlZE1ttZTudzlApgYNnQ2ZOmU1ZfQIe42Nn3ym" style="height: auto; max-width: 100%;" /></div>
<ul class="data-list__content" id="at-a-glance_orphanStatus" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li class="data-list__property" id="at-a-glance_origniator"><strong class="data-list__property-key">Originator </strong><span class="data-list__property-value">Vertex Pharmaceuticals</span></li>
<li class="data-list__property" id="at-a-glance_developer"><strong class="data-list__property-key">Developer </strong><span class="data-list__property-value">BioMed Valley Discoveries</span></li>
<li class="data-list__property" id="at-a-glance_class"><strong class="data-list__property-key">Class </strong><span class="data-list__property-value">Aminopyridines; Antineoplastics; Pyrroles; Small molecules</span></li>
<li class="data-list__property" id="at-a-glance_mechanismOfAction"><strong class="data-list__property-key">Mechanism of Action </strong><span class="data-list__property-value">Mitogen activated protein kinase 3 inhibitors; Mitogen-activated protein kinase 1 inhibitor</span></li>
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Highest Development Phases</h3>
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<li class="data-list__property"><strong class="data-list__property-key">Phase I/II </strong><span class="data-list__property-value">Acute myeloid leukaemia; Cancer; Myelodysplastic syndromes</span></li>
<li class="data-list__property"><strong class="data-list__property-key">Phase I </strong><span class="data-list__property-value">Pancreatic cancer</span></li>
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Most Recent Events</h3>
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<li class="data-list__property"><strong class="data-list__property-key">01 Mar 2016 </strong><span class="data-list__property-value property-value--event-details">Phase-I clinical trials in Pancreatic cancer (Combination therapy, First-line therapy, Metastatic disease) in USA (PO) (NCT02608229)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">23 Nov 2015 </strong><span class="data-list__property-value property-value--event-details">BioMed Valley Discoveries and Washington University School of Medicine plan a phase Ib trial for Pancreatic cancer (First-line therapy, Metastatic disease, Combination therapy) (PO) (NCT02608229)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">01 Nov 2014 </strong><span class="data-list__property-value property-value--event-details">Phase-I/II clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) and Myelodysplastic syndromes (Second-line therapy or greater) in USA (NCT02296242) (PO)</span></li>
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<li class="data-list__property"><img alt="" class="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/5/5a/VertexPharma-logo2.png" height="472" src="https://upload.wikimedia.org/wikipedia/commons/5/5a/VertexPharma-logo2.png" style="height: auto; max-width: 100%;" width="771" /></li>
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<span data-mce-style="color: #ff0000;" style="color: red;">INTRODUCTION</span></div>
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Ulixertinib is in phase I/II clinical trials for the treatment of acute myelogenous leukemia (AML), myelodysplasia and advanced solid tumors.</div>
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Members of the family of B-cell CLL/lymphoma 2 proteins (BCL-2) are apoptosis regulators. These proteins control mitochondrial outer</div>
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membrane permeabilization (MOMP). Expression of BCL-2 protein blocks cell death in response to various cellular injuries. A number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, may be caused by damage to the BCL-2 gene. Mutations in BCL-2 may also be a cause of resistance to cancer treatments. Unfortunately, resistance can quickly develop using conventional BCL-2 inhibitor therapies to treat cancer.</div>
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Extracellular-signal-regulated kinases (ERKs) are protein kinases that are involved in cell cycle regulation, including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Disruption of the ERK pathway is common in cancers. However, to date, little progress has been made developing effective ERK inhibitors for the treatment of cancer.</div>
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As the understanding of the molecular basis of cancer grows, there is an increased emphasis on developing drugs that specifically target particular nodes in pathways that lead to cancer. In view of the deficiencies noted above, there is, inter alia, a need for effective molecularly targeted cancer treatments, including combination therapies. The present invention is directed to meeting these and other needs.</div>
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<img alt="" data-mce-src="http://www.pmlive.com/__data/assets/image/0009/405945/Vertex-Pharma.jpg" src="http://www.pmlive.com/__data/assets/image/0009/405945/Vertex-Pharma.jpg" style="height: auto; max-width: 100%;" /></div>
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Mitogen-activated protein kinase (MAPK) pathways mediate signals which control diverse cellular processes including growth, differentiation, migration, proliferation and apoptosis. One MAPK pathway, the extracellular signal-regulated kinase (ERK) signaling pathway, is often found to be up-regulated in tumors. Pathway members, therefore, represent attractive blockade targets in the development of cancer therapies (Kohno and Pouyssegur, 2006). For example, U.S. Patent No. 7,354,939 B2 discloses, inter alia, compounds effective as inhibitors of ERK protein kinase. One of these compounds, 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide, is a compound according to formula (I):</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2016015829@@@id00000068085582@@@8076331@@@imgf000003_0001.gif" height="195" id="imgf000003_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2016015829@@@id00000068085582@@@8076331@@@imgf000003_0001.gif" style="height: auto; max-width: 100%;" width="324" /></div>
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Pharmaceutical compositions are often formulated with a crystalline solid of the active pharmaceutical ingredient (API). The specific crystalline form of the API can have significant effects on properties such as stability and solubility / bioavailability. Instability and solubility characteristics can limit the ability to formulate a composition with an adequate shelf life or to effectively deliver a desired amount of a drug over a given time frame (Peterson et al., 2006).</div>
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Synergistic combination comprising an ERK1/2 inhibitor (such as ulixertinib) and a BCL-2 family inhibitor (such as navitoclax), assigned to BioMed Valley Discoveries (BVD), naming Decrescenzo and Welsch. BVD, presumably under license from Vertex, is developing ulixertinib (phase 2 trial), a small-molecule ERK 1/2 inhibitor for treating cancers including acute myelogenous leukemia and myelodysplastic syndrome. In June 2015, clinical data were presented at the 51st ASCO meeting in Chicago, IL.</div>
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BIOMED VALLEY DISCOVERIES</h1>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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WO2005113541 PDT PATENT</div>
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I-9 COMPD</div>
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SEE BELOW</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123574&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123574&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription">WO-2016123574</a></div>
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Novel crystalline forms of 4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide (referred to as ulixertinib) can be prepared which exhibit improved properties, eg surprisingly improved stability and solubility characteristics. Also claimed is their use for treating cancer.</div>
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EXAMPLE 2</div>
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Preparation of Crystaline Free Base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide</div>
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4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide free base was prepared according to the following synthesis scheme.</div>
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Stepl</div>
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C<sub>5</sub>H<sub>2</sub>CIFIN</div>
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257.43 C<sub>8</sub>H<sub>10</sub>CIIN<sub>2</sub></div>
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ASYM-11 1606 296.54</div>
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ASYM-1 12060</div>
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ASYM-111938 ASYM-112393</div>
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ASYM-1 11935</div>
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In Step 1 , a clean and dry 200 L glass-lined reactor was evacuated to <-0.08 MPa, and then filled with nitrogen to normal pressure three times. Anhydrous ethanol (49.90 kg) was charged into the 200 L glass-lined reactor. ASYM-1 1 1606 (Asymchem) (12.70 kg) and isopropylamine (29.00 kg) were added into the mixture in turn. The mixture was heated to 65-75°C for refluxing. The mixture reacted at 65-75°C. After 20 h, the reaction was sampled and analyzed by HPLC every 4-6 h until the content of ASYM-1 1 1606 was <1 %. The mixture was cooled to 40-45°C and was concentrated at <45°C under reduced pressure (<-0.08 MPa) until 13-26 Lremained. The organic phase was washed with a sodium chloride solution and was stirred for 20-30 min and settled for 20-30 min before separation. The organic phase was concentrated at <30°C under reduced pressure (<-0.06 MPa) until 13-20 L remained. Petroleum ether (8.55 kg) was added into the concentrated mixture. The mixture was transferred into a 20 L rotary evaporator and continued concentrating at <30°C under reduced pressure (<-0.06 MPa) until 13-20 L remained. Then petroleum ether (8.55 kg) was added into the concentrated mixture. The mixture was cooled to 0-5°C and stirred for crystallization. After 1 h, the mixture was sampled and analyzed by wt% every 1 -2 h until the wt% of the mother liquor was <1 1 % or the change of the wt% between consecutive samples was <1 %. The mixture was filtered with a 10 L filter flask. The filter cake was sampled and analyzed for purity by HPLC. 10.50 kg of product was recovered as a brownish yellow solid at 99.39% purity.</div>
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In Step 2, a clean and dry 300 L glass-lined reactor was evacuated to <-0.08 MPa, and then filled with nitrogen to normal pressure three times. Glycol dimethyl ether (73.10 kg) was charged into the 300 L glass-lined reactor at 20-30°C. ASYM-1 12060 (Asymchem) (10.46 kg) and ASYM-1 1 1938 (Asymchem) (12.34 kg, 1 1 .64 kg after corrected) were added into the mixture in turn under the protection of nitrogen. Maintaining the temperature at 20-30°C, purified water (10.50 kg) and anhydrous sodium carbonate (5.67 kg) were added into the mixture. Palladium acetate (0.239 kg) and tricyclohexylphosphonium tetrafluoroborate (0.522 kg) were added into the mixture under the protection of nitrogen. After addition, the mixture was evacuated to <-0.06 MPa, and then filled with nitrogen to normal pressure. This was repeated for ten times until residual oxygen was <300 ppm. The mixture was heated to 75-85°C for refluxing. The mixture reacted at 75-85°C. After 4 h, the mixture was sampled and analyzed by HPLC every 2-3 h for content of ASYM-</div>
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1 12060. The content of AS YM-1 12060 was 6.18%, so additional ASYM-1 1 1938 (0.72 kg) was added and continued reaction until the content of ASYM-1 12060 was <3%. The mixture was cooled to 25-35°C and filtered with a 30 L stainless steel vacuum filter. The filter cake was soaked and washed twice with THF (14.10kg). The filtrate and washing liquor were combined and concentrated at <50°C under reduced pressure (<-0.08 MPa) until 10-15 L remained. The mixture was cooled to 15-25°C. Methanol (1 1 .05 kg) was added into the concentrated mixture. Then the mixture was stirred for crystallization. After 2 h, the mixture was sampled and analyzed by HPLC every 2-4 h until the wt% of the mother liquor was <2%. The mixture was filtered with a 30 L stainless steel vacuum filter. The filter cake was soaked and washed twice with methanol (8.30 kg). The filter cake was transferred into a 50 L plastic drum. Then ethyl acetate (7.10 kg) and petroleum ether (46.30 kg) were added into the drum. The mixture was stirred for 1.5-2 h and then filtered with a nutsche filter. The filter cake was soaked and washed with petroleum ether (20.50 kg). The filter cake was dried in the nutsche filter under nitrogen at 30-40°C. After 8 h, the solid was sampled and Karl Fischer (KF) analysis was performed in intervals of 4-8 h to monitor the drying process. Drying was completed when the KF result was <1 .0% water. During drying, the solid was turned over and mixed every 4-6 h. 12.15 kg of product was recovered as a brownish yellow solid at 98.32% purity.</div>
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In Step 3, a clean and dry 300 L glass-lined reactor was evacuated to <-0.08 MPa, and then filled with nitrogen to normal pressure three times. THF (62.58 kg) was charged into the 300 L glass-lined reactor at 15-30°C. Then the stirrer was started. ASYM-1 12393 (12.00 kg, 1 1 .70 kg after corrected) was added into the mixture. The mixture was stirred until the solid dissolved completely. Maintaining the temperature at 15-30°C, a lithium hydroxide solution which was</div>
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prepared with lithium hydroxide monohydrate (5.50 kg) in purified water (70.28 kg) was added into the mixture. Then diethylamine (3.86 kg) was added. The mixture was heated to 60-70°C for refluxing. The mixture reacted at 60-70°C. After 30 h, the reaction was sampled and analyzed by HPLC every 4-6 h until the content of intermediate at relative retention time (RRT)=1 .39-1 .44 was <1 % and the content of ASYM-1 12393 was <1 %. HPLC conditions for this analysis are set forth in Table 1 .</div>
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Table 1 : HPLC Parameters</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2016015829@@@id00000068085582@@@8076331@@@imgf000086_0001.gif" height="286" id="imgf000086_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2016015829@@@id00000068085582@@@8076331@@@imgf000086_0001.gif" style="height: auto; max-width: 100%;" width="495" /></div>
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The mixture was cooled to 25-35°C and MTBE (25.97 kg) was added into the mixture. The mixture was stirred for 20-30 min and filtered via an in-line fluid filter. The filtrate was transferred into a 300 L glass-lined reactor and settled for 20-30 min before separation. The pH of the obtained aqueous phase was adjusted with a 6 N hydrochloric acid solution which was prepared from concentrated hydrochloric acid (14.86 kg) in purified water (10.88 kg) at the rate of 5-8 kg/h at 15-25°C until the pH was 1 -2. The pH of the mixture was adjusted again with a saturated sodium carbonate solution which was prepared from sodium carbonate (5.03 kg) in purified water (23.56 kg) at the rate of 3-5 kg/h at 15-25°C until the pH was 6.4-6.7. Then the pH of the mixture was adjusted with a hydrochloric acid solution which was prepared from concentrated hydrochloric acid (1 .09 kg) in purified water (0.80 kg) until the pH was 6.2-6.4. The mixture was filtered with a nutsche filter. The filter cake was transferred into a 300 L glass-lined reactor and purified water (1 17.00 kg) was added. The mixture was stirred and sampled and analyzed by HPLC until the p-toluenesulfonic acid residue of the filter cake was <0.5%. Then the mixture was filtered. The filter cake was dried in the tray drier under nitrogen at 55-65°C until KF<10%. The solid and MTBE (8.81 kg) were charged into a 50 L stainless steel drum. The mixture was stirred for 1 -2 h. The mixture was filtered with a 30 L stainless steel vacuum filter. The filter cake was dried in the nutsche filter at 50-60°C. After 8 h, the solid was sampled and analyzed by KF every 4-8 h until KF<5%. During drying, the solid was turned over and mixed every 4-6 h. 6.3 kg of product was recovered as an off-white solid at 98.07% purity.</div>
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In Step 4, a dry and clean 50 L flask was purged with nitrogen for 20 min. DMF (30.20 kg) was charged into the 50 L flask reactor. Then the stirrer was started. Maintaining the temperature at 15-25°C, ASYM-1 12394 (3.22 kg, 2.76 kg after corrected) was added into the mixture. The mixture was stirred until the solid dissolved completely. The mixture was cooled to -10 to -20°C and 1 -hydroxybenzotriazole hydrate (2.10 kg) was added into the mixture at -10 to -20°C. Then EDCI (2.41 kg) was added into the mixture in five portions at an interval of about 5-10 min. The mixture was cooled to -20 to -30°C and ASYM-1 1 1888 (Asymchem) (1 .96 kg) was added into the mixture at -20 to -30°C. Then DIEA (1 .77 kg) was added into the mixture at the rate of 3-4 kg/h. The mixture was heated to 15-25°C at the rate of 5-10°C/h. The mixture was reacted at 15-25°C. After 6-8 h, the mixture was sampled and analyzed by HPLC every 2-4 h until the content of ASYM-1 12394 was <2%. The mixture was cooled to 0-10°C and the reaction mixture was quenched with a solution which was prepared from ethyl acetate (28.80 kg) in purified water (12.80 kg) at 0-10°C. The mixture was extracted three times with ethyl acetate (28.80 kg). For each extraction the mixture was stirred for 20-30 min and settled for 20-30 min before separation. The organic phases were combined and washed twice with purified water (12.80 kg). The mixture was stirred for 20-30 min and settled for 20-30 min before separation for each time. Then the obtained organic phase was filtered through an in-line fluid filter. The filtrate was transferred into a 300 L glass-lined reactor. The mixture was washed twice with a 5% acetic acid solution, which was prepared from acetic acid (2.24 kg) in purified water (42.50 kg). The solution was added at the rate of 10-20 kg/h. The organic phase was washed twice with a sodium carbonate solution, which was prepared from sodium carbonate (9.41 kg) in purified water (48.00 kg). The organic phase was washed twice with a sodium chloride solution, which was prepared from sodium chloride (16.00 kg) in purified water (44.80 kg). The organic phase was transferred into a 300 L glass-lined reactor. Anhydrous sodium sulfate (9.70 kg) was added into the mixture and the mixture was stirred for 2-4 h at 15-30°C. The mixture was filtered with a nutsche filter, which was pre-loaded with about 1 cm thick silica gel (7.50 kg). The filter cake was soaked and washed with ethyl acetate (14.40 kg) before filtration. The filtrates were combined and the combined filtrate was added into a 72 L flask through an in-line fluid filter. The mixture was concentrated at T≤40°C under reduced pressure (P<-0.08 MPa) until 3-4 L remained. Then MTBE (4.78 kg) was added into the mixture. The mixture was cooled to 0-10°C for crystallization with stirring. After 1 h, the mixture was sampled and analyzed by wt% every 1-2 h until the wt% of the mother liquor was <5% or the change of wt% between consecutive samples was <1%. The mixture was filtered with a vacuum filter flask and the filter cake was dried in the tray drier under nitrogen at 30-40°C until KF<0.5%. 3.55 kg of product was recovered as an off-white solid at 100% purity.</div>
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EXAMPLE 3A</div>
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Preparation of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C</div>
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4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C was prepared from 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide free base as follows. ASYM-1 1 1935 (10.4 kg) was added to a stirred mixture of anhydrous ethanol (73.9 kg), methanol (4.1 kg) and isopropanol (4.1 kg). The mixture was heated to 70-75°C and stirred until all the solids dissolved. Anhydrous HCI (37 wt%, 1 .1 eq) in a mixture of ethanol/methanol/isopropanol (90:5:5) was added and the mixture maintained at 70-75°C for 2 hours after the addition was completed. The mixture was then cooled to 15-25°C at a rate of 5-15°C per hour and stirred at this temperature until the desired polymorphic purity was reached. The end point of the crystallization/polymorph conversion was</div>
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determined by the absence of an XRPD peak at about 10.5° 2Θ in three successive samples.</div>
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The mixture was then filtered and washed successively with a pre-prepared solution of anhydrous ethanol (14.8 kg), methanol (0.8 kg) and isopropanol (0.8 kg), followed by MTBE (2 x 21 kg). Avoidance of delay in the washing of the filter cake is preferable because the polymorph may be unstable in the wet filter cake in the presence of reagent alcohol and improved stability was observed after the MTBE wash has been performed. The wet filter cake was then dried in a heated filter funnel or a tray drier at 40-50°C until dry. Typical yields were about 85-90%.</div>
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EXAMPLE 3B</div>
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Alternative Preparation of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2016015829@@@id00000068085582@@@8076331@@@imgf000094_0001.gif" height="186" id="imgf000094_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2016015829@@@id00000068085582@@@8076331@@@imgf000094_0001.gif" style="height: auto; max-width: 100%;" width="450" /></div>
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ASYM-1 15985</div>
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4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C was also prepared from 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide free base as follows. A dry and clean 72 L flask was purged with nitrogen for 20 min. Anhydrous ethanol (21 .35 kg) methanol (1 .17 kg) and isopropanol (1 .19 kg) were charged into the 72 L flask at 15-25°C and the mixture was stirred for 20-30 min. ASYM-1 1 1935 (3.01 kg) was added into the mixture and heated to 70-75°C at the rate of 15-25°C/h and stirred until the solid dissolved completely.</div>
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An alcohol / HCI solution was prepared as follows. Anhydrous ethanol (1.500 kg) methanol (0.088 kg) and isopropanol (0.087 kg) were charged into a 5 L flask at 15-25°C and the mixture was stirred for 20-30 min. The mixture was bubbled with hydrogen chloride through a dip tube under stirring at 10-25°C. After 2 h, the mixture was sampled and analyzed every 2-4 h until the wt% of hydrogen chloride was > 35%.</div>
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The alcohol / HCI solution (0.519 kg) prepared above was added dropwise into the mixture at the rate of 0.5-1.0 kg/h at 70-75°C. Seed crystal (0.009 kg) was added into the mixture and the alcohol / HCI solution (0.173 kg) prepared above was added into the mixture at the rate of 0.5-1 .0 kg/h at 70-75°C. After addition, the mixture was stirred for 1 -2 h at 70-75°C. The mixture was cooled to 15-25°C at the rate of 5-15°C/h and stirred for 4-6 h. The mixture was heated to 70-75°C at the rate of 15-25°C/h and stirred for 8-10 h at 70-75°C. The mixture was cooled to 15-25°C at the rate of 5-15°C/h and stirred for 4-6 h. The mixture was filtered with a vacuum filter flask. The filter cake was soaked and rinsed with a solution which was prepared from anhydrous ethanol (4.25 kg) and methanol (0.24 kg) and isopropanol (0.24 kg) before filtration. The filter cake was dried in a drying room under nitrogen at 40-50°C until the ethanol residue was <0.5% and methanol residue was <0.3% and isopropanol residue was <0.3%. 2.89 kg of product was recovered as a white solid at 99.97% purity.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<u>WO-2016123581</u></div>
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Novel crystalline malonate salt forms of 4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide (referred to as ulixertinib malonate) and composition comprising them. Also claimed is their use for treating cancer.</div>
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<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123581&redirectedID=true" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123581&redirectedID=true">https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123581&redirectedID=true</a></div>
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EXAMPLE 6</div>
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Aqueous Disolution of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Malonate Form A</div>
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Samples of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C and 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2 -carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide malonate Form A were each shaken at ambient temperature in fasting state simulated gastric fluid (FaSSGF) pH 1.6 for 30 minutes. Concentration of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide was measured at 5, 15 and 30 minutes.</div>
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After 30 minutes, the samples were removed from FaSSGF, placed in fasting state simulated intestinal fluid (FaSSIF) pH 6.5, with shaking, for an additional 5 hours. Concentration of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide was measured at 10, 30, 60 90, 120, 180, 270, and 300 minutes. Results are summarized in Table 13 and shown in FIG. 10A (FaSSGF) and FIG. 10B (FaSSIF).</div>
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Table 13: Solubility of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C and Malonate Form A.</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2016015843@@@id00000068085587@@@8013481@@@imgf000092_0001.gif" height="273" id="imgf000092_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2016015843@@@id00000068085587@@@8013481@@@imgf000092_0001.gif" style="height: auto; max-width: 100%;" width="477" /></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123574&redirectedID=true" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123574&redirectedID=true">WO2016123574</a></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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WO2015095834</div>
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<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015095834&redirectedID=true" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015095834&redirectedID=true">https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015095834&redirectedID=true</a></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<a data-mce-href="https://www.google.com/patents/WO2005113541A1?cl=en" href="https://www.google.com/patents/WO2005113541A1?cl=en">WO2005113541</a></div>
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<strong><a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-59.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-59.jpg" rel="attachment wp-att-8335"><img alt="STR1" class="alignnone size-full wp-image-8335" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-59.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-59.jpg" height="41" style="height: auto; max-width: 100%;" width="666" /></a></strong></div>
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Example 1 Compound 1-9 was prepared as follows:</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2005113541A1/imgf000040_0001.png" href="https://patentimages.storage.googleapis.com/WO2005113541A1/imgf000040_0001.png"><img alt="Figure imgf000040_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2005113541A1/imgf000040_0001.png" height="618" id="imgf000040_0001" src="https://patentimages.storage.googleapis.com/WO2005113541A1/imgf000040_0001.png" style="height: auto; max-width: 100%;" width="909" /></a></div>
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1-9</div>
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2,2,2-TrichIoro-l-(4-iodo-lH-pyrrol-2-yl)ethanone: To a stirred solution of 50 g (235 mmol, 1.0 equiv.) of 2,2,2-trichloro-l-(lH-pyrrol-2-yl)-ethanone in dry dichloromethane (400 mL) under nitrogen, a solution of iodine monochloride (39 g, 240 mmol, 1.02 equivalents) in of dichloromethane (200 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The solution was washed with 10% potassium carbonate, water, 1.0 M sodium thiosulfate, saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was recrystallized from hexanes/methyl acetate to afford the title compound (68.5g, 86%) as a colorless solid (86%). MS FIA: 335.8, 337.8 ES-.</div>
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4-Iodo-lH-pyrrole-2-carboxyIic acid methyl ester: To a stirred solution of 2,2,2- trichloro-l-(4-iodo-lH-pyrrol-2-yl)ethanone (68g, 201 mmol, 1.0 equivalent) in dry methanol (400 mL) under nitrogen, was added a solution of sodium methoxide in methanol (4.37 M, 54 mL, 235 mmol, 1.2 equivalents) over 10 minutes. The resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the crude was then partitioned between water and tert- butylmethyl ether. The organic phase was separated, washed two times with water, saturated sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (48g, 96%) as a colorless solid, that was used directly without further purification.</div>
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4-Iodo-l-(toluene-4-sulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester: 4-Iodo- lH-pyrrole-2-carboxylic acid methyl ester (24.6 g, 98 mmol, 1.0 equivalent) was dissolved in dichloromethane (150 mL) and triethylamine (30 mL, 215.6 mmol, 2.2 equivalents). 4-(Dimethylamino)pyridine (1.2 g, 9.8 mmol, 0.1 equivalent) and p- toluenesulfonylchloride (20.6 g, 107.8 mmol, 1.1 equivalents) were added and the reaction mixture was stirred for 16 hours at room temperature. The reaction was quenched with 1 M ΗC1 and the organic layer was washed with aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was removed under reduced pressure and the residue was crystallized from tert-butylmethyl ether, yielding the title compound as a pale yellow solid (30 g, 75%). R<sub>t</sub>(min) 8.259 minutes.</div>
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4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yI)-l-(toluene-4-sulfonyl)-lH- pyrrole-2-carboxylic acid methyl ester: To a degassed solution of 4-iodo-l- (toluene-4-sulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester (20 g, 49.4 mmol, 1.0 equivalent) and bis(pinacolato)diborane (15 g, 65 mmol, 1.3 equivalents) in DMF (200 mL) under nitrogen, was added dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3.6 g, 4.9 mmol, 0.1 equivalent). The reaction mixture was then stirred at 80 °C for 18 hours. After removing the DMF under reduced pressure, the resulting thick oil residue was suspended in diethyl ether (500 mL) and a solid precipitated immediately. This solid was removed by filtration and the filtrate was washed with IM HCl, water, brine and dried over MgS0 . Concentration afforded the title compound as a white solid and used without further purification (10 g, 50%). LC/MS: R<sub>t</sub>(min) 4.6; 406.4 ES+. MS FIA: 406.2 ES+. 'pfNMR δ 1.2 (s, 12H), 2.35 (s, 3H), 3.8 (s, 3H), 7.2 (m, 3H), 7.8 (d, 2H), 8.0 (s, IH).</div>
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N,N'-2-(5-Chloro-4-iodo-pyridyI)-isopropyIarnine:</div>
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Method A. (Microwave)</div>
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In a 10 mL microwave tube, 5-chloro-2-fluoro-4-iodopyridine (1.0 g, 3.9 mmol, 1.0 equivalent) was dissolved in DMSO (4.0 mL) and then ispropylamine (0.99 mL, 11.7 mmol, 3.0 equivalents) was added. The tube was sealed and placed under microwave irradiation for 600 sec at 150 °C. This reaction was repeated six times. The reaction mixtures were combined, then diluted in ethyl acetate and washed with water. After drying over sodium sulfate, the solvent was evaporated to afford the title compound as a thick brown oil (5.6 g, 80% ) which was used directly without further purification. R<sub>t</sub>(min) 4.614; MS FIA: 296.9 ES+. 'pfNMRsssssss δ 1.25 (d, 6H), 3.65 (m, IH), 7.15 (s, IH), 7.75 (s, IH).</div>
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Method B: (Thennal)</div>
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5-Chloro-2-fluoro-4-iodopyridine (400 mg, 1.55 mmol, 1.0 equivalent) was dissolved in ethanol (5.0 mL) and then isopropylamine (0.66 mL, 7.8 mmol, 5.0 equivalents) was added. The resulting solution was stirred at 80 °C for 48 hours. The reaction mixture was then diluted in ethyl acetate and washed with water. After drying over sodium sulfate, the solvent was evaporated and a thick brown oil was obtained, which was then purified by flash chromatography on silica gel eluting with mixtures of hexanes/ethyl acetate (from 99:1 to 80:20) to afford the title compound as a pale yellow solid (96 mg, 21%).</div>
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4-(5-Chloro-2-isopropylaminopyridin-4-yl)-l-(toluene-4-suIfonyl)-lH-pyrrole-2- carboxylic acid methyl ester: To a solution of N,N'-2-(5-chloro-4-iodo-pyridyl)- isopropylamine (0.53 g, 1.8 mmol, 1.0 equivalent) and 4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-l-(toluene-4-sulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester (0.78 g, 1.8 mmol, 1.0 equivalent) in DME (4.0 mL) was added a solution of aqueous 2 M sodium carbonate (1.0 mL) followed by Pd(PPh<sub>3</sub>)<sub>4</sub> (0.21 mg, 0.18 mmol, 0.1 equivalent). The microwave tube was sealed and the reaction mixture was irradiated by microwave for 1800 sec. at 170 °C. The cmde of six reactions were combined and diluted in ethyl acetate and washed with water. After drying the organic layer with sodium sulfate, the solvent was removed and the resulting thick oil was adsorbed on silica gel. The crude was then purified by flash chromatography on silica, eluting with hexanes/ethyl acetate mixtures (from 99:1 to 70:30) to afford the title compound as a yellow solid (3.1 g, 61% over two steps). R<sub>t</sub>(min) 6.556. MS FIA: 448.1 ES+. 'HNMR δ 1.45 (d, 6H), 2.5 (s, 3H), 3.81 (s, 3H), 6.8 (s, IH), 7.35 (s, IH),</div>
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7.4 (d, 2H), 8.0 (m ,3H), 8.3 (s, IH).</div>
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4-(5-Chloro-2-isopropylaminopyridin-4-yl)-l-(2,4,6-trimethylbenzenesulfonyl)- lH-pyrrole-2-carboxylic acid methyl ester: To a solution of N,N'-2-(5-chloro-4- iodo-pyridyl)-isopropylamine (96 mg, 0.32 mmol, 1.0 equivalent) and 4-(4,4,5,5- tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)- 1 -(2,4,6-trimethylbenzenesulfonyl)- lH-pyrrole- 2-carboxylic acid methyl ester (152 mg, 0.35 mmol, 1.1 equivalents) in DME (2 mL), was added a solution of aqueous 2 M sodium carbonate (0.2 mL) followed by Pd(PPh ) (37 mg, 0.032 mmol, 0.1 equivalent). The reaction mixture was stirred at 80 °C for 16 hours. The crude was diluted in ethyl acetate and washed with water. After drying the organic layer with sodium sulfate, the solvent was removed and the resulting thick oil was adsorbed on silica gel. The cmde was then purified by flash chromatography on silica, eluting with hexanes/ethyl acetate mixtures (from 99:1 to 80:20) to afford the title compound as a yellow solid (65 mg, 43%). R<sub>t</sub>(min) 7.290. MS FIA:476.1 ES+.</div>
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4-(5-Chloro-2-isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxyIic acid:</div>
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Method A. (Microwave)</div>
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A solution of 4-(5-chloro-2-isopropylaminopyridin-4-yl)-l-(toluene-4-sulfonyl)-lH- pyrrole-2-carboxylic acid methyl ester (3.1 g, 6.9 mmol, 1.0 equivalent) in TΗF (2.0 mL) was added to a solution of lithium hydroxide monohydrated (710 mg, 17.3 mmol,</div>
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2.5 equivalents) in water (3.0 mL). The microwave tube was sealed and the reaction mixture was irradiated by microwave for 1200 sec. at 150 °C. The cmde solution was acidified with aqueous 6Ν ΗC1. The solvent was evaporated off to afford the title compound which was used directly without further purification. R<sub>t</sub>(min): 3.574. FIA MS: 279.9 ES+; 278.2 ES-.</div>
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Method B: (Thermal)</div>
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A solution of 4-(5-chloro-2-isopropylaminoρyridin-4-yl)-l-(2,4,6- trimethylbenzenesulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester (0.69 g, 1.4 mmol, 1.0 equivalent) in TΗF (3.0 mL) was added to a solution of lithium hydroxide monohydrated (1.19 g, 29 mmol, 20.0 equivalents) in water (3.0 mL). The mixture was then refluxed for 8 hours. The cmde solution was acidified with aqueous 6N ΗC1 until cloudy, the organic solvent was partially removed and the product precipitated. The title compound was isolated by filtration and washed with water and diethyl ether, yielding a white solid (0.38 g, 96%).</div>
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4-(5-Chloro-2-isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxyIic acid [l-(3- ch!orophenyl)-2-hydroxyethyl] amide: To a suspension of 4-(5-chloro-2- isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxylic acid (1.93 g, 6.9 mmol, 1.0 equivalent) in DMF (5.0 mL) was added EDCI (1.45 g, 7.6 mmol, 1.1 equivalents), ΗOBt (0.94 g, 6.9 mmol, 1.0 equivalent) and (5)-3-chlorophenylglycynol (1.58 g, 7.6 mmol, 1.1 equivalents). Dusopropylethylamme (2.7 mL) was then added and the resulting mixture was stirred a room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was removed and the crude was adsorbed on silica gel. <strong><em><span data-mce-style="color: #ff0000;" style="color: red;">Purification was effected by flash chromatography on silica, eluting with mixtures of hexanes/acetone (from 80:20 to 60:40) to afford the title compound as white solid (1.9 g, 64%). R<sub>t</sub>(min) 4.981s. FIA MS: 433.1 ES+; 431.2 ES-. <sup>1</sup>ΗNMR (CD<sub>3</sub>OD) δ 1.31 (d, 6H), 3.85 (m, 3H), 5.15 (t, IH), 7.01 (s, IH), 7.25 (m, 3H), 7.4 (s, IH), 7.45 (s, IH), 7.7 (s, IH), 7.95 (s, IH).</span></em></strong></div>
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Example 2 Compound 1-9 was also prepared according to following alternate method:</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2005113541A1/imgf000045_0001.png" href="https://patentimages.storage.googleapis.com/WO2005113541A1/imgf000045_0001.png"><img alt="Figure imgf000045_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2005113541A1/imgf000045_0001.png" height="382" id="imgf000045_0001" src="https://patentimages.storage.googleapis.com/WO2005113541A1/imgf000045_0001.png" style="height: auto; max-width: 100%;" width="906" /></a></div>
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2,5-DichIoro-4-nitropyridine N-oxide: To a suspension of 2-chloro-5-chloropyridine (10 g, 0.067 mol) in acetic anhydride (25 mL) was added hydrogen peroxide 30% (25 mL) in small portions. This mixture was stirred at room temperature for 24 hours and then heated at 60 °C for 30 hours. After removing the excess of acetic acid under reduced pressure, the residue was added in small portions to concentrated sulfuric acid (15 mL). The resulting solution was added to a mixture of concentrated sulfuric acid (15 mL) and fuming nitric acid (25 mL) and then heated at 100 °C for 90 minutes. The reaction mixture was poured on ice, neutralized with solid ammonium carbonate and finally with aqueous ammonia until a basic pH was obtained and. A precipitate formed. The precipitate was collected by filtration to afford the title compound as a pale yellow solid (3.1 g), R<sub>t</sub>(min) 3.75. MS FIA shows no peak. 'pfΝMR (DMSO-de) δ 8.78 (s, IH), 9.15 (s, IH).</div>
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4-Bromo-2-chloro-5-N-isopropylpyridin-2-amine N-oxide: To 2,5-dichloro-4- nitropyridine Ν-oxide (400 mg, 1.9 mmol) was added acetyl bromide (2 mL) very slowly. The reaction mixture was then heated at 80 °C for 10 minutes. The solvent was removed under a stream of nitrogen and the cmde product was dried under high vacuum. The cmde material (165 mg, 0.62 mmol) was dissolved in ethanol (2 mL), z<sup>'</sup>so-propylamine (0.53 mL) added and the resulting mixture was heated at 80 °C for 2 hours. The cmde solution was then purified by reversed phase HPLC (acetonitrile/water/TFA 1%) to afford the title compound as a pale yellow solid (60 mg, 36.6%). R<sub>t</sub>(min) 5.275. MS FIA264.8, 266.9 ES+.</div>
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4-(5-chloro-2-isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxylic acid [l-(3- chlorophenyl)-2-hydroxyethyl] amide (1-9): 4-Bromo-2-chloro-5-N- isopropylpyridin-2-amine N-oxide (25 mg, 0.094 mmol, 1.0 equivalent) and 4- (4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l-(2,4,6-trimethylbenzensulfonyl)-lH- pyrrole-2-carboxylic acid methyl ester (39 mg, 0.094 mmol, 1.0 equivalent) were dissolved in benzene (5 mL) then aqueous 2M Νa<sub>2</sub>C0<sub>3</sub> (1 mL) and Pd(PPh<sub>3</sub>)<sub>4</sub> (115.6 mg, 0.1 mmol, 0.2 equivalent) were added and the resulting suspension was heated at reflux at 80 °C for 16 hours. The reaction mixture was diluted in ethyl acetate, washed with water and dried over anhydrous sodium sulfate to afford 4-(5-chloro-2- isopropylamino-pyridin-4-yl)- 1 -(2,4,6-trimethyl-benzenesulfonyl)- lH-pyrrole-2- carboxylic acid methyl ester N-oxide (R (min) 6.859. MS FIA: 492.0 ES+) which was then treated with a 2 M solution of PC1<sub>3</sub> in dichloromethane (1 mL) at room temperature. After 10 minutes, the solvent was removed under a stream of nitrogen and the cmde oil was dissolved in methanol (1 mL) and aqueous 1 M ΝaOΗ (1 mL). The resulting mixture was heated at reflux for 16 hours then the cmde solution was acidified using aqueous 1 M ΗC1 and the solvent was removed. The resulting 4-(5- chloro-2-isopropylamino-pyridin-4-yl)-lΗ-pyrrole-2-carboxylic acid (R (min) 3.527. MS FIA: 279.4 ES+; 278.2 Es-) was suspended in DMF (3 mL) together with EDCI (36 mg, 0.19 mmol, 2 equivalents), HOBt (26 mg, 0.19 mmol, 2 equivalents), (S)-3- chlorophenylglycinol HCl salt (59 mg, 0.28 mmol, 3 equivalents) and DIEA (0.12 mL, 0.75 mmol, 8 equivalents). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted in ethyl acetate, washed with water and dried over sodium sulfate. After removing the solvent under reduced pressure, the cmde product was purified by reversed phase HPLC (acetonitrile/water/TFA 1%) to afford the title compound as a white solid (4.8 mg, 8.1%).</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150051209.PGNR.&OS=DN/20150051209&RS=DN/20150051209" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150051209.PGNR.&OS=DN/20150051209&RS=DN/20150051209">US2015051209</a>2015-02-19COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK</div>
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<a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7354939.PN.&OS=PN/7354939&RS=PN/7354939" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7354939.PN.&OS=PN/7354939&RS=PN/7354939">US7354939</a>2008-04-08Pyrrole inhibitors of ERK protein kinase, synthesis thereof and intermediates thereto</div>
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Research scientist Tony Huang works in a laboratory at Vertex Pharmaceuticals Inc. in San Diego</div>
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REFERENCES</div>
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1 . Kohno M, Pouyssegur J (2006) Targeting the ERK signaling pathway in cancer therapy. Ann Med 38: 200-21 1 .</div>
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2. Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York.</div>
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3. Lee DC, Webb ML(2003) Pharmaceutical Analysis. John Wiley & Sons, Inc., New York: 255-257.</div>
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4. Peterson ML, Hickey MB, Zaworotko MJ and Almarsson O (2006) Expanding the Scope of Crystal Form Evaluation in Pharmaceutical Science. J Pharm Pharmaceut Sci 9(3):317-326.</div>
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5. Pierce Catalog and Handbook, 1994-1995; Pierce Chemical Co., Rockford, III.</div>
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6. Remington, The Science and Practice of Pharmacy (21 st Edition, Lippincott Williams and Wilkins, Philadelphia, PA.</div>
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7. The United States Pharmacopeia-National Formulary, The United States Pharmacopeial Convention, Rockville, MD.</div>
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<br />
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<a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Gabriel+Martinez-Botella%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Gabriel+Martinez-Botella%22">Gabriel Martinez-Botella</a></div>
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<img alt="Gabriel Martinez-Botella" data-mce-src="https://media.licdn.com/media/AAEAAQAAAAAAAAITAAAAJGI2ZmYyMjgyLWJkZWQtNGQxZi05Mzg4LWVlYTJhNTUwZmEyMQ.jpg" src="https://media.licdn.com/media/AAEAAQAAAAAAAAITAAAAJGI2ZmYyMjgyLWJkZWQtNGQxZi05Mzg4LWVlYTJhNTUwZmEyMQ.jpg" style="height: auto; max-width: 100%;" /></div>
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<h1>
<span class="fn"><span class="full-name" dir="auto">Gabriel Martinez-Botella</span></span></h1>
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</div>
<div id="headline-container" style="font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
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<div class="title" dir="ltr">
Director, Chemistry at Sage Therapeutics</div>
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<div class="background-experience edit-default" id="background-experience">
<h3>
Experience</h3>
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<header><h5 class="experience-logo">
<a data-mce-href="https://www.linkedin.com/company/2572806?trk=prof-exp-company-name" href="https://www.linkedin.com/company/2572806?trk=prof-exp-company-name"><span class="new-miniprofile-container /biz/miniprofile/2572806?pathWildcard=2572806"><img alt="" class="lazy-load" data-mce-src="https://media.licdn.com/media/p/4/000/160/0b4/282e5b1.png" src="https://media.licdn.com/media/p/4/000/160/0b4/282e5b1.png" style="height: auto; max-width: 100%;" /></span></a></h5>
<h4>
<a data-mce-href="https://www.linkedin.com/title/director%2C-chemistry?trk=mprofile_title" href="https://www.linkedin.com/title/director%2C-chemistry?trk=mprofile_title" title="Learn more about this title">Director, Chemistry</a></h4>
<h5>
<span class="new-miniprofile-container /biz/miniprofile/2572806?pathWildcard=2572806"><strong><a data-mce-href="https://www.linkedin.com/company/2572806?trk=prof-exp-company-name" href="https://www.linkedin.com/company/2572806?trk=prof-exp-company-name">Sage Therapeutics</a></strong></span></h5>
</header><span class="experience-date-locale">July 2012 – Present (4 years 2 months)</span></div>
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<header><h5 class="experience-logo">
<a data-mce-href="https://www.linkedin.com/company/1603?trk=prof-exp-company-name" href="https://www.linkedin.com/company/1603?trk=prof-exp-company-name"><span class="new-miniprofile-container /biz/miniprofile/1603?pathWildcard=1603"><img alt="" class="lazy-load" data-mce-src="https://media.licdn.com/media/AAEAAQAAAAAAAAPcAAAAJDY5NWUwNmQ5LTA0NGQtNDY5ZS1hNjdiLTRlMmU0NjcyOGQzZg.png" src="https://media.licdn.com/media/AAEAAQAAAAAAAAPcAAAAJDY5NWUwNmQ5LTA0NGQtNDY5ZS1hNjdiLTRlMmU0NjcyOGQzZg.png" style="height: auto; max-width: 100%;" /></span></a></h5>
<h4>
<a data-mce-href="https://www.linkedin.com/title/principal-scientist%2C-team-leader?trk=mprofile_title" href="https://www.linkedin.com/title/principal-scientist%2C-team-leader?trk=mprofile_title" title="Learn more about this title">Principal Scientist, Team Leader</a></h4>
<h5>
<span class="new-miniprofile-container /biz/miniprofile/1603?pathWildcard=1603"><strong><a data-mce-href="https://www.linkedin.com/company/1603?trk=prof-exp-company-name" href="https://www.linkedin.com/company/1603?trk=prof-exp-company-name">AstraZeneca</a></strong></span></h5>
</header><span class="experience-date-locale">March 2008 – July 2012 (4 years 5 months)</span></div>
</div>
<div class="editable-item section-item past-position" id="experience-48184175">
<div id="experience-48184175-view">
<header><h5 class="experience-logo">
<a data-mce-href="https://www.linkedin.com/company/6866?trk=prof-exp-company-name" href="https://www.linkedin.com/company/6866?trk=prof-exp-company-name"><span class="new-miniprofile-container /biz/miniprofile/6866?pathWildcard=6866"><img alt="" class="lazy-load" data-mce-src="https://media.licdn.com/media/p/1/000/01b/01c/28c5e3c.png" src="https://media.licdn.com/media/p/1/000/01b/01c/28c5e3c.png" style="height: auto; max-width: 100%;" /></span></a></h5>
<h4>
<a data-mce-href="https://www.linkedin.com/title/sr-scientist?trk=mprofile_title" href="https://www.linkedin.com/title/sr-scientist?trk=mprofile_title" title="Learn more about this title">Sr Scientist</a></h4>
<h5>
<span class="new-miniprofile-container /biz/miniprofile/6866?pathWildcard=6866"><strong><a data-mce-href="https://www.linkedin.com/company/6866?trk=prof-exp-company-name" href="https://www.linkedin.com/company/6866?trk=prof-exp-company-name">Vertex Pharmaceuticals</a></strong></span></h5>
</header><span class="experience-date-locale">2002 – 2008 (6 years)</span></div>
</div>
</div>
</div>
<div class="background-section" id="background-education-container">
<div class="background-education edit-default last" id="background-education">
<h3>
Education</h3>
<div class="editable-item section-item" id="education-24713442">
<div id="education-24713442-view">
<div class="education first">
<h5 class="education-logo">
<span class="new-miniprofile-container /edu/school-rich-mini-profile?id=12626&entityId=12626&entityType=SCHOOL"><img alt="Queen Mary, U. of London" class="lazy-load" data-mce-src="https://media.licdn.com/mpr/mpr/shrink_100_100/p/3/005/06a/3ca/2921d08.png" height="60" src="https://media.licdn.com/mpr/mpr/shrink_100_100/p/3/005/06a/3ca/2921d08.png" style="height: auto; max-width: 100%;" width="60" /></span></h5>
<header><h4 class="summary fn org">
<a data-mce-href="https://www.linkedin.com/edu/school?id=12626&trk=prof-edu-school-name" href="https://www.linkedin.com/edu/school?id=12626&trk=prof-edu-school-name" title="More details for this school">Queen Mary, U. of London</a></h4>
<h5>
<span class="degree">PhD</span></h5>
</header><span class="education-date">1996 – 1999</span><br />
<div class="notes summary-field-show-more" dir="ltr">
R Bonnett</div>
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</div>
</div>
<div class="editable-item section-item" id="education-24713444">
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<div class="education">
<h5 class="education-logo">
<span class="new-miniprofile-container /edu/school-rich-mini-profile?id=12252&entityId=12252&entityType=SCHOOL"><img alt="Universitat de Barcelona" class="lazy-load" data-mce-src="https://media.licdn.com/mpr/mpr/shrink_100_100/AAEAAQAAAAAAAAPsAAAAJGYyMjQzZjFiLWVjYmYtNDZhOC1hZjJmLTMxYmNjMGYyZTA0Mg.png" height="60" src="https://media.licdn.com/mpr/mpr/shrink_100_100/AAEAAQAAAAAAAAPsAAAAJGYyMjQzZjFiLWVjYmYtNDZhOC1hZjJmLTMxYmNjMGYyZTA0Mg.png" style="height: auto; max-width: 100%;" width="60" /></span></h5>
<header><h4 class="summary fn org">
<a data-mce-href="https://www.linkedin.com/edu/school?id=12252&trk=prof-edu-school-name" href="https://www.linkedin.com/edu/school?id=12252&trk=prof-edu-school-name" title="More details for this school">Universitat de Barcelona</a></h4>
</header><span class="education-date">1990 – 1995</span><br />
<br /></div>
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</div>
PIC NOT AVAILABLE<br />
<div class="editable-item section-item" id="education-24713444">
<div class="profile-header-personal lf js-wexp-profile-header hover">
<h1 class="profile-header-name">
<a data-mce-href="https://www.researchgate.net/profile/Michael_Hale2" href="https://www.researchgate.net/profile/Michael_Hale2">Michael R Hale</a></h1>
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<div class="clearfix meta profile-position js-widgetContainer" id="rgw5_57b2d51085cd0">
<div class="lf position truncate-single-line">
Director</div>
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</div>
<div class="header-institution-name" id="target-institution">
<div class="profile-institution js-widgetContainer" id="rgw6_57b2d51085cd0">
<div class="institution org truncate-single-line ga-institution-name-on-profile-header">
<a data-mce-href="https://www.researchgate.net/institution/Ra_Pharmaceuticals" href="https://www.researchgate.net/institution/Ra_Pharmaceuticals" title="Ra Pharmaceuticals">Ra Pharmaceuticals</a>, Cambridge · Medicinal Chemistry</div>
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</div>
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///////////ULIXERTINIB, BVD-523; BVD-ERK, BVD-ERK/HM, BVD-ERK/ST, VRT-0752271, VRT-752271, VX-271, <strong>уликсертиниб ,</strong><strong>أوليكسيرتينيب</strong> ,<strong>优立替尼</strong> , PHASE 2, <strong class="data-list__property-key"> </strong><span class="data-list__property-value">Vertex Pharmaceuticals, </span><span class="data-list__property-value">BioMed Valley Discoveries, UNII:16ZDH50O1U, <span class="">869886-67-9</span> </span><br />
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-1346483141860457136.post-35324606945554888582016-08-08T23:36:00.001-07:002016-08-09T00:18:24.504-07:00DOLUTEGRAVIR, ドルテグラビルナトリウム<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Dolutegravir.svg" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Dolutegravir.svg/620px-Dolutegravir.svg.png" src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Dolutegravir.svg/620px-Dolutegravir.svg.png" style="height: auto; max-width: 100%;" /><img alt="Dolutegravir ball-and-stick model.png" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/67/Dolutegravir_ball-and-stick_model.png/250px-Dolutegravir_ball-and-stick_model.png" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/67/Dolutegravir_ball-and-stick_model.png/250px-Dolutegravir_ball-and-stick_model.png" style="height: auto; max-width: 100%;" /></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Dolutegravir</h1>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ドルテグラビルナトリウム</td></tr>
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<li style="list-style: none; margin: 0px; padding: 0px; word-wrap: break-word;">Soltegravir</li>
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2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-, (4R,12aS)</div>
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(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide</div>
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(4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide<br />
Trade Name:Tivicay<br />
Synonym:GSK1349572, S-349572, GSK572<br />
Date of Approval: August 12, 2013 (US)<br />
Indication:HIV infection<br />
Drug class: Integrase strand transfer inhibitor<br />
Company: ViiV Healthcare,GlaxoSmithKline</div>
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INNOVATOR ...ViiV Healthcare<a data-mce-href="http://integrity.thomson-pharma.com/integrity/xmlxsl/pk_com_form.xml_com_card_pr?p_company_id=18241&p_session_id=" href="http://integrity.thomson-pharma.com/integrity/xmlxsl/pk_com_form.xml_com_card_pr?p_company_id=18241&p_session_id="> </a><br />
CAS number: 1051375-16-6</div>
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1051375-19-9 (Dolutegravir Sodium)</div>
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<i>MF:C20H19F2N3O5<br />MW:419.4</i></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>2H-Pyrido[1',2':4,5<wbr></wbr>]pyrazino[2,1-b][1,<wbr></wbr>3]oxazine-9-carboxa<wbr></wbr>mide, N-[(2,4-diflu<wbr></wbr>orophenyl)methyl]-3<wbr></wbr>,4,6,8,12,12a-hexah<wbr></wbr>ydro-7-hydroxy-4-me<wbr></wbr>thyl-6,8-dioxo-, (4<wbr></wbr>R,12aS)-</strong> <span class="synonym_ref" title="">[ACD/Index Name]</span></div>
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<strong>GSK 1349572</strong></div>
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<strong>S-349572</strong></div>
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Chemical Name: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a- hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide<br />
Patent: US8129385<br />
Patent expiration date: Oct 5, 2027<br />
PCT patent application: W02006116764</div>
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ドルテグラビルナトリウム<br />
Dolutegravir Sodium<br />
<a data-mce-href="http://jpdb.nihs.go.jp/jan/chemdraw5/Dolutegravir_Sodium.cdx" href="http://jpdb.nihs.go.jp/jan/chemdraw5/Dolutegravir_Sodium.cdx"><img alt="" data-mce-src="http://jpdb.nihs.go.jp/jan/gif/Dolutegravir_Sodium.png" src="http://jpdb.nihs.go.jp/jan/gif/Dolutegravir_Sodium.png" style="height: auto; max-width: 100%;" /></a><br />
C<sub>2</sub><sub>0</sub>H<sub>1</sub><sub>8</sub>F<sub>2</sub>N<sub>3</sub>NaO<sub>5</sub> : 441.36<br />
[1051375-19-9]</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<i>Dolutegravir (DTG, GSK1349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-1 infection by GlaxoSmithKline (GSK) on behalf of Shionogi-ViiV Healthcare LLC. DTG is metabolized primarily by uridine diphosphate glucuronyltransferase (UGT)1A1, with a minor role of cytochrome P450 (CYP)3A, and with renal elimination of unchanged drug being extremely low (< 1% of the dose).</i></div>
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Dolutegravir sodium was approved by the U.S. Food and Drug Administration (FDA) on Aug 12, 2013, then approved by European Medicine Agency (EMA) on Jan 16, 2014, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Mar 24, 2014, then approved by Center For Drug Evaluation (CFDA) on Dec 30, 2015. It was co-developed by GlaxoSmithKline & ViiV Healthcare Corporation, then marketed as Tivicay<sup>®</sup> by ViiV Healthcare in the US and EU and by GlaxoSmithKline & ViiV Healthcare Corporation in JP.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Dolutegravir sodium is an integrase inhibitor which blocks HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. It is in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children aged 12 years and older and weighing at least 40 kg.</div>
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Tivicay<sup>®</sup> is available as film-coated tablet for oral use, containing 50 mg of free Dolutegravir. The recommended dose is 50 mg Dolutegravir once daily without regards to meals.</div>
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<img alt="" data-mce-src="http://static.progressivemediagroup.com/uploads/imagelibrary/Tivicay%20DD.jpg" src="http://static.progressivemediagroup.com/uploads/imagelibrary/Tivicay%20DD.jpg" style="height: auto; max-width: 100%;" /></div>
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APPROVALS</div>
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<tr><th class="text-center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="78">Approval Date</th><th class="text-center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="78">Approval Type</th><th class="text-center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="78">Trade Name</th><th class="text-center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="78">Indication</th><th class="text-center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="79">Dosage Form</th><th class="text-center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="79">Strength</th><th class="text-center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="79">Company</th><th class="text-center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="79">Review Classification</th></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2013-08-12</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Marketing approval</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tivicay</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HIV infection</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tablet, Film coated</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Eq. 50 mg Dolutegravir</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ViiV</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Priority</td></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-01-16</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Marketing approval</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tivicay</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HIV infection</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tablet, Film coated</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">50 mg</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ViiV</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-03-24</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Marketing approval</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tivicay</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HIV infection</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tablet, Film coated</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">50 mg</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ViiV, GlaxoSmithKline</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-12-30</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Marketing approval</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tivicay/特威凯</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HIV infection</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tablet</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">50 mg</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">GlaxoSmithKline</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td></tr>
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<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
CLIP</h1>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="font-size: 14px; line-height: 1.5em;" style="font-size: 14px; line-height: 1.5em;">The European Commission has on 21 January 2014 Dolutegravir (Tivicay, ViiV) permit as part of combination therapy for the treatment of HIV-infected persons over the age of 12 years.Dolutegravir (Tivicay, ViiV) is an integrase inhibitor, in combination with other antiretroviral drugs in adults and adolescents can be used from 12 years for the treatment of HIV infection.</span></h1>
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<a data-mce-href="http://newdrugapprovals.files.wordpress.com/2014/01/894a2-dolutegravir.gif" href="http://newdrugapprovals.files.wordpress.com/2014/01/894a2-dolutegravir.gif"><img alt="" border="0" data-mce-src="http://newdrugapprovals.files.wordpress.com/2014/01/894a2-dolutegravir.gif" src="http://newdrugapprovals.files.wordpress.com/2014/01/894a2-dolutegravir.gif" style="height: auto; max-width: 100%;" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Source: <a data-mce-href="http://ec.europa.eu/health/documents/community-register/html/h892.htm#proc127569" href="http://ec.europa.eu/health/documents/community-register/html/h892.htm#proc127569">Communication from the European Commission</a></div>
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<b>Dolutegravir</b><sup id="cite_ref-1"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-1" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-1">[1]</a></sup> is a FDA-approved drug<sup id="cite_ref-2"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-2" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-2">[2]</a></sup> for the treatment of <a data-mce-href="http://en.wikipedia.org/wiki/HIV" href="http://en.wikipedia.org/wiki/HIV" title="HIV">HIV</a> infection. Dolutegravir is an <a data-mce-href="http://en.wikipedia.org/wiki/Discovery_and_development_of_integrase_inhibitors" href="http://en.wikipedia.org/wiki/Discovery_and_development_of_integrase_inhibitors" title="Discovery and development of integrase inhibitors">integrase inhibitor</a>. Known as S/GSK1349572 or just "572" the drug is marketed as Tivicay<sup id="cite_ref-3"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-3" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-3">[3]</a></sup> by <a data-mce-href="http://en.wikipedia.org/wiki/GlaxoSmithKline" href="http://en.wikipedia.org/wiki/GlaxoSmithKline" title="GlaxoSmithKline">GlaxoSmithKline</a> (GSK). In February, 2013 the <a data-mce-href="http://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="http://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> announced that it would fast track dolutegravir's approval process.<sup id="cite_ref-4"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-4" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-4">[4]</a></sup> On August 13, 2013, dolutegravir was approved by the FDA. On November 4, 2013, dolutegravir was approved by Health Canada.<sup id="cite_ref-5"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-5" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-5">[5]</a></sup></div>
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The oral HIV integrase inhibitor S-349572 was originated by Shionogi-GlaxoSmithKline and Shionogi-ViiV Healthcare. In 2013, the product was approved and launched in the U.S. for the treatment of HIV-1 in adults and children aged 12 years and older, in combination with other antiretroviral agents. A positive opinion was received in the E.U for this indication and, in 2014, approval was attained in Europe for this indication. Registration is pending in Japan.</div>
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In 2013, orphan drug designation in Japan was assigned to the compound.</div>
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Dolutegravir is approved for use in a broad population of HIV-infected patients. It can be used to treat HIV-infected adults who have never taken HIV therapy (treatment-naïve) and HIV-infected adults who have previously taken HIV therapy (treatment-experienced), including those who have been treated with other integrase strand transfer inhibitors. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naïve or treatment-experienced but have not previously taken other integrase strand transfer inhibitors.<sup id="cite_ref-6"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-6" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-6">[6]</a></sup></div>
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Dolutegravir has also been compared head-to-head with a preferred regimen from the DHHS guidelines in each of the three classes (i.e. 1.) nuc + non-nuc, 2.) nuc + boosted PI, and 3.) nuc + integrase inhibitor).</div>
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SPRING-2 compared dolutegravir to another integrase inhibitor, raltegravir, with both coformulated with a choice of <a data-mce-href="http://en.wikipedia.org/wiki/Tenofovir" href="http://en.wikipedia.org/wiki/Tenofovir" title="Tenofovir">TDF</a>/<a data-mce-href="http://en.wikipedia.org/wiki/Emtricitabine" href="http://en.wikipedia.org/wiki/Emtricitabine" title="Emtricitabine">FTC</a> or<a data-mce-href="http://en.wikipedia.org/wiki/Abacavir" href="http://en.wikipedia.org/wiki/Abacavir" title="Abacavir">ABC</a>/<a data-mce-href="http://en.wikipedia.org/wiki/Lamivudine" href="http://en.wikipedia.org/wiki/Lamivudine" title="Lamivudine">3TC</a>. After 48 weeks of treatment 88% of those on dolutegravir had less than 50 copies of HIV per mL compared to 85% in the raltegravir group, thus demonstrating non-inferiority.<sup id="cite_ref-9"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-9" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-9">[9]</a></sup></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The FLAMINGO study has been presented at scientific meetings but as of early 2014 has not yet been published. It is an open-label trial of dolutegravir versus darunavir boosted with ritonavir. In this trial 90% of those on dolutegravir based regimens had viral loads < 50 at 48 weeks compared to 83% in the darunavir/r.<sup id="cite_ref-10"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-10" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-10">[10]</a></sup> This 7% difference was statistically significant for superiority of the dolutegravir based regimens.</div>
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Another trial comparing dolutegravir to efavirenz, SINGLE, was the first trial to show statistical superiority to an <a data-mce-href="http://en.wikipedia.org/wiki/Atripla" href="http://en.wikipedia.org/wiki/Atripla" title="Atripla">efavirenz/FTC/TDF</a> coformulated regimen for treatment naive patients.<sup id="cite_ref-11"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-11" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-11">[11]</a></sup> After 48 weeks of treatment, 88% of the dolutegravir group had HIV RNA levels < 50 copies / mL versus 81% of the efavirenz group. This has led one commentator to predict that it may replace efavirenz as the first line choice for initial therapy as it can also be formulated in one pill, once-a-day regimens.<sup id="cite_ref-12"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-12" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-12">[12]</a></sup></div>
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Doultegravir has also been studied in patients who have been on previous antiretroviral medications. The VIKING trial looked at patients who had known resistance to the first generation integrase inhibitor <a data-mce-href="http://en.wikipedia.org/wiki/Raltegravir" href="http://en.wikipedia.org/wiki/Raltegravir" title="Raltegravir">raltegravir</a>. After 24 weeks 41% of patients on 50mg dolutegravir once daily and 75% of patients on 50mg twice daily (both along with an optimized background regimen) achieved an HIV RNA viral load of < 50 copies per mL. This demonstrated that there was little clinical cross-resistance between the two integrase inhibitors. <sup id="cite_ref-13"><a data-mce-href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-13" href="http://en.wikipedia.org/wiki/Dolutegravir#cite_note-13">[13]</a></sup></div>
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<strong data-mce-style="font-size: 13px;" style="font-size: 13px;">Dolutegravir</strong><span data-mce-style="font-size: 13px;" style="font-size: 13px;"> (also known as S/GSK1349572), a second-generation integrase inhibitor under development by GlaxoSmithKline and its Japanese partner Shionogi for the treatment of HIV infection, was given priority review status from the US Food and Drug Administration (FDA) in February, 2013.</span></div>
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GlaxoSmithKline marketed the first HIV drug <strong>Retrovir </strong>in 1987 before losing out to Gilead Sciences Inc. (GILD) as the world’s biggest maker of AIDS medicines. The virus became resistant to Retrovir when given on its own, leading to the development of therapeutic cocktails.<br />
The new once-daily drug <strong>Dolutegravir</strong>, which belongs to a novel class known as integrase inhibitors that block the virus causing AIDS from entering cells, is owned by ViiV Healthcare, a joint venture focused on HIV in which GSK is the largest shareholder.<br />
<strong>Raltegravir</strong> (brand name <strong>Isentress</strong>) received approval by the U.S. Food and Drug Administration (FDA) on 12 October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval. it is a potent and well tolerated antiviral agent. However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance, prompting the search for agents with once-daily dosing.<br />
<strong>Elvitegravir</strong>, approved by the FDA on August 27, 2012 as part of the<strong>elvitegravir</strong>/<strong>cobicistat</strong>/<strong>tenofovir disoproxil fumarate</strong>/<strong>emtricitabine</strong> fixed-dose combination pill (<strong>Quad pill</strong>, brand name <strong>Stribild</strong>) has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir.<br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-47.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-47.jpg" rel="attachment wp-att-8256"><img alt="STR1" class="alignnone size-full wp-image-8256" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-47.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-47.jpg" height="251" style="height: auto; max-width: 100%;" width="431" /></a>DOLUTEGRAVIR<br />
Gilead’s <strong>Atripla (Emtricitabine/Tenofovir/efavirenz)</strong>, approved in 2006 with loss of patent protection in 20121, is the top-selling HIV treatment. The $3.2 billion medicine combines three drugs in one pill, two compounds that make up Gilead’s <strong>Truvada</strong> (Emtricitabine/Tenofovir) and Bristol- Myers Squibb Co.’s <strong>Sustiva </strong>(Efavirenz).<br />
A three-drug combination containing dolutegravir and ViiV’s older two-in-one treatment <strong>Epzicom</strong>(<strong>Abacavir</strong>/<strong>Lamivudine</strong>, marketed outside US as <strong>Kivexa</strong>) proved better than Gilead’s market-leading Atripla in a clinical trial released in July, 2012 (<a data-mce-href="http://www.natap.org/2012/ICAAC/ICAAC_06.htm" href="http://www.natap.org/2012/ICAAC/ICAAC_06.htm" target="_blank">See the Full Conference Report Here</a>), suggesting it may supplant the world’s best-selling AIDS medicine as the preferred front-line therapy. In the latest Phase III study, after 48 weeks of treatment, 88% of patients taking the dolutegravir-based regimen had reduced viral levels to the goal compared with 81% of patients taking Atripla. More patients taking Atripla dropped out of the study because of adverse events compared with those taking dolutegravir — 10% versus just 2% — which was the main driver of the difference in efficacy. The result was the second positive final-stage clinical read-out for dolutegravir, following encouraging results against U.S. company Merck & Co’s rival Isentress in April, 2012 (<a data-mce-href="http://pag.aids2012.org/abstracts.aspx?aid=20990" href="http://pag.aids2012.org/abstracts.aspx?aid=20990" target="_blank">See the Conference Abstract Here</a>)..<br />
Dolutegravir is viewed by analysts as a potential multibillion-dollar-a-year seller, as its once-daily dosing is likely to be attractive to patients. The FDA is scheduled to issue a decision on the drug’s approval by August 17。<br />
TIVICAY contains dolutegravir, as dolutegravir sodium, an <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=3769" href="http://www.rxlist.com/script/main/art.asp?articlekey=3769" rel="dict">HIV</a> INSTI. The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C<sub>20</sub>H<sub>18</sub>F<sub>2</sub>N<sub>3</sub>NaO<sub>5</sub> and the molecular weight is 441.36 g/mol. It has the following structural formula:<br />
<table cellspacing="0" class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187); width: 327px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><img alt="TIVICAY (dolutegravir) Structural Formula Illustration" data-mce-src="http://images.rxlist.com/images/rxlist/tivicay1.gif" src="http://images.rxlist.com/images/rxlist/tivicay1.gif" height="156" style="height: auto; max-width: 100%;" width="327" /></td></tr>
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Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.<br />
Each film-coated tablet of TIVICAY for oral administration contains 52.6 mg of dolutegravir sodium, which is equivalent to 50 mg dolutegravir free acid, and the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients iron oxide yellow, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.<br />
<img alt="" data-mce-src="http://arznei-news.de/wp-content/uploads/dolutegravir-129x300.jpg" src="http://arznei-news.de/wp-content/uploads/dolutegravir-129x300.jpg" style="height: auto; max-width: 100%;" /><br />
DOLUTEGRAVIR<br />
<img alt="File:Synthese Dolutegravir.png" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a4/Synthese_Dolutegravir.png/468px-Synthese_Dolutegravir.png" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a4/Synthese_Dolutegravir.png/468px-Synthese_Dolutegravir.png" style="height: auto; max-width: 100%;" /></div>
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<b><u>Dolutegravir Synthesis</u></b></div>
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<b><u>Identifications:</u></b></div>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhiFtyhrpdysP3XOfzruQl19PsVoXfs4GB_3_ZExTwI36O0V0rnyyIflzpgvuXMUu_RxifiMGriluuxq9NdfSxdqt2rqIAgiKW1UwW6y-GisOEuxlaGZoO_xrJfz5JL3juw8iZogfe_qcyw/s1600/NMR-Dolutegravir.png" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhiFtyhrpdysP3XOfzruQl19PsVoXfs4GB_3_ZExTwI36O0V0rnyyIflzpgvuXMUu_RxifiMGriluuxq9NdfSxdqt2rqIAgiKW1UwW6y-GisOEuxlaGZoO_xrJfz5JL3juw8iZogfe_qcyw/s1600/NMR-Dolutegravir.png"><img alt="" border="0" data-mce-src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhiFtyhrpdysP3XOfzruQl19PsVoXfs4GB_3_ZExTwI36O0V0rnyyIflzpgvuXMUu_RxifiMGriluuxq9NdfSxdqt2rqIAgiKW1UwW6y-GisOEuxlaGZoO_xrJfz5JL3juw8iZogfe_qcyw/s640/NMR-Dolutegravir.png" height="204" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhiFtyhrpdysP3XOfzruQl19PsVoXfs4GB_3_ZExTwI36O0V0rnyyIflzpgvuXMUu_RxifiMGriluuxq9NdfSxdqt2rqIAgiKW1UwW6y-GisOEuxlaGZoO_xrJfz5JL3juw8iZogfe_qcyw/s640/NMR-Dolutegravir.png" style="height: auto; max-width: 100%;" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>1H NMR (Estimated) for Dolutegravir</b></td></tr>
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<b>Experimental:</b> <sup>1</sup>H NMR (CDCl<sub>3</sub>) δ 12.45 (s, 1H), 10.38 (br s, 1H), 8.30 (s, 1H), 7.40-7.30 (m, 1H), 6.85-6.75 (m, 2H), 5.26 (d, J = 5.8, 4.1 Hz, 2H), 5.05-4.95 (m, 1H), 4.64 (d, J = 5.9 Hz, 2H), 4.27 (dd, J = 13.4, 4.2 Hz, 1H), 4.12 (dd, J = 13.6, 6.0 Hz, 1H), 4.05 (t, J = 2.3 Hz, 1H), 4.02 (d, J = 2.2 Hz, 1H), 2.30-2.19 (m, 1H), 1.56 (dd, J = 14.0, 2.0 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H).</div>
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INTRODUCTION<br />
Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired.<br />
On the other hand, a combination therapy is reported to be efficient in treatment for AIDS because of the frequent emergence of the resistant mutant. Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent, however agents having the same mechanism of action often exhibit cross-resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.<br />
Under the circumstances above, an HIV integrase inhibitor has been focused on as an anti-HIV agent having a novel mechanism of action (Ref: Patent Documents 1 and 2). As an anti-HIV agent having such a mechanism of action, known are carbamoyl-substituted hydroxypyrimidinone derivative (Ref: Patent Documents 3 and 4) and carbamoyl-substituted hydroxypyrrolidione derivative (Ref: Patent Document 5). Further, a patent application concerning carbamoyl-substituted hydroxypyridone derivative has been filed (Ref: Patent Document 6, Example 8).<br />
Other known carbamoylpyridone derivatives include 5-alkoxypyridine-3-carboxamide derivatives and γ-pyrone-3-carboxamide derivatives, which are a plant growth inhibitor or herbicide (Ref: Patent Documents 7-9).<br />
Other HIV integrase inhibitors include N-containing condensed cyclic compounds (Ref: Patent Document 10).<br />
<ul>
<li id="ul0001-0001">[Patent Document 1] WO03/0166275</li>
<li id="ul0001-0002">[Patent Document 2] WO2004/024693</li>
<li id="ul0001-0003">[Patent Document 3] WO03/035076</li>
<li id="ul0001-0004">[Patent Document 4] WO03/035076</li>
<li id="ul0001-0005">[Patent Document 5] WO2004/004657</li>
<li id="ul0001-0006">[Patent Document 6] JP Patent Application 2003-32772</li>
<li id="ul0001-0007">[Patent Document 7] JP Patent Publication 1990-108668</li>
<li id="ul0001-0008">[Patent Document 8] JP Patent Publication 1990-108683</li>
<li id="ul0001-0009">[Patent Document 9] JP Patent Publication 1990-96506</li>
<li id="ul0001-0010">[Patent Document 10] WO2005/016927</li>
<li>Patent Document 1 describes compounds (I) and (II), which are useful as anti-HIV drugs and shown by formulae:<div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0001.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0001.png"><img alt="Figure imgb0001" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0001.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0001.png" height="116" id="ib0001" style="height: auto; max-width: 100%;" width="604" /></a></div>
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This document describes the following reaction formula as a method of producing compound (I).</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0002.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0002.png"><img alt="Figure imgb0002" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0002.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0002.png" height="20" id="ib0002" style="height: auto; max-width: 100%;" width="140" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0003.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0003.png"><img alt="Figure imgb0003" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0003.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0003.png" height="720" id="ib0003" style="height: auto; max-width: 100%;" width="600" /></a></div>
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Furthermore, Patent Documents 2 to 6 describe the following reaction formula as an improved method of producing compound (I).</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0004.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0004.png"><img alt="Figure imgb0004" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0004.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0004.png" height="20" id="ib0004" style="height: auto; max-width: 100%;" width="140" /></a></div>
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0005.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0005.png"><img alt="Figure imgb0005" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0005.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0005.png" height="408" id="ib0005" style="height: auto; max-width: 100%;" width="604" /></a></div>
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<ul>[PATENT DOCUMENTS]
<li><ul>
<li>[Patent Document 1] International publication No.2006/116764 pamphlet</li>
<li>[Patent Document 2] International publication No.2010/011812 pamphlet</li>
<li>[Patent Document 3] International publication No.2010/011819 pamphlet</li>
<li>[Patent Document 4] International publication No.2010/068262 pamphlet</li>
<li>[Patent Document 5] International publication No.2010/067176 pamphlet</li>
<li>[Patent Document 6] International publication No.2010/068253 pamphlet</li>
<li>[Patent Document 7] <a data-mce-href="http://www.google.com/patents/US4769380" href="http://www.google.com/patents/US4769380" id="pcit0001">US Patent 4769380A</a></li>
<li>[Patent Document 8] International applicationPCT/JP2010/055316</li>
</ul>
</li>
</ul>
[NON-PATENT DOCUMENTS]<br />
<ul>
<li><div>
</div>
<div>
<ul>
<li>[Non-Patent Document 1] Journal of Organic Chemistry, 1991, 56(16), 4963-4967</li>
<li>[Non-Patent Document 2] Science of Synthesis, 2005, 15, 285-387</li>
<li>[Non-Patent Document 3] Journal of Chemical Society Parkin Transaction. 1, 1997, Issue. 2, 163-169</li>
</ul>
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</li>
</ul>
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</li>
</ul>
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<strong style="font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;"><em><span data-mce-style="color: #ff0000;" style="color: red;">A clip and its own references</span></em></strong></div>
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Dolutegravir sodium (Tivicay®), developed and marketed by GlaxoSmithKline,45 was approved by the FDA in August 2013 as a novel integrase inhibitor for the treatment of HIV infection.46 Dolutegravir was fast-tracked by the FDA in February 2012,47 and joins an important class of drugs known as Integrase Strand Transfer inhibitors (INSTi’s).48 INSTi’s are characterized by their two-metal-chelating scaffolds, which are known to chelate Mg2+ cofactors in the enzyme active site,49, 50 interrupting function of HIV-1 integrase, which is essential for replication of viral DNA into host chromatin.49-51,52 Other drugs in this class, raltegravir and elvitegravir, are known to require either high dosages53 or PK boosting agents,54 respectively, with raltegravir also exhibiting substantial loss of potency in several major HIV-1 integrase mutation pathways.55 Dolutegravir was pursued with the goal of developing a INSTi with a once-daily, low-dosage treatment with improved resistance profile and without the</div>
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">need for the use of a PK boosting agent.51, 56 Dolutegravir sodium has been approved for treating a broad</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">population of HIV-infected patients, including adults undergoing their first treatment as well as those</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">who have been treated with other integrase transfer strand inhibiting agents.46 The most likely process-scale synthesis of dolutegravir sodium, as described in Scheme 8, began with benzyl protection and alkylation of pyrone 46 with benzaldehyde, yielding alcohol 47 in 74% over 2 steps (Scheme 8).57, 58 Alcohol mesylation and in-situ elimination provided the styrenyl olefin 48 in 94% yield, which further underwent an oxidative cleavage of the olefin to generate 49 by sequential addition of RuCl3/NaIO4 and NaClO2 (56% overall yield). Treatment of pyranone 49 with 3-amino-propane-2-diol (50) in ethanol at elevated temperatures delivered the corresponding pyridinone in 83% yield, and this was followed by esterification and sodium periodate-mediated diol cleavage to furnish </span><span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">intermediate 51 in 71% overall yield across the two-step sequence.57, 58 Next, the key ring-forming step in the</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">synthesis of dolutegravir sodium consisted of cyclization of 51 with (R)-3-amino-butan-1-ol, a process which relies on substrate control to provide the desired tricyclic carbamoylpyridone system 52 in high stereoselectivity (20/1 in favor of the desired isomer).51 Previously, cyclization of systems such as 51 with unsubstituted amino alcohols were found to yield a mixture of diastereomeric products, therefore indicating the pivotal role of the chiral amino alcohol in influencing stereochemical bias during the overall cyclization step.51, 56 In practice, reaction of 51 with (R)-3-amino-butan-1-ol at 90 °C led to isolation of a single cyclization product 52, after recrystallization from EtOAc.57, 58 From 52, Nbromosuccinimide (NBS) bromination and subsequent treatment with amine 53 under palladiumcatalyzed </span><span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">amidocarbonylative conditions led to amide 54 in 75% yield over 2 steps. Finally, removal of the benzyl group and subsequent crystallization using sodium hydroxide in water and ethanol provided dolutegravir sodium (VII) in 99% yield.57, 58</span><br />
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<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">45 Johns, B. A.; Kawasuji, T.; Taishi, T.; Taoda, Y. WO Patent 2006116764A1, 2006.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">46. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">47. http://newdrugapprovals.org/2013/07/16/dolutegravir-biggest-rival-to-worlds-best-selling-hivdrug-atripla-may-get-fda-approval-by-august-2013/.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">48. Pendri, A.; Meanwell, N. A.; Peese, K. M.; Walker, M. A. Expert Opin. Ther. Pat. 2011, 21,1173.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">49. Johns, B. A.; Svolto, A. C. Expert Opin. Ther. Pat. 2008, 18, 1225.60</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">50. Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.;</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">Jeffrey, J. L.; Miller, W. H. Bioorg. Med. Chem. Lett. 2009, 19, 1802.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">51. Johns, B. A.; Kawasuji, T.; Weatherhead, J. G.; Taishi, T.; Temelkoff, D. P.; Yoshida, H.;Akiyama, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Jeffrey, J.; Foster, S.A.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Johnson, M. N.; Garvey, E. P.; Fujiwara,</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">T. J. Med. Chem. 2013, 56, 5901.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">52. Kawasuji, T.; Johns, B. A.; Yoshida, H.; Taishi, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.;Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara, T. J. Med. Chem. 2012, 55, 8735.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">53. Lennox, J. L.; De Jesus, E.; Lazzarin, A.; Pollard, R. B.; Valdez Ramalho Madruga, J.; Berger,D. S.; Zhao, J.; Xu, X.; Williams-Diaz, A.; Rodgers, A. J.; Barnard, R. J. O.; Miller, M. D.; DiNubile, M. J.; Nguyen, B.-Y.; Leavitt, R.; Sklar, P. Lancet 2009, 374, 796.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">54. Ramanathan, S.; Mathias, A. A.; German, P.; Kearney, B. P. Clin. Pharmacokinet. 2011, 50,229.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">55. Ceccherini-Silberstein, F.; Malet, I.; D'Arrigo, R.; Antinori, A.; Marcelin, A.-G.; Perno, C.-F.AIDS Rev. 2009, 11, 17.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">56. Kawasuji, T.; Johns, B. A.; Yoshida, H.; Weatherhead, J. G.; Akiyama, T.; Taishi, T.; Taoda, Y.;Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Yoshinaga, T.; Seki, T.;Kobayashi, M.; Sato, A.; Garvey, E. P.; Fujiwara, T. J. Med. Chem. 2013, 56, 1124.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">57. Johns, B. A.; Duan, M.; Hakogi, T. WO Patent 2010068262A1, 2010.</span><br />
<span style="background-color: white; font-family: "georgia" , "times new roman" , "bitstream charter" , "times" , serif;">58. Yoshida, H.; Taoda, Y.; Johns, B. A. WO Patent 2010068253A1, 2010.</span><br />
CLIPS<br />
Dolutegravir synthesis (EP2602260, 2013). LiHMDS as the non-nucleophilic strong base pulling compound <strong>1</strong> carbonyl group proton alpha position with an acid chloride after <strong>2</strong> and ring closure reaction to obtain <strong>3</strong> , <strong>3</strong> via primary amine <strong>4</strong> ring opening ring closure to obtain <strong>5</strong> , NBS the bromine under acidic conditions to obtain aldehyde acetal becomes <strong>6</strong> , <strong>6</strong> of the aldehyde and amino alcohols <strong>7</strong> and turn off the condensation reaction obtained by the ring <strong>8</strong> , alkaline hydrolysis <strong>8</strong> of bromine into a hydroxyl group and hydrolyzable ester obtained <strong>9</strong> after the <strong>10</strong> occurred acid condensation Dolutegravir.<br />
<a data-mce-href="http://photo.blog.sina.com.cn/showpic.html#blogid=53891ebe0101mpa4&url=http://album.sina.com.cn/pic/53891ebegx6Cdyd9i6044" href="http://photo.blog.sina.com.cn/showpic.html#blogid=53891ebe0101mpa4&url=http://album.sina.com.cn/pic/53891ebegx6Cdyd9i6044" target="_blank"><img alt="" data-mce-src="http://s5.sinaimg.cn/mw690/53891ebegx6Cdyd9i6044&690" src="http://s5.sinaimg.cn/mw690/53891ebegx6Cdyd9i6044&690" height="369" id="image_operate_6321377708265651" style="height: auto; max-width: 100%;" title="" width="647" /></a><br />
CLIPS<br />
Synthesis of Dolutegravir (S/GSK1349572, GSK1349572)<br />
<img alt="" data-mce-src="http://www.yaopha.com/wp-content/uploads/2013/02/Synthesis-of-Dolutegravir-HIV-Integrase-Inhibitor-Shionogi-GSK-%E8%89%BE%E6%BB%8B%E7%97%85%E6%96%B0%E8%8D%AFDolutegravir%E7%9A%84%E5%88%B6%E5%A4%87%E6%96%B9%E6%B3%95.jpg" src="http://www.yaopha.com/wp-content/uploads/2013/02/Synthesis-of-Dolutegravir-HIV-Integrase-Inhibitor-Shionogi-GSK-%E8%89%BE%E6%BB%8B%E7%97%85%E6%96%B0%E8%8D%AFDolutegravir%E7%9A%84%E5%88%B6%E5%A4%87%E6%96%B9%E6%B3%95.jpg" height="404" style="height: auto; max-width: 100%;" width="486" /><br />
<br />
SYNTHESIS<br />
<img alt="" data-mce-src="http://www.chemrenblock.com/pic/big/172_0.jpg" src="http://www.chemrenblock.com/pic/big/172_0.jpg" height="252" style="height: auto; max-width: 100%;" width="310" /><br />
2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-, (4R,12aS) ...........dolutegravir<br />
PATENT<br />
<a data-mce-href="http://www.google.com/patents/US8129385" href="http://www.google.com/patents/US8129385">US8129385</a><br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-48.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-48.jpg" rel="attachment wp-att-8257"><img alt="STR1" class="alignnone size-full wp-image-8257" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-48.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-48.jpg" height="473" style="height: auto; max-width: 100%;" width="718" /></a> <a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-9.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-9.jpg" rel="attachment wp-att-8258"><img alt="STR2" class="alignnone size-full wp-image-8258" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-9.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-9.jpg" height="332" style="height: auto; max-width: 100%;" width="722" /></a><br />
<a data-mce-href="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00099.png" href="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00099.png"><img alt="Figure US08129385-20120306-C00099" data-mce-src="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00099.png" src="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00099.png" height="473" id="EMI-C00099" style="height: auto; max-width: 100%;" width="304" /></a><br />
Desired isomer<br />
Example Z-1<br />
(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide sodium salt<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00116.png" href="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00116.png"><img alt="Figure US08129385-20120306-C00116" data-mce-src="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00116.png" src="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00116.png" height="100" id="EMI-C00116" style="height: auto; max-width: 100%;" width="253" /></a></div>
a)<br />
(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide. To a solution of 16a (409 mg, 0.87 mmol) in dichloroethane (20 mL) was added (2R)-2-amino-1-propanol (0.14 mL, 1.74 mmol) and 10 drops of glacial acetic acid. The resultant solution was heated at reflux for 2 h. Upon cooling, Celite was added to the mixture and the solvents removed in vacuo and the material was purified via silica gel chromatography (2% CH<sub>3</sub>OH/CH<sub>2</sub>Cl<sub>2 </sub>gradient elution) to give (3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (396 mg, 92%) as a glass. <sup>1</sup>H NMR (CDCl<sub>3</sub>) δ 10.38 (m, 1H), 8.42 (s, 1H), 7.54-7.53 (m, 2H), 7.37-7.24 (m, 4H), 6.83-6.76 (m, 2H), 5.40 (d, J=10.0 Hz, 1H), 5.22 (d, J=10.0 Hz, 1H), 5.16 (dd, J=9.6, 6.0 Hz, 1H), 4.62 (m, 2H), 4.41 (m, 1H), 4.33-4.30 (m, 2H), 3.84 (dd, J=12.0, 10.0 Hz, 1H), 3.63 (dd, J=8.4, 7.2 Hz, 1H), 1.37 (d, J=6.0 Hz, 3H); ES<sup>+</sup>MS: 496 (M+1).<br />
b)<br />
(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide sodium salt. To a solution of (3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (396 mg, 0.80 mmol) in methanol (30 mL) was added 10% Pd/C (25 mg). Hydrogen was bubbled through the reaction mixture via a balloon for 2 h. The resultant mixture was filtered through Celite with methanol and dichloromethane.<br />
The filtrate was concentrated in vacuo to give (3R,11aS)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide , DOLUTEGRAVIR as a pink tinted white solid (278 mg, 86%).<br />
<sup>1</sup>H NMR (CDCl<sub>3</sub>) δ 11.47 (m, 1H), 10.29 (m, 1H), 8.32 (s, 1H), 7.36 (m, 1H), 6.82 (m, 2H), 5.31 (dd, J=9.6, 3.6 Hz, 1H), 4.65 (m, 2H), 4.47-4.38 (m, 3H), 3.93 (dd, J=12.0, 10.0 Hz, 1H), 3.75 (m, 1H), 1.49 (d, J=5.6 Hz, 3H); ES<sup>+</sup> MS: 406 (M+1).<br />
DOLUTEGRAVIR NA SALT<br />
The above material (278 mg, 0.66 mmol) was taken up in ethanol (10 mL) and treated with 1 N sodium hydroxide (aq) (0.66 ml, 0.66 mmol). The resulting suspension was stirred at room temperature for 30 min. Ether was added and the liquids were collected to provide the sodium salt of the title compound as a white powder (291 mg, 99%). <sup>1</sup>H NMR (DMSO-d<sub>6</sub>) δ 10.68 (m, 1H), 7.90 (s, 1H), 7.35 (m, 1H), 7.20 (m, 1H), 7.01 (m, 1H), 5.20 (m, 1H), 4.58 (m, 1H), 4.49 (m, 2H), 4.22 (m, 2H), 3.74 (dd, J=11.2, 10.4 Hz, 1H), 3.58 (m, 1H), 1.25 (d, J=4.4 Hz, 3H).<br />
UNDESIRED ISOMER<br />
Example Z-9<br />
(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide sodium salt<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00124.png" href="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00124.png"><img alt="Figure US08129385-20120306-C00124" data-mce-src="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00124.png" src="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00124.png" height="100" id="EMI-C00124" style="height: auto; max-width: 100%;" width="253" /></a></div>
The title compound was made in two steps using a similar process to that described in example Z-1. 16a (510 mg, 1.08 mmol) and (25)-2-amino-1-propanol (0.17 mL, 2.17 mmol) were reacted in 1,2-dichloroethane (20 mL) with acetic acid to give (3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (500 mg, 93%). This material was hydrogenated in a second step as described in example Z-1 to give (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (386 mg, 94%) as a tinted white solid. <sup>1</sup>H NMR (CDCl<sub>3</sub>) δ 11.46 (m, 1H), 10.28 (m, 1H), 8.32 (s, 1H), 7.35 (m, 1H), 6.80 (m, 2H), 5.30 (dd, J=10.0, 4.0 Hz, 1H), 4.63 (m, 2H), 4.48-4.37 (m, 3H), 3.91 (dd, J=12.0, 10.0 Hz, 1H), 3.73 (m, 1H), 1.48 (d, J=6.0 Hz, 3H); ES<sup>+</sup> MS: 406 (M+1). This material (385 mg, 0.95 mmol) was treated with sodium hydroxide (0.95 mL, 1.0 M, 0.95 mmol) in ethanol (15 mL) as described in example Z-1 to provide its corresponding sodium salt (381 mg, 94%) as a white solid. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>) δ 10.66 (m, 1H), 7.93 (s, 1H), 7.33 (m, 1H), 7.20 (m, 1H), 7.01 (m, 1H), 5.19 (m, 1H), 4.59 (m, 1H), 4.48 (m, 2H), 4.22 (m, 2H), 3.75 (m, 1 H), 3.57 (m, 1H), 1.24 (d, J=5.6 Hz, 3H).<br />
SYNTHESIS OF INTERMEDIATES<br />
<img alt="Figure US08129385-20120306-C00090" data-mce-src="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00090.png" src="http://patentimages.storage.googleapis.com/US8129385B2/US08129385-20120306-C00090.png" height="971" style="height: auto; max-width: 100%;" width="667" /><br />
IN ABOVE SCHEME SYNTHESIS UPTO COMPD 9 MAY BE USEFUL IN SYNTHESIS BUT READERS DISCRETION IS SOUGHT IN THIS ?????????????????<br />
1) Maltol 1 (189 g, 1.5 mol) was dissolved in dimethylformamide (1890 ml), and benzyl bromide (184 ml, 1.5 mol) was added. After the solution was stirred at 80° C. for 15 minutes, potassium carbonate (228 g, 1.65 mol) was added, and the mixture was stirred for 1 hour. After the reaction solution was cooled to room temperature, an inorganic salt was filtered, and the filtrate was distilled off under reduced pressure. To the again precipitated inorganic salt was added tetrahydrofuran (1000 ml), this was filtered, and the filtrate was distilled off under reduced pressure to obtain the crude product (329 g, >100%) of 3-benzyloxy-2-methyl-pyran-4-one 2 as a brown oil.<br />
NMR (CDCl<sub>3</sub>) δ: 2.09 (3H, s), 5.15 (2H, s), 6.36 (1H, d, J=5.6 Hz), 7.29-7.41 (5H, m), 7.60 (1H, d, J=5.6 Hz).<br />
2) The compound 2 (162.2 g, 750 mmol) was dissolved in ethanol (487 ml), and aqueous ammonia (28%, 974 ml) and a 6N aqueous sodium hydroxide solution (150 ml, 900 mmol) were added. After the reaction solution was stirred at 90° C. for 1 hour, this was cooled to under ice-cooling, and ammonium chloride (58 g, 1080 mmol) was added. To the reaction solution was added chloroform, this was extracted, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, isopropyl alcohol and diethyl ether were added to the residue, and precipitated crystals were filtered to obtain 3-benzyloxy-2-methyl-1H-pyridine-4-one 3 (69.1 g, 43%) as a pale yellow crystal.<br />
NMR (DMSO-d<sub>6</sub>) δ: 2.05 (3H, s), 5.04 (2H, s), 6.14 (1H, d, J=7.0 Hz), 7.31-7.42 (5H, m), 7.46 (1H, d, J=7.2 Hz), 11.29 (1H, brs).<br />
3) The above compound 3 (129 g, 699 mmol) was suspended in acetonitrile (1300 ml), and N-bromosuccinic acid imide (117 g, 659 mmol) was added, followed by stirring at room temperature for 90 minutes. Precipitated crystals were filtered, and washed with acetonitrile and diethyl ether to obtain 3-benzyloxy-5-bromo-2-methyl-pyridine-4-ol 4 (154 g, 88%) as a colorless crystal.<br />
NMR (DMSO-d<sub>6</sub>) δ: 2.06 (3H, s), 5.04 (2H, s), 7.32-7.42 (5H, m), 8.03 (1H, d, J=5.5 Hz), 11.82 (1H, brs).<br />
4) To a solution of the compound 4 (88 g, 300 mmol), palladium acetate (13.4 g, 60 mmol) and 1,3-bis(diphenylphosphino)propane (30.8 g, 516 mmol) in dimethylformamide (660 ml) were added methanol (264 ml) and triethylamine (210 ml, 1.5 mol) at room temperature. The interior of a reaction vessel was replaced with carbon monoxide, and the material was stirred at room temperature for 30 minutes, and stirred at 80 degree for 18 hours. A vessel to which ethyl acetate (1500 ml), an aqueous saturated ammonium chloride solution (1500 ml) and water (1500 ml) had been added was stirred under ice-cooling, and the reaction solution was added thereto. Precipitates were filtered, and washed with water (300 ml), ethyl acetate (300 ml) and diethyl ether (300 ml) to obtain 5-benzyloxy-4-hydroxy-6-methyl-nicotinic acid methyl ester 5 (44.9 g, 55%) as a colorless crystal.<br />
NMR (DMSO-d<sub>6</sub>) δ: 2.06 (3H, s), 3.72 (3H, s), 5.02 (2H, s), 7.33-7.42 (5H, m), 8.07 (1H, s).<br />
5) After a solution of the compound 5 (19.1 g, 70 mmol) in acetic anhydride (134 ml) was stirred at 130° C. for 40 minutes, the solvent was distilled off under reduced pressure to obtain 4-acetoxy-5-benzyloxy-6-methyl-nicotinic acid methyl ester 6 (19.9 g, 90%) as a flesh colored crystal.<br />
NMR (CDCl<sub>3</sub>) δ: 2.29 (3H, s), 2.52 (3H, s), 3.89 (3H, s), 4.98 (2H, s), 7.36-7.41 (5H, m), 8.85 (1H, s).<br />
6) To a solution of the compound 6 (46.2 g, 147 mmol) in chloroform (370 ml) was added metachloroperbenzoic acid (65%) (42.8 g, 161 mmol) in portions under ice-cooling, and this was stirred at room temperature for 90 minutes. To the reaction solution was added a 10% aqueous potassium carbonate solution, and this was stirred for 10 minutes, followed by extraction with chloroform. The organic layer was washed with successively with a 10% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under induced pressure, and the residue was washed with diisopropyl ether to obtain 4-acetoxy-5-benzyloxy-6-methyl-1-oxy-nicotinic acid methyl ester 7 (42.6 g, 87%) as a colorless crystal.<br />
NMR (CDCl<sub>3</sub>) δ: 2.30 (3H, s), 2.41 (3H, s), 3.90 (3H, s), 5.02 (2H, s), 7.37-7.39 (5H, m), 8.70 (1H, s).<br />
7) To acetic anhydride (500 ml) which had been heated to stir at 130° C. was added the compound 7 (42.6 g, 129 mmol) over 2 minutes, and this was stirred for 20 minutes. The solvent was distilled off under reduced pressure to obtain 4-acetoxy-6-acetoxymethyl-5-benzyloxy-nicotinic acid methyl ester 8 (49.6 g, >100%) as a black oil.<br />
NMR (CDCl<sub>3</sub>) δ: 2.10 (3H, s), 2.28 (3H, s), 3.91 (3H, s), 5.07 (2H, s), 5.20 (2H, s), 7.35-7.41 (5H, m), 8.94 (1H, s).<br />
8) To a solution of the compound 8 (46.8 g, 125 mmol) in methanol (140 ml) was added a 2N aqueous sodium hydroxide solution (376 ml) under ice-cooling, and this was stirred at 50° C. for 40 minutes. To the reaction solution were added diethyl ether and 2N hydrochloric acid under ice-cooling, and precipitated crystals were filtered. Resulting crystals were washed with water and diethyl ether to obtain 5-benzyloxy-4-hydroxy-6-hydroxymethyl-nicotinic acid 9 (23.3 g, 68%) as a colorless crystal.<br />
NMR (DMSO-d<sub>6</sub>) δ: 4.49 (2H, s), 5.19 (2H, s), 5.85 (1H, brs), 7.14-7.20 (2H, m), 7.33-7.43 (7H, m), 8.30 (1H, s), 10.73 (1H, t, J=5.8 Hz), 11.96 (1H, brs).<br />
9) To a solution of the compound 9 (131 g, 475 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (219 g, 1140 mmol) and 1-hydroxybenzotriazole (128 g, 950 mmol) in dimethylformamide (1300 ml) was added 4-fluorobenzylamine (109 ml, 950 mmol), and this was stirred at 80° C. for 1.5 hours. After the reaction solution was cooled to room temperature, hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with a 5% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture (175 g) of 10 and 11. the resulting mixture was dissolved in acetic acid (1050 ml) and water (1050 ml), and zinc (31.1 g, 475 mmol) was added, followed by heating to reflux for 1 hour. After the reaction solution was cooled to room temperature, a 10% aqueous potassium carbonate solution was added, followed by extraction with ethyl acetate. The extract was washed with an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, this was washed with diethyl ether to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-4-hydroxy-6-hydroxymethyl-nicotinic acid amide 10 (107 g, 59%) as a colorless crystal.<br />
NMR (DMSO-d<sub>6</sub>) δ: 4.45 (2H, d, J=4.3 Hz), 4.52 (2H, d, J=5.8 Hz), 5.09 (2H, s), 6.01 (1H, brs), 7.36-7.43 (5H, m), 8.31 (1H, s), 12.63 (1H, brs).<br />
PATENT<br />
SYNTHESIS<br />
<a data-mce-href="http://www.google.com/patents/EP2602260A1?cl=en" href="http://www.google.com/patents/EP2602260A1?cl=en">EP2602260A1</a><br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-49.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-49.jpg" rel="attachment wp-att-8259"><img alt="STR1" class="alignnone size-full wp-image-8259" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-49.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-49.jpg" height="343" style="height: auto; max-width: 100%;" width="751" /></a><br />
Example 3<br />
<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0128.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0128.png"><img alt="Figure imgb0128" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0128.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0128.png" height="492" id="ib0128" style="height: auto; max-width: 100%;" width="584" /></a><br />
3H IS DOLUTEGRAVIR<br />
Step 1<br />
N,N-dimethylformamide dimethyl acetal (4.9 ml, 36.5 mmol) was added dropwise to compound 3A (5.0 g, 30.4 mmol) under cooling at 0°C. After stirring at 0°C for 1 hour, 100 ml of ethyl acetate was added to the reaction solution, and the organic layer was washed with a 0.5 N aqueous hydrochloric acid solution (50 ml). The aqueous layer was separated, followed by extraction with ethyl acetate (50 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate: 1:1 (v/v) → ethyl acetate) to obtain 4.49 g (yield: 67%) of compound 3B as an oil.<br />
<sup>1</sup>H-NMR (CDCl<sub>3</sub>)δ:1.32 (3H, t, J = 7.1 Hz), 2.90 (3H, br s), 3.29 (3H, br s), 4.23 (2H, q, J = 7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).<br />
Step 2<br />
Lithium hexamethyldisilazide (1.0 M solution in toluene, 49 ml, 49.0 mmol) was diluted with tetrahydrofuran (44 ml). A tetrahydrofuran (10 ml) solution of compound 3B (4.49 g, 20.4 mmol) was added dropwise thereto under cooling at -78°C, and a tetrahydrofuran (10 ml) solution of ethyl oxalyl chloride (3.35 g, 24.5 mmol) was then added dropwise to the mixture. The mixture was stirred at -78°C for 2 hours and then heated to 0°C. 2 N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 20 minutes, followed by extraction with ethyl acetate (200 ml x 2). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate: 7:3 → 5:5 → 0:10 (v/v)) to obtain 1.77 g (yield: 31%) of compound 3C as a white solid.<br />
<sup>1</sup>H-NMR (CDCl<sub>3</sub>)δ:1.36-1.46 (6H, m), 4.35-4.52 (8H, m), 8.53 (1H, s).<br />
Step 3<br />
Aminoacetaldehyde dimethyl acetal (0.13 ml, 1.20 mmol) was added to an ethanol (6 ml) solution of compound 3C (300 mg, 1.09 mmol) at 0°C, and the mixture was stirred at 0°C for 1.5 hours, then at room temperature for 18 hours, and at 60°C for 4 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (n-hexane-ethyl acetate: 5:5 → 0:10 (v/v)) to obtain 252 mg (yield: 64%) of compound 3D as an oil.<br />
<sup>1</sup>H-NMR (CDCl<sub>3</sub>)δ:1.36-1.47 (6H, m), 3.42 (6H, s), 3.90 (2H, d, J = 5.2 Hz), 4.37 (3H, q, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 8.16 (1H, s).<br />
Step 4<br />
62% H<sub>2</sub>SO<sub>4</sub> (892 mg, 5.64 mmol) was added to a formic acid (10 ml) solution of compound 3D (1.02 g, 2.82 mmol), and the mixture was stirred at room temperature for 16 hours. The formic acid was distilled off under reduced pressure. To the residue, methylene chloride was added, and the mixture was pH-adjusted to 6.6 by the addition of a saturated aqueous solution of sodium bicarbonate. The methylene chloride layer was separated, while the aqueous layer was subjected to extraction with methylene chloride. The methylene chloride layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 531.8 mg of compound 3E as a yellow oil.<br />
1H-NMR (CDCl3) δ: 1.28-1.49 (6H, m), 4.27-4.56 (4H, m), 4.84 (2H, s), 8.10 (1H, s), 9.72 (1H, s).<br />
Step 5<br />
Methanol (0.20 ml, 5.0 mmol), (R)-3-amino-butan-1-ol (179 mg, 2.0 mmol), and acetic acid (0.096 ml, 1.70 mmol) were added to a toluene (5 ml) solution of compound 3E (531 mg, 1.68 mmol), and the mixture was heated to reflux for 4 hours. The reaction solution was cooled to room temperature, then diluted with chloroform, and then washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was subjected to extraction with chloroform. The chloroform layers were combined, washed with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol: 100:0 → 90:10) to obtain 309.4 mg of compound 3F as a brown oil.<br />
1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.1 Hz), 1.40 (3H, d, J = 7.1 Hz), 1.55-1.61 (1H, m), 2.19-2.27 (1H, m), 4.00 (1H, d, J = 1.5 Hz), 4.03 (1H, d, J = 2.5 Hz), 4.10 (1H, dd, J = 13.2, 6.3 Hz), 4.26 (1H, dd, J = 13.2, 3.8 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.00-5.05 (1H, m), 5.31 (1H, dd, J = 6.4, 3.9 Hz), 8.10 (1H, s).<br />
Step 6<br />
Potassium trimethylsilanolate (333 mg, 2.34 mmol) was added to a 1,2-dimethoxyethane (2 ml) solution of compound 3F (159 mg, 0.47 mmol), and the mixture was stirred at room temperature for 7 hours. 1 N hydrochloric acid and saturated saline were added to the reaction solution, followed by extraction with chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 34.4 mg (yield: 25%) of compound 3G as an orange powder.<br />
1H-NMR (CDCl3) δ: 1.46 (3H, d, J = 3.5 Hz), 1.58-1.65 (1H, m), 2.26-2.30 (1H,m), 4.06-4.10 (2H, m), 4.31 (1H, dd, J = 13.8, 5.6 Hz), 4.48 (1H, dd, J = 13.6, 3.9 Hz), 5.03 (1H, t, J = 6.4 Hz), 5.36 (1H, dd, J = 5.5, 4.0 Hz), 8.44 (1H, s), 12.80 (1H, s), 14.90 (1H, s).<br />
Step 7<br />
Compound 3G (16 mg, 0.054 mmol) and 2,4-difluorobenzylamine (17 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1 ml). To the solution, N,N,N',N'-tetramethyl-O-(7-aza-benzotriazol-1-yl)uronium hexafluorophosphate (HATU) (53 mg, 0.14 mmol) and N-methylmorpholine (0.031 ml, 0.28 mmol) were added, and the mixture was stirred at room temperature for 16 hours. 2,4-difluorobenzylamine (17 mg, 0.12 mmol), HATU (64 mg, 0.17 mmol), and N-methylmorpholine (0.037 ml, 0.34 mmol) were further added thereto, and the mixture was stirred at room temperature for additional 16 hours. 0.5 N hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layers were combined, washed with 0.5 N hydrochloric acid and then with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by preparative high-performance liquid chromatography to obtain 12.5 mg (yield: 55%) of compound 3H as an orange solid.<br />
DOLUTEGRAVIR<br />
1H-NMR (DMSO-d6) δ: 1.36 (3H, d, J = 6.9 Hz), 1.55-1.60 (1H, m), 2.01-2.05 (1H, m), 3.92-3.94 (1H, m), 4.04 (1H, t, J = 12.6 Hz), 4.38-4.41 (1H, m), 4.57-4.60 (1H, m), 4.81-4.83 (1H, m), 5.46-5.49 (1H, m), 7.08-7.11 (1H, m), 7.25-7.30 (1H, m), 7.41 (1H, dd, J = 15.3, 8.7 Hz), 8.53 (1H, s), 10.38 (1H, s), 12.53 (1H, s).<br />
ISOMERS OF DOLUTEGRAVIR<br />
Reference Example 1<br />
<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0145.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0145.png"><img alt="Figure imgb0145" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0145.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0145.png" height="20" id="ib0145" style="height: auto; max-width: 100%;" width="160" /></a><br />
<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0146.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0146.png"><img alt="Figure imgb0146" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0146.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0146.png" height="512" id="ib0146" style="height: auto; max-width: 100%;" width="608" /></a><br />
Step 1<br />
Acetic acid (180 mg, 3.00 mmol) was added to a toluene (90 ml) solution of compound A-1 (4.39 g, 9.33 mmol) and (R)-3-aminobutan-1-ol (998 mg, 11.2 mmol), and the mixture was stirred at 50°C for 90 minutes. The reaction solution was allowed to cool to room temperature and then poured to a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, while the aqueous layer was subjected to extraction three times with ethyl acetate. The combined extracts were washed with saturated saline and then dried over sodium sulfate. The solvent was distilled off to obtain 4.29 g of crude product A-2.<br />
Step 2<br />
The crude product A-2 obtained in the preceding step was dissolved in ethanol (40 ml). To the solution, a 2 N aqueous sodium hydroxide solution (20 ml) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was neutralized to pH 7 using a 2 N aqueous hydrochloric acid solution. The solvent was directly distilled off. The obtained crude product A-3 was subjected to azeotropy with toluene (100 ml) and used in the next step without being purified.<br />
Step 3<br />
HOBt (1.65 g, 12.2 mmol) and WSC HCl (2.34 g, 12.2 mmol) were added at room temperature to a DMF (100 ml) solution of the crude product A-3 obtained in the preceding step, and the mixture was stirred at the same temperature for 15 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate. The combined extracts were washed with water three times and then dried over sodium sulfate. The solvent was distilled off, and the obtained oil was subjected to silica gel column chromatography for purification. Elution was performed first with n-hexane-ethyl acetate (3:7, v/v) and then with only ethyl acetate. The fraction of interest was concentrated, and the obtained oil was then dissolved in ethyl acetate. The solution was crystallized with diisopropyl ether as a poor solvent. The obtained crystals were collected by filtration and dissolved again in ethyl acetate. The solution was recrystallized to obtain 1.84 g of compound A-4.<br />
<sup>1</sup>HNMR (CDCl<sub>3</sub>) δ: 1.49 (3H, d, J = 6.6 Hz), 1.88-1.96 (1H, m), 2.13-2.26 (1H, m), 3.90-4.17 (4H, m), 4.42-4.47 (1H, m), 4.63 (2H, d, J = 6.0 Hz), 5.12-5.17 (1H, m), 5.17 (1H, d, J = 9.9 Hz), 5.33 (1H, d, J = 9.9 Hz), 6.77-6.87 (2H, m), 7.27-7.42 (4H, m), 7.59-7.62 (2H, m), 8.35 (1H, s), 10.41 (1H, t, J = 5.7 Hz).<br />
Step 4<br />
The compound A-4 was subjected to the hydroxy deprotection reaction described in Step F of the paragraph [0088] to obtain compound A-5.<br />
<sup>1</sup>HNMR (DMSO-d<sub>6</sub>) δ:1.41 (3H, d, J = 6.3 Hz), 1.85-1.92 (1H, m), 1.50-1.75 (1H, m), 4.02-4.09 (3H, m), 4.28-4.34 (1H, m), 4.53 (2H, d, J = 5.7 Hz), 4.64 (1H, dd, J = 3.9 Hz, 12.6 Hz), 5.45 (1H, dd, J = 3.6 Hz, 9.3 Hz), 7.06 (1H, ddd, J = 2.7 Hz, 8.4 Hz, 8.4 Hz), 7.20-7.28 (1H, m), 7.35-7.42 (1H, m), 8.43 (1H, s),10.37 (1H, t, J = 6.0 Hz),12.37 (1H, brs).<br />
Reference Example 2<br />
<a data-mce-href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0147.png" href="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0147.png"><img alt="Figure imgb0147" data-mce-src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0147.png" src="http://patentimages.storage.googleapis.com/EP2602260A1/imgb0147.png" height="488" id="ib0147" style="height: auto; max-width: 100%;" width="572" /></a><br />
Compound A-1 was reacted with (S)-3-aminobutan-1-ol in Step 1. Compound B-5 was obtained in the same way as in Reference Example 1.<br />
<ul>
<li><sup>1</sup>HNMR (DMSO-d<sub>6</sub>) δ:1.41 (3H, d, J = 6.3 Hz), 1.85-1.92 (1H, m), 1.50-1.75 (1H, m), 4.02-4.09 (3H, m), 4.28-4.34 (1H, m), 4.53 (2H, d, J = 5.7 Hz), 4.64 (1H, dd, J = 3.9 Hz, 12.6 Hz), 5.45 (1H, dd, J = 3.6 Hz, 9.3 Hz), 7.06 (1H, ddd, J = 2.7 Hz, 8.4 Hz, 8.4 Hz), 7.20-7.28 (1H, m), 7.35-7.42 (1H, m), 8.43 (1H, s),10.37 (1H, t, J = 6.0 Hz),12.37 (1H, brs).</li>
</ul>
PATENT<br />
<a data-mce-href="http://www.google.com/patents/WO2006116764A1?cl=en" href="http://www.google.com/patents/WO2006116764A1?cl=en">W02006116764</a><br />
<img alt="Figure imgf000122_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2006116764A1/imgf000122_0001.png" src="http://patentimages.storage.googleapis.com/WO2006116764A1/imgf000122_0001.png" height="307" style="height: auto; max-width: 100%;" width="629" /><br />
ENTRY 68<br />
PATENT<br />
WO 2010068262<br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-50.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-50.jpg" rel="attachment wp-att-8260"><img alt="STR1" class="alignnone size-full wp-image-8260" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-50.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-50.jpg" height="594" style="height: auto; max-width: 100%;" width="729" /></a><br />
PATENT<br />
WO 2010068253<br />
PATENT<br />
WO 2011119566<br />
PATENT<br />
Synthesis<br />
<a data-mce-href="http://www.google.com/patents/WO2012018065A1?cl=en" href="http://www.google.com/patents/WO2012018065A1?cl=en">WO 2012018065</a><br />
Example 3<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2012018065A1/JPOXMLDOC01-appb-C000176.png" href="http://patentimages.storage.googleapis.com/WO2012018065A1/JPOXMLDOC01-appb-C000176.png"><img alt="Figure JPOXMLDOC01-appb-C000176" data-mce-src="http://patentimages.storage.googleapis.com/WO2012018065A1/JPOXMLDOC01-appb-C000176.png" src="http://patentimages.storage.googleapis.com/WO2012018065A1/JPOXMLDOC01-appb-C000176.png" height="465px" style="height: auto; max-width: 100%;" width="572px" /></a></div>
I was under cooling added dropwise at 0 ℃ (4.9 ml, 36.5 mmol) and N, N-dimethylformamide dimethyl acetal (5.0 g, 30.4 mmol) in the first step compound 3A. After stirring for 1 hour at 0 ℃, ethyl acetate was added to 100ml, the reaction mixture was washed with 0.5N aqueous hydrochloric acid (50 ml). Was extracted with ethyl acetate (50ml) and solution was separated and the aqueous layer. The organic layers were combined, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, silica gel column chromatography and the residue obtained was - and purified by (n-hexane (v / v) → ethyl acetate 1:1) to an oil (67% yield) of Compound 3B 4.49 g I got a thing.<br />
<sup>1</sup> H-NMR (CDCl <sub>3)</sub><sup>δ:</sup> 1.32 (3H, t, J = 7.1 Hz), 2.90 (3H, br s), 3.29 (3H, br s), 4.23 (2H, q, J = 7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).<br />
Diluted with tetrahydrofuran (44 ml) (1.0M toluene solution, 49 ml, 49.0 mmol) the second step lithium hexamethyldisilazide, under cooling at -78 ℃, compound 3B (4.49 g, 20.4 mmol) in this After dropwise tetrahydrofuran (10 ml) was added dropwise tetrahydrofuran (3.35 g, 24.5 mmol) of ethyl oxalyl chloride and (10 ml) solution. After stirring for 2 hours at -78 ℃, I was warmed to 0 ℃. After washing (200 ml x 2), saturated aqueous sodium bicarbonate solution and the organic layer with saturated brine After stirring for 20 minutes, extracted with ethyl acetate by adding 2N hydrochloric acid, the reaction solution was dried over anhydrous sodium sulfate. After removal of the solvent, silica gel column chromatography and the residue obtained - was purified (n-hexane (v / v) ethyl acetate 7:3 → 5:5 → 0:10), compound 3C 1.77 g (yield I as a white solid 31%).<br />
<sup>1</sup> H-NMR (CDCl <sub>3)</sub><sup>δ :1.36-1</sup> .46 (6H, m), 4.35-4.52 (8H, m), 8.53 (1H, s).<br />
Was added at 0 ℃ (0.13 ml, 1.20 mmol) the aminoacetaldehyde dimethyl acetal ethanol (300 mg, 1.09 mmol) of the third step compound 3C to (6 ml) solution, 1 hour and 30 minutes at 0 ℃, 18 hours at room temperature , then I was stirred for 4 hours at 60 ℃. After the solvent was evaporated under reduced pressure and the reaction mixture by silica gel column chromatography and the residue obtained was - and purified by (n-hexane (v / v) ethyl acetate 5:5 → 0:10), compound 3D 252 mg (yield: I got as an oil 64%) rate.<br />
<sup>1</sup> H-NMR (CDCl <sub>3)</sub><sup>δ :1.36-1</sup> .47 (6H, m), 3.42 (6H, s), 3.90 (2H, d, J = 5.2 Hz), 4.37 (3H, q, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 8.16 (1H, s).<br />
Was added (892 mg, 5.64 mmol) and <sub>2</sub> SO <sub>4</sub> 62-H% formic acid (1.02 g, 2.82 mmol) in a fourth step the compound for 3D (10 ml) solution was stirred at room temperature for 16 hours. Methylene chloride was added to the residue Shi distilled off under reduced pressure and formic acid was adjusted to pH = 6.6 by addition of saturated aqueous sodium bicarbonate. The solution was separated methylene chloride layer was extracted with methylene chloride and the aqueous layer. I was dried over anhydrous sodium sulfate combined methylene chloride layers. The solvent was then distilled off and was obtained as a yellow oil 531.8 mg compound 3E.<br />
1H-NMR (CDCl3) δ: 1.28-1.49 (6H, m), 4.27-4.56 (4H, m), 4.84 (2H, s), 8.10 (1H, s), 9.72 (1H, s).<br />
Amino - - butane - 1 - ol (179 mg, 2.0 mmol), methanol (0.20 ml, 5.0 mmol), (R) -3 toluene (531 mg, 1.68 mmol) in the fifth step to compound 3E (5 ml) solution was added (0.096 ml, 1.70 mmol) acetic acid was heated under reflux for 4 hours. After dilution with chloroform, cooled to room temperature, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with chloroform. After washing with saturated brine combined chloroform layer was dried over anhydrous sodium sulfate. The solvent was then distilled off, silica gel column chromatography and the residue obtained - and (chloroform methanol 100:0 → 90:10), was obtained as a brown oil 309.4 mg compound 3F.<br />
1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.1 Hz), 1.40 (3H, d, J = 7.1 Hz), 1.55-1.61 (1H, m), 2.19-2.27 (1H, m), 4.00 (1H, d, J = 1.5 Hz), 4.03 (1H, d, J = 2.5 Hz), 4.10 (1H, dd, J = 13.2, 6.3 Hz), 4.26 (1H, dd, J = 13.2, 3.8 Hz ), 4.38 (2H, q, J = 7.1 Hz), 5.00-5.05 (1H, m), 5.31 (1H, dd, J = 6.4, 3.9 Hz), 8.10 (1H, s).<br />
1,2 (159 mg, 0.47 mmol) in the sixth step compound 3F - was added (333 mg, 2.34 mmol) and potassium trimethylsilanolate dimethoxyethane (2 ml) solution was stirred for 7 hours at room temperature. Brine was added to the 1N-hydrochloric acid to the reaction mixture, followed by extraction with chloroform. The combined chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation, and I as an orange powder (25% yield) of compound 3G 34.4 mg.<br />
1H-NMR (CDCl3) δ: 1.46 (3H, d, J = 3.5 Hz), 1.58-1.65 (1H, m), 2.26-2.30 (1H, m), 4.06-4.10 (2H, m), 4.31 (1H , dd, J = 13.8, 5.6 Hz), 4.48 (1H, dd, J = 13.6, 3.9 Hz), 5.03 (1H, t, J = 6.4 Hz), 5.36 (1H, dd, J = 5.5, 4.0 Hz) , 8.44 (1H, s), 12.80 (1H, s), 14.90 (1H, s).<br />
2,4 (16 mg, 0.054 mmol) and the seventh step compound 3G - was dissolved in N, N-dimethylformamide (1 ml) (17 mg, 0.12 mmol) difluorobenzyl amine, N, N, N ', N was added (0.031 ml, 0.28 mmol) and N-methylmorpholine uronium hexafluorophosphate (HATU) (53 mg, 0.14 mmol), and '- tetramethyl-O-(yl 7 - aza - - benzo triazolopyrimidine -1) I was stirred at room temperature for 16 h. 2,4 - was added (0.037 ml, 0.34 mmol) and N-methylmorpholine (64 mg, 0.17 mmol) and (17 mg, 0.12 mmol), HATU difluorobenzylamine, and the mixture was stirred for 16 hours at room temperature. I was extracted with ethyl acetate addition of 0.5N-hydrochloric acid to the reaction mixture. 0.5N-hydrochloric acid and then was washed with saturated brine, and dried over anhydrous sodium sulfate and combined ethyl acetate layer. The solvent was then distilled off, and purified by preparative high performance liquid chromatography residue was obtained as an orange solid (55% yield) of compound 3H 12.5 mg.<br />
1H-NMR (DMSO-d6) δ: 1.36 (3H, d, J = 6.9 Hz), 1.55-1.60 (1H, m), 2.01-2.05 (1H, m), 3.92-3.94 (1H, m), 4.04 (1H, t, J = 12.6 Hz), 4.38-4.41 (1H, m), 4.57-4.60 (1H, m), 4.81-4.83 (1H, m), 5.46-5.49 (1H, m), 7.08-7.11 (1H, m), 7.25-7.30 (1H, m), 7.41 (1H, dd, J = 15.3, 8.7 Hz), 8.53 (1H, s), 10.38 (1H, s), 12.53 (1H, s)<br />
PAPER<br />
<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm400645w" href="http://pubs.acs.org/doi/abs/10.1021/jm400645w">http://pubs.acs.org/doi/abs/10.1021/jm400645w</a><br />
<h1 class="articleTitle">
<span class="hlFld-Title">Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)</span></h1>
<div id="articleMeta">
<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Johns%2C+Brian+A" href="http://pubs.acs.org/author/Johns%2C+Brian+A" id="authors">Brian A. Johns</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm400645w#cor1" href="http://pubs.acs.org/doi/abs/10.1021/jm400645w#cor1">*</a><span class="NLM_xref-aff">†</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kawasuji%2C+Takashi" href="http://pubs.acs.org/author/Kawasuji%2C+Takashi" id="authors">Takashi Kawasuji</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Weatherhead%2C+Jason+G" href="http://pubs.acs.org/author/Weatherhead%2C+Jason+G" id="authors">Jason G. Weatherhead</a></span><span class="NLM_xref-aff">†</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Taishi%2C+Teruhiko" href="http://pubs.acs.org/author/Taishi%2C+Teruhiko" id="authors">Teruhiko Taishi</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Temelkoff%2C+David+P" href="http://pubs.acs.org/author/Temelkoff%2C+David+P" id="authors">David P. Temelkoff</a></span><span class="NLM_xref-aff">†</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Yoshida%2C+Hiroshi" href="http://pubs.acs.org/author/Yoshida%2C+Hiroshi" id="authors">Hiroshi Yoshida</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Akiyama%2C+Toshiyuki" href="http://pubs.acs.org/author/Akiyama%2C+Toshiyuki" id="authors">Toshiyuki Akiyama</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Taoda%2C+Yoshiyuki" href="http://pubs.acs.org/author/Taoda%2C+Yoshiyuki" id="authors">Yoshiyuki Taoda</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Murai%2C+Hitoshi" href="http://pubs.acs.org/author/Murai%2C+Hitoshi" id="authors">Hitoshi Murai</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kiyama%2C+Ryuichi" href="http://pubs.acs.org/author/Kiyama%2C+Ryuichi" id="authors">Ryuichi Kiyama</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Fuji%2C+Masahiro" href="http://pubs.acs.org/author/Fuji%2C+Masahiro" id="authors">Masahiro Fuji</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Tanimoto%2C+Norihiko" href="http://pubs.acs.org/author/Tanimoto%2C+Norihiko" id="authors">Norihiko Tanimoto</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Jeffrey%2C+Jerry" href="http://pubs.acs.org/author/Jeffrey%2C+Jerry" id="authors">Jerry Jeffrey</a></span><span class="NLM_xref-aff">†</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Foster%2C+Scott+A" href="http://pubs.acs.org/author/Foster%2C+Scott+A" id="authors">Scott A. Foster</a></span><span class="NLM_xref-aff">†</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Yoshinaga%2C+Tomokazu" href="http://pubs.acs.org/author/Yoshinaga%2C+Tomokazu" id="authors">Tomokazu Yoshinaga</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Seki%2C+Takahiro" href="http://pubs.acs.org/author/Seki%2C+Takahiro" id="authors">Takahiro Seki</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kobayashi%2C+Masanori" href="http://pubs.acs.org/author/Kobayashi%2C+Masanori" id="authors">Masanori Kobayashi</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Sato%2C+Akihiko" href="http://pubs.acs.org/author/Sato%2C+Akihiko" id="authors">Akihiko Sato</a></span><span class="NLM_xref-aff">‡</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Johnson%2C+Matthew+N" href="http://pubs.acs.org/author/Johnson%2C+Matthew+N" id="authors">Matthew N. Johnson</a></span><span class="NLM_xref-aff">†</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Garvey%2C+Edward+P" href="http://pubs.acs.org/author/Garvey%2C+Edward+P" id="authors">Edward P. Garvey</a></span><span class="NLM_xref-aff">†</span><span class="NLM_x">, and </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Fujiwara%2C+Tamio" href="http://pubs.acs.org/author/Fujiwara%2C+Tamio" id="authors">Tamio Fujiwara</a></span><span class="NLM_xref-aff">‡</span></span></div>
<div class="affiliations">
<div id="aff1">
<sup>†</sup> <span class="institution">GlaxoSmithKline Research & Development</span>, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States</div>
<div id="aff2">
<sup>‡</sup> Shionogi Pharmaceutical Research Center, <span class="institution">Shionogi & Co., Ltd.</span>, 3-1-1 Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan</div>
</div>
<div id="citation">
<cite>J. Med. Chem.</cite>, <span class="citation_year">2013</span>, <span class="citation_volume">56</span> (14), pp 5901–5916</div>
<div id="doi">
<strong>DOI: </strong>10.1021/jm400645w</div>
</div>
<a data-mce-href="http://cyber.sci-hub.bz/MTAuMTAyMS9qbTQwMDY0NXc=/johns2013.pdf?download=true" href="http://cyber.sci-hub.bz/MTAuMTAyMS9qbTQwMDY0NXc=/johns2013.pdf?download=true" target="_blank"><em>J. Med. Chem.</em> <strong>2013</strong>, <em>56</em>, 5901-5916</a>.<br />
<div id="absImg">
<img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2013/jmcmar.2013.56.issue-14/jm400645w/production/images/medium/jm-2013-00645w_0016.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2013/jmcmar.2013.56.issue-14/jm400645w/production/images/medium/jm-2013-00645w_0016.gif" style="height: auto; max-width: 100%;" /></div>
<div class="articleBody_abstractText">
We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (<b>3</b>) and S/GSK1265744 (<b>4</b>). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure–activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of <b>3</b> and <b>4</b>, which are currently in clinical development.</div>
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-51.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-51.jpg" rel="attachment wp-att-8261"><img alt="STR1" class="alignnone size-full wp-image-8261" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-51.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-51.jpg" height="427" style="height: auto; max-width: 100%;" width="725" /></a><br />
(4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino-<br />
[2,1-b][1,3]oxazine-9-carboxamide (3). 1H NMR (CDCl3) δ 12.45 (s, 1H),10.38 (br s, 1H), 8.30 (s, 1H), 7.40−7.30 (m, 1H), 6.85−6.75 (m, 2H),5.26 (d, J = 5.8, 4.1 Hz, 2H), 5.05−4.95 (m, 1H), 4.64 (d, J = 5.9 Hz,2H), 4.27 (dd, J = 13.4, 4.2 Hz, 1H), 4.12 (dd, J = 13.6, 6.0 Hz, 1H), 4.05(t, J = 2.3 Hz, 1H), 4.02 (d, J = 2.2 Hz, 1H), 2.30−2.19 (m, 1H), 1.56(dd, J = 14.0, 2.0 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H). ES+ LC/MS: m/zcalcd 419.13; found 420.13 (M + 1)+.<br />
(4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino-<br />
[2,1-b][1,3]oxazine-9-carboxamide (3) sodium salt.<br />
1H NMR(DMSO-d6) δ 10.70 (t, J = 6.0 Hz, 1H), 7.89 (s, 1 H), 7.40−7.30 (m, 1H), 7.25−7.16 (m, 1H), 7.06−6.98 (m, 1H), 5.22−5.12 (m, 1H), 4.87−4.74 (m, 1H), 4.51 (d, J = 5.4 Hz, 2H), 4.35−4.25 (m, 1 H), 4.16 (dd, J =1.8, 14.1 Hz, 1 H), 4.05−3.90 (m, 1H), 3.86−3.74 (m, 1 H), 2.00−1.72(m, 1 H), 1.44−1.32 (m, 1 H), 1.24 (d, J = 6.9 Hz, 3H).<br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-52.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-52.jpg" rel="attachment wp-att-8264"><img alt="STR1" class="alignnone size-full wp-image-8264" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-52.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-52.jpg" height="254" style="height: auto; max-width: 100%;" width="406" /></a><br />
MORE UPDATES.................................</div>
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Process for preparing integrase inhibitors such as dolutegravir and cabotegravir and their analogs, useful for treating viral infections eg HIV infection. Also claims a process for preparing intermediates of dolutegravir and cabotegravir.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(4R, 12aS)-N-[(2,4-Difluorophenyl)methyl]-3 ,4,6,8, 12, 12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1-b][1 ,3]oxazine-9-carboxamide (Formula A):</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000002_0001.gif" height="154" id="imgf000002_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000002_0001.gif" style="height: auto; max-width: 100%;" width="257" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Formula A</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
known by the INN name dolutegravir, is a new efficient antiviral agent from the group of HIV integrase inhibitors which is used in combination with some other antiviral agents for treatment of HIV infections, such as AIDS. The compound, which belongs to condensed polycyclic pyridines and was first disclosed in WO2006/1 16764, is marketed.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Another compound disclosed in WO2006/1 16764 is (3S, 1 1 aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 1 1 ,1 1 a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide (Formula</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000002_0002.gif" height="144" id="imgf000002_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000002_0002.gif" style="height: auto; max-width: 100%;" width="256" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Formula C</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
known by the INN name cabotegravir.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The complex structures of dolutegravir and cabotegravir present a synthetic challenge. The first description of the synthesis in WO2006/1 16764 shows a 16-steps synthesis (see Scheme A), which is industrially impractical due to its length and low overall yield.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000003_0001.gif" height="606" id="imgf000003_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000003_0001.gif" style="height: auto; max-width: 100%;" width="894" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Scheme A</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
WO 2010/068253 and WO 2006/1 16764 describe an alternative synthesis. The 1 1 -step synthesis, shown in Scheme B1 and Scheme B2, is based on bromination of the 9-position for further introduction of the carboxylic group. The synthesis relies on the use of expensive palladium catalysts and toxic selenium compounds. Furthermore, some variations of these approaches involve pyrone intermediates in several steps. In some cases pyrones are liquids which can complicate purification, while further reactions form complex mixtures.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000004_0001.gif" height="80" id="imgf000004_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000004_0001.gif" style="height: auto; max-width: 100%;" width="856" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000004_0002.gif" height="261" id="imgf000004_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000004_0002.gif" style="height: auto; max-width: 100%;" width="839" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000004_0003.gif" height="531" id="imgf000004_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000004_0003.gif" style="height: auto; max-width: 100%;" width="892" /> doiutegravir</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Scheme B2</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
In further alternative syntheses, acetoacetates were used as starting materials. Such an approach is challenging in terms of introducing the hydroxy group in the 7-position. The variation in Scheme C1 , described in WO2012/018065, starts from 4-benzyloxyacetoacetate. The procedure requires 9 steps, but use expensive reagents like palladium catalysts. Moreover, there is described a possibility of formation a co-crystal between an intermediate and hydroquinone, wherein however the additional step may diminish yields and make the process longer and time consuming.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000005_0001.gif" height="588" id="imgf000005_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000005_0001.gif" style="height: auto; max-width: 100%;" width="900" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Scheme C1</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The variation in Scheme C2, described in WO2012/018065, starts from 4-chloroacetoacetate. The process is not optimal because of problems in steps which include pyrones and because of problems with conversion of 7-chloro to 7-hydroxy group which includes a disadvantageous use of silanolates with low yield (25%).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000006_0001.gif" height="287" id="imgf000006_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000006_0001.gif" style="height: auto; max-width: 100%;" width="902" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Scheme C2</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The variation in Scheme C3, described in WO201 1/1 19566, starts from unsubstituted acetoacetate. For the introduction of the 7-hydroxy group, bromination is used and substitution of bromo with hydroxy is performed by a use of silanolates. The substitution of the bromine is achieved in a 43% yield.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000006_0002.gif" height="299" id="imgf000006_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000006_0002.gif" style="height: auto; max-width: 100%;" width="904" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Scheme C3</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The variation in Scheme C4, described in WO201 1/1 19566, starts from 4-methoxyacetoacetate aiming at preparing dolutegravir or cabotegravir. The process uses lithium bases to affect a difficult to control selective monohydrolysis of a diester.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000007_0001.gif" height="413" id="imgf000007_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000007_0001.gif" style="height: auto; max-width: 100%;" width="880" /></div>
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<br /></div>
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<br /></div>
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PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016113372&redirectedID=true" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016113372&redirectedID=true">WO 2016113372</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Carbotegravir, New Patent, WO 2016113372, Lek Pharmaceutical and Chemical Co DD</div>
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<b>LEK PHARMACEUTICALS D.D.</b> [SI/SI]; Verovskova 57 1526 Ljubljana (SI)</div>
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<b>MARAS, Nenad</b>; (SI).<br />
<b>SELIC, Lovro</b>; (SI).<br />
<b>CUSAK, Anja</b>; (SI)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
ViiV Healthcare is developing cabotegravir (first disclosed in WO2006088173), which in July 2016, was reported to be in phase 2 clinical development.</div>
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<u>WO-2016113372</u></div>
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The object of the present invention is to provide short, simple, cost-effective, environmentally friendly and industrially suitable processes for beneficially providing dolutegravir and analogues thereof and cabotegravir and analogues thereof, in particular dolutegravir.</div>
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Scheme 1</div>
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<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000046_0001.gif" height="412" id="imgf000046_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000046_0001.gif" style="height: auto; max-width: 100%;" width="887" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
According to an embodiment of the process of the invention the building block 3-aminobutanol can suitably be substituted with other aminoalcohols to give dolutegravir analogues. For example, using (S)-alaninol gives cabotegravir as the final product. Similarly, using amines other than 2,4-difluorobenzylamine in the amidation step results in the synthesis of other dolutegravir analogues.</div>
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According to the another preferred embodiment cabotegravir or a pharmaceutically acceptable salt thereof is prepared by the analogue process, which comprises providing a compound of formula (5c)</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000046_0002.gif" height="116" id="imgf000046_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000046_0002.gif" style="height: auto; max-width: 100%;" width="213" /></div>
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5c</div>
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converting the compound of formula (5c) to a compound of formula (6c)</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000047_0001.gif" height="116" id="imgf000047_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000047_0001.gif" style="height: auto; max-width: 100%;" width="215" /></div>
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6c</div>
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by carrying out a chlorination reaction, and converting the compound of formula (6c) to cabotegravir and/or a pharmaceutically acceptable salt thereof.</div>
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The compound of formula (5c) can preferably be provided by converting a compound of formula (3) to a compound of formula (4c)</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000047_0002.gif" height="126" id="imgf000047_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000047_0002.gif" style="height: auto; max-width: 100%;" width="134" /></div>
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Scheme 2</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000048_0001.gif" height="97" id="imgf000048_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000048_0001.gif" style="height: auto; max-width: 100%;" width="445" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
1. ) EtOCOCI, Et<sub>3</sub>N / Me<sub>2</sub>CO</div>
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2. ) 2,4-difiuorobenzylamine</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000048_0002.gif" height="96" id="imgf000048_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000048_0002.gif" style="height: auto; max-width: 100%;" width="410" /></div>
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Scheme 3</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000048_0003.gif" height="100" id="imgf000048_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000048_0003.gif" style="height: auto; max-width: 100%;" width="485" /></div>
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Analogous compound of formula 7c is a useful intermediate in the synthesis of cabotegravir. Scheme 3a</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000048_0004.gif" height="108" id="imgf000048_0004" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000048_0004.gif" style="height: auto; max-width: 100%;" width="522" /></div>
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Scheme 4</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000049_0001.gif" height="296" id="imgf000049_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000049_0001.gif" style="height: auto; max-width: 100%;" width="507" /></div>
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Examples</div>
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The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way. The examples and modifications or other equivalents thereof will become apparent to those versed in the art in the light of the present entire disclosure. Particularly, all Examples related to the preparation of dolutegravir and intermediates thereof can be used by the analogy for the preparation of cabotegravir and intermediates thereof.</div>
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Example 1 :</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000063_0001.gif" height="69" id="imgf000063_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000063_0001.gif" style="height: auto; max-width: 100%;" width="153" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Methyl acetoacetate (1 , 25.22 g) and dimethylformamide dimethyl acetal (DMFDMA, 35 mL) was heated at 50-55°C for 2 h, then methanol (60 mL), aminoacetaldehyde dimethyl acetal (24 mL) and acetic acid (4 mL) was added an the mixture was heated under reflux for one hour, then concentrated. MTBE (100 mL) was added and the mixture was kept at 5 °C overnight to crystallize. Upon filtration 46 g (92%) of product 2 was recovered.</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 2.31 (s, 3H), 3.30 (s, 6H), 3.49 (m, 2H), 3.61 (s, 3H), 4.43 (m, 1 H), 8.02 (d, 1 H), 10.8 (bs, 1 H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 30.52, 35.48, 50.53, 54.23, 98.99, 102.47, 160.70, 166.92, 197.21 .</div>
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Example 2:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000063_0002.gif" height="82" id="imgf000063_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000063_0002.gif" style="height: auto; max-width: 100%;" width="352" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound 2 (5.00 g) was dissolved in 2-propanol, dimethyl oxalate (7.02 g) was added and heated to 40 °C. Sodium methylate (25% in methanol; 20 mL) was slowly (10 min) added, the mixture was then heated to 50-55 °C and stirred at that temperature for 2-2.5 h. The mixture was cooled to ambient temperature, then sodium hydroxide solution (1 M, 65 mL) was added to the mixture and stirred for another 2 h, followed by addition of concentrated hydrochloric acid (1 1 mL) and stirred for another 2 h. The precipitate was filtered and dried to give 8.08 g (NMR assay 47%; 65% yield) of compound 3.</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 2.50 (m, 2H), 3.30 (s. 6H), 4.49 (m, 1 H), 7.06 (s, 1 H); 8.70 (s, 1 H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 55.23, 55.37, 102.34, 1 15.47, 120.24, 145.17, 162.71 , 165.22, 178.55.</div>
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Example 3:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000064_0001.gif" height="95" id="imgf000064_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000064_0001.gif" style="height: auto; max-width: 100%;" width="284" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound 2 (158.37 g) was dissolved in methanol (548 mL), followed by the addition of dimethyl oxalate (202.2 g). While keeping the temperature below 30°C, potassium ferf-butoxide (192.1 g) was added and reaction mixture was heated at 50 °C overnight. The suspension was then filtered and the filter cake washed with methanol. The filtrate was concentrated (approximately to 680 mL), then water (680 mL) was added, followed by addition of lithium hydroxide hydrate (143.7 g) while keeping the temperature below 40 °C. The suspension was then stirred at ambient temperature overnight and filtered. To the obtained filtrate, concentrated hydrochloric acid (339 mL) was added while keeping the temperature below 30 °C. The suspension was aged for 2 h and filtered to give 4 as a white powder (95.6 g, NMR assay 100%; 52% yield).</div>
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Example 4:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000064_0002.gif" height="79" id="imgf000064_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000064_0002.gif" style="height: auto; max-width: 100%;" width="242" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound 2 (5.00 g) was dissolved in 2-propanol, dimethyl oxalate (7.02 g) was added and heated to 40 °C. Sodium methylate (25% in methanol; 15 mL) was slowly (10 min) added then the mixture was heated to 50-55 °C and stirred at that temperature for 72 h. The mixture was concentrated and components were separated by flash column chromatography (ethyl acetate/methanol 9:1 to 6:4). Early fractions gave compound 22 upon concentration, late fractions gave compound 23.</div>
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Compound 22: <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 2.49 (m, 2H), 3.28 (s, 6H), 3.73 (s, 3H), 3.85 (s, 3H), 4.41 (m, 1 H), 4.50 (m, 1 H), 6.65 (s, 1 H), 8.36 (s, 1 H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 51.63, 53.36, 54.25, 55.47, 102.71 , 1 18.24, 123.60, 140.81 , 150.21 , 162.44, 164.49, 173.43.</div>
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Compound 23: <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 2.49 (m, 2H), 3.26 (s, 6H); 3.70 (s, 3H); 4.33 (d, 1 H); 4.60 (m, 1 H), 6.19 (s, 1 H), 8.12 (s, 1 H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 50.03, 51.34, 54.59, 54.85, 102.91 , 1 16.04, 1 18.19, 148.32, 152.12, 163.46, 165.24, 174.99</div>
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Example 5:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000065_0001.gif" height="80" id="imgf000065_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000065_0001.gif" style="height: auto; max-width: 100%;" width="218" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound 3 (5.5 g; assay 53%) was suspended in acetonitrile, acetic acid (6 mL) and methanesulfonic acid (2.5 mL) were added followed by the heating of mixture to 70 °C for 4 h. The suspension was filtered and filtrate cooled to ambient temperature. Triethylamine (6.6 mL) and (R)-3-amino-butan-1 -ol (1.24 mL) was added followed by heating the mixture at reflux temperature for 20-24 h. The mixture was filtered, filtrate concentrated and 1 M HCI (100 mL) was added, followed by extraction with dichloromethane (3 x 50 mL). Combined organic fractions were concentrated, 2-propanol was added (10 mL) and suspension was stirred at 70-80 °C for 10 min, left to cool to ambient temperature then filtered to give 2.19 g of compound 4 (73%).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sup>1</sup>H NMR (DMSO-de): δ 1.31 (d, 3H), 1.52 (m, 1 H), 1 .97 (m, 1 H), 3.89 (m, 1 H), 4.01 (m, 1 H), 4.46 (m, 1 H), 4.64 (m, 1 H), 4.78 (m, 1 H), 5.50 (m, 1 H), 7.29 (s, 1 H), 8.88 (s, 1 H), 15.83 (s, 1 H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 15.22, 29.14, 45.26, 51.13, 62.09, 76.03, 1 16.31 , 1 18.79, 140.53, 146.79, 155.36, 165.24, 178.75.</div>
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Example 6:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000065_0002.gif" height="99" id="imgf000065_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000065_0002.gif" style="height: auto; max-width: 100%;" width="305" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound 3 (14.55 g; assay 49%) was suspended in acetonitrile (125 mL), acetic acid (15 mL) and methanesulfonic acid (6.25 mL) were added followed by the heating of mixture to 70 °C for 4 h. The suspension was filtered and filtrate cooled to ambient temperature. Triethylamine (16.5 mL) and (S)-2-aminopropanol (2.45 mL) was added followed by heating the mixture at reflux temperature for 24 h. The insoluble product was filtered, washed with 2-propanol (20 mL) and dried to give (3S, 1 1 aR)-3-methyl-5,7-dioxo-2,3,5,7, 1 1 ,1 1 a-hexahydrooxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxylic acid (5.2 g, 75%).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 1.31 (d, J = 6.3 Hz, 3H), 3.65 (dd, J = 8.6, 6.8 Hz, 1 H), 4.13 (dd, J = 1 1.7, 10.3 Hz, 1 H), 4.28 (m, 1 H), 4.39 (dd, J = 8.6, 6.8 Hz, 1 H), 4.92 (dd, J = 12.3, 4.2 Hz, 1 H), 5.45 (dd, J = 10.2, 4.1 Hz, 1 H), 7.16 (s, 1 H), 8.84 (s, 1 H), 15.74 (s, 1 H).</div>
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Example 7:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000066_0001.gif" height="84" id="imgf000066_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000066_0001.gif" style="height: auto; max-width: 100%;" width="278" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound 4 (0.63 g) was dissolved in dichloromethane (15 mL), cooled to 5°C, then triethylamine (0.31 mL) was added, followed by ethyl chloroformate (0.26 mL), followed by slow (30 min) addition of 2,4-difluorobenzylamine. The mixture was then stirred at ambient temperature for 24 h. Water (10 mL) was added, organic phase was separated and washed with 1 M HCI (15 mL) and water (15 mL), concentrated and treated with 2-propanol to give the product 5 in a quantitative yield.</div>
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<sup>1</sup>H NMR (CDCI<sub>3</sub>): δ 1.39 (d, 3H), 1.52 (s, 1 H), 2.19 (m, 1 H), 4.00 (m, 2H), 4.16 (m, 1 H), 4.31 (m, 1 H), 4.62 (d, 2H), 5.00 (m, 1 H), 5.27 (m, 1 H), 6.80 (m 2H), 7.33 (m, 2H), 8.49 (s, 1 H), 10.48 (s, 1 H). <sup>13</sup>C NMR (CDCI<sub>3</sub>): 15.50, 29.22, 36.43, 45.19, 51.83, 62.79, 103.71 , 103.91 , 1 1 1 .0, 1 1 1 .18, 120.59, 123.04, 130.40, 137.41 , 144.58, 156.27, 163. 87, 177.83.</div>
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Example 8:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000066_0002.gif" height="84" id="imgf000066_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000066_0002.gif" style="height: auto; max-width: 100%;" width="278" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a suspension of 4 (2.84 g, 10 mmol) in a mixture of triethylamine (2.24 mL, 16 mmol) and acetone (50 mL) stirring on an ice bath was added ethyl chloroformate (1 .20 mL, 12 mmol). After stirring for 10 min, 2,4-difluorobenzylamine (1.21 mL, 10 mmol) was added and the mixture left stirring at room temperature for 1 h. The product was isolated by slowly diluting the reaction mixture with water (50 mL), partial concentration, filtration, washing with water (2 50 mL) and drying. There was obtained 5 as a white powder (3.48 g, 86%): mp 181.0-184.7 °C.<sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 1.29 (d, J = 7.0 Hz, 3H), 1 .56 (dd, J = 13.9, 2.0 Hz, 1 H), 1 .93-2.06 (m, 1 H), 3.90 (ddd, J = 1 1.6, 5.0, 2.1 Hz, 1 H), 3.98 (td, J = 12.0, 2.2 Hz, 1 H), 4.45 (dd, J = 13.6, 6.6 Hz, 1 H), 4.72 (dd, J = 13.6, 3.8 Hz, 1 H), 4.74-4.81 (m, 1 H), 5.44 (dd, J = 6.6, 3.8 Hz, 1 H), 8.93 (s, 1 H), 15.14 (s, 1 H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 15.78, 29.13, 44.89, 52.88, 61 .63, 75.61 , 1 13.54, 128.49, 136.42, 145.64, 154.62, 164.58, 174.58</div>
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Example 9:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000067_0001.gif" height="89" id="imgf000067_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000067_0001.gif" style="height: auto; max-width: 100%;" width="265" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a suspension of 4 (1 1.36 g, 40 mmol) in acetonitrile (80 mL) stirring at room temperature was added TCCA (9.29 g, 38 mmol) and DABCO (0.23 g, 5 mol%). After stirring at room temperature for 1 h, the reaction was quenched with a mixture of DMSO (5.26 mL) and water (1.33 mL). The insoluble cyanuric acid was removed by filtration and the filtrate evaporated under reduced pressure to give viscous oil. This was triturated in methanol (20 mL) to induce crystallization. The product was filtered, washed with cold methanol (10 mL) and dried to give 7 as a yellowish powder (5.13 g, 41 %): mp 191 .3-198.7 °C.</div>
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Example 10:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000067_0002.gif" height="72" id="imgf000067_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000067_0002.gif" style="height: auto; max-width: 100%;" width="216" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Attempted chlorination of 23: Compound 23 (0.54g) was suspended in acetonitrile (10 mL) and trichlorocyanuric acid (0.44 g) was added and the solution was stirred at ambient temperature overnight. Precipitate was filtered. Only traces of a product corresponding to the compound 26 could be detected in the reaction mixture by LC-MS analysis. Conversion did not improve with time.</div>
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Example 11 :</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000067_0003.gif" height="72" id="imgf000067_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000067_0003.gif" style="height: auto; max-width: 100%;" width="209" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Attempted chlorination of 3: Compound 3 (0.30 g) was suspended in acetonitrile (5 mL) and trichlorocyanuric acid (0.13 g) was added. The suspension was stirred at ambient temperature overnight. Only traces of a product corresponding to the compound 24 could be detected in the reaction mixture by LC-MS analysis.</div>
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Example 12:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000068_0001.gif" height="68" id="imgf000068_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000068_0001.gif" style="height: auto; max-width: 100%;" width="217" /></div>
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9 10</div>
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Trichloroisocyanuric acid (0.23 g) was added in a single portion to a stirred solution of the diethyl 1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (9, 0.66 g) in dry acetonitrile (4 mL) at room temperature. The resulting suspension was stirred at room temperature for ca. 24 h. The reaction mixture was diluted with dichloromethane and filtrated. The filtrate was then concentrated in vacuo to afford crude oil (0.86 g). Purification by flash chromatography (eluting ethyl acetate/cyclohexane) furnished diethyl 3-chloro-1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate, 10 as a yellow semi-solid (0.38 g). <sup>1</sup>H NMR (CDCI<sub>3</sub>): δ 1.28 (t, J=7A Hz, 3H), 1 .37 (t, J=7.2 Hz, 3H), 3.35 (s, 6H), 3.89 (d, J=5.0 Hz, 2H), 4.27 (q, J=l A Hz, 2H), 4.43 (q, J=l A Hz, 2H), 4.48 (t, J=4.9 Hz, 1 H), 8.15 (s, 1 H). <sup>13</sup>C NMR (CDCI<sub>3</sub>): δ 13.83, 14.13, 55.82, 57.09, 61.41 , 63.72, 102.52, 1 17.35, 126.90, 140.22, 146.92, 160.67, 164.13, 168.95.</div>
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Example 13:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000068_0002.gif" height="77" id="imgf000068_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000068_0002.gif" style="height: auto; max-width: 100%;" width="257" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Diethyl 1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (9, 0.64 g) was dissolved in anhydrous acetonitrile (6 mL) and treated sequentially with acetic acid (560 μί) and methanesulfonic acid (40 μί). The resulting mixture was heated to 62 °C and stirred for 4 h and more methanesulfonic acid (40 μΙ_) was added. After additional 2 h, more methanesulfonic acid (80 μΙ_) was added. This was repeated after additional 2 h, when more methanesulfonic acid (80 μΙ_) was added. The reaction mixture was stirred additional 17 h at 62 °C then was treated with a mixture of (R)-3-aminobutanol (0.22 g), triethylamine (0.5 mL) and acetonitrile (0.7 mL). The reaction mixture was stirred additional 22 h at 62 °C and then concentrated in vacuo. The crude material was partitioned between dichloromethane and 1 M HCI solution (15 mL). The combined organic phases were dried (Na<sub>2</sub>S0<sub>4</sub>), filtered and concentrated in vacuo to afford the crude (4R, 12aS)-ethyl 4-methyl-6,8-dioxo-3,4,6,8, 12,12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 -b][1 ,3]oxazine-9-carboxylate (11 ) as a brownish oil (0.61 g).</div>
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<sup>1</sup>H NMR (CD<sub>3</sub>OD): δ 8.44 (s, 1 H), 7.16 (m, 1 H), 5.48 (t, J=4.8 Hz, 1 H), 4.86 (m, 1 H), 4.49 (dd, J=13.6, 4.0 Hz, 1 H), 4.30-4.25 (m, 3H), 4.09 (dt, J=12.1 , 2.3 Hz, 1 H), 3.96 (ddd, J=1 1.7, 5.0, 2.1 Hz, 1 H), 2.18-2.10 (m, 1 H), 1.60-1 .56 (m, 1 H) 1 .39 (d, J=7A Hz, 3H), 1.33 (t, J=7A Hz, 3H). <sup>13</sup>C NMR (CDCI<sub>3</sub>): δ 8.45, 14.08, 15.39, 29.17, 45.04, 45.72, 51 .56, 60.86, 62.61 , 76.33, 1 19.54, 123.72, 136.96, 145.67, 156.26, 163.68, 175.43</div>
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Example 14:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000069_0001.gif" height="72" id="imgf000069_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000069_0001.gif" style="height: auto; max-width: 100%;" width="255" /></div>
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<sup>10</sup></div>
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Diethyl 3-chloro-1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (10, 1.23 g) was dissolved in 85% formic acid (25 mL) at room temperature. The mixture was warmed to 40 °C and stirred for 23 h. The reaction mixture was concentrated in vacuo, and then partitioned between dichloromethane and aqueous NaHC0<sub>3</sub> solution. The combined organic phases were dried (Na<sub>2</sub>S0<sub>4</sub>), filtered and concentrated in vacuo to afford brownish oil (0.49 g). The crude oil was dissolved in anhydrous toluene (5 mL) and treated sequentially with (R)-3-aminobutanol (0.19 g), methanol (0.2 mL) and acetic acid (96 μί). The resulting mixture was heated to 90 °C and stirred for 20 h. The reaction mixture was cooled to room temperature and then partitioned between dichloromethane and aqueous NaHC0<sub>3</sub> solution. The combined organic phases were dried (Na<sub>2</sub>S0<sub>4</sub>), filtered and concentrated in vacuo to afford the crude (4R,12aS)-Ethyl 7-chloro-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5] pyrazino [2, 1-b][1 ,3]oxazine-9-carboxylate (12) as a brownish oil (0.24 g).</div>
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Example 15:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000069_0002.gif" height="86" id="imgf000069_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000069_0002.gif" style="height: auto; max-width: 100%;" width="270" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a solution of 4 (5.68 g, 20 mmol) in dichloromethane (50 mL) stirring in an ice bath was added triethylamine (5.6 mL, 40 mmol), followed by ethyl chloroformate (2.61 mL, 26 mmol). After 20 min, ethanol (50 mL) was added. The mixture was then left stirring 24 h at room temperature and concentrated under reduced pressure. The residue was triturated in acetone (80 mL). The insoluble salt (triethylamine hydrochloride) was removed by filtration. The filtrate was evaporated under reduced pressure to give 11 as an amorphous solid in a quantitative yield (6.1 g).</div>
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Example 16:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000070_0001.gif" height="84" id="imgf000070_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000070_0001.gif" style="height: auto; max-width: 100%;" width="259" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a stirring solution of 11 (0.94 g, 3.0 mmol) in acetonitrile (8 mL) heated at 40 °C was added TCCA in portions during 1 h (0.44 g, 1 .8 mmol). After an additional 1 h, the reaction mixture was diluted with a solution of NaHS0<sub>3</sub> (0.60 g) in water (60 mL), extracted with dichloromethane (50 mL) and the extract evaporated under reduced pressure to give a crude product which was purified by flash chromatography (CH<sub>2</sub>CI<sub>2</sub> : MeOH, from 98 : 2 to 80 : 20) to give 12 (0.45 g, 44%).</div>
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<sup>1</sup>H NMR (CDCI<sub>3</sub>): δ 1.37 (t, J = 7.1 Hz, 3H), 1.38 (d, J = 7.0 Hz, 3H), 1 .56 (dq, J = 13.9, 2.2 Hz, 1 H), 2.21 (m, 1 H), 3.99 (d, J = 2.3 Hz, 1 H), 4.00 (t, J = 1.8 Hz, 1 H), 4.10 (dd, J = 13.2, 6.6 Hz, 1 H), 4.37-4.27 (m, 3H), 4.98 (m, 1 H), 5.35 (dd, J = 6.6, 3.8 Hz, 1 H), 8.07 (s, 1 H).</div>
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<sup>13</sup>C NMR (CDCI<sub>3</sub>): δ 14.20, 16.09, 29.34, 44.87, 53.73, 61.49, 62.29, 76.01 , 1 16.22, 133.1 1 , 134.18, 144.52, 155.48, 163.88, 169.98.</div>
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Example 17:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000070_0002.gif" height="84" id="imgf000070_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000070_0002.gif" style="height: auto; max-width: 100%;" width="245" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a mixture of 7 (3.89 g, 12.2 mmol) in methanol (12 mL) was added sodium methylate (22.3 mL, 97.6 mmol). The reaction mixture was stirred for 24 h at 30 °C and then quenched with a slow addition of 3M hydrochloric acid (35 mL) while stirring in an ice bath. The mixture was concentrated under reduced pressure to remove most of the methanol, then extracted with dichloromethane (2 30 mL), the combined extracts washed with water (30 mL) and evaporated under reduced pressure. Methanol (20 mL) was added to the obtained amorphous residue and removed under reduced pressure to yield the solid 8 (3.69 g, 98%).</div>
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<sup>1</sup>H NMR (CDCI<sub>3</sub>): δ 15.04 (s, 1 H), 8.42 (s, 1 H), 5.29 (dd, J=5.6, 3.9 Hz, 1 H), 5.01 -4.96 (m, 1 H), 4.42 (dd, J=13.6, 3.6 Hz, 1 H), 4.25 (dd, J=13.6, 6.0 Hz, 1 H), 4.05 (s, 3H), 4.00-3.97 (m, 2H), 2.21 -2-14 (m, 1 H), 1.53 (dd, J=14.1 , 1.9 Hz, 1 H), 1.36 (d, J=7 Hz, 3H). <sup>13</sup>C NMR (CDCI<sub>3</sub>): δ 176.35, 165.94, 155.03, 153.70, 143.08, 130.90, 1 15.94, 76.05, 62.65, 61.45, 53.86, 44.96, 29.43, 16.06.</div>
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Example 18:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000071_0001.gif" height="77" id="imgf000071_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000071_0001.gif" style="height: auto; max-width: 100%;" width="257" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a suspension of 7 (2.55 g, 8.0 mmol) in a mixture of triethylamine (1 .46 mL, 10.4 mmol) and acetone (32 mL) stirring on an ice bath was added ethyl chloroformate (0.88 mL, 8.8 mmol). After stirring for 10 min, 2,4-difluorobenzylamine (1.07 mL, 8.8 mmol) was added and the mixture left stirring at room temperature for 1 h. The product was isolated by slowly diluting the reaction mixture with water (40 mL), filtration, washing with water (2 30 mL) and drying. There was obtained 2.91 g of 6 as a white powder (83%).</div>
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<sup>1</sup>H NMR (CDCI<sub>3</sub>): δ 1.30 (d, J = 7.0 Hz, 3H), 1 .49 (dd, J = 14.0, 2.2 Hz, 1 H), 2.14 (ddd, J = 14.6, 1 1.1 , 6.4 Hz, 1 H), 3.89-3.95 (m, 2H), 4.09-4.15 (m, 1 H), 4.26 (dd, J = 13.4, 3.8 Hz, 1 H), 4.55 (d, J = 5.8 Hz, 2H), 4.89-4.98 (m, 1 H), 5.18 (dd, J = 6.2, 3.8 Hz, 1 H), 6.68-6.79 (m, 2H), 7.23-7.31 (m, 1 H), 8.41 (s, 1 H), 10.24 (t, J = 5.8 Hz, 1 H). <sup>13</sup>C NMR (CDCI<sub>3</sub>): δ 16.09, 26.95, 29.30, 36.79, 45.1 1 , 45.28, 53.86, 62.47, 75.93, 103.87 (t, J = 25.4 Hz), 1 1 1 .21 (dd, J = 21 .0, 3.4 Hz), 1 17.32, 130.58 (dd, J = 9.3, 5.8 Hz), 133.40, 143.54, 155.34, 163.16, 163.25, 163.35, 172.88.</div>
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Example 19:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000071_0002.gif" height="79" id="imgf000071_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000071_0002.gif" style="height: auto; max-width: 100%;" width="319" /></div>
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To a suspension of 5 (1 .67 g, 4 mmol) in acetonitrile (20 mL) was added DABCO (23 mg, 5 mol%) and TCCA (0.62 g, 2.52 mmol). The mixture was stirred 18 h at 40 °C protected from light and then quenched with a mixture of DMSO (0.48 mL) and water (0.12 mL). The insoluble cyanuric acid was removed by filtration and washed with acetonitrile (5 mL). The filtrate was evaporated under reduced pressure to give viscous oil that was crystallized from a mixture of methanol (6 mL) and water (3 mL), by slowly cooling the solution from 60 °C to room</div>
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temperature. The product 6 was filtered, washed with cold methanol (5 mL) and dried to give an off-white powder (1.07 g, 61 %).</div>
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<sup>1</sup>H NMR (CDCI<sub>3</sub>): δ 1.30 (d, J = 7.0 Hz, 3H), 1 .49 (dd, J = 14.0, 2.2 Hz, 1 H), 2.14 (ddd, J = 14.6, 1 1.1 , 6.4 Hz, 1 H), 3.89-3.95 (m, 2H), 4.09-4.15 (m, 1 H), 4.26 (dd, J = 13.4, 3.8 Hz, 1 H), 4.55 (d, J = 5.8 Hz, 2H), 4.89-4.98 (m, 1 H), 5.18 (dd, J = 6.2, 3.8 Hz, 1 H), 6.68-6.79 (m, 2H), 7.23-7.31 (m, 1 H), 8.41 (s, 1 H), 10.24 (t, J = 5.8 Hz, 1 H). <sup>13</sup>C NMR (CDCI<sub>3</sub>): δ 16.09, 26.95, 29.30, 36.79, 45.1 1 , 45.28, 53.86, 62.47, 75.93, 103.87 (t, J = 25.4 Hz), 1 1 1 .21 (dd, J = 21.0, 3.4 Hz), 1 17.32, 130.58 (dd, J = 9.3, 5.8 Hz), 133.40, 143.54, 155.34, 163.16, 163.25, 163.35, 172.88.</div>
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Example 20:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000072_0001.gif" height="83" id="imgf000072_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000072_0001.gif" style="height: auto; max-width: 100%;" width="340" /></div>
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To a suspension of 6 (0.44 g) in anhydrous methanol (1 mL) was added a 25% methanolic solution of sodium methylate (1 .14 mL) and the mixture stirred for 4 h at 40 °C. The reaction was quenched with acetic acid (0.4 mL), diluted with water (8 mL), extracted with 2-methyltetrahydrofuran (12 mL), the extract washed with 1 M NaOH(aq) (8 mL), water (8 mL) and evaporated under reduced pressure. To the oily residue was added methanol (8 mL) and evaporated under reduced pressure to give 27 as a white solid (0.38 g, 88%).</div>
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Example 21 :</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000072_0002.gif" height="68" id="imgf000072_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000072_0002.gif" style="height: auto; max-width: 100%;" width="303" /></div>
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The suspension of (4R, 12aS)-7-chloro-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 -b][1 ,3]oxazine-9-carboxamide (6, 0.44 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2 mL) was stirred at room temperature for 24 h. The reaction was quenched with 2M H<sub>2</sub>S0<sub>4</sub> (1 .18 mL) and left stirring for 2 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with water (2 x 2 mL). The obtained white precipitate (0.38 g) was suspended in THF-water (1 :1 , 4.5 mL) and stirred at room temperature for ca. 2 h. The reaction mixture was filtered through fitted funnel rinsing with water (2 <sup>χ</sup> 1 mL) and dried in vacuo at 40°C to afford pure dolutegravir as a white solid (0.33 g, HPLC purity: 99.38%).</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 12.51 (s, 1 H), 10.36 (t, J=5.9 Hz, 1 H), 8.50 (s, 1 H), 7.41-7.36 (m, 1 H), 7.26-7.21 (m, 1 H), 7.07-7.03 (m, 1 H), 5.45 (dd, J=5.4, 4.3 Hz, 1 H), 4.81 -4.76 (m, 1 H), 4.59-4.53 (m, 3H), 4.36 (dd, J=13.8, 5.8 Hz, 1 H), 4.05-4.00 (m, 1 H), 3.91-3.88 (m, 1 H), 2.05-1 .97 (m, 1 H), 1.55-1.52 (m, 1 H), 1 .33 (d, J=7.1 Hz, 3H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 170.27, 163.68, 162.29, 161 .78 (dd), 159.82 (dd), 154.61 , 140.64, 130.74 (d), 130.67 (d), 122.37 (d), 1 16.73, 1 15.38, 1 1 1 .33 (d), 103.80 (t), 62.01 , 51 .16, 44.69, 35.74, 29.13, 15.21.</div>
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Example 22:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000073_0001.gif" height="68" id="imgf000073_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000073_0001.gif" style="height: auto; max-width: 100%;" width="299" /></div>
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A suspension of dolutegravir (0.31 g) in methanol (4 mL) was cooled to 0 °C.25% Solution of sodium methoxide in methanol was added to the mixture and the resulting suspension was stirred at 0 °C for 2 h, then at room temperature for 23 h. The reaction mixture was then filtered through fitted funnel rinsing with methanol (3 x 10 mL). The white precipitate was dried overnight at room temperature to afford pure dolutegravir sodium as a white solid (0.26 g, HPLC purity: 99.84%).</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 10.70 (t, J=5.8, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J=6.4Hz, 1H), 4.51 (d, J=5.5Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J=14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J=12.9 Hz, 1H), 1.24 (d, J=7.0Hz, 3H).<sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.</div>
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Example 23:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000073_0002.gif" height="65" id="imgf000073_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000073_0002.gif" style="height: auto; max-width: 100%;" width="288" /></div>
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The suspension of 6 (0.44 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2 mL) was stirred at room temperature for 24 h. The reaction was diluted with absolute ethanol (10 mL) and left stirring for ca. 30 min at room temperature. The reaction mixture was filtered through fitted funnel rinsing with absolute ethanol (3 x 10 mL) and dried in vacuo at room temperature to afford dolutegravir sodium as a pale yellow solid (0.43 g, HPLC purity: 98.80%). <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 10.70 (t, J = 5.8 Hz, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J = 6.4 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J= 14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J = 12.9 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H).<sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.</div>
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Example 24:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000074_0001.gif" height="66" id="imgf000074_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000074_0001.gif" style="height: auto; max-width: 100%;" width="288" /></div>
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The suspension of (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-6][1,3]oxazine-9-carboxamide (27, 0.43 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2.5 mL) was stirred at room temperature for ca.24 h. The reaction was diluted with mixture of water/ethanol (5 mL, 1:1) and left stirring for ca. 1.5 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with mixture of water/ethanol (3 x 5 mL, 1:1) and dried in vacuo at room temperature to afford 15 as a pale yellow solid (0.41 g, HPLC purity: 98.87%).</div>
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<sup>1</sup>H NMR (DMSO-de): δ 10.70 (t, J = 5.8 Hz, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J = 6.4 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J = 14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J = 12.9 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H).<sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.</div>
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Example 25:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000074_0002.gif" height="58" id="imgf000074_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000074_0002.gif" style="height: auto; max-width: 100%;" width="237" /></div>
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The suspension of {4R, 12aS)-7-chloro-4-methyl-6,8-dioxo-3,4, 6,8, 12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-6][1,3]oxazine-9-carboxylic acid (7, 0.31 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2.5 mL) was stirred at 50 °C for 3 days. The reaction was quenched with 2M H<sub>2</sub>S0<sub>4</sub> (1.2 mL) and left stirring for 7 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with water (3×5 mL) and ethanol (5 mL) dried in vacuo at 40°C to afford 28 as a pale yellow solid (0.17 g).</div>
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<sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 15.37 (s, 1H), 12.76 (s, 1H), 8.66 (s, 1H), 5.51-5.49 (m, 1H), 4.80-4.78 (m, 1H), 4.65 (dd, J=13.8, 3.7 Hz, 1H), 4.43 (dd, J=13.8, 5.9 Hz, 1H), 4.05 (t, J^^.b Hz, 1H), 3.91 (dd, J=11.4, 3.1 Hz, 1H), 2.07-2.00 (m, 1H), 1.56 (d, J=13.8 Hz, 1H), 1.34 (d, J=7.0 Hz, 3H).<sup>13</sup>C NMR (DMSO-de): δ 172.21, 165.39, 161.73, 153.61, 141.11, 118.66, 112.99, 75.95, 62.03, 51.50, 44.90, 29.08, 15.18.</div>
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Example 26:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000075_0001.gif" height="92" id="imgf000075_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000075_0001.gif" style="height: auto; max-width: 100%;" width="346" /></div>
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The suspension of (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8, 12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 ,3]oxazine-9-carboxamide (27, 0.88 g) and solid sodium hydroxide (0.24 g) in absolute ethanol (20 mL) was stirred at 30 °C for 1.5 h. The reaction was quenched with 2M H<sub>2</sub>S0<sub>4</sub> (1 .5 mL) and left stirring for 3 hours at room temperature. The reaction mixture was filtered through fritted funnel and rinsed with water (3 x 2 mL) and ethanol (4 mL), and dried in vacuo at 40 °C to afford O-ethyl dolutegravir (29) as a pale yellow solid (0.25 g). The filtrate was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over MgS0<sub>4</sub>, filtered and concentrated, then dried in vacuo at 40 °C to afford more 29 as a pale yellow solid (0.27 g).</div>
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<sup>1</sup>H NMR (CDCI<sub>3</sub>): δ 10.37 (t, J = 5.8 Hz, 1 H), 8.36 (s, 1 H), 7.37-7.32 (m, 1 H), 6.83-6.77 (m, 2H), 5.19 (dd, J = 5.9, 3.8 Hz, 1 H), 5.04-4.98 (m, 1 H), 4.61 (d, J = 6Hz, 2H), 4.26-4.22 (m, 3H), 4.1 1 (dd, J = 13.4, 5.9 Hz, 1 H), 3.97 (t, J = 2.4 Hz, 1 H), 3.96 (d, J = 2.4 Hz, 1 H), 2.21-2.14 (m, 1 H), 1.51 (dq, J = 14.0, 2.3 Hz, 1 H), 1 .47 (t, J = 7.0 Hz, 3H), 1 .35 (d, J = 7.1 Hz, 3H).</div>
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<sup>13</sup>C NMR (CDCI<sub>3</sub>): δ 174.78, 164.17, 162.49 (dd), 160.51 (dd), 155.72, 154.08, 142.32, 130.60 (dd), 129.33, 121 .51 (dd), 1 18.67, 1 1 1 .23 (dd), 103.78 (t), 76.15, 69.74, 62.58, 53.42, 44.58, 36.50 (d), 29.44, 16.04, 15.64.</div>
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Example 27:</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000075_0002.gif" height="64" id="imgf000075_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000075_0002.gif" style="height: auto; max-width: 100%;" width="354" /></div>
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The suspension of (4R, 12aS)-7-(benzyloxy)-4-methyl-3,4, 12,12a-tetrahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1-b][1 ,3]oxazine-6,8-dione (30, 0.68 g, prepared according to prior art) and solid sodium hydroxide (0.40 g) in absolute ethanol (5 mL) was stirred at 50 °C for 14 h. The reaction was quenched with formic acid (0.35 mL), water (2 mL) was added and mixture was left stirring for additional 1 h at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 5 mL) and the combined organic layers concentrated to afford a crude oil. Purification by flash chromatography (eluting with CH<sub>2</sub>CI<sub>2</sub>/methanol) afforded 32 as an orange solid (0.26 g, 52 %).</div>
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The above procedure if done at room temperature in same time period, affords 31 as orange oil (0.24 g, 43 %).</div>
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Compound 32: <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 7.64 (d, J = 7.4 Hz, 1 H), 6.20 (d, J = 7.3 Hz, 1 H), 5.40 (dd, J = 5.1 , 4.2 Hz, 1 H), 4.83-4.78 (m, 1 H), 4.35 (dd, J = 13.6, 3.9 Hz, 1 H), 4.13 (dd, J = 13.6, 5.4 Hz, 1 H), 4.05-4.00 (m, 1 H), 3.90-3.85 (m, 1 H), 2.03-1.95 (m, 1 H), 1.52 (dd, J = 13.9, 1 .9 Hz, 1 H), 1.33 (d, J = 7.1 Hz, 3H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 170.96, 163.01 , 153.48, 137.96, 1 16.83, 1 13.52, 76.18, 62.05, 50.39, 44.53, 29.21 , 15.28.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound 31 : <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 7.67 (d, J = 7.4 Hz, 1 H), 6.28 (d, J = 7.4 Hz, 1 H), 5.29 (dd, J = 5.4, 3.8 Hz, 1 H), 4.82-4.75 (m, 1 H), 4.32 (dd, J = 13.6, 3.6 Hz, 1 H), 4.10 (dd, J = 13.5, 5.6 Hz, 1 H), 4.03-3.93 (m, 3H), 3.85 (ddd, J = 1 1 .6, 5.0, 2.2 Hz, 1 H), 1.97-1 .89 (m, 1 H), 1 .48 (dd, J = 13.8, 2.1 Hz, 1 H), 1.27 (d, J = 7.1 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H). <sup>13</sup>C NMR (DMSO-d<sub>6</sub>): δ 174.38, 156.1 1 , 150.82, 139.48, 1 16.39, 1 13.52, 75.92, 67.31 , 61 .80, 51 .36, 44.22, 29.29, 15.76, 15.36.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Exa</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000076_0001.gif" height="95" id="imgf000076_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000076_0001.gif" style="height: auto; max-width: 100%;" width="480" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The transformation of 6 to dolutegravir with sodium hydroxide in ethanol was monitored for the interconversion of intermediates. The suspension of 6 (0.44 g) and solid sodium hydroxide (0.20 g) in ethanol (3.33 ml.) was stirred at 22 °C. Samples of the reaction mixture were taken after 3, 8 and 24 h for UPLC analysis. After 24 h, the reaction mixture was quenched with 2 M H<sub>2</sub>S0<sub>4</sub> (5 ml_), and left stirring at room temperature. The reaction mixture was filtered through fritted funnel, the product rinsed with water (30 ml.) and dried in vacuo at 50 °C overnight to afford dolutegravir as a white solid (0.27 g, 64 %).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The results of reaction monitoring:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Time UPLC analysis (area%)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Entry</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(h) compound 6 compound 29 dolutegravir</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
1 3 h 37.50 20.63 39.99</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
2 8 h 0.78 15.46 80.32</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
3 24h 0.31 8.56 88.21</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Example 29:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000077_0001.gif" height="76" id="imgf000077_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000077_0001.gif" style="height: auto; max-width: 100%;" width="347" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 27 (0.86 g) in MeOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2 ml.) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The results of reaction monitoring demethylation of 27 in MeOH:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000077_0003.gif" height="108" id="imgf000077_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000077_0003.gif" style="height: auto; max-width: 100%;" width="485" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Example 30:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000077_0002.gif" height="73" id="imgf000077_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000077_0002.gif" style="height: auto; max-width: 100%;" width="480" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 6 (0.88 g) in EtOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2 mL) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The results of reaction monitoring of the transformations of 6 in ethanol with NaOH:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000077_0004.gif" height="124" id="imgf000077_0004" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000077_0004.gif" style="height: auto; max-width: 100%;" width="531" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
dol. = dolutegravir</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Exa</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000078_0001.gif" height="94" id="imgf000078_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000078_0001.gif" style="height: auto; max-width: 100%;" width="480" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 27 (0.88 g) in EtOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2ml_) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The results of reaction monitoring of the transformations of 27 in ethanol with NaOH:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000078_0003.gif" height="124" id="imgf000078_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000078_0003.gif" style="height: auto; max-width: 100%;" width="531" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
dol. = dolutegravir</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Example 32:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000078_0002.gif" height="99" id="imgf000078_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2016050716@@@id00000067886259@@@7982055@@@imgf000078_0002.gif" style="height: auto; max-width: 100%;" width="304" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound 3 (30 g, 1 10 mmol; assay 99%) was suspended in acetonitrile (450 mL), acetic acid (73 mL) and methanesulfonic acid (25 mL) were added. The reaction mixture was stirred 4 h at 70 °C. The clear red solution was cooled to 25 °C. Triethylamine (77 mL) and (S)-2-aminopropanol (17 mL) were added and the mixture was stirred at reflux temperature for 20 h. The reaction mixture was cooled to 25 °C and the insoluble product filtered, washed with 1 M HCI(aq) (60 mL), water (3 * 60 mL) and dried to give 4c (19.49 g, 67%): mp = 313-315 °C; <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ 1.31 (d, J = 6.3 Hz, 3H), 3.65 (dd, J = 8.6, 6.8 Hz, 1 H), 4.13 (dd, J = 1 1.7, 10.3 Hz, 1 H), 4.28 (m, 1 H), 4.39 (dd, J = 8.6, 6.8 Hz, 1 H), 4.92 (dd, J = 12.3, 4.2 Hz, 1 H), 5.45 (dd, J = 10.2, 4.1 Hz, 1 H), 7.16 (s, 1 H), 8.84 (s, 1 H), 15.74 (s, 1 H); <sup>13</sup>C NMR (DMSO-d<sub>6</sub>) 16.5, 51.6, 52.9, 72.4, 81.6, 1 15.8, 1 18.1 , 141.5, 147.6, 153.4, 165.3, 179.0.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016016279&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016016279&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription">WO2016016279,</a> NOVEL HYDRATES OF DOLUTEGRAVIR SODIUM</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b>LEK PHARMACEUTICALS D.D.</b> [SI/SI]; Verovskova 57 1526 Ljubljana (SI).<br />
<b>SANDOZ AG</b> [CH/CH]; Lichtstrasse 35 CH-4056 Basel (CH)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b>HOTTER, Andreas</b>; (AT).<br />
<b>THALER, Andrea</b>; (AT).<br />
<b>LEBAR, Andrija</b>; (SI).<br />
<b>JANKOVIC, Biljana</b>; (SI).<br />
<b>NAVERSNIK, Klemen</b>; (SI).<br />
<b>KLANCAR, Uros</b>; (SI).<br />
<b>ABRAMOVIC, Zrinka</b>; (SI)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The present invention relates to novel hydrates of sodium dolutegravir and their methods of preparation. In addition, the invention relates to a novel crystalline form of sodium dolutegravir, which is a useful intermediate for the preparation of one of the new hydrates. The invention also relates to the use of the new hydrates for the production of pharmaceutical compositions.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Finally, the invention relates to pharmaceutical compositions comprising an effective amount of the novel hydrates, oral dosage forms comprising these pharmaceutical compositions, a process for preparing said oral dosage forms, and the use of such pharmaceutical compositions or dosage forms in the treatment of retroviral infections such as HIV infections -1.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Dolutegravir, chemically designated (4f?, 12aS)-/V-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8, 12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1- ?][1 ,3]oxazine-9-carboxamide, is a human immunodeficiency virus type 1 (HIV-1 ) integrase strand transfer inhibitor (INSTI) indicated in combination with other a nti retroviral agents for the treatment of HIV-1 infection. The marketed finished dosage form (TIVICAY™) contains dolutegravir as its sodium salt, chemically denominated sodium (4f?,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1- ?][1 ,3]oxazin-7-olate, which is represented by the following general chemical formula (I):</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2015067329@@@id00000061466964@@@8092043@@@imgf000002_0001.gif" height="110" id="imgf000002_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@EP2015067329@@@id00000061466964@@@8092043@@@imgf000002_0001.gif" style="height: auto; max-width: 100%;" width="275" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(I)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
WO 2010/068253 A1 discloses a monohydrate and an anhydrous form of dolutegravir sodium as well as a crystalline form of the free compound. Processes for the preparation of said forms are also provided in the application.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
WO 2013/038407 A1 discloses amorphous dolutegravir sodium and processes for preparing the same.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Hydrates of pharmaceutical drug substances are of particular interest as they provide new opportunities for preparing novel pharmaceutical compositions with improved quality, activity and/or compliance. This is due to the fact that hydrates have different physicochemical properties compared to their anhydrous counterparts such as melting point, density, habitus, chemical and physical stability, hygroscopicity, dissolution rate, solubility, bioavailability etc., which influence the formulation process and also impact the final drug product.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
If an anhydrous form is selected, phase changes during the formulation process induced by hydrate formation must be avoided. This can be particularly difficult if for example wet granulation is used with a substance that is able to form hydrates like dolutegravir sodium.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Hence, a stable hydrate of dolutegravir sodium would allow to easily formulate dolutegravir sodium in a controlled manner and subsequently also facilitate storage and packaging.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
However, the so far known dolutegravir sodium monohydrate disclosed in WO 2010/068253 A1 shows excessive water uptake when exposed to moisture and on the other hand already dehydrates below 30% relative humidity.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Therefore, there is a need for hydrates of dolutegravir sodium with improved physicochemical properties, e.g. for hydrates which are stable over a broad humidity range, in particular for hydrates absorbing only low amounts of water at elevated humidity and on the other hand preserving their crystal structure also at dry conditions. In addition, there is a need for pharmaceutical compositions comprising these hydrates, and thus also for hydrates that allow for improved formulation of dolutegravir sodium in pharmaceutical compositions.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
SUMMARY OF THE INVENTION</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The present invention relates to novel hydrates of dolutegravir sodium and to processes for their preparation. Specifically, the present invention provides crystalline forms of dolutegravir sodium of formula (I) according to respective claims 1 , 5 and 6, with preferred embodiments being set forth in sub-claim 2. The present invention also provides processes for their preparation according to respective claims 3, 7 and 8, with preferred process embodiments being set forth in sub-claim 4. The present invention further provides the uses according to claims 9 and 16, and a pharmaceutical composition according to claim 10, and preferred embodiments thereof according to sub-claims 1 1 and 12. The present invention also provides a process for the preparation of the pharmaceutical composition according to claim</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
13, and preferred embodiments thereof according to sub-claim 14. The pharmaceutical composition for therapeutic use is set forth in claim 15.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The novel hydrates are physically and chemically stable over a broad humidity range, show only low water uptakes when exposed to moisture and are even stable at dry conditions. Therefore, the novel hydrates are especially suitable for the preparation of pharmaceutical compositions, e.g. in terms of time and costs.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
In particular, it has been found that crystal Form HxA exhibits improved properties which allow for improved formulation of Form HxA in pharmaceutical compositions.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
In addition, the present invention relates to a novel crystalline form of dolutegravir sodium, which, for the first time, allows the preparation of one of the novel hydrates and is therefore a valuable intermediate.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
1361/CHE/2013</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Dolutegravir (I) is chemically known as (4/?,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2//-pyrido[r,2′:4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxamide. Dolutegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Dolutegravir is being marketed under the trade name Tivicay®. US 8,129,385 disclosed Dolutegravir or its pharmaceutically acceptable salts thereof. US ‘385 also discloses a process for the preparation of Dolutegravir (I). The process involves the condensation of 5-benzyloxy-4-hydroxy-6-hydroxymethyl nicotinic acid (II) with 2,4-difluorobenzylamine (III) to produce 5-benzyloxy-N-(2,4-difluorobenzyl)-4-hydroxy-6-hydroxymethyl nicotinic acid amide (IV), which is further under goes oxidation using manganese dioxide (Mn02) to produce 5-benzyloxy-N-(2,4-difluorobenzyl)-6-formyl-4-hydroxy-nicotinic acid amide (V). This amide compound (V) is reacted with sodium chlorite (NaClCh) to produce 3-benzyloxy-5-(2,4-difluorobenzylcarbamoyl)-4- hydroxy-pyridine-2-carboxylic acid (VI), which is further treated with methanol (MeOH) to produce 3-benzyloxy-5-(2,4-difluorobenzyl)-4-hydroxy-pyridine-2-carboxylic acid methyl ester (VII).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://i0.wp.com/image.slidesharecdn.com/aurobindopharmaltd-genericlicensing-110614073144-phpapp02/95/aurobindo-pharma-ltd-generic-licensing-1-728.jpg" height="0" src="https://i0.wp.com/image.slidesharecdn.com/aurobindopharmaltd-genericlicensing-110614073144-phpapp02/95/aurobindo-pharma-ltd-generic-licensing-1-728.jpg" srcset="https://i0.wp.com/image.slidesharecdn.com/aurobindopharmaltd-genericlicensing-110614073144-phpapp02/95/aurobindo-pharma-ltd-generic-licensing-1-728.jpg?zoom=2 1.5x" style="height: auto; max-width: 100%;" width="2" /></div>
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The methyl ester compound (VII) is reacted with 3-bromopropene to produce l-allyl-3-benzyloxy-5-(2,4-difluorobenzyl)-4-oxo-l,4-dihydro-pyridine-2- carboxylic acid methyl ester (VIII), which is further reacted with potassium osmate dihydrate (K2OSO4.2H2O) to produce 3-benzyloxy-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-l-(2-oxo-ethyl)-l,4-dihydropyridine-2-carboxylic acid methyl ester (IX). The compound (IX) is reacted with (R)-3-amino-l-butanol (X) to produce benzyloxy Dolutegravir (XI), which is deprotected by treating with TFA to produce Dolutegravir (I). The process is as shown in scheme-I below:</div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2015/08/scheme1.png" href="https://newdrugapprovals.files.wordpress.com/2015/08/scheme1.png"><img alt="scheme1" class="alignnone wp-image-14307" data-mce-src="https://newdrugapprovals.files.wordpress.com/2015/08/scheme1.png?w=1019&h=567" height="567" src="https://newdrugapprovals.files.wordpress.com/2015/08/scheme1.png?w=1019&h=567" style="height: auto; max-width: 100%;" width="1019" /></a></div>
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The major disadvantage with the above prior-art process is that it involves large no of steps and tedious work-up procedures to isolate the required product. This results a longer period of time cycle is required to produce Dolutegravir (I), which in turn renders the process more costly and less eco friendly. Further the above processes are low yielding and with less purity. US 8,217,034 discloses variant process for the preparation of Dolutegravir.</div>
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This process involves the reaction of methyl l-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-l,4-dihydro-2-pyridine carboxylate (XII) with (R)-3-amino-l-butanol (X) to produce (4R, 12o5)-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2//-pyrido[ 1 \2′,4,5] pyrazino[2,l-b][l,3]oxazine-6,8-dione (XIII), which is further undergoes bromination using NBS to produce (4R,12aS)-9-bromo-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H-pyrido[r,2′:4,5]pyrazino[2,l-b][l,3]oxazine-6,8-dione (XIV). The bromo Compound (XIV) is condensed with 2,4-difluorobenzylamine (III) in the presence of Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) to produce benzyloxy Dolutegravir (XI), which is hydrogenated in the presence of Pd/C to produce Dolutegravir (I). The process is as shown in Scheme-II below:</div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2015/08/scheme2.png" href="https://newdrugapprovals.files.wordpress.com/2015/08/scheme2.png"><img alt="scheme2" class="alignnone wp-image-14308" data-mce-src="https://newdrugapprovals.files.wordpress.com/2015/08/scheme2.png?w=1020&h=568" height="568" src="https://newdrugapprovals.files.wordpress.com/2015/08/scheme2.png?w=1020&h=568" style="height: auto; max-width: 100%;" width="1020" /></a></div>
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The major disadvantage with the above prior art process of preparing Dolutegravir is the use of expensive reagent tetrakis(triphenylphosphine)palladium (Pd(PPh3)4> in coupling step. Use of this reagent on industrial scale is not preferred, which makes the process more expensive. WO 2011/119566 discloses another variant process for the preparation of Dolutegravir.</div>
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This process involves the reaction of l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l,4-dihydropyridine-3-carboxylic acid (XV) with acetic acid in presence of methane sulfonic acid to produce 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI), which is further condensed with (R)-3-amino-l-butanol (X) to produce (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2//-pyrido[ 1 ‘,2’:4,5]pyrazino[2,1 -b] [ 1,3]-oxazine-9-carboxylic acid (XVII). This acid Compound XVII is acylated with 2,4-difluorobenzylamine (III) in the presence of carbonyldiimidazole (CDI) to produce methoxy Dolutegravir (XVIII), which is demethylated in the presence of lithium bromide (LiBr) to produce Dolutegravir (I).</div>
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The process is as shown in Scheme-3 below:</div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2015/08/scheme3.png" href="https://newdrugapprovals.files.wordpress.com/2015/08/scheme3.png"><img alt="scheme3" class="alignnone wp-image-14309" data-mce-src="https://newdrugapprovals.files.wordpress.com/2015/08/scheme3.png?w=1044&h=581" height="581" src="https://newdrugapprovals.files.wordpress.com/2015/08/scheme3.png?w=1044&h=581" style="height: auto; max-width: 100%;" width="1044" /></a></div>
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The major disadvantage of the above prior art process of preparing Dolutegravir is the use of expensive and highly moisture sensitive reagent, 1,1-carbonyldiimidazole (CDI), during acylation. Use of this reagent on industrial scale is not preferred due to anhydrous conditions required in the process. However, there is always a need for alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity. Hence, there is a need to develop cost effective and commercially viable process for the preparation of Dolutegravir of formula (I). The present invention is related to a process for the preparation of pure Dolutegravir of formula (I), wherein optically active acid addition salt of (R)-3-amino-l-butanol (X) is directly condensed with 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI) instead of condensing with free base of (R)-3-amino-1-butanol (X). The present invention is also related to a process for the preparation of pure Dolutegravir of formula (I), wherein, inexpensive and easily handling condensing reagents in the condensation of (4R, 12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2//-pyrido[l’,2′:4,5]pyrazino [2,l-b][l,3]oxazine-9-carboxylic acid (XVII) with 2,4-difluorobenzylamine (III).</div>
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In another embodiment, 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4- dihydropyridine-3-carboxylic acid (XVI) used in the present invention is prepared by reacting 4-methoxyacetoacetate (XIX) with N,N-dimethyl-l,l- bis(methyloxy)methanamine (DMF-DMA) (XX) to produce methyl-2- (dimethylaminomethylene)-4-methoxy-3-oxo-butanoate(methyl-3-(dimethylamino)-2 [(methyloxy)acetyl]-2-propenoate) (XXI), which is reacted with aminoacetaldehyde dimethyl acetal (XXII) to produce methyl-2-(2,2-dimethoxyethylaminomethylene)-4-methoxy-3-oxo-butanoate(methyl-3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy) acetyl]-2-propenoate) (XXIII).</div>
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The compound (XXIII) is contacted with dimethyl ethanedioate in presence of alkali metal alkoxide to produce dimethyl-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-l ,4-dihydropyridine-2,5-dicarboxylate (XXIV), which is selectively hydrolyzed with a base to produce l-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l ,4-dihydro-3-pyridinecarboxylic acid (XV). The compound (XV) is treated with a catalytic amount of a strong protic acid in the presence of acetic acid in an organic solvent to produce a reaction mixture containing 5- methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI), The process is as shown in Scheme-IV below:</div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2015/08/scheme4.png" href="https://newdrugapprovals.files.wordpress.com/2015/08/scheme4.png"><img alt="scheme4" class="alignnone wp-image-14305" data-mce-src="https://newdrugapprovals.files.wordpress.com/2015/08/scheme4.png?w=997&h=555" height="555" src="https://newdrugapprovals.files.wordpress.com/2015/08/scheme4.png?w=997&h=555" style="height: auto; max-width: 100%;" width="997" /></a></div>
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The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.</div>
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Example-1:</div>
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EXAMPLES: Example-1: Process for the preparation of Dolutegravir</div>
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Step-i: Preparation of (/?)-3-amino-l-butanol tartarate salt: D-(+) Tartaric acid (12.7 g, 0.085 mol) was added in to a solution of (i?,5)-3-amino-l-butnaol (7.5 g, 0.084 mol) in methanol (100 ml) at 40 °C. The reaction mixture was stirred for about 1 hour at 35-40 °C and the reaction mass was cooled to 0-5°C and maintained for 30-40 minutes. The obtained solid was filtered and washed with chilled methanol (10 ml) at 0-5 °C. The solid was dried to get (i?)-3-amino-l-butanol tartarate salt (8.0 g, 40%).</div>
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Step-ii: Preparation of (4rt,12a£)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[l’,2′;4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxylic acid (XVII): l-[2,2-Bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l,4-dihydro-3-pyridinecarboxylic acid (XV) (lOOg; 0.3175 moles) was suspended in acetonitrile (800 ml) and heated to 80-82°C. A mixture of acetic acid (95.25 g), methanesulfonic acid (9.14 g; 0.09525 moles) and acetonitrile (200 ml) were added to the slurry at 80-82°C. The reaction mass was continued at 80-82°C to complete the reaction. After completion of the reaction, anhydrous sodium acetate (65 g) and (/?)-3-amino-l-butanol tartrate salt (79.68g; 0.3334 moles) were added at 20-25°C and stirred at 60-65°C to complete the reaction. The reaction mass was concentrated and acidified with IN aqueous hydrochloric acid (750 ml) and extracted with methylene chloride (1500 ml) at ice cold temperature. The organic layer was separated, concentrated, treated with hot methanol (350 ml) for 2 h, filtered, washed with methanol and dried to yield (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1′ ,2′ :4,5]pyrazino[2,1 -b] [ 1,3]oxazine-9-carboxylic acid (XVII) (72 g; HPLC purity: 99.07%).</div>
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Step-iii: Process for the preparation of Dolutegravir (I). Method A: Triethylamine (3.61 g; 0.0357 moles) was added to the suspension of (4R,12aS)-7- methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1′ ,2′ :4,5]pyrazino[2,1 – b][l,3]oxazine-9-carboxylic acid (XVII) (10 g; 0.0325 moles) in methylene chloride (50 ml), and cooled to 10-15°C. Pivaloyl chloride (4.3 g; 0.0357 moles) was added to the reaction mass, and stirred at 10-15°C for 1 h. Thereafter, 2,4-difiuorobenzylamine (5.58 g; 0.0389 moles) was added at 10-15°C and then warmed to 20-25°C to complete the reaction. After completion of the reaction, IN aqueous hydrochloric acid (20 ml) was added, organic layer was separated, washed with 5% w/w aqueous sodium bicarbonate solution (10 ml) followed by 15% w/w aqueous sodium chloride solution (10 ml) and concentrated. To the concentrated mass, acetonitrile (100 ml) and Lithium bromide (5.08 g; 0.0584 moles) were added and heated to 65-70°C for 3 h to complete the reaction. After completion of the reaction, the reaction mass was acidified with 5N aqueous hydrochloric acid (40 ml), concentrated to about 50 ml and DM water was added to crystallize the product at 20-25°C. The slurry was stirred for 2 h, filtered, washed with DM water and dried to yield (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a,-hexahydro-2H-pyrido[ 1′ ,2′ :4,5]pyrazino[2,1 -b] [ 1,3]oxazine-9-carboxamide (I) (11.5 g, HPLC purity: 99.63%).</div>
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Method B: Isobutyl chloroformate (4.65 gm, 0.03404 moles) in methylene chloride (10 ml) was added to the solution of N-methylmorpholine (3.45 gm, 0.03410 moles) and (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1′ ,2′ :4,5]pyrazino-[2,1 -b][l,3]oxazine-9-carboxy!ic acid (XVII) (10.0 gm, 0.03245 moles) in methylene chloride (60 ml) at -10 to 0°C in about 1 h. 2,4-Difloro benzyl amine (4.88 gm, 0.03409 moles) in methylene chloride (10 ml) was added to the cold reaction mass, and stirred at 20-30°C for completion of reaction. After completion of reaction, the reaction mass was washed with 5%w/w aqueous sodium bicarbonate solution (20 ml), IN hydrochloric acid (20 ml), DM water (20 ml) and concentrated. Acetonitrile (120 ml) and lithium bromide (4.8 gm, 0.05516 moles) were added to the concentrated mass, and stirred at 70-80°C for 3 h to complete the reaction. After completion of reaction, the reaction mass was acidified with 5N aqueous hydrochloric acid (40 ml) and concentrated to about 50 ml. DM Water (100 ml) was added to the concentrated reaction mass and stirred for 2 h at 25-30°C to crystallize the product. The product was filtered, washed with DM Water (50 ml) and dried to yield Dolutegravir (I) (10.7 gm, HPLC purity: 99.60%).</div>
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Example-2: Process for the preparation of Dolutegravir (I) (4R, 12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a,-hexahydro-2H-pyrido[r,2′:4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxamide (XVIII) (2 g, 0.0046 moles) was suspended in isopropyl alcohol (20 ml) and lithium bromide (0.8 g, 0.00924 moles) was added and stirred at 70-80°C for 15 h to complete the reaction. After completion of reaction the reaction mass was acidified with 5N aqueous hydrochloric acid (5 ml) and concentrated. DM Water (20 ml) was added to the concentrated mass and stirred at 25-30°C to crystallize the product. The product was filtered, washed with DM Water and dried to yield Dolutegravir (I) (1.5 g, HPLC purity: 97.93%).</div>
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<h1>
<span class="common_name">Dolutegravir</span></h1>
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<b>Experimental:</b><br />
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<sup>1</sup>H NMR (CDCl<sub>3</sub>) δ 12.45 (s, 1H), 10.38 (br s, 1H), 8.30 (s, 1H), 7.40-7.30 (m, 1H), 6.85-6.75 (m, 2H), 5.26 (d, J = 5.8, 4.1 Hz, 2H), 5.05-4.95 (m, 1H), 4.64 (d, J = 5.9 Hz, 2H), 4.27 (dd, J = 13.4, 4.2 Hz, 1H), 4.12 (dd, J = 13.6, 6.0 Hz, 1H), 4.05 (t, J = 2.3 Hz, 1H), 4.02 (d, J = 2.2 Hz, 1H), 2.30-2.19 (m, 1H), 1.56 (dd, J = 14.0, 2.0 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H).<a data-mce-href="http://www.rsc.org/suppdata/c5/nj/c5nj00698h/c5nj00698h1.pdf" href="http://www.rsc.org/suppdata/c5/nj/c5nj00698h/c5nj00698h1.pdf">/////////</a>///LINK</div>
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<h3 class="post-title entry-title">
<a data-mce-href="https://orgspectroscopyint.blogspot.in/2016/08/dolutegravir-sodium.html" href="https://orgspectroscopyint.blogspot.in/2016/08/dolutegravir-sodium.html">Dolutegravir sodium</a></h3>
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<img alt="DOLUTEGRAVIR SODIUM.png" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=46216142&t=l" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=46216142&t=l" style="height: auto; max-width: 100%;" /><br />
<span class="title2">DOLUTEGRAVIR SODIUM; UNII-1Q1V9V5WYQ; Dolutegravir (sodium); GSK1349572A; GSK 1349572A; </span><a data-mce-href="https://www.ncbi.nlm.nih.gov/pcsubstance/?term=%221051375-19-9%22%5BCompleteSynonym%5D%20AND%2046216142%5BStandardizedCID%5D" href="https://www.ncbi.nlm.nih.gov/pcsubstance/?term=%221051375-19-9%22%5BCompleteSynonym%5D%20AND%2046216142%5BStandardizedCID%5D" rel="nofollow">1051375-19-9</a><br />
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<table class="top-summary-items mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Formula:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C20H18F2N3NaO5&sort=mw&sort_dir=asc" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C20H18F2N3NaO5&sort=mw&sort_dir=asc" title="Find all compounds with formula C20H18F2N3NaO5">C20H18F2N3NaO5</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Weight:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">441.360596 g/mol</td></tr>
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<span class="title2"><br /></span><span class="title2">sodium;(4R,12aS)-9-[(2,4-difluorophenyl)methylcarbamoyl]-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro-2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazin-7-olate</span><br />
<span class="title2"><br /></span><span class="title2"><br /></span><span class="title2" id="d6153e1007">Sodium(4<i>R</i>,12a<i>S</i>)-9-{[(2,4-Difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12<i>a</i>-hexahydro-2<i>H</i>-pyrido[1′,2′:4,5]pyrazino[2,1-<i>b</i>][1,3]oxazol-7-olate (<b>1</b>)</span><br />
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Characterization data of <b>1</b>:</div>
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1H NMR (400 MHz, DMSO-<i>d</i>6) δ 10.6–10.7 (t, <i>J</i> = 6.0 Hz, 1H), 7.8 (s, 1H), 7.3 (dd, <i>J</i> = 8.4 and 7.2 Hz, 1H), 7.1–7.2 (m, 1H), 7.0 (t, <i>J</i> = 8.0 Hz, 1H), 5.1 (bs, 1H), 4.7–4.8 (m, 1H), 4.5 (d, <i>J</i> = 5.6 Hz, 2H), 4.2–4.3 (d, <i>J</i> = 11.2 Hz, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.7–3.8 (m, 1H), 1.8 (m, 1H), 1.3 (d, <i>J</i> = 13.2 Hz, 1H), 1.2 (d, <i>J</i> = 6.8 Hz, 3H);</div>
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13C NMR (400 MHz, DMSO-d6) δ 177.9, 167.0, 166.0, 161.0, 159.9, 160.0, 162.4, 162.5, 158.6, 158.8, 161.1, 161.2, 134.2, 130.4, 130.5, 122–8, 123.0, 114.8, 111.0, 111.3, 108.6, 103.3, 103.8, 75.5, 61.8, 53.1, 42.9, 35.3, 29.1, 15.3;</div>
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IR (KBr, cm–1): 3165, 3072, 2974, 2941, 2873, 1643, 1539, 1504, 1101;</div>
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ESI-MS <i>m</i>/<i>z</i>: 418.17.</div>
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<a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00156/suppl_file/op6b00156_si_001.pdf" href="http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00156/suppl_file/op6b00156_si_001.pdf">//////LI</a>NK</div>
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<span data-mce-style="font-size: 1.5em; line-height: 1.5em;" style="font-size: 1.5em; line-height: 1.5em;">References</span><br />
<ol>
<li id="cite_note-1"><a data-mce-href="http://www.ama-assn.org/resources/doc/usan/dolutegravir.pdf" href="http://www.ama-assn.org/resources/doc/usan/dolutegravir.pdf" rel="nofollow">[1]</a> American Medical Association (AMA), STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL (Dolutegravir) Accessed 3 December 2011.</li>
<li id="cite_note-2"> FDA approves new drug to treat HIV infection <a data-mce-href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm" href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm" rel="nofollow">http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm</a> Aug. 12, 2013</li>
<li id="cite_note-3"><a data-mce-href="http://www.reuters.com/article/2013/08/12/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812" href="http://www.reuters.com/article/2013/08/12/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812" rel="nofollow">"U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay"</a>. <i><a data-mce-href="http://en.wikipedia.org/wiki/Reuters" href="http://en.wikipedia.org/wiki/Reuters" title="Reuters">Reuters</a></i>. 12 August 2013. Retrieved 13 February 2013.</li>
<li id="cite_note-4"><a data-mce-href="http://news.yahoo.com/gsk-wins-priority-status-hiv-drug-u-140116042--finance.html" href="http://news.yahoo.com/gsk-wins-priority-status-hiv-drug-u-140116042--finance.html" rel="nofollow">"GSK wins priority status for new HIV drug in U.S"</a>. <i><a data-mce-href="http://en.wikipedia.org/wiki/Reuters" href="http://en.wikipedia.org/wiki/Reuters" title="Reuters">Reuters</a></i>. 16 February 2013. Retrieved 18 February 2013.</li>
<li id="cite_note-5"><a data-mce-href="http://www.viivhealthcare.ca/com/pdf/news-releases/en/Tivicay_Media_Release_English.pdf" href="http://www.viivhealthcare.ca/com/pdf/news-releases/en/Tivicay_Media_Release_English.pdf" rel="nofollow">"ViiV Healthcare receives approval for Tivicay™ (dolutegravir) in Canada for the treatment of HIV"</a>. Retrieved 11 November 2013.</li>
<li id="cite_note-6">FDA approves new drug to treat HIV infection <a data-mce-href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm" href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm" rel="nofollow">http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm</a> Aug. 12, 2013</li>
<li id="cite_note-7"> U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay <a data-mce-href="http://www.reuters.com/article/2013/08/12/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812" href="http://www.reuters.com/article/2013/08/12/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812" rel="nofollow">http://www.reuters.com/article/2013/08/12/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812</a> Mon Aug 12, 2013 6:40pm EDT</li>
<li id="cite_note-8"><a data-mce-href="http://www.viivhealthcare.com/media/58599/us_tivicay.pdf" href="http://www.viivhealthcare.com/media/58599/us_tivicay.pdf" rel="nofollow">"Dolutegravir Prescribing Information"</a>. Retrieved 3 January 2014.</li>
<li id="cite_note-9"> Raffi, F; Jaeger, H; Quiros-Roldan, E; Albrecht, H; Belonosova, E; Gatell, JM; Baril, JG; Domingo, P; Brennan, C; Almond, S; Min, S; extended SPRING-2 Study, Group (Nov 2013). "Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial.". <i>The Lancet infectious diseases</i><b>13</b> (11): 927–35. <a data-mce-href="http://en.wikipedia.org/wiki/PubMed_Identifier" href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a><a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/24074642" href="http://www.ncbi.nlm.nih.gov/pubmed/24074642" rel="nofollow">24074642</a>.</li>
<li id="cite_note-10"><a data-mce-href="http://www.natap.org/2013/ICAAC/ICAAC_24.htm" href="http://www.natap.org/2013/ICAAC/ICAAC_24.htm" rel="nofollow">http://www.natap.org/2013/ICAAC/ICAAC_24.htm</a></li>
<li id="cite_note-11"> Walmsley, Sharon L.; Antela, Antonio; Clumeck, Nathan; Duiculescu, Dan; Eberhard, Andrea; Gutiérrez, Felix; Hocqueloux, Laurent; Maggiolo, Franco; Sandkovsky, Uriel; Granier, Catherine; Pappa, Keith; Wynne, Brian; Min, Sherene; Nichols, Garrett (7 November 2013). "Dolutegravir plus Abacavir–Lamivudine for the Treatment of HIV-1 Infection". <i>New England Journal of Medicine</i><b>369</b> (19): 1807–1818. <a data-mce-href="http://en.wikipedia.org/wiki/Digital_object_identifier" href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a data-mce-href="http://dx.doi.org/10.1056%2FNEJMoa1215541" href="http://dx.doi.org/10.1056%2FNEJMoa1215541" rel="nofollow">10.1056/NEJMoa1215541</a>.</li>
<li id="cite_note-12"> Sax, Paul. <a data-mce-href="http://blogs.jwatch.org/hiv-id-observations/index.php/single-study-underscores-waning-of-the-efavirenz-era-but-probably-just-in-the-usa/2013/11/06/" href="http://blogs.jwatch.org/hiv-id-observations/index.php/single-study-underscores-waning-of-the-efavirenz-era-but-probably-just-in-the-usa/2013/11/06/" rel="nofollow">"SINGLE Study Underscores Waning of the Efavirenz Era — But Probably Just in the USA - See more at:http://blogs.jwatch.org/hiv-id-observations/index.php/single-study-underscores-waning-of-the-efavirenz-era-but-probably-just-in-the-usa/2013/11/06/#sthash.A39SderN.dpuf"</a>. Retrieved 19 December 2013.</li>
<li id="cite_note-13"> Eron, JJ; Clotet, B; Durant, J; Katlama, C; Kumar, P; Lazzarin, A; Poizot-Martin, I; Richmond, G; Soriano, V; Ait-Khaled, M; Fujiwara, T; Huang, J; Min, S; Vavro, C; Yeo, J; VIKING Study, Group (2013 Mar 1). "Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study.". <i>The Journal of infectious diseases</i><b>207</b> (5): 740–8. <a data-mce-href="http://en.wikipedia.org/wiki/PubMed_Identifier" href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a><a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/23225901" href="http://www.ncbi.nlm.nih.gov/pubmed/23225901" rel="nofollow">23225901</a>.</li>
<li><table class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2010011812A1?cl=en" href="http://www.google.com/patents/WO2010011812A1?cl=en">WO2010011812A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 23, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jan 28, 2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Smithkline Beecham Corporation</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical compounds</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2010011819A1?cl=en" href="http://www.google.com/patents/WO2010011819A1?cl=en">WO2010011819A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 23, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jan 28, 2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Smithkline Beecham Corporation</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical compounds</td></tr>
</tbody></table>
</li>
<li><ul>
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<li>[Patent Document 1] International publication No.2006/116764 pamphlet</li>
<li>[Patent Document 2] International publication No.2010/011812 pamphlet</li>
<li>[Patent Document 3] International publication No.2010/011819 pamphlet</li>
<li>[Patent Document 4] International publication No.2010/068262 pamphlet</li>
<li>[Patent Document 5] International publication No.2010/067176 pamphlet</li>
<li>[Patent Document 6] International publication No.2010/068253 pamphlet</li>
<li>[Patent Document 7] <a data-mce-href="http://www.google.com/patents/US4769380" href="http://www.google.com/patents/US4769380" id="pcit0001">US Patent 4769380A</a></li>
<li>[Patent Document 8] International applicationPCT/JP2010/055316</li>
</ul>
</li>
</ul>
[NON-PATENT DOCUMENTS]<br />
<ul>
<li><div>
</div>
<div>
<ul>
<li>[Non-Patent Document 1] Journal of Organic Chemistry, 1991, 56(16), 4963-4967</li>
<li>[Non-Patent Document 2] Science of Synthesis, 2005, 15, 285-387</li>
<li>[Non-Patent Document 3] Journal of Chemical Society Parkin Transaction. 1, 1997, Issue. 2, 163-169</li>
</ul>
</div>
</li>
</ul>
</li>
</ol>
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<a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/18160521" href="http://www.ncbi.nlm.nih.gov/pubmed/18160521" target="_blank"><em>Antimicrob. Agents Chemother.</em> <strong>2008</strong>, <em>52</em>, 901-908.</a><br />
<a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/21807982" href="http://www.ncbi.nlm.nih.gov/pubmed/21807982" target="_blank"><em>Antimicrob. Agents Chemother.</em> <strong>2011</strong>, <em>55</em>, 4552-4559.</a><br />
<a data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000PharmR.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000PharmR.pdf" target="_blank">Drug@FDA, NDA204790 Microbiology Review(s).</a><br />
. <a data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000PharmR.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000PharmR.pdf" target="_blank">Drug@FDA, NDA204790 Pharmacology Review(s).</a><br />
<a data-mce-href="http://www.pmda.go.jp/drugs/2014/P201400046/index.html" href="http://www.pmda.go.jp/drugs/2014/P201400046/index.html" target="_blank">Japan PMDA.</a><br />
<a data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000ClinPharmR.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000ClinPharmR.pdf" target="_blank">Drug@FDA, NDA204790 Clinical Pharmacology Biopharmaceutics Review(s).</a></div>
</div>
</div>
<div class="NLM_p last">
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Dolutegravir">Dolutegravir</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Dolutegravir.svg" href="https://en.wikipedia.org/wiki/File:Dolutegravir.svg"><img alt="Dolutegravir.svg" data-file-height="254" data-file-width="620" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Dolutegravir.svg/250px-Dolutegravir.svg.png" height="102" src="https://upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Dolutegravir.svg/250px-Dolutegravir.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Dolutegravir.svg/375px-Dolutegravir.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/1/1f/Dolutegravir.svg/500px-Dolutegravir.svg.png 2x" style="height: auto; max-width: 100%;" width="250" /></a></td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Dolutegravir_ball-and-stick_model.png" href="https://en.wikipedia.org/wiki/File:Dolutegravir_ball-and-stick_model.png"><img alt="Dolutegravir ball-and-stick model.png" data-file-height="965" data-file-width="2350" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/67/Dolutegravir_ball-and-stick_model.png/250px-Dolutegravir_ball-and-stick_model.png" height="103" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/67/Dolutegravir_ball-and-stick_model.png/250px-Dolutegravir_ball-and-stick_model.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/6/67/Dolutegravir_ball-and-stick_model.png/375px-Dolutegravir_ball-and-stick_model.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/6/67/Dolutegravir_ball-and-stick_model.png/500px-Dolutegravir_ball-and-stick_model.png 2x" style="height: auto; max-width: 100%;" width="250" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">(4<i>R</i>,12a<i>S</i>)-<i>N</i>-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2<i>H</i>-pyrido[1',2':4,5]pyrazino[2,1-<i>b</i>][1,3]oxazine-9-carboxamide</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Tivicay</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/mtm/dolutegravir.html" href="https://www.drugs.com/mtm/dolutegravir.html" rel="nofollow">Multum Consumer Information</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/MedlinePlus" href="https://en.wikipedia.org/wiki/MedlinePlus" title="MedlinePlus">MedlinePlus</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.nlm.nih.gov"><a class="external text" data-mce-href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a613043.html" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a613043.html" rel="nofollow">a613043</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">License data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small>EU</small> <a data-mce-href="https://en.wikipedia.org/wiki/European_Medicines_Agency" href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency">EMA</a>: <span title="www.ema.europa.eu"><a class="external text" data-mce-href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Dolutegravir" href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Dolutegravir" rel="nofollow">Dolutegravir</a></span></li>
<li><small>US</small> <span title="www.accessdata.fda.gov"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" title="U.S. Food and Drug Administration">FDA</a>: <a class="external text" data-mce-href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Dolutegravir&SearchType=BasicSearch" href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Dolutegravir&SearchType=BasicSearch" rel="nofollow">Dolutegravir</a></span></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" title="Pregnancy category">B</a> (No risk in non-human studies)</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oral</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United Kingdom">UK</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">POM</a> (Prescription only)</li>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Bioavailability" href="https://en.wikipedia.org/wiki/Bioavailability" title="Bioavailability">Bioavailability</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">n/a<sup class="reference" id="cite_ref-PI_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Dolutegravir#cite_note-PI-1" href="https://en.wikipedia.org/wiki/Dolutegravir#cite_note-PI-1">[1]</a></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Plasma_protein_binding" href="https://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">≥98.9%</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_metabolism" href="https://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/UDP_glucuronosyltransferase_1_family,_polypeptide_A1" href="https://en.wikipedia.org/wiki/UDP_glucuronosyltransferase_1_family,_polypeptide_A1" title="UDP glucuronosyltransferase 1 family, polypeptide A1">UGT1A1</a> and <a data-mce-href="https://en.wikipedia.org/wiki/CYP3A" href="https://en.wikipedia.org/wiki/CYP3A" title="CYP3A">CYP3A</a></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Biological_half-life" href="https://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">~14 hours</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Excretion" href="https://en.wikipedia.org/wiki/Excretion" title="Excretion">Excretion</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feces (53%) and urine (18.9%)</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=1051375-16-6" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=1051375-16-6" rel="nofollow">1051375-16-6</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_J05" href="https://en.wikipedia.org/wiki/ATC_code_J05" title="ATC code J05">J05AX12</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=J05AX12" href="http://www.whocc.no/atc_ddd_index/?code=J05AX12" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=54726191" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=54726191" rel="nofollow">54726191</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/IUPHAR/BPS" href="https://en.wikipedia.org/wiki/IUPHAR/BPS" title="IUPHAR/BPS">IUPHAR/BPS</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.guidetopharmacology.org"><a class="external text" data-mce-href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7365" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7365" rel="nofollow">7365</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.25051637.html" href="http://www.chemspider.com/Chemical-Structure.25051637.html" rel="nofollow">25051637</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=DKO1W9H7M1" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=DKO1W9H7M1" rel="nofollow">DKO1W9H7M1</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEMBL" href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1229211" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1229211" rel="nofollow">CHEMBL1229211</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/NIAID_ChemDB" href="https://en.wikipedia.org/wiki/NIAID_ChemDB" title="NIAID ChemDB">NIAID ChemDB</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="chemdb.niaid.nih.gov"><a class="external text" data-mce-href="http://chemdb.niaid.nih.gov/CompoundDetails.aspx?AIDSNO=538122" href="http://chemdb.niaid.nih.gov/CompoundDetails.aspx?AIDSNO=538122" rel="nofollow">538122</a></span></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>20</sub><span title="Hydrogen">H</span><sub>19</sub><span title="Fluorine">F</span><sub>2</sub><span title="Nitrogen">N</span><sub>3</sub><span title="Oxygen">O</span><sub>5</sub></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">419.38 g/mol</td></tr>
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///////////<strong>GSK 1349572, </strong><strong>S-349572, </strong>GSK 1349572, GSK-134<wbr></wbr>9572, GSK1349572, Tivicay®, GSK1349572, GSK-1349572, S/GSK 1349572, S/GSK1349572, S/GSK1349572 (GSK13<wbr></wbr>49572), S/GSK1349572, UNII:DKO1W9H7M1, <strong>1051375-16-6, DOLUTEGRAVIR, 1051375-19-9, ドルテグラビルナトリウム</strong></div>
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C[C@@H]1CCO[C@@H]2N1C(=O)c3c(c(=O)c(cn3C2)C(=O)NCc4ccc(cc4F)F)O</div>
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CC1CCOC2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)NCC4=C(C=C(C=C4)F)F)[O-].[Na+]</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com7tag:blogger.com,1999:blog-1346483141860457136.post-51166822729503837052016-08-08T00:41:00.001-07:002016-08-08T00:41:34.117-07:00Nacubactam, A diazabicyclooctane beta-lactamase inhibitor, for treating bacterial infection<div dir="ltr" style="text-align: left;" trbidi="on">
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Nacubactam</div>
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RG-6080, FPI-1459, OP-0595, WK ?, WK-?, WK?</div>
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CAS 1452458-86-4<span data-mce-style="background-color: #d5d5d5;" style="background-color: #d5d5d5;">, MF </span>C<sub>9</sub> H<sub>16</sub> N<sub>4</sub> O<sub>7</sub> S, MW 324.31</div>
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Sulfuric acid, mono[(1<em>R</em>,2<em>S</em>,5<em>R</em>)-2-[[(2-aminoethoxy)amino]carbonyl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester,</div>
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(2S,5R)-N-(2-amino ethoxy)-6-(sulfooxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide</div>
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Beta lactamase inhibitor</div>
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Roche, under license from Meiji Seika Pharma and Fedora Pharmaceuticals is developing nacubactam hydrate</div>
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<span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Meiji+Seika+Pharma+Co.,+Ltd.%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Meiji+Seika+Pharma+Co.,+Ltd.%22">Meiji Seika Pharma Co., Ltd.</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22%EF%BC%AD%EF%BD%85%EF%BD%89%EF%BD%8A%EF%BD%89+%EF%BC%B3%EF%BD%85%EF%BD%89%EF%BD%8B%EF%BD%81%E3%83%95%E3%82%A1%E3%83%AB%E3%83%9E%E6%A0%AA%E5%BC%8F%E4%BC%9A%E7%A4%BE%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22%EF%BC%AD%EF%BD%85%EF%BD%89%EF%BD%8A%EF%BD%89+%EF%BC%B3%EF%BD%85%EF%BD%89%EF%BD%8B%EF%BD%81%E3%83%95%E3%82%A1%E3%83%AB%E3%83%9E%E6%A0%AA%E5%BC%8F%E4%BC%9A%E7%A4%BE%22">Meiji Seikaファルマ株式会社</a></span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A diazabicyclooctane beta-lactamase inhibitor, for treating bacterial infection. In July 2016, nacubactam was reported to be in phase 1 clinical development</div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #800080;" style="color: purple;"><strong><em>PATENTS , IN2015MU287, <a data-mce-href="https://patentscope.wipo.int/search/mobile/detail.jsf;jsessionid=177E3F5DEED4FB3B9DE0DCC710F47992.wapp1nC?docId=WO2016116878&recNum=570&office=&queryString=&prevFilter=&sortOption=Pub+Date+Desc&maxRec=2890964" data-mce-style="color: #800080;" href="https://patentscope.wipo.int/search/mobile/detail.jsf;jsessionid=177E3F5DEED4FB3B9DE0DCC710F47992.wapp1nC?docId=WO2016116878&recNum=570&office=&queryString=&prevFilter=&sortOption=Pub+Date+Desc&maxRec=2890964" style="color: purple;">WO2016116878</a>, <a class="ng-binding" data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016120752&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription" data-mce-style="color: #800080;" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016120752&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription" style="color: purple;">WO 2016120752</a>, INDICATE INTEREST FROM WOCKHARDT</em></strong></span></h1>
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Sulfuric acid, mono[(1<em>R</em>,2<em>S</em>,5<em>R</em>)-2-[[(2-aminoethoxy)amino]carbonyl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester</div>
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<i class="pull-left icon-bq icon-blackRed icon-Green">Phase I</i><br />
<span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Meiji+Seika+Pharma+Co.,+Ltd.%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Meiji+Seika+Pharma+Co.,+Ltd.%22">Meiji Seika Pharma Co., Ltd.</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22%EF%BC%AD%EF%BD%85%EF%BD%89%EF%BD%8A%EF%BD%89+%EF%BC%B3%EF%BD%85%EF%BD%89%EF%BD%8B%EF%BD%81%E3%83%95%E3%82%A1%E3%83%AB%E3%83%9E%E6%A0%AA%E5%BC%8F%E4%BC%9A%E7%A4%BE%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22%EF%BC%AD%EF%BD%85%EF%BD%89%EF%BD%8A%EF%BD%89+%EF%BC%B3%EF%BD%85%EF%BD%89%EF%BD%8B%EF%BD%81%E3%83%95%E3%82%A1%E3%83%AB%E3%83%9E%E6%A0%AA%E5%BC%8F%E4%BC%9A%E7%A4%BE%22">Meiji Seikaファルマ株式会社</a></span></div>
A β-lactamase inhibitor potentially for the treatment of bacterial infections.<br />
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<img alt="" class="" data-mce-src="https://blogger.googleusercontent.com/img/proxy/AVvXsEiUkBxwMYtFTDuIvTl4kwgSq0su0a5JJWuNEo1zRbBU373Q8xthlr9AtvzN7LLpA0gNJvj4mtaQJPCwA8Wbph0N2im3HQxyJAAqIs4a148P9wG8JS5BGs4A0g_V-Vnw4M6kcV0KXpqZeh-LmsyTQFiDB4gTAaU=" height="71" src="https://blogger.googleusercontent.com/img/proxy/AVvXsEiUkBxwMYtFTDuIvTl4kwgSq0su0a5JJWuNEo1zRbBU373Q8xthlr9AtvzN7LLpA0gNJvj4mtaQJPCwA8Wbph0N2im3HQxyJAAqIs4a148P9wG8JS5BGs4A0g_V-Vnw4M6kcV0KXpqZeh-LmsyTQFiDB4gTAaU=" style="height: auto; max-width: 100%;" width="497" /></div>
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<div class="addr yfdm">
<span class="f-red f_n">RG-6080; FPI-1459; OP-0595</span></div>
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<span class="f-red">CAS No. </span><span class="f-red f-cas">1452458-86-4</span></div>
<table border="1"><tbody>
<tr><td style="font-family: inherit; font-size: inherit;">Molecular Formula</td><td style="font-family: inherit; font-size: inherit;">C<sub>9</sub> H<sub>16</sub> N<sub>4</sub> O<sub>7</sub> S</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Formula Weight</td><td style="font-family: inherit; font-size: inherit;">324.31</td></tr>
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<ul class="data-list__content" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li class="data-list__property" id="at-a-glance_origniator"><strong class="data-list__property-key">Originator </strong><span class="data-list__property-value">Fedora Pharmaceuticals</span></li>
<li class="data-list__property" id="at-a-glance_developer"><strong class="data-list__property-key">Developer </strong><span class="data-list__property-value">Meiji Seika Pharma</span></li>
<li class="data-list__property" id="at-a-glance_class"><strong class="data-list__property-key">Class </strong><span class="data-list__property-value">Antibacterials; Azabicyclo compounds</span></li>
<li class="data-list__property" id="at-a-glance_mechanismOfAction"><strong class="data-list__property-key">Mechanism of Action </strong><span class="data-list__property-value">Beta lactamase inhibitors</span></li>
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<ul class="data-list__content data-list__content--highest-dev-phases" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li class="data-list__property"><strong class="data-list__property-key">Phase I </strong><span class="data-list__property-value">Bacterial infections</span></li>
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<h3 class="data-list__heading" id="at-a-glance_mostRecentEvents" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Most Recent Events</h3>
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<li class="data-list__property"><strong class="data-list__property-key">13 Jan 2015 </strong><span class="data-list__property-value property-value--event-details">OP 0595 licensed to Roche worldwide, except Japan ,</span></li>
<li class="data-list__property"><strong class="data-list__property-key">30 Nov 2014 </strong><span class="data-list__property-value property-value--event-details">Meiji Seika Pharma completes a phase I trial in Healthy volunteers in Australia (NCT02134834)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">01 May 2014 </strong><span class="data-list__property-value property-value--event-details">Phase-I clinical trials in Bacterial infections (in volunteers) in Australia (IV)</span></li>
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In September 2014, preclinical data were presented at the 54th ICAAC Meeting in Washington, DC. Nacubactam hydratedemonstrated Ki values of 0.24, 3 and 0.79 microM against AmpC P99 derived from Enterobacter cloacae, KPC-3, and CTX-M-15 enzymes, respectively; the Ki values were lower than that of <a href="https://www.blogger.com/null">cefepime</a></div>
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Bacterial infections continue to remain one of the major causes contributing towards human diseases. One of the key challenges in treatment of bacterial infections is the ability of bacteria to develop resistance to one or more antibacterial agents over time. Examples of such bacteria that have developed resistance to typical antibacterial agents include: Penicillin-resistant Streptococcus pneumoniae, Vancomycin-resistant Enterococci, and Methicillin-resistant Staphylococcus aureus. The problem of emerging drug-resistance in bacteria is often tackled by switching to newer antibacterial agents, which can be more expensive and sometimes more toxic. Additionally, this may not be a permanent solution as the bacteria often develop resistance to the newer antibacterial agents as well in due course. In general, bacteria are particularly efficient in developing resistance, because of their ability to multiply very rapidly and pass on the resistance genes as they replicate.<br />
The persistent exposure of bacterial strains to a multitude of beta- lactam antibacterial agents has led to overproduction and mutation of beta-lactamases. These new extended spectrum beta-lactamases (ESBL) are capable of hydrolyzing penicillins, cephalosporins, monobactams and even carbapenems. Such a wide spread resistance to many of the existing beta-lactam antibacterial agents, either used alone or in combination with other agents, is posing challenges in treating serious bacterial infections.<br />
Due to various reasons, the oral therapeutic options for treating bacterial infections (including those caused by ESBL strains) are limited. For example, a combination of amoxicillin and clavulanic acid is effective against Class A ESBLs producing bacteria. However, the usefulness of this combination is compromised against bacteria producing multiple or mixed beta-lactamase enzymes (such as, for example, bacteria producing Class A and Class C ESBLs concurrently), and Klebsiella pneumoniae carbapenemases (KPCs). Therefore, oral antibacterial agents or combinations with activity against a range of bacterial strains (including those producing multiple ESBLs and KPCs) are urgently desired.<br />
Cephalosporin antibacterial agents are known for treatment for various bacterial infections. Surprisingly, it has been found that pharmaceutical compositions comprising a cephalosporin antibacterial agent and certain nitrogen containing bicyclic compound (disclosed in PCT/IB2013/053092, PCT/JP2013/064971 and PCT/IB 2012/002675) exhibit unexpectedly synergistic antibacterial activity, even against highly resistant bacterial strains.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">SYNTHESIS</span></h1>
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WO 2015046207,</div>
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CONTD.......................</div>
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CONTD......................................</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-21.png" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-21.png" rel="attachment wp-att-7599"><img alt="STR1" class="alignnone size-full wp-image-7599" data-mce-src="https://blogger.googleusercontent.com/img/proxy/AVvXsEi78bkHEg_T8Bpm8tSVPW6Wt0o_O-iBFwTqJkwnYbZr2AIWiuswoTmi3KnrkbpnFI0bcUqt9TGgrqGcGRb8yZ28-I2g2SXJ4fqnr6wgp2dXMa8LlQOXvggcJ_O0xXUJmPz-UOcw2roKz05KBSKlgFn3ors7kwVCbjfQjAd2YaQ8DgA=" height="768" src="https://blogger.googleusercontent.com/img/proxy/AVvXsEi78bkHEg_T8Bpm8tSVPW6Wt0o_O-iBFwTqJkwnYbZr2AIWiuswoTmi3KnrkbpnFI0bcUqt9TGgrqGcGRb8yZ28-I2g2SXJ4fqnr6wgp2dXMa8LlQOXvggcJ_O0xXUJmPz-UOcw2roKz05KBSKlgFn3ors7kwVCbjfQjAd2YaQ8DgA=" style="height: auto; max-width: 100%;" width="703" /></a></div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">Patent</span></em></strong></h1>
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<a data-mce-href="https://www.google.com/patents/WO2015053297A1?cl=en" href="https://www.google.com/patents/WO2015053297A1?cl=en">WO 2015053297</a></div>
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The novel heterocyclic compound in Japanese Patent 4515704 (Patent Document 1), preparation and shown for their pharmaceutical use, sodium trans-7-oxo-6- (sulfooxy) as a representative compound 1,6-diazabicyclo [3 .2.1] discloses an octane-2-carboxamide (NXL104). Preparation in regard to certain piperidine derivatives which are intermediates Patent 2010-138206 (Patent Document 2) and JP-T 2010-539147 (Patent Document 3) are shown at further WO2011 / 042560 (Patent Document 4) NXL104 to disclose a method for producing the crystals.</div>
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In Patent 5038509 (Patent Document 5) (2S, 5R) -7- oxo -N- (piperidin-4-yl) -6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane - 2- carboxamide (MK7655) is shown, discloses the preparation of certain piperidine derivatives with MK7655 at Patent 2011-207900 (Patent Document 6) and WO2010 / 126820 (Patent Document 7).</div>
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The present inventors also disclose the novel diazabicyclooctane derivative represented by the following formula (VII) in Japanese Patent Application 2012-122603 (Patent Document 8).</div>
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Patent Document 1: Japanese Patent No. 4515704 Pat<br />
Patent Document 2: Japanese Patent Publication 2010-138206 Pat<br />
Patent Document 3: Japanese patent publication 2010-539147 Pat<br />
Patent Document 4: International Publication No. WO2011 / 042560 Patent<br />
Patent Document 5: Japanese Patent No. 5038509 Pat<br />
Patent Document 6: Japanese Patent Publication 2011-207900 Pat<br />
Patent Document 7: International Publication No. WO2010 / 126820 Patent<br />
Patent Document 8: Japanese Patent application 2012-122603 Pat.</div>
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[Chemical formula 1] (In the formula, R <sup>3</sup> are the same as those described below)<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028818652@@@11187448@@@520@@@121@@@jpoxmldoc01-appb-c000031.tif" height="121" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028818652@@@11187448@@@520@@@121@@@jpoxmldoc01-appb-c000031.tif" style="height: auto; max-width: 100%;" width="520" /></div>
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<img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028818652@@@11187448@@@520@@@169@@@jpoxmldoc01-appb-c000063.tif" height="277" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028818652@@@11187448@@@520@@@169@@@jpoxmldoc01-appb-c000063.tif" style="height: auto; max-width: 100%;" width="852" /></div>
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Reference Example<br />
5 of 5 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)<br />
Formula 43]</div>
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step 1 tert-butyl {2 - [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate (IV-1)(2S, 5R)-6-(benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid (4 .30g, dehydrated ethyl acetate (47mL) solution of 15.56mmol) was cooled to -30 ℃, isobutyl chloroformate (2.17g, washing included dehydration ethyl acetate 1mL), triethylamine (1.61g, washing included dehydration ethyl acetate 1 mL), successively added dropwise, and the mixture was stirred 1 hour at -30 ° C.. To the reaction solution tert- butyl 2-dehydration of ethyl acetate (amino-oxy) ethyl carbamate (3.21g) (4mL) was added (washing included dehydration ethyl acetate 1mL), raising the temperature over a period of 1.5 hours to 0 ℃, It was further stirred overnight. The mixture of 8% aqueous citric acid (56 mL), saturated aqueous sodium bicarbonate solution (40 mL), sequentially washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to 5 mL, up to 6mL further with ethanol (10 mL) It was replaced concentrated. Ethanol to the resulting solution (3mL), hexane the (8mL) in addition to ice-cooling, and the mixture was stirred inoculated for 15 minutes. The mixture was stirred overnight dropwise over 2 hours hexane (75 mL) to. Collected by filtration the precipitated crystals, washing with hexane to give the title compound 5.49g and dried in vacuo (net 4.98 g, 74% yield). HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 50/50, 1.0 mL / min, UV 210 nm, Retweeted 4.4 min; <sup>1</sup> H NMR (400 MHz, CDCl <sub>3</sub> ) [delta] 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br.d., J = 11.6 Hz , 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br. . s, 1H), 7.34-7.48 (yd, 5H), 9.37 (Br.S., 1H); MS yd / z 435 [M + H] <sup>+</sup> .<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028818652@@@11187448@@@520@@@105@@@jpoxmldoc01-appb-c000076.tif" height="105" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028818652@@@11187448@@@520@@@105@@@jpoxmldoc01-appb-c000076.tif" style="height: auto; max-width: 100%;" width="520" /></div>
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Step 2</div>
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tert-butyl {2 - [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate<br />
(V-1) tert-butyl {2 - [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl ] carbonyl} amino) oxy] ethyl} carbamate (3.91 g, to a methanol solution (80 mL) of 9.01mmol), 10% palladium on carbon catalyst (50% water, 803 mg) was added, under hydrogen atmosphere and stirred for 45 minutes . The reaction mixture was filtered through Celite, after concentrated under reduced pressure to give 3.11g of the title compound (quantitative).<br />
HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 75/25, 1.0 mL / min, UV 210 nm, Retweeted 3.9 from min; <sup>1</sup> H NMR (400 MHz, CD <sub>3</sub> OD) [delta] 1.44 (s, 9H) , 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br.dd., J = 15.0, 7.0 Hz, 1H), 3.03 (d, J= 12.0 Hz, 1H), 3.12 (br.d., J = 12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS M / Z 345 [M Tasu H] <sup>Tasu</sup> .</div>
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Step 3<br />
Tetrabutylammonium tert- butyl {2 - [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate<br />
(VI-1) tert-butyl {2 - [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct 2-yl] carbonyl} amino) oxy] ethyl} carbamate (3.09g, in dichloromethane (80mL) solution of 8.97mmol), 2,6- lutidine (3.20mL), sulfur trioxide - pyridine complex (3 .58g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into half-saturated aqueous sodium bicarbonate solution, washed the aqueous layer with chloroform, tetrabutylammonium hydrogen sulfate to the aqueous layer and (3.47 g) chloroform (30 mL) was added and stirred for 10 minutes. The aqueous layer was extracted with chloroform, drying the obtained organic layer with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound 5.46g (91% yield).<br />
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 80/20, 1.0ML / Min, UV210nm, RT 2.0 Min; <sup>1</sup> H NMR (400 MHz, CDCl <sub>3</sub> ) Deruta 1.01 (T, J = 7.4 Hz, 12H), 1.37-1.54 (m , 8H), 1.45 (s, 9H), 1.57-1.80 (m, 9H), 1.85-1.98 (m, 1H), 2.14-2.24 (m, 1H), 2.30- 2.39 (m, 1H), 2.83 (d, J = 11.6 Hz, 1H), 3.20-3.50 (m, 11H), 3.85-3.99 (m, 3H), 4.33-4.38 (m, 1H), 5.51 (br s , 1H), 9.44 (Br.S., 1H); MS yd / z 425 [M-Bu <sub>4</sub> N + 2H] <sup>+</sup> .</div>
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<div class="paragraph" id="paragraph0132" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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Step 4 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)<br />
tetra butylammonium tert- butyl {2 - [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (5.20g, 7.82mmol) in dichloromethane (25mL) solution of ice-cold under trifluoroacetic acid (25mL), and the mixture was stirred for 1 hour at 0 ℃. The reaction mixture was concentrated under reduced pressure, washed the resulting residue with diethyl ether, adjusted to pH7 with aqueous sodium bicarbonate, subjected to an octadecyl silica gel column chromatography (water), after freeze drying, 1.44 g of the title compound obtained (57% yield).<br />
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 99/1, 1.0ML / Min, UV210nm, RT 3.1 Min; <sup>1</sup> H NMR (400 MHz, D <sub>2</sub>O) Deruta 1.66-1.76 (M, 1H), 1.76-1.88 (m, 1H ), 1.91-2.00 (m, 1H), 2.00-2.08 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 3.15 (t, J = 5.0 Hz , 2H), 3.18 (br d , J = 12.0 Hz, 1H), 3.95 (dd, J = 7.8, 2.2 Hz, 1H), 4.04 (t, J = 5.0 Hz, 2H), 4.07 (dd, J = 6.4 3.2 Hz &, 1H); MS yd / z 325 [M + H] <sup>+</sup> .</div>
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<h1>
<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></em></strong></h1>
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<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015046207" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015046207">WO 2015046207</a></div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028657096@@@11234585@@@520@@@105@@@jpoxmldoc01-appb-c000024.tif" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028657096@@@11234585@@@520@@@105@@@jpoxmldoc01-appb-c000024.tif" style="height: auto; max-width: 100%;" /></div>
<div class="paragraph" id="paragraph0380" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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<span class="goog-text-highlight">Example </span><br />
<span class="goog-text-highlight">64 tert-butyl {2 - [({[( 2S, 5R) -6- </span><span class="goog-text-highlight">hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy ] ethyl} carbamate (V-1) </span><br />
<span class="goog-text-highlight">[of 124] </span><br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028657096@@@11234585@@@520@@@90@@@jpoxmldoc01-appb-c000144.tif" height="90" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028657096@@@11234585@@@520@@@90@@@jpoxmldoc01-appb-c000144.tif" style="height: auto; max-width: 100%;" width="520" /></div>
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tert- butyl {2 - [({[(2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } carbamate (example 63q, net 156.42g, 360mmol) in methanol solution (2.4L) of 10% palladium carbon catalyst (50% water, 15.64g) was added, under an atmosphere of hydrogen, stirred for 1.5 hours did. The catalyst was filtered through celite, filtrate was concentrated under reduced pressure until 450mL, concentrated to 450mL by adding acetonitrile (1.5 L), the mixture was stirred ice-cooled for 30 minutes, collected by filtration the precipitated crystals, washing with acetonitrile, and vacuum dried to obtain 118.26g of the title compound (net 117.90g, 95% yield). Equipment data of the crystals were the same as those of the step 2 of Reference Example 3.<a data-mce-href="https://www.blogger.com/null" href="https://www.blogger.com/null" name="0382"></a></div>
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Example<br />
65 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VI-1)<br />
<br />
<img alt="" class="newline" data-mce-src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028657096@@@11234585@@@520@@@93@@@jpoxmldoc01-appb-c000145.tif" height="93" src="https://patentscope.wipo.int/search/docservice_image_ft/WO@@@id00000028657096@@@11234585@@@520@@@93@@@jpoxmldoc01-appb-c000145.tif" style="height: auto; max-width: 100%;" width="520" /></div>
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<div class="paragraph" id="paragraph0383" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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tert- butyl {2 - [({[(2S, 5R) -1,6- -6- hydroxy-7-oxo-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (example 64,537.61g, 1.561mol) in acetonitrile (7.8L) solution of 2,6-lutidine (512.08g), sulfur trioxide - pyridine complex (810.3g) was added, at room temperature in the mixture was stirred overnight. Remove insolubles and the mixture was filtered, the filtrate concentrated to 2.5 L, diluted with ethyl acetate (15.1L). The mixture was extracted with 20% phosphoric acid 2 hydrogencarbonate aqueous solution (7.8L), the resulting aqueous layer into ethyl acetate (15.1L), added tetrabutylammonium hydrogen sulfate (567.87g), was stirred for 20 min. The organic layer was separated layers, dried over anhydrous magnesium sulfate (425 g), after filtration, concentration under reduced pressure, substituted concentrated tetrabutylammonium tert- butyl with dichloromethane (3.1L) {2 - [({[(2S, 5R ) -7-oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate was obtained 758g (net 586.27g, Osamu rate 84%).</div>
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<div class="paragraph" id="paragraph0384" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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The tetra-butyl ammonium salt 719g (net 437.1g, 0.656mol) in dichloromethane (874mL) solution was cooled to -20 ℃, dropping trifluoroacetic acid (874mL) at 15 minutes, 1 the temperature was raised to 0 ℃ It was stirred time. The reaction was cooled to -20 ° C. was added dropwise diisopropyl ether (3.25L), and the mixture was stirred for 1 hour the temperature was raised to 0 ° C.. The precipitate is filtered, washed with diisopropyl ether to give the title compound 335.36g of crude and vacuum dried (net 222.35g, 99% yield).</div>
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<div class="paragraph" id="paragraph0385" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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The title compound of crude were obtained (212.99g, net 133.33g) and ice-cold 0.2M phosphate buffer solution of pH5.3 mix a little at a time, alternating between the (pH6.5,4.8L). The solution was concentrated under reduced pressure to 3.6L, it was adjusted to pH5.5 at again 0.2M phosphate buffer (pH6.5,910mL). The solution resin purification (Mitsubishi Kasei, SP207, water ~ 10% IPA solution) is subjected to, and concentrated to collect active fractions, after lyophilization, to give the title compound 128.3 g (96% yield). Equipment data of the crystals were the same as those of step 3 of Reference Example 3.</div>
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PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
US 20140288051</div>
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WO 2014091268</div>
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WO 2013180197</div>
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US 20130225554</div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
IN2015MU287</div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<em><span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></em></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/WO2013180197A1?cl=en" href="https://www.google.com/patents/WO2013180197A1?cl=en">WO2013180197</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Example 59</span><br /><span class="notranslate">(2S, 5R) -N- (2- aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (II-059)</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000130.png" href="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000130.png"><img alt="Figure JPOXMLDOC01-appb-C000130" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000130.png" height="125" src="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000130.png" style="height: auto; max-width: 100%;" width="640" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Step 1</span><br /><span class="notranslate">tert- butyl {2 - [({[(2S, 5R) -6- Benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } carbamate</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000131.png" href="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000131.png"><img alt="Figure JPOXMLDOC01-appb-C000131" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000131.png" height="118" src="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000131.png" style="height: auto; max-width: 100%;" width="640" /></a></div>
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<span class="notranslate">Acid of Example 9 or 16 (6b, 1.34g, 4.87mmol) in methylene chloride (35mL) solution of triethylamine (2.71mL), N- ethyl -N '- (3- dimethylaminopropyl) carbodiimide hydrochloride (1.41g), 1- hydroxybenzotriazole monohydrate (1.15g), were added tert- butyl of Reference Example 9, wherein 2- (amino-oxy) ethyl carbamate (1.12g), room temperature It was stirred overnight Te.</span><span class="notranslate">Water was added to the reaction solution to a residue obtained by concentration under reduced pressure, and extracted with ethyl acetate.</span> <span class="notranslate">The resulting organic layer with 0.1M hydrochloric acid, saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated.</span><span class="notranslate">The resulting residue was purified by silica gel column and purified by chromatography (hexane / ethyl acetate = 8 / 2-0 / 10) to give the title compound 1.77g (84% yield).</span><br /><span class="notranslate">[Α] <sub>D</sub> <sup>20</sup> -0.08 ° (c 0.29, CHCl <sub>3);</sub> <sup>1</sup> H NMR (400 MHz, CDCl <sub>3),</sub> δ: 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m , 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br d, J = 11.6 Hz, 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br s, 1H), 7.34-7.48 (m, 5H), 9.37 (br s, 1H); MS m / z 435 [M <sup>+</sup> H] +; enantiomeric excess of 99.9% or higher ee (CHIRALPAK AD-H, 4.6x150mm, hexane / ethanol = 2/1, UV210nm, flow rate 1mL / min, retention time 4.95min (2R, 5S), 6.70min (2S, 5R).</span></div>
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<span class="notranslate">Step 2</span><br /><span class="notranslate">tert- butyl {2 - [({[(2S, 5R) -1,6- -6- hydroxy-7-oxo-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate</span></div>
<div class="patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000132.png" href="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000132.png"><img alt="Figure JPOXMLDOC01-appb-C000132" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000132.png" height="119" src="https://patentimages.storage.googleapis.com/WO2013180197A1/JPOXMLDOC01-appb-C000132.png" style="height: auto; max-width: 100%;" width="640" /></a></div>
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<span class="notranslate">Compound of the above Step 1 (3.91g, 9.01mmol) in methanol (80mL), 10% palladium on carbon catalyst (50% water, 803mg) was added, under hydrogen atmosphere and stirred for 45 minutes.</span> <span class="notranslate">The reaction mixture was filtered through Celite, then concentrated under reduced pressure, to give 3.11g of the title compound (quantitative).</span><br /><span class="notranslate"><sup>1</sup> H NMR (400 MHz, CD <sub>3</sub> OD), <sup>δ:</sup> 1.44 (s, 9H), 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 ( br dd, J = 15.0, 7.0 Hz, 1H), 3.03 (d, J = 12.0 Hz, 1H), 3.12 (br d, J = 12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS m / z 345 [M <sup>+</sup> H] +.</span></div>
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<span class="notranslate">Step 3</span><br /><span class="notranslate">(2S, 5R) -N- (2- aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide The above step 2 compound (3. 09g, in methylene chloride (80mL) solution of 8.97mmol), 2,6- lutidine (3.20mL), sulfur trioxide - was added pyridine complex (3.58g), and stirred at room temperature overnight.</span> <span class="notranslate">The reaction mixture was poured into half-saturated aqueous sodium bicarbonate solution, and washed the aqueous layer with chloroform, and tetrabutylammonium hydrogen sulfate (3.47g) and chloroform (30mL) was added to the aqueous layer and stirred for 10 minutes.</span> <span class="notranslate">After extracting the aqueous layer with chloroform, drying the resulting organic layer over anhydrous sodium sulfate, filtered, concentrated under reduced pressure tetrabutylammonium tert- butyl {2 - [({[(2S, 5R) -7- oxo - 6- (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate was obtained 5.46g (91% yield).</span><br /><span class="notranslate"><sup>1</sup> H NMR (400 MHz, CDCl <sub>3),</sub> <sup>δ:</sup> 1.01 (t, J = 7.4 Hz, 12H), 1.37-1.54 (m, 8H), 1.45 (s, 9H), 1.57-1.80 (m, 9H), 1.85-1.98 (m, 1H), 2.14-2.24 (m, 1H), 2.30-2.39 (m, 1H), 2.83 (d, J = 11.6 Hz, 1H), 3.20-3.50 (m, 11H), 3.85- 3.99 (m, 3H), 4.33-4.38 (m, 1H), 5.51 (br s, 1H), 9.44 (br s, 1H); MS m / z 425 [M-Bu <sub>4</sub> N <sup>+</sup> 2H] +.</span></div>
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<span class="notranslate">The tetrabutyl ammonium salt (5.20g, 7.82mmol) in methylene chloride (25mL) solution of under ice-cooling trifluoroacetic acid (25mL), and the mixture was stirred for 1 hour at 0 ℃.</span> <span class="notranslate">The reaction mixture was concentrated under reduced pressure, washed resulting residue with diethyl ether, at aqueous sodium bicarbonate was adjusted to pH7, it performs an octadecyl silica gel column chromatography (water), after freeze-drying, 1.44g of the title compound The obtained (57% yield).</span><br /><span class="notranslate">[Α] <sub>D</sub> <sup>24</sup> -63.5 ° (c 0.83, H <sub>2</sub> O); <sup>1</sup> H NMR (400 MHz, <sub>D 2</sub> O), δ: 1.66-1.76 (m, 1H), 1.76-1.88 (m, 1H), 1.91 -2.00 (m, 1H), 2.00-2.08 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 3.15 (t, J = 5.0 Hz, 2H), 3.18 (br d, J = 12.0 Hz , 1H), 3.95 (dd, J = 7.8, 2.2 Hz, 1H), 4.04 (t, J = 5.0 Hz, 2H), 4.07 (dd, J = 6.4, 3.2 Hz, 1H); MS m / z 325 [ M <sup>+</sup> H] +.</span></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<em><span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></em></h1>
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<a data-mce-href="https://patentscope.wipo.int/search/mobile/detail.jsf;jsessionid=177E3F5DEED4FB3B9DE0DCC710F47992.wapp1nC?docId=WO2016116878&recNum=570&office=&queryString=&prevFilter=&sortOption=Pub+Date+Desc&maxRec=2890964" href="https://patentscope.wipo.int/search/mobile/detail.jsf;jsessionid=177E3F5DEED4FB3B9DE0DCC710F47992.wapp1nC?docId=WO2016116878&recNum=570&office=&queryString=&prevFilter=&sortOption=Pub+Date+Desc&maxRec=2890964">WO2016116878</a></div>
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<img class="" data-mce-src="http://jobbuzz.timesjobs.com/ndata_images/logos/000793.gif" height="299" src="http://jobbuzz.timesjobs.com/ndata_images/logos/000793.gif" style="height: auto; max-width: 100%;" width="598" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
ANTIBACTERIAL COMPOSITIONS OF A BETA-LACTAMASE INHIBITOR WITH A CEPHALOSPORIN<b>Abstract:</b></div>
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Pharmaceutical compositions comprising: (a) at least one cephalosporin antibacterial agent and (b) a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof are disclosed. Formula (I)</div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<em><span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></em></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="ng-binding" data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016120752&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016120752&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription">WO 2016120752</a>, WOCKHARDT, NEW PATENT, Nacubactam</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="http://www.wockhardt.com/images/Wockhardt-new-logo-big.jpg" src="http://www.wockhardt.com/images/Wockhardt-new-logo-big.jpg" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Formula (I), chemically known as (25, 5i?)-N-(2-aminoethoxy)-6-(sulfooxy)-7-oxo-l ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide has antibacterial properties and is disclosed in PCT International Patent Application No. PCT/IB2013/053092, PCT/JP2013/064971 and PCT/IB2012/002675. The present invention discloses a process for preparation of a compound of Formula (I).</div>
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Formula (I)</div>
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<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000002_0001.gif" height="84" id="imgf000002_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000002_0001.gif" style="height: auto; max-width: 100%;" width="176" /></div>
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<br /></div>
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<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000011_0001.gif" height="92" id="imgf000011_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000011_0001.gif" style="height: auto; max-width: 100%;" width="534" /></div>
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(VII) (VIII) (IX)</div>
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Scheme 2</div>
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Example 1</div>
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Synthesis of fert-butyl-r2-(aminooxy) ethyllcarbamate (III)</div>
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Preparation of fert-butyl-2-hydroxy ethylcarbamate (VIII):</div>
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Formula (VIII)</div>
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<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000012_0001.gif" height="63" id="imgf000012_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000012_0001.gif" style="height: auto; max-width: 100%;" width="78" /></div>
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To a stirred solution of ethanolamine (50.0 g, 0.8186 mol) in dichloromethane (1000 ml), was added triethylamine (124 g, 1.228 mol) at 0°C. After 10 minutes, di-teri-butyl dicarbonate (VII, 214.15 g, 0.9823 mol) was added drop wise at 0°C under continuous stirring. Then reaction mass was allowed to warm to 25°C and stirred further for 3 hours. After completion of reaction, the resulting reaction mixture was poured into water (250 ml) and the organic layer was separated and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure to obtain 130 g of the titled product as colorless oil in 98% yield.</div>
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Analysis:</div>
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Mass: 162 (M+l); for Molecular Weight of 161.2 and Molecular Formula of C7H15NO3.</div>
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1H NMR (400MHz, CDC1<sub>3</sub>): δ 4.92(br s,lH), 3.72-3.68(q,2H), 3.30-3.26(q,2H), 2.33(br s,lH), 1.44(s,9H).</div>
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Preparation of A<sup>7</sup>-Boc-2-(2-aminoethoxy)isoindoline-l,3-dione (IX):</div>
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<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000013_0001.gif" height="96" id="imgf000013_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000013_0001.gif" style="height: auto; max-width: 100%;" width="202" /></div>
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To a stirred solution of teri;butyl-2-hydroxy-ethylcarbamate (VIII, 50 g, 0.3106 mol) in tetrahydrofuran (500 ml), was added triphenylphosphine (89.5 g, 0.3416 mol) at 25°C. After stirring for 10 minutes, a solution of N-hydroxyphthalimide (50.66 g, 0.3106 mol) in dichloromethane (250 ml) was added to the reaction mass at 25 °C over a period of 10 minutes. After stirring for further 10 minutes, diisopropyl azodicarboxylate (69.1 g, 0.3416 mol) was added to the reaction mass in small portions (exothermic reaction was observed up to 34°C). The resulting reaction mass was stirred further at 25°C. After 16 hours, the reaction mass was concentrated under reduced pressure to obtain colorless oily material. The oily residue was diluted with diisopropyl ether (200 ml) and stirred for 30 minutes. The separated solid was filtered under suction. The filtrate was evaporated under reduced pressure and the residue subjected to di-isopropyl ether treatment (200 ml). This procedure was repeated once again. The filtrate was concentrated to obtain a solid product. The obtained solid was washed with diisopropyl ether (50 ml) and dried under reduced pressure. This solid contains small amount of triphenylphosphine oxide, along with the product. This was used as such for the next reaction without further purification.</div>
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Analysis:</div>
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Mass: 307.2 (M+l); for Molecular Weight of 306.3 and Molecular Formula of Ci<sub>5</sub>Hi<sub>8</sub>N<sub>2</sub>0<sub>5</sub>; 1H NMR of purified material (400MHz, CDC1<sub>3</sub>): 7.85-7.25 (m,4H), 5.62(br s,lH), 4.26-4.23(t,2H), 3.46-3.42(q,2H), 1.46(s,9H).</div>
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Step 3: Preparation of fert-butyl-[ -(aminooxy) ethyl]carbamate (III):</div>
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Formula (III)</div>
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<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000014_0001.gif" height="63" id="imgf000014_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000014_0001.gif" style="height: auto; max-width: 100%;" width="97" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a stirred solution of N-Boc-2-(2-aminoethoxy)isoindoline-l ,3-dione (IX, 97 g, 0.3167 mol) in dichloromethane (970 ml) was added hydrazine hydrate (31.7 g, 0.6334 mol) , at 0°C, drop wise, over a period of 45 minutes and the stirring continued further. After 2 hours, the reaction mass was filtered under suction. Filtrate was washed with water (485 ml), and the organic layer was diluted with an aq. solution of 10% potassium hydrogen sulfate (485 ml) and stirred for 15 minutes. The aqueous layer was separated, neutralized with solid sodium hydrogen carbonate and extracted with dichloromethane (2 x 485 ml). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain colorless oil, this was used as such for further reaction immediately (28g, overall yield of step II and step III was 60%)</div>
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Analysis:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Mass: 177.2 (M+l) for Molecular Weight of 176.2 and Molecular Formula of C7H16N2O<sub>3</sub>.</div>
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Example 2</div>
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Synthesis of (25,5R)-jV-(2-aminoethoxy)-6-(sulfooxy)-7-oxo-l,6-diaza-bicvclor3.2.11octane-2- carboxamide (I)</div>
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Step 1: Preparation of (25,5R)-iV-(2-Boc-aminoethoxy)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (IV):</div>
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<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000014_0002.gif" height="81" id="imgf000014_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000014_0002.gif" style="height: auto; max-width: 100%;" width="228" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a clear solution of sodium (25,5i?)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylate (II, 42.67 g, 0.143 mol; prepared according to the procedure disclosed in Indian Patent Application No. 699/MUM/2013) in water (426 ml) was added EDC.HC1 (67.1 g, 0.349 mol) at 15°C</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
under stirring. After 10 minutes, a solution of teri-butyl-[2-(aminooxy) ethyl]carbamate (III, 28.0g, 0.159 mol; prepared as per the literature procedure depicted in Scheme 2) in dimethylformamide (56 ml) was added drop wise at 10°C under continuous stirring. The temperature of the reaction mass was allowed to warm to 25°C and then HOBt (21.5g, 0.159 mol) was added in small portions over a period of 15 minutes and the resulting mixture was further stirred at room temperature for 16 hours. The reaction was continuously monitored using thin layer chromatography using mixture of acetone and hexane (35 :65) as solvent system. After completion of reaction, the resulting mixture was filtered and the residue was washed with water (130 ml). The obtained white residue was suspended in water (130 ml) and the mixture stirred at 50°C for 3 hours. The resulting suspension was filtered, the residue dried under reduced pressure to obtain 51 g of (2S,5R)-N-(2-Boc-aminoethoxy)-6-(benzyloxy)-7-oxo-l ,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (IV) as off white solid in 73% yield.</div>
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Analysis:</div>
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Mass: 433.4 (M-l ); for Molecular Weight of 434.5 and Molecular Formula of C21H<sub>3</sub>0N4O6;</div>
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1H-NMR (400MHz, CDC1<sub>3</sub>): δ 9.32 (br s, 1H), 7.41 -7.26(m,5H), 5.41(br s, 1H), 5.06-4.88(dd, 2H), 3.98-3.96(d,lH), 3.91-3.90(m,2H), 3.39(m, 1H), 3.31-3.26(m, 2H), 3.04-3.01(d,lH), 2.77-2.74(d, 1H), 2.33-2.28(m, 1H), 2.03-1.93(m, 2H), 1.67-1.64(m, 1H), 1.44(s, 9H);</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Purity as determined by HPLC: 99.4%.</div>
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Step 2: Preparation of (2S,5R)-iV-(2-Boc-aminoethoxy)-6-(hydroxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (V):</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000015_0001.gif" height="82" id="imgf000015_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000015_0001.gif" style="height: auto; max-width: 100%;" width="219" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A solution of (25,5i?)-N-(2-Boc-aminoethoxy)-6-(benzyloxy)-7-oxo-l ,6-diaza-bicyclo[3.2.1] octane-2-carboxamide (IV, 38 g, 0.0875 mol) in a mixture of dimethylformamide and dichloromethane (2: 8, 76 ml: 304 ml), containing 10% Pd/C (7.6 g, 50% wet) was hydrogenated at 50 psi hydrogen atmosphere at 25°C for 3 hours. The resulting mixture was filtered through a celite pad. The residue was washed with dichloromethane (75 ml). The solvent from the combined filtrate was evaporated</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
under reduced pressure to obtain 30 g (25,5i?)-N-(2-Boc-aminoethoxy)-6-(hydroxy)-7-oxo-l ,6-diaza-bicyclo[3.2.1 ]octane-2-carboxamide (V) as an oil, which was used as such for the next reaction without further purification.</div>
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Analysis:</div>
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Mass: 343.3 (M-l ) for Molecular Weight of 344.3 and Molecular Formula of C14H24N4O6.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Step 3: Preparation of (25,5R)-iV-(2-Boc-aminoethoxy)-6-(sulfooxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxamide,tetrabutyl ammonium salt (VI):</div>
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<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000016_0001.gif" height="84" id="imgf000016_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000016_0001.gif" style="height: auto; max-width: 100%;" width="242" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a stirred solution of (25,5i?)-N-(2-Boc-aminoethoxy)-6-(hydroxy)-7-oxo-l ,6-diaza-bicyclo[3.2.1 ]octane-2-carboxamide (V, 30.0 g, 0.0875 mol) in dimethylformamide (150 ml) was added sulphur trioxide dimethylformamide complex (16.06 g, 0.105 mol) in one portion, at 10°C. The reaction mass was stirred at the same temperature for 30 minutes and then allowed to warm to room temperature. After 2 hours, a solution of tetrabutylammonium acetate (31.6 g, 0.105 mol) in water (95 ml) was slowly added to the reaction mixture and stirred for another 2 hours. The solvent from the reaction mixture was evaporated under reduced pressure to obtain an oily residue. The oily mass was co-evaporated with xylene (2 x 60 ml) to obtain thick mass. This mass was partitioned between 1 : 1 mixture of dichloromethane (300 ml) and water (300 ml). The organic layer was separated and the aqueous layer re-extracted with dichloromethane (150 ml). The combined organic extracts were washed with water (3 x 150 ml) and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the resulting oily mass was triturated with ether (3 x 60 ml). Each time the ether layer was decanted and the residue was finally concentrated under reduced pressure to obtain the sticky mass. The so obtained material was purified by column chromatography over silica gel using mixture of methanol and dichloromethane as elution solvent. The solvent from the combined fractions was evaporated to obtain 47.5 g of (25,5i?)-N-(2-Boc-aminoethoxy)-6-(sulfooxy)-7-oxo-l ,6-diaza-bicyclo[3.2.1 ]octane-2-carboxamide,tetrabutyl ammonium salt as white foam in 70% yield.</div>
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Analysis:</div>
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Mass: 423.4 (M-l) as free sulphonic acid; for Molecular Weight of 665.9 and Molecular Formula of C<sub>3</sub>0H59N5O9 S;</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
1H- NMR (400MHz, CDC1<sub>3</sub>): δ 9.52(br s, 1H), 5.53(br s, 1H), 4.33(s, 1H), 3.95-3.92(m,3H), 3.37-3.27(m, 1 1H), 2.87-2.84(d, 1H), 2.35-2.30(m, 1H), 2.17(m, 1H), 1.96-1.88(m, 2H), 1.74-1.60(m,8 H), 1.47-1.40(m, 17H), 1.02-0.98(m, 12H).</div>
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Step 4: Preparation of (2S R)-iV-(2-aminoethoxy)-6-(sulfooxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (I):</div>
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Formula (I)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000017_0001.gif" height="84" id="imgf000017_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IB2016050264@@@id00000068085166@@@7950629@@@imgf000017_0001.gif" style="height: auto; max-width: 100%;" width="176" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a stirred solution of (2S,5i?)-N-(2-Boc-aminoethoxy)-6-(sulfooxy)-7-oxo-l ,6-diaza-bicyclo[3.2.1 ]octane-2-carboxamide, tetrabutyl ammonium salt (VI, 17 g, 0.0225 mol) in dichloromethane (85 ml) was added trifluoroacetic acid (85 ml) drop wise at -10°C over a period of 45 minutes. The resulting mass was further stirred at same temperature for 1 hour. The resulting reaction mixture was poured into cyclohexane (850 ml), stirred well for 30 minutes and the separated oily layer was collected. This procedure was repeated one more time and finally the separated oily layer was added to tert-butyl methyl ether (170 ml) under vigorous stirring at 25°C. The ether layer was removed by decantation from the precipitated solid. This procedure was repeated twice again with tert-butyl methyl ether (2 x 170 ml). The solid thus obtained was stirred with fresh dichloromethane (170 ml) for 30 minutes and filtered. The residual solid was dried at 45°C under reduced pressure to yield 7.3g of the titled compound in crude form. The obtained solid was further dissolved in water, (7.3 ml) and to this solution was added basic resin (Amberlyst A-26 -OH ion exchange resin, 4.4 g) under stirring. After 0.5 hour, the resin was filtered and to the filtrate isopropanol (51 ml) was added slowly at 25°C. The solution was further stirred for 12 hours. The separated solid was filtered and washed with additional isopropanol (7.5 ml) and dried under reduced pressure to obtain 4.3 g of (2S ,5R)-N-(2-aminoethoxy)-6-(sulfooxy)-7-oxo-l ,6-diaza-bicyclo[3.2.1 ]octane-2-carboxamide as off-white solid in 52 % yield.</div>
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Analysis:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Mass: 323.1 (M-l); for Molecular Weight of 324.31 and Molecular Formula of C<sub>9</sub>H16N4O7S; 1H-NMR (400MHz, D<sub>2</sub>0): δ 4.07-4.06(d, 1H), 4.05-4.03(t, 2H), 3.96-3.94(d, 1H), 3.20(br s, 1H), 3.16-3.13(t, 2H), 3.02-2.99(d, 1H), 2.04-1.68(m, 4H);</div>
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Purity as determined by HPLC: 94.88%.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="https://media.licdn.com/media/AAEAAQAAAAAAAAcOAAAAJGJmNDc3NjYyLTJmNTEtNDc3Ni05YjZlLTQzODQ2N2MyNzdhMA.png" src="https://media.licdn.com/media/AAEAAQAAAAAAAAcOAAAAJGJmNDc3NjYyLTJmNTEtNDc3Ni05YjZlLTQzODQ2N2MyNzdhMA.png" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
REF</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.pewtrusts.org/~/media/assets/2015/02/antibioticsinnovationproject_datatable_201502_v3.pdf?la=en" href="http://www.pewtrusts.org/~/media/assets/2015/02/antibioticsinnovationproject_datatable_201502_v3.pdf?la=en">http://www.pewtrusts.org/~/media/assets/2015/02/antibioticsinnovationproject_datatable_201502_v3.pdf?la=en</a></div>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/US9309245" href="https://www.google.com/patents/US9309245">US9309245</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 2, 2013</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 12, 2016</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Entasis Therapeutics Limited</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Beta-lactamase inhibitor compounds</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/US9393239" href="https://www.google.com/patents/US9393239">US9393239</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 15, 2014</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 19, 2016</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Fedora Pharmaceuticals Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Bicyclic compounds and their use as antibacterial agents and betalactamase inhibitors</td></tr>
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/////////////IN2015MU287, <a class="ng-binding" href="https://www.blogger.com/null">WO-2016120752, nacubactam, WOCKHARDT, NEW PATENT, </a>WK ?, WK-?, WK?, CAS 1452458-86-4<span data-mce-style="background-color: #d5d5d5;" style="background-color: #d5d5d5;">, </span>C<sub>9</sub> H<sub>16</sub> N<sub>4</sub> O<sub>7</sub> S, 324.31, Beta lactamase inhibitor, Roche, Meiji Seika Pharma, Fedora Pharmaceuticals, nacubactam hydrate , PHASE 1, A diazabicyclooctane beta-lactamase inhibitor, bacterial infection, July 2016, phase 1 clinical development, RG-6080, 1452458-86-4, FPI-1459, OP-0595, <i class="pull-left icon-bq icon-blackRed icon-Green">Phase I</i> , β-lactamase inhibitor, bacterial infections, Fedora parmaceuticals, <span class="data-list__property-value">Meiji Seika Pharma</span></div>
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NCCONC(=O)[C@@H]2CC[C@@H]1C[N@]2C(=O)N1OS(=O)(=O)O</div>
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<a data-mce-href="http://en.wikipedia.org/wiki/File:Eribulin.svg" href="http://en.wikipedia.org/wiki/File:Eribulin.svg"><img alt="" data-mce-src="http://upload.wikimedia.org/wikipedia/commons/thumb/4/43/Eribulin.svg/300px-Eribulin.svg.png" src="http://upload.wikimedia.org/wikipedia/commons/thumb/4/43/Eribulin.svg/300px-Eribulin.svg.png" height="226" style="height: auto; max-width: 100%;" width="300" /></a></div>
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Eribulin</div>
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<img alt="" data-mce-src="http://t0.gstatic.com/images?q=tbn:ANd9GcSHNfrdPG56YyzeV89Chr1Epo6KP830iZO8Qca_XsmNBddl0pvuYcSojDo8VA" src="http://t0.gstatic.com/images?q=tbn:ANd9GcSHNfrdPG56YyzeV89Chr1Epo6KP830iZO8Qca_XsmNBddl0pvuYcSojDo8VA" height="164" id="il_fi" style="height: auto; max-width: 100%;" width="308" /></div>
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Eribulin mesylate</div>
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エリブリンメシル酸塩</div>
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CAS 441045-17-6 MESYLATE</div>
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<a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C41H63NO14S&sort=mw&sort_dir=asc" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C41H63NO14S&sort=mw&sort_dir=asc" title="Find all compounds with formula C41H63NO14S">C<sub>41</sub>H<sub>63</sub>NO<sub>14</sub>S</a>, 826.00222 g/mol</div>
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halichrondrin B analog, B1939, E7389, ER-086526,Halaven</div>
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CAS <a data-mce-href="http://www.molbase.com/en/253128-41-5-moldata-1570257.html" href="http://www.molbase.com/en/253128-41-5-moldata-1570257.html"><b id="on_casno">253128-41-5</b> </a> FREE FORM</div>
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(1S,3S,4R)-3-tert-butoxycarbonylamino-4-hydroxycyclopentanecarboxylic acid methyl ester;</div>
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(1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,33R,35R,36S)-20-[(2S)-3-Amino-2-hydroxypropyl]-21-methoxy-14-methyl-8,15-bis(methylene)-2,19,30,34,37,39,40,41-octaoxanonacyclo[24.9.2.13,32.13,33.16,9.112,16.018,22.029,36.031,35]hentetracontan-24-one;</div>
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2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9<i>H</i>,15<i>H</i>-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4<i>H</i>)-one</div>
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<i id="yui_3_5_0_3_1470380821943_485">(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-((2S)-3-amino-2-hydroxypropyl)-3-methoxy-26-methyl-20,27-dimethylidenehexacosahydro-11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3':5,6)pyrano(4,3-b)(1,4)dioxacyclopentacosin-5(4H)-one methanesulfonate (salt)</i></h4>
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<i id="yui_3_5_0_3_1470380821943_499">11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3':5,6)pyrano(4,3-b)(1,4)dioxacyclopentacosin-5(4H)-one, 2-((2S)-3- amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, 2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt)</i></h4>
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<img alt="" class="" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/c/cb/Eisai_logo.svg/1280px-Eisai_logo.svg.png" height="475" src="https://upload.wikimedia.org/wikipedia/en/thumb/c/cb/Eisai_logo.svg/1280px-Eisai_logo.svg.png" style="height: auto; max-width: 100%;" width="792" /></div>
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エリブリンメシル酸塩<br />
Eribulin Mesilate<br />
<a data-mce-href="http://jpdb.nihs.go.jp/jan/chemdraw5/Eribulin_Mesilate.cdx" href="http://jpdb.nihs.go.jp/jan/chemdraw5/Eribulin_Mesilate.cdx"><img alt="" data-mce-src="http://jpdb.nihs.go.jp/jan/gif/Eribulin_Mesilate.png" src="http://jpdb.nihs.go.jp/jan/gif/Eribulin_Mesilate.png" style="height: auto; max-width: 100%;" /></a><br />
C<sub>4</sub><sub>0</sub>H<sub>5</sub><sub>9</sub>NO<sub>1</sub><sub>1</sub><img alt="▪" class="emoji" data-mce-src="https://s.w.org/images/core/emoji/72x72/25aa.png" src="https://s.w.org/images/core/emoji/72x72/25aa.png" style="background-attachment: initial !important; background-clip: initial !important; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; border: none !important; box-shadow: none !important; display: inline !important; height: 1em !important; margin: 0px 0.07em !important; max-width: 100%; padding: 0px !important; vertical-align: -0.1em !important; width: 1em !important;" />CH<sub>4</sub>O<sub>3</sub>S : 826<br />
[441045-17-6]</div>
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Eribulin mesylate is the mesylate salt of a synthetic analogue of halichondrin B, a substance derived from a marine sponge (Lissodendoryx sp.) with antineoplastic activity.</div>
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E7389 is the mesylate salt of a synthetic analogue of <a class="pubchem-internal-link multiple-CIDs" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/halichondrin%20B" href="https://pubchem.ncbi.nlm.nih.gov/compound/halichondrin%20B" rel="nofollow">halichondrin B</a>, a substance derived from a marine sponge (Lissodendoryx sp.) with antineoplastic activity. <a class="pubchem-internal-link CID-11354606" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/Eribulin" href="https://pubchem.ncbi.nlm.nih.gov/compound/Eribulin">Eribulin</a> binds to the vinca domain of tubulin and inhibits the polymerization of tubulin and the assembly of microtubules, resulting in inhibition of mitotic spindle assembly, induction of cell cycle arrest at G2/M phase, and, potentially, tumor regression.</div>
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Halichondrin B, a large polyether macrolide, was isolated 25 years ago from the marine sponge Halichondria okadai</div>
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<img align="center" alt="Halichondria okadai" border="0" class="" data-mce-src="http://www.chm.bris.ac.uk/motm/eribulin/sponge.jpg" src="http://www.chm.bris.ac.uk/motm/eribulin/sponge.jpg" height="632" hspace="20" style="height: auto; max-width: 100%;" title="Halichondria okadai" width="840" /><img alt="Halaven.png" class="" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=17755248&t=l" height="878" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=17755248&t=l" style="height: auto; max-width: 100%;" width="878" /></div>
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ERBULIN</div>
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The anti-cancer drug made from a sea-sponge<b>Eribulin</b> is an anticancer drug marketed by <a data-mce-href="http://en.wikipedia.org/wiki/Eisai_Co." href="http://en.wikipedia.org/wiki/Eisai_Co." title="Eisai Co.">Eisai Co.</a> under the trade name <b>Halaven</b>. Eribulin <a data-mce-href="http://en.wikipedia.org/wiki/Mesylate" href="http://en.wikipedia.org/wiki/Mesylate" title="Mesylate">mesylate</a> was approved by the <a data-mce-href="http://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" href="http://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" title="U.S. Food and Drug Administration">U.S. Food and Drug Administration</a> on November 15, 2010, to treat patients with <a data-mce-href="http://en.wikipedia.org/wiki/Metastatic_breast_cancer" href="http://en.wikipedia.org/wiki/Metastatic_breast_cancer" title="Metastatic breast cancer">metastatic breast cancer</a> who have received at least two prior chemotherapy regimens for late-stage disease, including both <a data-mce-href="http://en.wikipedia.org/wiki/Anthracycline" href="http://en.wikipedia.org/wiki/Anthracycline" title="Anthracycline">anthracycline</a>- and <a data-mce-href="http://en.wikipedia.org/wiki/Taxane" href="http://en.wikipedia.org/wiki/Taxane" title="Taxane">taxane</a>-based <a data-mce-href="http://en.wikipedia.org/wiki/Chemotherapy" href="http://en.wikipedia.org/wiki/Chemotherapy" title="Chemotherapy">chemotherapies</a>.<sup id="cite_ref-1"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-1" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-1">[1]</a></sup> It was approved by <a data-mce-href="http://en.wikipedia.org/wiki/Health_Canada" href="http://en.wikipedia.org/wiki/Health_Canada" title="Health Canada">Health Canada</a> on December 14, 2011 for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. <sup id="cite_ref-2"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-2" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-2">[2]</a></sup></h3>
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Eribulin is also being investigated by Eisai Co. for use in a variety of other solid tumors, including <a data-mce-href="http://en.wikipedia.org/wiki/Non-small_cell_lung_cancer" href="http://en.wikipedia.org/wiki/Non-small_cell_lung_cancer" title="Non-small cell lung cancer">non-small cell lung cancer</a>, <a data-mce-href="http://en.wikipedia.org/wiki/Prostate_cancer" href="http://en.wikipedia.org/wiki/Prostate_cancer" title="Prostate cancer">prostate cancer</a> and <a data-mce-href="http://en.wikipedia.org/wiki/Sarcoma" href="http://en.wikipedia.org/wiki/Sarcoma" title="Sarcoma">sarcoma</a>.<sup id="cite_ref-3"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-3" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-3">[3]</a></sup></div>
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Eribulin has been previously known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389.</div>
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Eribulin mesylate is an analogue of halichondrin B, which in 1986 was isolated from the marine sponge Halichondria okadai toxic Pacific.Halichondrin B has a significant anti-tumor activity. The Eribulin synthetically obtained has a simpler but still complex molecular structure.Taxanes such as to inhibit the spindle apparatus of the cell, but it is engaged in other ways.</div>
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Drug substance, eribulin mesylate, is a It is a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondira okadai. Eribulin mesylate is a white powder which is freely soluble in water, methanol, ethanol, 1-octanol, benzyl alcohol, dichloromethane, dimethylsulfoxide, N-methylpyrrolidone and ethyl acetate. It is soluble in acetone, sparingly soluble in acetonitrile, and practically insoluble in tertbutyl methyl ether, n-heptane and n-pentane. Eribulin mesylate is characterized by ion chromatography for counter ion content, and spectroscopic analyses (mass, ultraviolet, nuclear magnetic resonance, single crystal X-ray crystallography, and circular dichroism) for molecular structure and absolute configuration. Bulk drug substance is hygroscopic and sensitive to light, heat, and acid hydrolysis,,,,,,........<a data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201532orig1s000chemr.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201532orig1s000chemr.pdf">http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201532orig1s000chemr.pdf</a></div>
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Melvin Yu received his B.S. from MIT, and both his M.A. and Ph.D. degrees from Harvard University while studying under Professor Yoshito Kishi. In 1985, he joined Eli Lilly, and in 1993 he relocated to Eisai Inc. where he led the chemistry team that discovered Halaven . He was then responsible for the initial route nding and synthesis scale-up effort that ultimately provided the rst multi-gram batch of eribulin mesylate. Mel retains a strong interest in natural products as the inspiration of new chemotherapeutic agents, and in this context recently expanded his area of research to include cheminformatics and compound library design.</div>
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Wanjun Zheng received a Ph.D. in organic chemistry from Wesleyan University in 1994 under the direction of Professor Peter A. Jacobi working on synthetic methodology development and its application in natural product synthesis. He spent over two years as a postdoctoral research fellow in Harvard University under Professor Yoshito Kishi working on the complete structure determination of maitotoxin. He joined Eisai in 1996 and has since been contributing and leading many drug discovery projects including project in the discovery of Halaven .</div>
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Boris M. Seletsky earned his PhD in 1987 from Shemyakin Institute of Bioorganic Chemistry in Moscow, Russia working on new methods in steroid synthesis under direction of Dr George Segal and Professor Igor Torgov. Aer several years of natural product research at the same Institute, he moved on to postdoctoral studies in stereoselective synthesis with Professor Wolfgang Oppolzer at the University of Geneva, Switzerland, and Professor James A. Marshall at the University of South Carolina. Boris joined Eisai in 1994, and has contributed to many oncology drug discovery projects with considerable focus on natural products as chemical leads, culminating in the discovery of Halaven .</div>
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PAPER</div>
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<a data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X">http://www.sciencedirect.com/science/article/pii/S0960894X0401100X</a></div>
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<a class="cLink" data-mce-href="http://www.sciencedirect.com/science/journal/0960894X" href="http://www.sciencedirect.com/science/journal/0960894X" title="Go to Bioorganic & Medicinal Chemistry Letters on ScienceDirect">Bioorganic & Medicinal Chemistry Letters</a></div>
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<a class="S_C_volIss" data-mce-href="http://www.sciencedirect.com/science/journal/0960894X/14/22" href="http://www.sciencedirect.com/science/journal/0960894X/14/22" title="Go to table of contents for this volume/issue">Volume 14, Issue 22</a>, 15 November 2004, Pages 5551–5554</div>
<h1 class="svTitle" id="" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Macrocyclic ketone analogues of halichondrin B</h1>
<div class="dedicated" id="" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
This paper is dedicated to memory of Bruce F. Wels, our friend and colleague</div>
<ul class="authorGroup noCollab svAuthor" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999a8b8">Wanjun Zheng</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999a948">Boris M. Seletsky</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999a9d8">Monica H. Palme</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999aa68">Paul J. Lydon</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999aaf8">Lori A. Singer</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999ab88">Charles E. Chase</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999ac18">Charles A. Lemelin</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999b9f0">Yongchun Shen</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999ba80">Heather Davis</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999bb10">Lynda Tremblay</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999bba0">Murray J. Towle</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" id="baff2" title="Affiliation: b"><sup>b</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999bc30">Kathleen A. Salvato</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" id="baff2" title="Affiliation: b"><sup>b</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999bcc0">Bruce F. Wels</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" id="baff2" title="Affiliation: b"><sup>b</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999bd50">Kimberley K. Aalfs</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" id="baff2" title="Affiliation: b"><sup>b</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999bde0">Yoshito Kishi</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff3" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff3" id="baff3" title="Affiliation: c"><sup>c</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999be70">Bruce A. Littlefield</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff2" id="baff2" title="Affiliation: b"><sup>b</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#" id="authname_N8972e5e0N8999bf00">Melvin J. Yu</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#aff1" id="baff1" title="Affiliation: a"><sup>a</sup></a><sup>, </sup><a class="intra_ref auth_corr" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#cor1" href="http://www.sciencedirect.com/science/article/pii/S0960894X0401100X#cor1" id="bcor1" title="Corresponding author contact information"></a><sup>,</sup></li>
</ul>
<ul class="affiliation authAffil smh" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li class="smh5plus" id="aff1"><sup>a</sup> <span id="">Department of Medicinal Chemistry, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA</span></li>
<li class="smh5plus" id="aff2"><sup>b</sup> <span id="">Department of Anticancer Research, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA</span></li>
<li class="smh5plus" id="aff3"><sup>c</sup> <span id="">Advisory Board, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA</span></li>
</ul>
<dl class="extLinks nonEmpty" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><dd class="doiLink"></dd><dd class="doi"><a class="S_C_ddDoi" data-mce-href="http://dx.doi.org/10.1016/j.bmcl.2004.08.069" href="http://dx.doi.org/10.1016/j.bmcl.2004.08.069" id="ddDoi" target="doilink">doi:10.1016/j.bmcl.2004.08.069</a></dd><dd class="doi"><img alt="Image for unlabelled figure" data-mce-src="http://ars.els-cdn.com/content/image/1-s2.0-S0960894X0401100X-fx1.jpg" src="http://ars.els-cdn.com/content/image/1-s2.0-S0960894X0401100X-fx1.jpg" style="height: auto; max-width: 100%;" /></dd></dl>
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PAPER</div>
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From micrograms to grams: scale-up synthesis of eribulin mesylate</h2>
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<span class="author_link"><a data-mce-href="http://pubs.rsc.org/is/results?searchtext=Author%3AMelvin%20J.%20Yu" href="http://pubs.rsc.org/is/results?searchtext=Author%3AMelvin%20J.%20Yu">Melvin J. Yu</a>,*<sup>a</sup> </span> <span class="author_link"><a data-mce-href="http://pubs.rsc.org/is/results?searchtext=Author%3AWanjun%20Zheng" href="http://pubs.rsc.org/is/results?searchtext=Author%3AWanjun%20Zheng">Wanjun Zheng</a><sup>a</sup> and </span> <span class="author_link"><a data-mce-href="http://pubs.rsc.org/is/results?searchtext=Author%3ABoris%20M.%20Seletsky" href="http://pubs.rsc.org/is/results?searchtext=Author%3ABoris%20M.%20Seletsky">Boris M. Seletsky</a><sup>a</sup> </span></div>
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*Corresponding authors</div>
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<sup class="affiliation_sup">a</sup>Eisai Inc., Andover, USA<br />
<b>E-mail: </b><a data-mce-href="mailto:Melvin_Yu@eisai.com" href="mailto:Melvin_Yu@eisai.com" title="Melvin_Yu@eisai.com">Melvin_Yu@eisai.com</a></div>
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<i><strong>Nat. Prod. Rep.</strong></i>, 2013,<strong>30</strong>, 1158-1164</div>
<span class="DOILink"><strong>DOI: </strong>10.1039/C3NP70051H, <a data-mce-href="http://pubs.rsc.org/is/content/articlelanding/2013/np/c3np70051h#!divAbstract" href="http://pubs.rsc.org/is/content/articlelanding/2013/np/c3np70051h#!divAbstract">http://pubs.rsc.org/is/content/articlelanding/2013/np/c3np70051h#!divAbstract</a></span></div>
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Covering: 1993 to 2002<br />
The synthesis of eribulin mesylate from microgram to multi-gram scale is described in this<em>Highlight</em>. Key coupling reactions include formation of the C30a to C1 carbon–carbon bond and macrocyclic ring closure through an intramolecular Nozaki–Hiyama–Kishi reaction.<br />
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<img alt="Graphical abstract: From micrograms to grams: scale-up synthesis of eribulin mesylate" data-mce-src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=C3NP70051H" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=C3NP70051H" id="imgGALoader" style="height: auto; max-width: 100%;" title="Graphical abstract" /></div>
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<img alt="" data-mce-src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2013/NP/c3np70051h/c3np70051h-f6.gif" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2013/NP/c3np70051h/c3np70051h-f6.gif" style="height: auto; max-width: 100%;" />The synthesis of the C27–C35 tetrahydrofuran fragment.</div>
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<img alt="" data-mce-src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2013/NP/c3np70051h/c3np70051h-f7.gif" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2013/NP/c3np70051h/c3np70051h-f7.gif" style="height: auto; max-width: 100%;" />The synthesis of the C14–C21 aldehyde subfragment.</div>
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CLIP</div>
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In 1986, two Japanese chemists Hirata and Uemura<span data-mce-style="color: #ff0000;" style="color: red;"> [Y. Hirata, D. Uemura, <i>Pure Appl. Chem</i>. <b>58</b> (1986) 701.]</span> isolated a naturally-occurring compound from the marine sponge <i>Halichondria okadai</i> (picture above, right). The compound was named <i><b>Halichondrin B</b></i>, and it immediately began to generate great excitement when it was realised that it was extremely potent at killing certain types of cancer cells in small-scale tests. As a result of this discovery, it was immediately given top priority to be tested against a wide range of other cancers, and became one of the first compounds to be evaluated using the novel <a data-mce-href="http://www.dtp.nci.nih.gov/branches/btb/ivclsp.html" href="http://www.dtp.nci.nih.gov/branches/btb/ivclsp.html">60-cell line method</a> developed by the US <a data-mce-href="http://www.cancer.gov/" href="http://www.cancer.gov/">National Cancer Institute</a> (NCI). In this technique, 60 different types of human tumor cells (including leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney) are tested with the potential anti-cancer molecule delivered at a single dose of 10 μM concentration. This process can be run in parallel, with dozens of different molecules being tested against all 60 cancer cell lines at the same time in a huge array. Any molecules which exhibit significant growth inhibition are prioritised, and the test repeated on them, but this time at five different concentration levels.</div>
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<a data-mce-href="http://www.chm.bris.ac.uk/motm/eribulin/halicB.mol" href="http://www.chm.bris.ac.uk/motm/eribulin/halicB.mol"><img align="middle" alt="Halichondrin B" border="0" data-mce-src="http://www.chm.bris.ac.uk/motm/eribulin/halicB.gif" src="http://www.chm.bris.ac.uk/motm/eribulin/halicB.gif" height="263" style="height: auto; max-width: 100%;" title="Halichondrin B - click for 3D structure file" width="595" /></a><br />
Halichondrin B - the part of the molecule used to make Eribulin is shown in blue.</div>
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</h2>
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Unfortunately, the concentration of Halichondrin B in the sea sponge wasn’t enough to enable commercial production for use in chemotherapy. For example, a ton of sea sponges could only produce 300 mg of Halichondrin B! The race was on to try to synthesise Halichondrin B in the lab, which wasn't easy due to its large size (molecular weight 1110) and complex structure. However, only 6 years later, chemists at Harvard University published the complete chemical synthesis of this molecule...........<span data-mce-style="color: #ff0000;" style="color: red;">T.D. Aicher, K.R. Buszek, F.G. Fang, C.J. Forsyth, S.H. Jung, Y. Kishi, M.C. Matelich, P.M. Scola, D.M. Spero, S.K. Yoon, <i>J. Am. Chem. Soc</i>. <b>114</b> (1992) 3162</span></div>
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Although this was a great achievement, Halichondrin B was still far too complex and the sythesis route too expensive to do on a large scale. The molecule needed to be stripped down to its essential components, while keeping, or even improving, its anti-cancer efficacy. Many tests were performed, but eventually the work led to te development of the structurally-simplified and pharmaceutically-optimized analog, which was named <b><i>Eribulin</i></b> [3,4]. Eribulin mesylate was approved by the U.S. Food and Drug Administration in 2010, to treat patients with metastatic breast cancer [5], and it is currently being marketed by <a data-mce-href="http://en.wikipedia.org/wiki/Eisai_Co." href="http://en.wikipedia.org/wiki/Eisai_Co.">Eisai Co.</a> under the trade name<b><i>Halaven</i></b> . It is also being investigated for use in a variety of other solid tumors, including lung cancer, prostate cancer and sarcoma .</div>
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<a data-mce-href="http://www.chm.bris.ac.uk/motm/eribulin/eribulin.mol" href="http://www.chm.bris.ac.uk/motm/eribulin/eribulin.mol"><img align="middle" alt="Eribulin" border="0" data-mce-src="http://www.chm.bris.ac.uk/motm/eribulin/eribulin.gif" src="http://www.chm.bris.ac.uk/motm/eribulin/eribulin.gif" height="314" style="height: auto; max-width: 100%;" title="Eribulin - click for 3D structure file" width="418" /></a>ERIBULIN</div>
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M.J. Towle, K.A. Salvato, J. Budrow, B.F. Wels, G. Kuznetsov, K.K. Aalfs, S. Welsh, W. Zheng, B.M. Seletsk, M.H. Palme, G.J. Habgood, L.A. Singer, L.V. Dipietro, Y. Wang, J.J. Chen, D.A. Quincy, A. Davis, K. Yoshimatsu, Y. Kishi, M.J. Yu, B.A. Littlefield, <i>Cancer Res.</i> <b>61</b> (2001) 1013.</div>
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M.J. Yu, Y. Kishi, B.A. Littlefield, in D.J. Newman, D.G.I. Kingston, G.M. Cragg, <i>Anticancer agents from natural products</i>, Washington, DC, Taylor and Francis (2005).</div>
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<a data-mce-href="http://healthmad.com/conditions-and-diseases/breast-cancer-cure-from-the-sea/" href="http://healthmad.com/conditions-and-diseases/breast-cancer-cure-from-the-sea/">http://healthmad.com/conditions-and-diseases/breast-cancer-cure-from-the-sea/</a></div>
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<a data-mce-href="http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389" href="http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389">http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389</a></div>
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M.A. Jordan, L. Wilson, <i>Nature Revs: Cancer</i> <b>4</b> (2004) 253.</div>
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ERIBULIN</div>
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Patent Data</h3>
<table border="0" cellpadding="3" class="mce-item-table" id="sample" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px; width: 940px;"><thead class="toprow">
<tr><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Appl No</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Prod No</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Patent No</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Patent<br />Expiration</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Drug Substance<br />Claim</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Drug Product<br />Claim</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Patent Use<br />Code</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Delist<br />Requested</b></th></tr>
</thead><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx">N201532</a></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top">001</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP">6214865</td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top">Jul 20, 2023</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><b>Y</b></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx">N201532</a></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top">001</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP">6469182</td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top">Jun 16, 2019</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><strong>U - 1096</strong></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx">N201532</a></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top">001</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP">7470720</td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top">Jun 16, 2019</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><b>Y</b></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx">N201532</a></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top">001</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP">8097648</td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top">Jan 22, 2021</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><strong>U - 1096</strong></td><td bgcolor="ffdab9" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"></td></tr>
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Exclusivity Data</h3>
<table border="0" cellpadding="3" class="mce-item-table" id="sample" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px; width: 940px;"><thead class="toprow">
<tr><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Appl No</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Prod No</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Exclusivity Code</b></th><th scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Exclusivity Expiration</b></th></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><b><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=201532&TABLE1=OB_Rx">N201532</a></b></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><b>001</b></td><td bgcolor="" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><strong>NCE</strong></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="TOP"><b>Nov 15, 2015</b></td></tr>
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The substance inhibits the polymerization of tubulin into microtubules and encapsulates tubulin molecules in non-productive aggregates from. The lack of training of the spindle apparatus blocks the mitosis and ultimately induces apoptosis of the cell. Eribulin differs from known microtubule inhibitors such as taxanes and vinca alkaloids by the binding site on microtubules, also it does not affect the shortening. This explains the effectiveness of the new cytostatic agent in taxane-resistant tumor cell lines with specific tubulin mutations.</div>
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<img alt="" data-mce-src="http://www.pharmafile.com/system/files/imagecache/news_full/eisai_halaven_eribulin_0.jpg" src="http://www.pharmafile.com/system/files/imagecache/news_full/eisai_halaven_eribulin_0.jpg" style="height: auto; max-width: 100%;" /></div>
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Structure and mechanism</h2>
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Structurally, eribulin is a fully synthetic macrocyclic ketone <a data-mce-href="http://en.wikipedia.org/wiki/Analog_(chemistry)" href="http://en.wikipedia.org/wiki/Analog_(chemistry)" title="Analog (chemistry)">analogue</a> of the marine sponge natural product <a data-mce-href="http://en.wikipedia.org/wiki/Halichondrin_B" href="http://en.wikipedia.org/wiki/Halichondrin_B" title="Halichondrin B">halichondrin B</a>,<sup id="cite_ref-pmid11221827_4-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid11221827-4" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid11221827-4">[4]</a></sup><sup id="cite_ref-isbn0-8493-1863-7_5-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-isbn0-8493-1863-7-5" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-isbn0-8493-1863-7-5">[5]</a></sup> the latter being a potent naturally-occurring <a data-mce-href="http://en.wikipedia.org/wiki/Mitotic_inhibitor" href="http://en.wikipedia.org/wiki/Mitotic_inhibitor" title="Mitotic inhibitor">mitotic inhibitor</a> with a unique <a data-mce-href="http://en.wikipedia.org/wiki/Mechanism_of_action" href="http://en.wikipedia.org/wiki/Mechanism_of_action" title="Mechanism of action">mechanism of action</a> found in the <i><a data-mce-href="http://en.wikipedia.org/wiki/Halichondria" href="http://en.wikipedia.org/wiki/Halichondria" title="Halichondria">Halichondria</a></i> genus of <a data-mce-href="http://en.wikipedia.org/wiki/Demosponge" href="http://en.wikipedia.org/wiki/Demosponge" title="Demosponge">sponges</a>.<sup id="cite_ref-Hirata_1986_6-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-Hirata_1986-6" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-Hirata_1986-6">[6]</a></sup><sup id="cite_ref-pmid1874739_7-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid1874739-7" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid1874739-7">[7]</a></sup> Eribulin is a mechanistically-unique <a data-mce-href="http://en.wikipedia.org/wiki/Microtubule#Chemical_effects_on_microtubule_dynamics" href="http://en.wikipedia.org/wiki/Microtubule#Chemical_effects_on_microtubule_dynamics" title="Microtubule">inhibitor of microtubule dynamics</a>,<sup id="cite_ref-pmid16020666_8-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid16020666-8" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid16020666-8">[8]</a></sup><sup id="cite_ref-pmid18645010_9-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid18645010-9" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid18645010-9">[9]</a></sup> binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.<sup id="cite_ref-pmid20030375_10-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid20030375-10" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid20030375-10">[10]</a></sup> Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade.<sup id="cite_ref-pmid15313917_11-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid15313917-11" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid15313917-11">[11]</a></sup><sup id="cite_ref-pmid21127197_12-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid21127197-12" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid21127197-12">[12]</a></sup></div>
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A new synthetic route to E7389 was published in 2009.<sup id="cite_ref-pmid19807076_13-0"><a data-mce-href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid19807076-13" href="http://en.wikipedia.org/wiki/Eribulin#cite_note-pmid19807076-13">[13]</a></sup></div>
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clip</div>
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<span class="patent-bibdata-value-list"><span class="patent-bibdata-value"><a data-mce-href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Eisai+R%26D+Management+Co.,+Ltd.%22" href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Eisai+R%26D+Management+Co.,+Ltd.%22">Eisai R&D Management Co., Ltd.</a></span></span></div>
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13/9/2013</div>
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Halaven is a novel anticancer agent discovered and developed in-house by Eisai and is currently approved in more than 50 countries, including Japan, the United States and in Europe. In Russia, Halaven was approved in July 2012 for the treatment of locally advanced or metastatic breast cancer previously treated with at least two chemotherapy regimens including an anthracycline and a taxane. Approximately 50,000 women in Russia are newly diagnosed with breast cancer each year, with this type of cancer being the leading cause of death in women aged 45 to 55 years. read all at.........................</div>
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<a data-mce-href="http://www.dddmag.com/news/2013/09/eisai-launches-halaven-cancer-drug-russia" href="http://www.dddmag.com/news/2013/09/eisai-launches-halaven-cancer-drug-russia">http://www.dddmag.com/news/2013/09/eisai-launches-halaven-cancer-drug-russia</a></div>
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<img alt="" data-mce-src="http://photos.prnewswire.com/prnvar/20120413/MM87168LOGO?max=400" src="http://photos.prnewswire.com/prnvar/20120413/MM87168LOGO?max=400" style="height: auto; max-width: 100%;" /></div>
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Eribulin mesylate (Halaven; Eisai) — a synthetic analogue of the marine natural product halichondrin B that interferes with microtubule dynamics — was approved in November 2010 by the US Food and Drug Administration for the treatment of metastatic breast cancer.</div>
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Family members of the product patent, WO9965894, have SPC protection in the EU until 2024 and one of its Orange Book listed filings, US8097648, has US154 extension till January 2021.</div>
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The drug also has NCE exclusivity till November 2015.</div>
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<img alt="" data-mce-src="http://images.ddccdn.com/pro/images/c73426c4-387c-4513-abd6-f8a4624845a0/halaven-03.jpg" src="http://images.ddccdn.com/pro/images/c73426c4-387c-4513-abd6-f8a4624845a0/halaven-03.jpg" height="189" id="il_fi" style="height: auto; max-width: 100%;" width="406" /></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
HALAVEN (eribulin mesylate) Injection is a non-taxane microtubule dynamics inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge <i>Halichondria okadai</i>. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt).<br />
It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C<sub>40</sub>H<sub>59</sub>NO<sub>11</sub> •CH<sub>4</sub>O<sub>3</sub>S. Eribulin mesylate has the following structural formula:<br />
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><img alt="HALAVEN® (eribulin mesylate) Structural Formula Illustration" data-mce-src="http://images.rxlist.com/images/rxlist/halaven1.gif" src="http://images.rxlist.com/images/rxlist/halaven1.gif" height="228" style="height: auto; max-width: 100%;" width="463" /></td></tr>
</tbody></table>
HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95).<br />
<a data-mce-href="http://www.sciencedirect.com/science/article/pii/S0968089611010674#gr6" href="http://www.sciencedirect.com/science/article/pii/S0968089611010674#gr6" title="Full-size image (23 K)"><img alt="Full-size image (23 K)" border="0" data-mce-src="http://ars.els-cdn.com/content/image/1-s2.0-S0968089611010674-gr6.sml" src="http://ars.els-cdn.com/content/image/1-s2.0-S0968089611010674-gr6.sml" height="111" style="height: auto; max-width: 100%;" width="219" /></a><br />
<a data-mce-href="http://www.sciencedirect.com/science/article/pii/S0968089611010674#fx1" href="http://www.sciencedirect.com/science/article/pii/S0968089611010674#fx1" title="Full-size image (15 K)"><img alt="Full-size image (15 K)" border="0" data-mce-src="http://ars.els-cdn.com/content/image/1-s2.0-S0968089611010674-fx1.sml" src="http://ars.els-cdn.com/content/image/1-s2.0-S0968089611010674-fx1.sml" height="143" id="gabsImg" style="height: auto; max-width: 100%;" width="439" /></a><br />
complete syn is available here<br />
<a data-mce-href="http://www.sciencedirect.com/science/article/pii/S0968089611010674" href="http://www.sciencedirect.com/science/article/pii/S0968089611010674">http://www.sciencedirect.com/science/article/pii/S0968089611010674</a><br />
<img alt="" data-mce-src="http://www.drugdevelopment-technology.com/projects/halaven-cancer/images/1-halaven.jpg" src="http://www.drugdevelopment-technology.com/projects/halaven-cancer/images/1-halaven.jpg" style="height: auto; max-width: 100%;" /><br />
<a data-mce-href="http://www.drugdevelopment-technology.com/projects/halaven-cancer/halaven-cancer1.html" href="http://www.drugdevelopment-technology.com/projects/halaven-cancer/halaven-cancer1.html">http://www.drugdevelopment-technology.com/projects/halaven-cancer/halaven-cancer1.html</a><br />
<img alt="" data-mce-src="http://focus-blog.pharmxplorer.at/wp-content/uploads/2009/12/eribulin.jpg" src="http://focus-blog.pharmxplorer.at/wp-content/uploads/2009/12/eribulin.jpg" height="349" style="height: auto; max-width: 100%;" width="360" /><br />
<table border="0" cellpadding="0" cellspacing="0" class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187); width: 387px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><img align="top" alt="" border="0" data-mce-src="http://www.pharmazeutische-zeitung.de/uploads/pics/pha-eribulin_3d-22_I_63459.jpg" src="http://www.pharmazeutische-zeitung.de/uploads/pics/pha-eribulin_3d-22_I_63459.jpg" height="225" style="height: auto; max-width: 100%;" width="387" /></td></tr>
<tr><td align="left" colspan="1" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><img alt="" border="0" data-mce-src="http://www.pharmazeutische-zeitung.de/clear.gif" src="http://www.pharmazeutische-zeitung.de/clear.gif" height="5" style="height: auto; max-width: 100%;" title="" width="1" /><br />
<div>
Nitrogen: dark blue, oxygen: red, hydrogen: light blue<br />
graphics: Wurglics, Frankfurt am Main</div>
</td></tr>
</tbody></table>
clip<br />
Macrocyclization process for preparing a macrocyclic intermediate of halichondrin B analogs, in particular eribulin, from a non-macrocyclic compound, using a carbon-carbon bond-forming reaction.<br />
<img alt="" data-mce-src="http://www.pnas.org/content/108/17/6699/F1.large.jpg" src="http://www.pnas.org/content/108/17/6699/F1.large.jpg" height="145" style="height: auto; max-width: 100%;" width="461" /><br />
<a data-mce-href="http://www.pnas.org/content/108/17/6699/F1.expansion.html" href="http://www.pnas.org/content/108/17/6699/F1.expansion.html">http://www.pnas.org/content/108/17/6699/F1.expansion.html</a><br />
<img alt="" data-mce-src="http://www.nature.com/nrd/journal/v8/n1/images/nrd2487-f6.jpg" src="http://www.nature.com/nrd/journal/v8/n1/images/nrd2487-f6.jpg" height="457" style="height: auto; max-width: 100%;" width="288" /><br />
<a data-mce-href="http://www.nature.com/nrd/journal/v8/n1/fig_tab/nrd2487_F6.html" href="http://www.nature.com/nrd/journal/v8/n1/fig_tab/nrd2487_F6.html">http://www.nature.com/nrd/journal/v8/n1/fig_tab/nrd2487_F6.html</a><br />
UPDATED<br />
<span class="dataTableCaption">WO 2015066729</span><br />
Eisai has developed and launched eribulin mesylate for treating breast cancer. Follows on from WO2014208774, claiming use of a combination comprising eribulin mesylate and lenvatinib mesylate, for treating cancer.</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin B</h2>
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<div class="detailWho">
<span class="detailWhoLabel">By: </span>Fang, Francis G.; Kim, Dae-Shik; Choi, Hyeong-Wook; Chase, Charles E.; Lee, Jaemoon</div>
<div class="detailWho">
<span class="detailWhoLabel">Assignee:</span> Eisai R&D Management Co., Ltd., Japan</div>
</div>
<div class="abstract" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compds. useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for prepg. the same.</div>
<div class="abstract" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
CLIPS</div>
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<a data-mce-href="http://www.chemistry-blog.com/2012/09/15/from-natural-product-to-pharmaceutical/" href="http://www.chemistry-blog.com/2012/09/15/from-natural-product-to-pharmaceutical/">http://www.chemistry-blog.com/2012/09/15/from-natural-product-to-pharmaceutical/</a></div>
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In a recent discussion (<a data-mce-href="http://pipeline.corante.com/archives/2012/09/11/nicolaou_moving_others.php" href="http://pipeline.corante.com/archives/2012/09/11/nicolaou_moving_others.php">Nicolau</a>), about the suggested move of Prof. NicoIau from Scripps, the issue of the practicality of natural product total synthesis was raised. Here is a wonderful example of just that very usefulness, a wonderful piece of science extending over many years. It concerns the journey from Halichondrin B to Eribulin (E7389) a novel anti-cancer drug. The two compounds have the following structures:</div>
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<a data-mce-href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/Halichondrin.jpg" href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/Halichondrin.jpg"><img alt="" class="aligncenter wp-image-7887" data-mce-src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/Halichondrin.jpg" src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/Halichondrin.jpg" height="510" style="display: block; height: auto; margin-left: auto; margin-right: auto; max-width: 100%;" width="488" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
I think you can see the relationship and as a development chemist I am glad they managed to simplify things (a bit).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Both compounds have an enormous number of possible isomers: Halichondrin B, with 32 stereocenters has 2<sup>32</sup>possible isomers; Eribulin has 19 with 2<sup>19</sup> isomers (if I have counted correctly, it does not really matter, there are lots of isomers). Remarkable is the fact that only one of these isomers is active in the given area of anti-cancer agents.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
An excellent review of the biology and chemistry of these compounds has been published by Phillips etal<sup>1</sup>. This review is an excellent read and is to be commended. Another one written by Kishi<sup>2</sup>, is also full of information about the discovery of E7389 and I hope you will all get a chance to read this chapter.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The history of Halichondrin B goes back to 1987 when Blunt<sup>2-5</sup> isolated it with other similar compounds from extraction of 200Kg of a sponge. Independently Pettit isolated the same compound from a different species<sup>4</sup>. The appearance of this compound in different species of sponge may indicate that it is produced by a symbiote.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The biological activity of Halichondrin B is amazing. When evaluated against B-16 melanoma cells it was found to have an IC<sub>50</sub> of 0.093ng/mL. Against various cancers, generated in mice, it was shown to be affective at a daily dose of 5ug/kg, which resulted in a doubling of the survival rate. It has also been demonstrated that Halichondrin acts as a microtubule destabiliser and mitoitic spindle poison. It was proven that it is has tremendous <em>in vivo</em> activity against a variety of drug resistant cancers, lung, colon, breast, ovarian to mention a few. Consequently the National Cancer Institute selected it for pre-clinical trials and it’s here that the problems began. According to reference 1 the <em>entire</em> clinical development would require some <em>10g</em>, and if successful the annual production amount would be between 1-5 kg. Blunt and co-workers managed to isolate 310mg from 1000kg-harvested sponge therefore, the only way to obtain the amounts required is total chemical synthesis. But synthesising 1-5 kg of such a compound would indeed be a mammoth task.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Kishi synthesised this compound<sup>7</sup> in 1992 starting from carbohydrate precursors employing the Nozaki-Hiyama-Kishi Ni/Cr reaction, several times, in the long synthetic sequence<sup>8, 9</sup>. Now as an aside I have used this reaction on scale several times and although it works well its success is very dependant upon the quality of the chromium source and also the presence of other trace transition metals.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
In collaboration with Eisai work on the SAR of Halichondrin began. They had a good start: Thanks to the total syntheses of Kishi several advanced intermediates were available for biological screening and one popped out of the screen as being very active:</div>
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<a data-mce-href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/lead.jpg" href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/lead.jpg"><img alt="" class="aligncenter wp-image-7911" data-mce-src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/lead.jpg" src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/lead.jpg" height="295" style="display: block; height: auto; margin-left: auto; margin-right: auto; max-width: 100%;" width="442" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The first active lead compound</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
As one can see the complete left hand side of Halichondrin has gone! However, this compound was not active <em>in vivo</em>. Many derivatives and analogues of this compound were prepared: furans, diols, ketones and so on and a lead emerged from this complex SAR study, ER-076349. The vicinal diol was used as a handle for further refinement and lead ultimately to E7389, the clinical candidate.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/two-leads.jpg" href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/two-leads.jpg"><img alt="" class="aligncenter wp-image-7893" data-mce-src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/two-leads-1024x468.jpg" src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/two-leads-1024x468.jpg" height="281" style="display: block; height: auto; margin-left: auto; margin-right: auto; max-width: 100%;" width="614" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
It can be synthesised in around 35 steps from simple starting materials.</div>
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Going through all this work in a few sentences really belittles the tremendous amount of effort that went into discovery and development of this compound and the people involved are to be applauded for their dedication.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Kishi continues to optimise the synthesis of Eribulin as judged by a recent publication<sup>10</sup>. Where he describes an approach to the amino-alcohol-tetrahydrofuran part of Eribulin (top left fragment, compound 1 below). The retro-synthetic analysis is shown below. The numbering corresponds to that of Eribulin.</div>
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<a data-mce-href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/retro.jpg" href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/retro.jpg"><img alt="" class="aligncenter wp-image-7897" data-mce-src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/retro-1024x730.jpg" src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/retro-1024x730.jpg" height="438" style="display: block; height: auto; margin-left: auto; margin-right: auto; max-width: 100%;" width="614" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The first generation synthesis consisted of 20 steps and delivered compound 1 about 5% yield, the second-generation route was completed in <em>12 steps with a yield of 48%</em>. One of the highlights includes a remarkable asymmetric hydrogenation<sup>11</sup> with Crabtree’s catalyst<sup>12</sup>:</div>
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<a data-mce-href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/hydrog1.jpg" href="http://www.chemistry-blog.com/wp-content/uploads/2012/09/hydrog1.jpg"><img alt="" class="aligncenter wp-image-7900" data-mce-src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/hydrog1.jpg" src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/hydrog1.jpg" height="271" style="display: block; height: auto; margin-left: auto; margin-right: auto; max-width: 100%;" width="563" /></a></div>
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This selectivity was not just luck; it seems to quite general, at least in this system. I always wonder how long it took them to stumble across this catalyst, but then I suppose that Eisai like most of the large pharma. companies has a hydrogenation group that probably indulges in catalyst screening.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The C34-C35 diol was obtained by a Sharpless asymmetric hydroxylation, here the diastereoisomeric ratio was not very high, only about 3:1 in favour of the desired isomer. Fortunately the undesired isomer could be removed<em>completely</em> by crystallisation.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
This is a remarkable story and references 1 and 2 are worth reading to obtain the complete picture and learn lots of new chemistry as well. Eisai filed a NDA and the FDA approved the compound in 2010 for the treatment of metastatic breast cancer.</div>
<div class="abstract" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/retro.jpg" src="http://www.chemistry-blog.com/wp-content/uploads/2012/09/retro.jpg" style="height: auto; max-width: 100%;" /></div>
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Patent</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/WO2013142999A1?cl=en" href="https://www.google.com/patents/WO2013142999A1?cl=en">https://www.google.com/patents/WO2013142999A1?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
EXAM PLE 23 : Preparation of Eribulin :</div>
<div class="patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentimages.storage.googleapis.com/WO2013142999A1/imgf000049_0001.png" href="https://patentimages.storage.googleapis.com/WO2013142999A1/imgf000049_0001.png"><img alt="Figure imgf000049_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2013142999A1/imgf000049_0001.png" height="128" id="imgf000049_0001" src="https://patentimages.storage.googleapis.com/WO2013142999A1/imgf000049_0001.png" style="height: auto; max-width: 100%;" width="528" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
[00120] Compound E-12A (133 mg, 160 μηιοΙ, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL) and cooled to 0 °C. To this solution was sequentially added 2,6-lutidine (0.09 m L, 0.8 mmol, 5.0 eq), and trimethyl silyl triflate (TMSOTf) (0.12 m L, 0.64 mmol, 4.0 eq) and the cooling bath was removed . The reaction was stirred at room temperature for 1.5 hours and another portion of 2,6-lutidine (5.0 eq) and TMSOTf (4.0 eq) were added at room temperature. The reaction was further stirred for 1 hour and quenched with water (10 m L). The layers were separated and the organic phase was washed with additional water (2x 10 m L), brine (10 m L), dried over MgS0<sub>4</sub> and concentrated under reduced pressure. The residue was dissolved in MeOH (10 m L), a catalytic amount of K<sub>2</sub>C0<sub>3</sub> was added at room temperature and the resulting mixture was stirred for 2 hours. The reaction was diluted with dichloromethane and quenched with water (10 mL). The layers were separated and the aqueous phase was further extracted with dichloromethane (5 x 10 m L). The combined organic layers were washed with brine (20 m L), dried over MgS0<sub>4</sub>, filtered and concentrated. The residue was dissolved in dichloromethane and purified by column chromatography on silica gel, using 1 : 9 MeOH : CH<sub>2</sub>CI<sub>2</sub> to 1 : 9 : 90 N H<sub>4</sub>OH : MeOH : CH<sub>2</sub>CI<sub>2</sub> as eluent. The product was afforded as a white amorphous solid (103 mg, 88%) . [00121] EXAMPLE 23 : Preparation of compound of formula 4a</div>
<div class="patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentimages.storage.googleapis.com/WO2013142999A1/imgf000050_0001.png" href="https://patentimages.storage.googleapis.com/WO2013142999A1/imgf000050_0001.png"><img alt="Figure imgf000050_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2013142999A1/imgf000050_0001.png" height="96" id="imgf000050_0001" src="https://patentimages.storage.googleapis.com/WO2013142999A1/imgf000050_0001.png" style="height: auto; max-width: 100%;" width="484" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
D-Gulonolactone 4a</div>
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[00122] The compound of formula 4a was prepared from D-Gulonolactone according to the conditions described in PCT publication number WO 2005/118565. [00123] EXAMPLE 24: Preparation of Eribulin mesylate (3)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
[00124] Eribulin mesylate (3) was prepared from Eribulin according to the conditions described in US patent application publication number US</div>
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2011/0184190.</div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/EP2528914A1?cl=en" href="https://www.google.com/patents/EP2528914A1?cl=en">https://www.google.com/patents/EP2528914A1?cl=en</a></div>
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Halichondrin B analogs, e.g., eribulin or pharmaceutically acceptable salts thereof, can be synthesized from the C14-C35 fragment as described in U.S. Patent No. 6,214,865 and International Publication No. WO 2005/118565. In one example described in these references, the C14-C35 portion, e.g., ER- 804028, of the molecule is coupled to the C1-C13 portion, e.g., ER-803896, to produce ER-804029, and additional reactions are carried out to produce eribulin (Scheme 1):</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2011094339A1/imgf000022_0001.png" href="https://patentimages.storage.googleapis.com/WO2011094339A1/imgf000022_0001.png"><img alt="Figure imgf000022_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2011094339A1/imgf000022_0001.png" height="740" id="imgf000022_0001" src="https://patentimages.storage.googleapis.com/WO2011094339A1/imgf000022_0001.png" style="height: auto; max-width: 100%;" width="524" /></a></div>
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Scheme 1</div>
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eribulin, eribulin mesylate</div>
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Scheme 2</div>
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ER-804028</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2011094339A1/imgf000042_0001.png" href="https://patentimages.storage.googleapis.com/WO2011094339A1/imgf000042_0001.png"><img alt="Figure imgf000042_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2011094339A1/imgf000042_0001.png" height="156" id="imgf000042_0001" src="https://patentimages.storage.googleapis.com/WO2011094339A1/imgf000042_0001.png" style="height: auto; max-width: 100%;" width="564" /></a></div>
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Compound AE (280 mg, 0.281 mmol, 1 eq) was dissolved in CH<sub>2</sub>C1<sub>2</sub> and cooled to 0 °C. Pyridine (0.045 ml, 0.56 mmol, 2.0 eq) was added followed by Ms<sub>2</sub>0 (58.8 mg, 0.338 mmol, 1.20 eq). The reaction was allowed to warm to room temperature, and stirring was continued for an additional 1 h. The reaction mixture was cooled to 0 °C, diluted with MTBE (5.6 ml), washed with saturated NaHC0<sub>3</sub> (0.84 g), and concentrated to give crude product as colorless film. The crude was azeotropically dried with heptane (3 ml <sup>χ</sup> 2) and re-dissolved in THF (7.0 ml). The mixture was cooled to 0 °C and treated with 25 wt% NaOMe (0.13 ml). After 10 min, the reaction was allowed to warm to room temperature, and stirring was continued for an additional 30 min. The mixture was treated with additional 25 wt% NaOMe (0.045 ml), and stirring was continued for an additional 20 min. The reaction mixture was diluted with heptane (7.0 ml) and washed with water (1.4 ml). The organic layer was separated, sequentially washed with: 1) 20 wt% NH<sub>4</sub>C1 (0.84 g) and 2) 20 wt% NaCl (3 g), and concentrated to give crude product as brownish oil. The crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-MTBE 2:3 v/v) to give ER-804028 (209 mg, 0.245 mmol, 87%) as pale yellow oil. 1H NMR (400 MHz, CDC1<sub>3</sub>): δ 7.89 (2H, m), 7.64 (IH, m), 7.56 (2H, m), 4.85 (IH, d, J= 1.6 Hz), 4.80 (IH, s), 4.72 (IH, s), 4.61 (IH, d, J= 1.6 Hz), 4.23 (IH, br), 3.91 (IH, m), 3.79 (IH, m), 3.76 (2H, m), 3.63 (IH, m), 3.50-3.60 (4H, m), 3.43 (IH, dd, J= 5.6 Hz, 10.0 Hz), 3.38 (3H, s), 3.32 (IH, m), 2.98 (2H, m), 2.61 (IH, br), 2.56 (IH, m), 2.50 (IH, m), 2.08-2.22 (3H, m), 1.96 (IH, m), 1.84 (IH, m), 1.78 (IH, m), 1.70 (IH, m), 1.42-1.63 (6H, m), 1.28-1.42 (2H, m), 1.01 (3H, d, J= 6.8 Hz), 0.84 (18H, s), 0.05 (3H, s), 0.04 (3H, s), 0.00 (3H, s), -0.01 (3H, s); and <sup>13</sup>C NMR (100 MHz, CDC1<sub>3</sub>): δ 150.34, 150.75, 139.91, 134.18, 129.73 (2C), 128.14 (2C), 105.10, 85.97, 80.92, 79.72, 78.50, 77.45, 77.09, 75.53, 71.59, 68.04, 62.88, 58.27, 57.73, 43.51, 42.82, 39.16, 37.68, 35.69, 33.31, 32.41, 31.89, 31.48, 29.79, 26.21 (3C), 26.17 (3C), 18.58, 18.38, 18.13, -3.85, - 4.71, -5.12 (2C).</div>
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CLIP</div>
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Eribulin mesylate (Halaven)<br />
Eribulin is a highly potent cytotoxic agent approved in the US for the treatment of metastatic breast cancer for patients who have<br />
received at least two previous chemotherapeutic regimens.30 Eribulin was discovered and developed by Eisai and it is currently<br />
undergoing clinical evaluation for the treatment of sarcoma (PhIII) and non-small cell lung cancer which shows progression after platinum-based chemotherapy and for the treatment of prostate cancer (PhII). Early stage clinical trials are also underway to evaluate<br />
eribulin’s efficacy against a number of additional cancers. Eribulin is a structural analog of the marine natural product halichondrin B.<br />
Its mechanism of action involves the disruption of mitotic spindle formation and inhibition of tubulin polymerization which results<br />
in the induction of cell cycle blockade in the G2/M phase and apoptosis.31 Several synthetic routes for the preparation of eribulin have<br />
been disclosed,32–35 each of which utilizes the same strategy described by Kishi and co-workers for the total synthesis of halichondrin B.36 Although the scales of these routes were not disclosed in all cases, this review attempts to highlight what appears to be the production-scale route based on patent literature.37,38 Nonetheless, the synthesis of eribulin represents a significant accomplishment in the field of total synthesis and brings a novel chemotherapeutic option to cancer patients.<br />
The strategy to prepare eribulin mesylate (V) employs a convergent synthesis featuring the following: the late stage coupling of<br />
sulfone 22 and aldehyde 23 followed by macrocyclization under Nozaki–Hiyami–Kishi coupling conditions, formation of a challenging<br />
cyclic ketal, and installation of the primary amine (Scheme 5).Sulfone 22 was further simplified to aldehyde 24 and vinyl triflate 25 which were coupled through a Nozaki–Hiyami–Kishi reaction.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-37.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-37.jpg" rel="attachment wp-att-8198"><img alt="STR1" class="alignnone size-full wp-image-8198" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-37.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-37.jpg" height="318" style="height: auto; max-width: 100%;" width="571" /></a> <a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-6.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-6.jpg" rel="attachment wp-att-8199"><img alt="STR2" class="alignnone size-full wp-image-8199" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-6.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-6.jpg" height="547" style="height: auto; max-width: 100%;" width="515" /></a><br />
The schemes that follow will describe the preparation of fragments 23, 24 and 25 along with how the entire molecule was assembled.<br />
The synthesis of the C1–C13 aldehyde fragment 23 is described in Scheme 6. L-Mannonic acid-lactone 26 was reacted with cyclohexanone in p-toluene sulfonic acid (p-TSA) to give the biscyclohexylidene ketal 27 in 84% yield. Lactone 27 was reduced with<br />
diisobutylaluminum hydride (DIBAL-H) to give lactol 28 followed by condensation with the ylide generated from the reaction of<br />
methoxymethylene triphenylphosphorane with potassium tertbutoxide to give a mixture of E and Z vinyl ethers 29 in 81% yield.<br />
Dihydroxylation of the vinyl ether of 29 using catalytic osmium teteroxide and N-methylmorpholine-N-oxide (NMO) with concomitant cyclization produced diol 30 in 52% yield. Bis-acetonide 30 was then reacted with acetic anhydride in acetic acid in the presence of ZnCl2 which resulted in selective removal of the pendant ketal protecting group. These conditions also affected peracylation, giving rise to tetraacetate 31 in 84% yield. Condensation of 31 with methyl 3-(trimethylsilyl)pent-4-enoate in the presence of boron trifluoride etherate in acetonitrile provided alkene 32. Saponification conditions using Triton B(OH) removed the acetate protecting groups within 32 and presumably induced isomerization of the alkene into conjugation with the terminal ester, triggering an intramolecular Michael attack of the 2-hydroxyl group, ultimately resulting in the bicylic-bispyranyl diol methyl ester 33 as a crystalline solid in 38% yield over two steps. Oxidative cleavage of the vicinal diol of 33 with sodium periodate gave aldehyde 34 which was coupled to (2-bromovinyl)trimethylsilane under Nozaki–Hiyami–Kishi conditions to give an 8.3:1 mixture of allyl alcohols 35 in 65% yield over two steps. Hydrolysis of the cyclohexylidine ketal 35 with aqueous acetic acid followed by recrystallization gave diastereomerically pure triol 36 which was reacted with tert-butyldimethylsilyl triflate (TBSOTf) to afford the tris-TBS ether 37 in good yield. Vinyl silane 37 was treated with NIS and catalytic tert-butyldimethylsilyl chloride (TBSCl) to give vinyl iodide 38 in 90% yield.<br />
Reduction of the ester with DIBAL-H produced the key C1–C14 fragment 23 in 93% yield.<br />
The preparation of the tetra-substituted tetrahydrofuran intermediate 24 is described in Scheme 7. D-Glucurono-6,3-lactone<br />
39 was reacted with acetone and sulfuric acid to give the corresponding acetonide and the 5-hydroxyl group was then removed by converting it to its corresponding chloride through reaction with sulfuryl chloride (SO2Cl2) followed by hydrogenolysis<br />
to give lactone 40 in good overall yield. Reduction of the lactone 40 with DIBAL-H gave the corresponding lactol which was condensed<br />
with (trimethylsilyl)methylmagnesium chloride to afford silane 41. Elimination of the silyl alcohol of 41 was accomplished<br />
under Peterson conditions with potassium hexamethyldisilazide (KHMDS) to afford the corresponding terminal alkene in 94% yield.<br />
The secondary alcohol of this intermediate was alkylated with benzyl bromide to afford ether 42 in 95% yield. Asymmetric dihydroxylation of the alkene of 42 under modified Sharpless conditions using potassium osmate (VI) dehydrate (K2OsO4), potassium<br />
ferricyanide (K3Fe(CN)6) and the (DHQ)2AQN ligand produced the vicinal diol which was then reacted with benzoyl chloride,<br />
N-methylmorpholine, and DMAP to give di-benzoate 43 in excellent yield as a 3:1 mixture of diastereomeric alcohols. Allyl trimethylsilane was added to the acetal of 43 using TiCl3(OiPr) as the Lewis acid to give 44 in 83% yield. Re-crystallization of 44 from<br />
isopropanol and n-heptane afforded 44 in >99.5% de in 71% yield.<br />
Oxidation of the secondary alcohol of 44 under the modified Swern conditions generated the corresponding ketone which was condensed with the lithium anion of methyl phenyl sulfone to give a mixture of E and Z vinyl sulfones 45. Debenzylation of 45 using iodotrimethylsilane (TMSI) followed by chelation-controlled reduction of the vinyl sulfone through reaction with NaBH(OAc)3, and<br />
then basic hydrolysis of the benzoate esters using K2CO3 in MeOH resulted in triol 46 as a white crystalline solid in 57% yield over the<br />
five steps after re-crystallization. The vicinal diol of 46 was protected as the corresponding acetonide through reaction with 2,2-<br />
dimethoxypropane and sulfuric acid and this was followed by methyl iodide-mediated methylation of the remaining hydroxyl<br />
group to give methyl ether 47. The protecting groups within acetonide 47 were then converted to the corresponding bis-tert-butyldimethylsilyl ether by first acidic removal of the acetonide with aqueous HCl and reaction with TBSCl in the presence of imidazole to give bis-TBS ether 48. Then, ozonolysis of the olefin of 48 followed by hydrogenolysis in the presence of Lindlar catalyst afforded the key aldehyde intermediate 24 in 68% yield over the previous five steps after re-crystallization from heptane.<br />
Two routes to the C14–C26 fragment 25 will be described as both are potentially used to prepare clinical supplies of eribulin.<br />
The first route features a convergent and relatively efficient synthesis of 25, however it is limited by the need to separate enantiomers<br />
and mixture of diastereomers via chromatographic methods throughout the synthesis.37 The second route to 25 is a<br />
much lengthier synthesis from a step-counting perspective; however it takes full advantage of the chiral pool of starting materials<br />
and requires no chromatographic separations and all of the products were carried on as crude oils until they could be isolated as<br />
crystalline solids.38 The first route to fragment 25 is described in Scheme 8 and was initiated by the hydration of 2,3-dihydrofuran (49) using an aqueous suspension of Amberlyst 15 to generate the intermediate tetrahydro-2-furanol (50) which was then immediately reacted with 2,3-dibromopropene in the presence of tin and catalytic HBr to afford diol 51 in 45% for the two steps.</div>
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The primary alcohol of 51 was selectively protected as its tert-butyldiphenylsilyl ether using TBDPSCl and imidazole and the racemate was then separated using simulated moving bed (SMB) chromatography to give enantiopure 52 in 45% yield over the two steps. The secondary alcohol of 52 was reacted with p-toluenesulfonyl chloride and DMAP to give tosylate 53 in 78% yield which was used as a coupling partner later in the synthesis of this fragment. The synthesis of the appropriate coupling partner was initiated by condensing diethylmalonate with (R)-2-(3-butenyl)oxirane (54), followed by decarboxylation to give lactone 55 in 71% yield for the two step process. Methylation of the lactone with LHMDS and MeI provided 56 in 68% yield as a 6:1 mixture of diastereomers. The lactone 56 was reacted with the aluminum amide generated by the reaction of AlMe3 and N,O-dimethylhydroxylamine to give the corresponding Weinreb amide which was protected as its tert-butyldimethylsilyl ether upon reaction with TBSCl and imidazole to give 57 in 91% yield over the two steps. Dihydroxylation of the olefin of 57 by reaction with OsO4 and NMO followed by oxidative cleavage with NaIO4 gave the desired coupling partner aldehyde 58 in 93% yield. Aldehyde 58 was coupled with vinyl bromide 53 using an asymmetric Nozaki–Hiyami– Kishi reaction using CrCl2, NiCl2, Et3N and chiral ligand 66 (described in Scheme 9 below). The reaction mixture was treated with ethylene diamine to remove the heavy metals and give the secondary alcohol 59. This alcohol was stirred with silica gel in isopropanol to affect intramolecular cyclization to give the tetrahydrofuran 60 in 48% yield over the three step process. The Weinreb amide of 60 was reacted with methyl magnesium chloride to generate the corresponding methyl ketone which was converted to vinyl triflate 61 upon reaction with KHMDS and Tf2NPh. De-silylation of the primary and secondary silyl ethers with methanolic HCl gave the corresponding diol in 85% yield over two steps and the resulting mixture of diastereomers was separated using preparative HPLC to provide the desired diastereomer in 56% yield. The primary alcohol was protected as its pivalate ester with the use of pivaloyl chloride, DMAP and collidine; the secondary alcohol was converted to a mesylate upon treatment with methanesulfonyl chloride (MsCl) and Et3N to give the C15–C27 fragment 25 in high yield.<br />
The preparations of the chiral ligand 66 used in the coupling reaction in Scheme 8 along with the chiral ligand 67 utilized later<br />
in the synthesis are described in Scheme 9. 2-Amino-3-methylbenzoic acid (62) was reacted with triphosgene to give benzoxazine<br />
dione 63 in 97% yield, which then was reacted with either D- or L-valinol in DMF followed by aqueous LiOH to give alcohols 64<br />
and 65, respectively in 65–75% yield for the two steps. Reaction of alcohol 64 or 65 with MsCl in the presence of DMAP effected formation of the dihydrooxazole ring and mesylation of the aniline to give the corresponding (R)-ligand 66 derived from D-valinol or the (S)-ligand 67 derived from L-valinol, respectively in high yield.<br />
An alternative route to intermediate 25 is described in Scheme 10 and although much lengthier than the route described in<br />
Scheme 8, it avoids chromatographic purifications as all of the products are carried on crude until a crystalline intermediate<br />
was isolated and purified by re-crystallization. Quinic acid (68) was reacted with cyclohexanone in sulfuric acid to generate a protected<br />
bicyclic lactone in 73% yield and the resulting tertiary alcohol was protected as its trimethylsilyl ether 69. Reduction of the<br />
lactone 69 was accomplished with DIBAL-H and the resulting lactol was treated with acetic acid to remove the TMS group and the resulting compound was reacted with acetic anhydride, DMAP and Et3N to give bis-acetate 70 in 65% yield for the three steps after re-crystallization. Methyl 3-(trimethylsilyl)pent-4-enoate was coupled to the acetylated lactol 70 in the presence of boron trifluoride etherate and trifluoroacetic anhydride to give adduct 71 in 62% yield. The acetate of 71 was removed upon reaction with sodium methoxide in methanol and the resulting tertiary alcohol cyclized on to the isomerized enone alkene to give the fused pyran ring. Reduction of the methyl ester with lithium aluminum hydride provided pyranyl alcohol 72. Mesylation of the primary alcohol was followed by displacement with cyanide anion to give nitrile 73.<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-38.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-38.jpg" rel="attachment wp-att-8200"><img alt="STR1" class="alignnone size-full wp-image-8200" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-38.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-38.jpg" height="579" style="height: auto; max-width: 100%;" width="627" /></a> <a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-7.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-7.jpg" rel="attachment wp-att-8201"><img alt="STR2" class="alignnone size-full wp-image-8201" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-7.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-7.jpg" height="586" style="height: auto; max-width: 100%;" width="614" /></a></div>
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The nitrile was methylated upon reaction with KHMDS and MeI and the resulting product was purified by re-crystallization<br />
to provide nitrile 74 in 66% over the previous five steps in a 34:1 diastereomeric ratio. Acid hydrolysis of the ketal of 74 liberated<br />
the corresponding diol in 72% yield and this was reacted with 2-acetoxy-2-methylpropionyl bromide to give bromo acetate 75.<br />
Elimination of the bromide was accomplished upon treatment with 1,8-diazabicycloundec-7-ene (DBU) to give alkene 76 in 63%<br />
yield for two steps. Ozonolysis of the cyclohexene ring followed by reductive work-up with NaBH4 and basic hydrolysis of the acetate<br />
produced a triol which upon reaction with NaIO4 underwent oxidative cleavage to give cyclic hemiacetal 77 in 75% yield over<br />
the previous four steps. Wittig condensation with carbomethoxymethylene triphenylphosphorane gave the homologated unsaturated<br />
ester 78. Catalytic hydrogenation of the alkene using PtO2 as the catalyst was followed by converting the primary alcohol to the<br />
corresponding triflate prior to displacement with sodium iodide resulted in iodide 79 in 75% yield over four steps. The ester of 79<br />
was reduced to the corresponding primary alcohol upon reaction with LiBH4 in 89% yield and the resulting iodoalcohol was treated<br />
with Zn dust to affect reductive elimination of the iodide and decomposition of the pyran ring system to give the tetrahydrofuran<br />
diol 80 in 90% yield. This diol was treated with methanolic HCl to affect an intramolecular Pinner reaction and this was followed<br />
by protection of the primary alcohol as its tert-butyldiphenylsilyl ether to give lactone 81 The lactone was reacted with the<br />
aluminum amide generated from AlMe3 and N,O-dimethylhydroxylamine and the resulting secondary alcohol was protected as<br />
its tert-butyldimethylsilyl ether to give Weinreb amide 82 in 99% crude yield over four steps. Compound 82 is the diastereomerically<br />
pure version of compound 60 and can be converted to compound 25 by the methods described in Scheme 8 absent the required<br />
HPLC separation of diastereomers. With the three key fragments completed, the next step was to assemble them and complete the synthesis of eribulin. Aldehyde 24 was coupled to vinyl triflate 25 using an asymmetric Nozaki– Hiyami–Kishi reaction using CrCl2, NiCl2, Et3 N and chiral ligand 67 (Scheme 9) to give alcohol 83 (Scheme 11).</div>
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Formation of the THP ring was accomplished by reaction with KHMDS which allowed for displacement of the mesylate with the secondary alcohol and provided the THP containing product in 72% yield for the three steps. The pivalate ester group was removed with DIBAL-H to give the western fragment 22 in 92% yield.<br />
The completion of the synthesis of eribulin is illustrated in Scheme 12. The lithium anion of sulfone 22 generated upon reaction<br />
with nBuLi was coupled to aldehyde 23 to give diol 84 in 84% yield. Both of the alcohol functional groups of 84 were oxidized<br />
using a Dess–Martin oxidation in 90% yield and the resulting sulfone was removed via a reductive cleavage upon reaction with<br />
SmI2 to give keto-aldehyde 85 in 85% yield. Macrocyclization of 85 was accomplished via an asymmetric Nozaki–Hiyami–Kishi<br />
reaction using CrCl2, NiCl2, Et3N and chiral ligand 67 to give alcohol 86 in 70% yield. Modified Swern oxidation of the alcohol provided the corresponding ketone in 91% yield and this was followed by removal of the five silyl ether protecting groups upon reaction with TBAF and subsequent cyclization to provide ketone 87. Compound 87 was treated with PPTS to provide the ‘caged’ cyclic ketal 88 in 79% over two steps. The vicinal diol of 88 was reacted with Ts2O in collidine to affect selective tosylation of the primary alcohol and this crude product was reacted with ammonium hydroxide to install the primary amine to give eribulin which was treated<br />
with methanesulfonic acid in aqueous ammonium hydroxide to give eribulin mesylate (V) in 84% yield over the final three steps.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-39.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-39.jpg" rel="attachment wp-att-8203"><img alt="STR1" class="alignnone size-full wp-image-8203" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-39.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-39.jpg" height="553" style="height: auto; max-width: 100%;" width="455" /></a> <a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-8.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-8.jpg" rel="attachment wp-att-8205"><img alt="STR2" class="alignnone size-full wp-image-8205" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-8.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-8.jpg" height="351" style="height: auto; max-width: 100%;" width="567" /></a> <a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR3-4.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR3-4.jpg" rel="attachment wp-att-8206"><img alt="STR3" class="alignnone size-full wp-image-8206" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR3-4.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR3-4.jpg" height="589" style="height: auto; max-width: 100%;" width="463" /></a></div>
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30. Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singer, L. A.; Chase, C. E.;<br />
Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay, L.; Towle, M. J.; Salvato, K. A.;<br />
Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.; Yu, M. J. Bioorg. Med. Chem.<br />
Lett. 2004, 14, 5551.<br />
31. Wang, Y.; Serradell, N.; Bolós, J.; Rosa, E. Drugs Future 2007, 32, 681.<br />
32. Chiba, H.; Tagami, K. J. Synth. Org. Chem. Jpn. 2011, 69, 600.<br />
33. Choi, H.; Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan, Z.-<br />
K.; Xie, C. Pure Appl. Chem. 2003, 75, 1.<br />
34. Kishi, Y.; Fang, F.; Forsyth, C. J.; Scola, P. M.; Yoon, S. K. WO 9317690 A1, 1993.<br />
35. Littlefield, B. A.; Palme, M.; Seletsky, B. M.; Towle, M. J.; Yu, M. J.; Zheng, W.<br />
WO 9965894 A1, 1999.<br />
36. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.;<br />
Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992,<br />
114, 3162.<br />
37. Austad, B.; Chase, C. E.; Fang, F. G. WO 2005118565 A1, 2005.<br />
38. Chase, C.; Endo, A.; Fang, F. G.; Li, J. WO 2009046308 A1, 2009.</div>
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CLIP</div>
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<a data-mce-href="http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product" href="http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product">http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product</a></div>
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Eribulin (Halaven)</h3>
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<a data-mce-href="http://www.chemspider.com/Chemical-Structure.10370065.html" href="http://www.chemspider.com/Chemical-Structure.10370065.html">Halichondrin B</a> is a wicked molecule. In tests in mice, it is an extremely potent cancer cell killer, active at around 80 picomolar concentration. It also possesses a fiendish macrocyclic polyketide structure, with 32 stereocentres meaning that it could adopt over four billion different isomers – with just one that fights cancer.</div>
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<img alt="Eribulin and halichondrin B" data-mce-src="http://www.rsc.org/chemistryworld/sites/default/files/upload/CW0715_SupplementFeature_F6_630m.jpg" src="http://www.rsc.org/chemistryworld/sites/default/files/upload/CW0715_SupplementFeature_F6_630m.jpg" style="height: auto; max-width: 100%;" />Eribulin is a cut-down derivative of halichondrin B, which maintains most of its activity with significantly reduced complexity</div>
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Its power is therefore inherently hard to harness. Halichondrin B was found in various sea sponge species in the 1980s, but getting 400mg of the compound from a tonne of sponge was doing well. Clinical development required at least 10g, and annual production takes kilograms.</div>
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Although developing a synthetic route to halichondrin B looked just as tough as trying to extract it from sponges, <a data-mce-href="http://chemistry.harvard.edu/people/yoshito-kishi" href="http://chemistry.harvard.edu/people/yoshito-kishi">Yoshito Kishi</a>’s group at Harvard University in the US accepted the challenge. Frank Fang, one of the team, recalls how the Nozaki–Hiyama–Kishi (NHK) coupling reaction would prove critical. ‘Another feature that was impressed upon me was the importance of crystalline intermediates,’ Fang adds. These allowed simple purification by recrystallisation, rather than expensive and time-consuming chromatography.</div>
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Published in 1992, their method used several NHK couplings, forming carbon–carbon bonds between multifunctional vinyl halides and aldehydes via a nickel-catalysed, chromium-mediated process.<a data-mce-href="http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product#ref1" href="http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product#ref1" title="T D Aicher et al, J. Am. Chem. Soc., 1992, 114, 3162 (DOI: 10.1021/ja00034a086)"><sup>4</sup></a> The sprawling convergent synthesis, whose longest linear sequence involved 47 steps, prompted Japanese pharmaceutical company <a data-mce-href="http://www.eisai.com/" href="http://www.eisai.com/">Eisai</a> to collaborate with Kishi in exploring halichondrin B’s structure–activity relationship. On screening the team’s intermediates, one featuring the macrocyclic half of halichondrin B proved especially active. A series of medicinal chemistry refinements led to what would eventually become<a data-mce-href="http://www.chemspider.com/Chemical-Structure.24721813.html" href="http://www.chemspider.com/Chemical-Structure.24721813.html">eribulin</a> (marketed by Eisai as Halaven), promising a slightly simpler synthesis. It has ‘just’ 19 stereocentres, which along with other structural restrictions cuts the possible number of isomers to a mere 16,384.</div>
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Fang joined Eisai in 1998 as it selected eribulin for further development, and worked to develop a production process for a route that produced it from three fragments. He again strove to exploit recrystallisation and use the NHK reaction, although making it reliable enough for manufacturing was challenging. ‘There was an appreciation for the somewhat sensitive nature of the reaction, particularly the asymmetric variant,’ he recalls.</div>
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The Eisai researchers therefore studied the NHK procedure as they applied it to redesigning the synthesis for part of the eribulin molecule they refer to as the C14–C26 fragment. Featuring just one ring, this fragment isn’t the most structurally complex of the three, but is still very difficult to make. That’s because it is a long chain with several stereocentres, whose stereochemistry is hard to link together.</div>
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Fang’s team initially broke this section down into two sub-fragments, C14–C19 and C20–C26, using asymmetric NHK reactions on each, learning about the reaction’s parameters as they did so.<a data-mce-href="http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product#ref1" href="http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product#ref1" title="5 B C Austad et al, Synlett, 2013, 24, 0327 (DOI: 10.1055/s-0032-1317920)"><sup>5</sup></a> They then used what they’d found out to devise NHK reactions linking the two sub-fragments and attaching the two fragments on either side, which included closing the eribulin macrocycle. ‘We gained knowledge through our studies on the C19–C20 NHK coupling and were ultimately able to utilise that knowledge to try to execute an asymmetric NHK reaction in fixed equipment on multi-kilogram scale and construct the C19–C20, C26–C27, and C13–C14 bonds,’ Fang explains.</div>
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<img alt="Synthesis of eribulin " data-mce-src="http://www.rsc.org/chemistryworld/sites/default/files/upload/CW0715_SupplementFeature_F5_630m.jpg" src="http://www.rsc.org/chemistryworld/sites/default/files/upload/CW0715_SupplementFeature_F5_630m.jpg" style="height: auto; max-width: 100%;" />Synthesis of eribulin relies heavily on Nozaki–Hiyama–Kishi (NHK) coupling reactions to make key C–C bonds</div>
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Halaven was approved in the US in 2010 to treat breast cancer and earned ¥2.89 billion in sales (£159 million) in 2014. The commercial route initially took 62 steps across a convergent synthesis bringing together three fragments, with a longest linear sequence of 30 steps. Fang’s team has since added seven steps to the C14–C26 fragment route, which counterintuitively cuts costs and waste by 80% by eliminating chromatography.<a data-mce-href="http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product#ref1" href="http://www.rsc.org/chemistryworld/2015/06/longest-organic-syntheses-natural-product#ref1" title="6 F Belanger et al, Angew. Chem., Int. Ed., 2015, 54, 5108 (DOI: 10.1002/anie.201501143)"><sup>6</sup></a> ‘I am hopeful that we can find the lessons applicable in future work,’ Fang says.</div>
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Cheaper synthesis would appear welcome, given that Halaven’s price tag has been criticised. In the UK it currently costs £2,000 per 21 day treatment cycle according to data from the <a data-mce-href="http://www.bnf.org/bnf/index.htm" href="http://www.bnf.org/bnf/index.htm">British National Formulary</a>and the country’s <a data-mce-href="http://www.nice.org.uk/" href="http://www.nice.org.uk/">National Institute for Health and Clinical Excellence</a> (Nice). As a result, Nice refused to cover the drug, and in January 2015 the remaining funding in England looked set to be closed off with Halaven being taken off the Cancer Drugs Fund (CDF)’s list. But Eisai was told in March that the drug would stay on the list, pending reconsideration, after an appeal against the decision.</div>
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In defence, Fang claims that Halaven is actually one of the most affordable breast cancer treatments on the CDF. ‘Eisai was given no opportunity to lower the price of Halaven before NHS England announced that the treatment would be removed from the fund, despite this being something we were, and still are, very willing to do,’ he adds.</div>
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<tr class="patent-data-table"><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cited Patent</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Filing date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Publication date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title</th></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2009124237A1?cl=en" href="https://www.google.com/patents/WO2009124237A1?cl=en">WO2009124237A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 3, 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oct 8, 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Eisai R&D Management Co., Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Halichondrin b analogs</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/US6214865" href="https://www.google.com/patents/US6214865">US6214865</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 16, 1999</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 10, 2001</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Eisai Co., Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Macrocyclic analogs and methods of their use and preparation</td></tr>
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<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><thead class="patent-data-table-thead">
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<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DONG, C.-G. ET AL.: "<a data-mce-href="http://scholar.google.com/scholar?q=%22New+Syntheses+of+E7389+C+14-C35+and+Halichondrin+C+14-+C38+Building+Blocks%3A+Reductive+Cyclization+and+Oxy-Michael+Cyclization+Approaches%22" href="http://scholar.google.com/scholar?q=%22New+Syntheses+of+E7389+C+14-C35+and+Halichondrin+C+14-+C38+Building+Blocks%3A+Reductive+Cyclization+and+Oxy-Michael+Cyclization+Approaches%22">New Syntheses of E7389 C 14-C35 and Halichondrin C 14- C38 Building Blocks: Reductive Cyclization and Oxy-Michael Cyclization Approaches</a>", J. AM. CHEM. SOC., vol. 131, 2009, pages 15642 - 15646, XP002629056</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">See also references of <a data-mce-href="http://www.google.com/patents/EP2831082A4#npl-citations" href="http://www.google.com/patents/EP2831082A4#npl-citations">EP2831082A4</a></td></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2015000070A1?cl=en" href="https://www.google.com/patents/WO2015000070A1?cl=en">WO2015000070A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 30, 2014</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jan 8, 2015</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Alphora Research Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Synthetic process for preparation of macrocyclic c1-keto analogs of halichondrin b and intermediates useful therein including intermediates containing -so2-(p-tolyl) groups</td></tr>
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<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><tbody>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://google.com/patents/US7982060" href="http://google.com/patents/US7982060">US7982060</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 3, 2005</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 19, 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Eisai R&D Management Co., Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Intermediates for the preparation of analogs of Halichondrin B</td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<div class="autores">
<span data-mce-style="color: #800000;" style="color: maroon;">P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.</span></div>
</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
References</h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<ol>
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</ol>
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<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
SEE <a data-mce-href="https://wordpress.com/post/newdrugapprovals.org/3955" href="https://wordpress.com/post/newdrugapprovals.org/3955">https://wordpress.com/post/newdrugapprovals.org/3955</a></div>
<table class="infobox mce-item-table" data-mce-style="height: 1020px;" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: 1020px; line-height: 24px; width: 752px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Eribulin">Eribulin</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Eribulin.svg" href="https://en.wikipedia.org/wiki/File:Eribulin.svg"><img alt="Eribulin.svg" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/43/Eribulin.svg/300px-Eribulin.svg.png" height="226" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/43/Eribulin.svg/300px-Eribulin.svg.png" style="height: auto; max-width: 100%;" width="300" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9<i>H</i>,15<i>H</i>-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4<i>H</i>)-one</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Halaven</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/cdi/eribulin.html" href="https://www.drugs.com/cdi/eribulin.html" rel="nofollow">Consumer Drug Information</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/MedlinePlus" href="https://en.wikipedia.org/wiki/MedlinePlus" title="MedlinePlus">MedlinePlus</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.nlm.nih.gov"><a class="external text" data-mce-href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a611007.html" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a611007.html" rel="nofollow">a611007</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">License data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small>US</small> <span title="www.accessdata.fda.gov"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" title="U.S. Food and Drug Administration">FDA</a>: <a class="external text" data-mce-href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Eribulin&SearchType=BasicSearch" href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Eribulin&SearchType=BasicSearch" rel="nofollow">Eribulin</a></span></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" title="Pregnancy category">D</a> (Evidence of risk)</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Intravenous</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=253128-41-5" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=253128-41-5" rel="nofollow">253128-41-5</a></span><sup> <img alt="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_L01" href="https://en.wikipedia.org/wiki/ATC_code_L01" title="ATC code L01">L01XX41</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=L01XX41" href="http://www.whocc.no/atc_ddd_index/?code=L01XX41" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=17755248" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=17755248" rel="nofollow">17755248</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.21396142.html" href="http://www.chemspider.com/Chemical-Structure.21396142.html" rel="nofollow">21396142</a></span><sup> <img alt="Yes" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=LR24G6354G" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=LR24G6354G" rel="nofollow">LR24G6354G</a></span><sup> <img alt="Yes" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEMBL" href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1237028" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1237028" rel="nofollow">CHEMBL1237028</a></span><sup> <img alt="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>40</sub><span title="Hydrogen">H</span><sub>59</sub><span title="Nitrogen">N</span><span title="Oxygen">O</span><sub>11</sub></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">729.90 g/mol</td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
////////<b><i>Halaven, ERIBULIN, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Anticancer_drug" href="https://en.wikipedia.org/wiki/Anticancer_drug" title="Anticancer drug">anticancer drug</a> , <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Eisai_Co." href="https://en.wikipedia.org/wiki/Eisai_Co." title="Eisai Co.">Eisai Co.</a> E7389, ER-086526, US NCI designation, NSC-707389. breast cancer, liposarcoma, halichrondrin B analog, B1939, E7389, ER-086526, 441045-17-6, FDA 2010, <a data-mce-href="http://www.molbase.com/en/253128-41-5-moldata-1570257.html" href="http://www.molbase.com/en/253128-41-5-moldata-1570257.html"><b id="on_casno">253128-41-5</b> </a>, ERIBULIN MESYLATE, </i></b><i id="yui_3_5_0_3_1470380821943_583">Antineoplastic, エリブリンメシル酸塩</i></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
CC1CC2CCC3C(=C)CC(O3)CCC45CC6C(O4)C7C(O6)C(O5)C8C(O7)CCC(O8)CC(=O)CC9C(CC(C1=C)O2)OC(C9OC)CC(CN)O.CS(=O)(=O)O</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
C[C@@H]1C[C@@H]2CC[C@H]3C(=C)C[C@@H](O3)CC[C@]45C[C@@H]6[C@H](O4)[C@H]7[C@@H](O6)[C@@H](O5)[C@@H]8[C@@H](O7)CC[C@@H](O8)CC(=O)C[C@H]9[C@H](C[C@H](C1=C)O2)O[C@@H]([C@@H]9OC)C[C@@H](CN)O.CS(=O)(=O)O</div>
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C[C@@H]1C[C@@H]2CC[C@H]3C(=C)C[C@@H](O3)CC[C@]45C[C@@H]6[C@H](O4)[C@H]7[C@@H](O6)[C@@H](O5)[C@@H]8[C@@H](O7)CC[C@@H](O8)CC(=O)C[C@H]9[C@H](C[C@H](C1=C)O2)O[C@@H]([C@@H]9OC)C[C@@H](CN)O.CS(=O)(=O)O</div>
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CREDIT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.chm.bris.ac.uk/motm/eribulin/eribulinh.htm" href="http://www.chm.bris.ac.uk/motm/eribulin/eribulinh.htm">http://www.chm.bris.ac.uk/motm/eribulin/eribulinh.htm</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="http://pic9.molbase.net/molpic/01/56/01569257.png?222x264" src="http://pic9.molbase.net/molpic/01/56/01569257.png?222x264" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.molbase.com/en/253128-41-5-moldata-1570257.html" href="http://www.molbase.com/en/253128-41-5-moldata-1570257.html"><b id="on_casno">253128-41-5</b> </a> CAS</div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Eribulin</h1>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-1346483141860457136.post-51416626200046291932016-08-05T01:13:00.001-07:002016-08-05T01:13:47.631-07:00PAZOPANIB パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид<div dir="ltr" style="text-align: left;" trbidi="on">
<img alt="Pazopanib3Dan.gif" data-mce-selected="1" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/77/Pazopanib3Dan.gif/200px-Pazopanib3Dan.gif" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/77/Pazopanib3Dan.gif/200px-Pazopanib3Dan.gif" style="background-color: white; color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: auto; line-height: 24px; max-width: 100%; outline: rgb(119, 119, 119) solid 1px; resize: none;" /><br />
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-33.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-33.jpg" rel="attachment wp-att-8178"><img alt="STR1" class="alignnone size-full wp-image-8178" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-33.jpg" height="411" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-33.jpg" style="height: auto; max-width: 100%;" width="537" /></a></div>
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<img alt="" data-mce-src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/ab/Pazopanib_structure.svg/220px-Pazopanib_structure.svg.png" src="http://upload.wikimedia.org/wikipedia/commons/thumb/a/ab/Pazopanib_structure.svg/220px-Pazopanib_structure.svg.png" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Pazopanib</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
パゾパニブ塩酸塩</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Пазопаниба Гидрохлорид</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009.</div>
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<em><span data-mce-style="color: #ff0000;" style="color: red;">Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3,</span></em><br /><em><span data-mce-style="color: #ff0000;" style="color: red;">PDGFR-a/b, and c-kit that blocks tumor growth and inhibits angiogenesis. It was approved for renal cell carcinoma by the U.S. Food </span></em><em><span data-mce-style="color: #ff0000;" style="color: red;">and Drug Administration in 2009 and is marketed under the trade name Votrient by the drug’s manufacturer, GlaxoSmithKline.</span></em></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
GW 786034</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
M.Wt: 437.53<br />C21H23N7O2S</div>
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Pazopanib CAS No.: 444731-52-6</div>
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CAS No.: 635702-64-6 (PAZOPANIB HYDROCHLORIDE)</div>
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<img alt="ChemSpider 2D Image | Pazopanib Hydrochloride | C21H24ClN7O2S" data-mce-src="http://www.chemspider.com/ImagesHandler.ashx?id=9700526&w=250&h=250" src="http://www.chemspider.com/ImagesHandler.ashx?id=9700526&w=250&h=250" style="height: auto; max-width: 100%;" /></div>
<h1 class="h4" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_WrapTitle">Pazopanib Hydrochloride</span></h1>
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CAS No.: 635702-64-6 (PAZOPANIB HYDROCHLORIDE)</div>
<ul class="struct-props" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li><span class="prop_title">MF</span><span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_prop_MF">C<sub>21</sub>H<sub>24</sub>ClN<sub>7</sub>O<sub>2</sub>S</span></li>
<li><span class="prop_title">MW</span>473.979</li>
</ul>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">GW786034;Votrient;A<wbr></wbr>rmala;GW 786034;GW-<wbr></wbr>786034</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">GW786034GW786034, V<wbr></wbr>OTRIENT</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>5-({4-[(2,3-Dimethy<wbr></wbr>l-2H-indazol-6-yl)(<wbr></wbr>methyl)amino]-2-pyr<wbr></wbr>imidinyl}amino)-2-m<wbr></wbr>ethylbenzenesulfona<wbr></wbr>mide hydrochloride <wbr></wbr>(1:1)</strong></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Antineoplastic; Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors; Renal Cell Carcinoma Therpay; Soft Tissue Sarcoma Therapy</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">パゾパニブ塩酸塩<br />Pazopanib Hydrochloride<br /><a data-mce-href="http://jpdb.nihs.go.jp/jan/chemdraw5/Pazopanib_Hydrochloride.cdx" href="http://jpdb.nihs.go.jp/jan/chemdraw5/Pazopanib_Hydrochloride.cdx"><img alt="" data-mce-src="http://jpdb.nihs.go.jp/jan/gif/Pazopanib_Hydrochloride.png" src="http://jpdb.nihs.go.jp/jan/gif/Pazopanib_Hydrochloride.png" style="height: auto; max-width: 100%;" /></a><br />C<sub>2</sub><sub>1</sub>H<sub>2</sub><sub>3</sub>N<sub>7</sub>O<sub>2</sub>S<img alt="▪" class="emoji" data-mce-placeholder="1" data-mce-resize="false" data-wp-emoji="1" draggable="false" src="https://s.w.org/images/core/emoji/72x72/25aa.png" style="background-attachment: initial !important; background-clip: initial !important; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; border-radius: 0px; border: none !important; box-shadow: none !important; display: inline !important; height: 1em !important; margin: 0px 0.07em !important; max-width: 100%; outline: 0px; padding: 0px; vertical-align: -0.1em !important; width: 1em !important;" />HCl : 473.98<br />[635702-64-6]</td></tr>
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<b>Pazopanib</b> (trade name <b>Votrient</b>) is a potent and selective multi-targeted receptor <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Tyrosine_kinase_inhibitor" href="https://en.wikipedia.org/wiki/Tyrosine_kinase_inhibitor" title="Tyrosine kinase inhibitor">tyrosine kinase inhibitor</a> that blocks tumour growth and inhibits <a data-mce-href="https://en.wikipedia.org/wiki/Angiogenesis" href="https://en.wikipedia.org/wiki/Angiogenesis" title="Angiogenesis">angiogenesis</a>. It has been approved for <a data-mce-href="https://en.wikipedia.org/wiki/Renal_cell_carcinoma" href="https://en.wikipedia.org/wiki/Renal_cell_carcinoma" title="Renal cell carcinoma">renal cell carcinoma</a> and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Soft_tissue_sarcoma" href="https://en.wikipedia.org/wiki/Soft_tissue_sarcoma" title="Soft tissue sarcoma">soft tissue sarcoma</a> by numerous regulatory administrations worldwide.<sup class="reference" id="cite_ref-DM_2-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-DM-2" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-DM-2">[2]</a></sup><sup class="reference" id="cite_ref-EMA_3-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-EMA-3" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-EMA-3">[3]</a></sup><sup class="reference" id="cite_ref-EMC_4-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-EMC-4" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-EMC-4">[4]</a></sup><sup class="reference" id="cite_ref-TGA_5-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-TGA-5" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-TGA-5">[5]</a></sup></div>
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Pazopanib (Votrient®; GlaxoSmithKline, Brentford, U.K.) is currently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of patients with metastatic renal cell carcinoma (mRCC)</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Medical_uses">Medical uses</span></h2>
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It is approved by numerous regulatory administrations worldwide (including the <a data-mce-href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">FDA</a> (19 October 2009), <a data-mce-href="https://en.wikipedia.org/wiki/European_Medicines_Agency" href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency">EMA</a> (14 June 2010), <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Medicines_and_Healthcare_Products_Regulatory_Agency" href="https://en.wikipedia.org/wiki/Medicines_and_Healthcare_Products_Regulatory_Agency" title="Medicines and Healthcare Products Regulatory Agency">MHRA</a>(14 June 2010) and <a data-mce-href="https://en.wikipedia.org/wiki/Therapeutic_Goods_Administration" href="https://en.wikipedia.org/wiki/Therapeutic_Goods_Administration" title="Therapeutic Goods Administration">TGA</a> (30 June 2010)) for use as a treatment for advanced/metastatic <a data-mce-href="https://en.wikipedia.org/wiki/Renal_cell_carcinoma" href="https://en.wikipedia.org/wiki/Renal_cell_carcinoma" title="Renal cell carcinoma">renal cell carcinoma</a> and advanced <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Soft_tissue_sarcoma" href="https://en.wikipedia.org/wiki/Soft_tissue_sarcoma" title="Soft tissue sarcoma">soft tissue sarcomas</a>.<sup class="reference" id="cite_ref-MSR_1-4"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1">[1]</a></sup><sup class="reference" id="cite_ref-DM_2-1"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-DM-2" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-DM-2">[2]</a></sup><sup class="reference" id="cite_ref-EMA_3-1"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-EMA-3" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-EMA-3">[3]</a></sup><sup class="reference" id="cite_ref-EMC_4-1"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-EMC-4" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-EMC-4">[4]</a></sup><sup class="reference" id="cite_ref-TGA_5-1"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-TGA-5" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-TGA-5">[5]</a></sup> In Australia and New Zealand, it is subsidised under the <a data-mce-href="https://en.wikipedia.org/wiki/Pharmaceutical_Benefits_Scheme" href="https://en.wikipedia.org/wiki/Pharmaceutical_Benefits_Scheme" title="Pharmaceutical Benefits Scheme">PBS</a> and by <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Pharmaceutical_Management_Agency" href="https://en.wikipedia.org/wiki/Pharmaceutical_Management_Agency" title="Pharmaceutical Management Agency">Pharmac</a> respectively, under a number of conditions, including:<sup class="reference" id="cite_ref-PBS_6-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-PBS-6" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-PBS-6">[6]</a></sup><sup class="reference" id="cite_ref-7"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-7" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-7">[7]</a></sup></div>
<ul style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li>The medication is used to treat clear cell variant renal cell carcinoma.</li>
<li>The treatment phase is continuing treatment beyond 3-months.</li>
<li>The patient has been issued an authority prescription for pazopanib</li>
<li>The patient must have stable or responding disease according to the Response Evaluation Criteria In Solid Tumours (RECIST)</li>
<li>This treatment must be the sole tyrosine kinase inhibitor subsidised for this condition.</li>
</ul>
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It has also demonstrated initial therapeutic properties in patients with ovarian and non-small cell lung cancer,<sup class="reference" id="cite_ref-FierceBiotech_8-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-FierceBiotech-8" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-FierceBiotech-8">[8]</a></sup> though plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country.<sup class="reference" id="cite_ref-Reut_9-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-Reut-9" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-Reut-9">[9]</a></sup><sup class="reference" id="cite_ref-ov_press_10-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-ov_press-10" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-ov_press-10">[10]</a></sup></div>
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<img alt="" data-mce-src="http://img.tradeindia.com/fp/1/002/077/207.jpg" src="http://img.tradeindia.com/fp/1/002/077/207.jpg" style="height: auto; max-width: 100%;" /><img alt="Pazopanib" data-mce-src="http://www.nature.com/nrd/journal/v9/n1/images/nrd3073-i1.jpg" src="http://www.nature.com/nrd/journal/v9/n1/images/nrd3073-i1.jpg" style="height: auto; max-width: 100%;" /></div>
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SYNTHESIS</div>
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<strong>Pazopanib hydrochloride drug substance is manufactured by Glaxo Wellcome Manufacturing Pte. Limited, Jurong, Singapore</strong></div>
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NDA 22-465 was submitted by GlaxoSmithKline (GSK) for VOTRIENT™ (pazopanib), an immediate release tablet for oral administration containing either 200 mg or 400 mg of pazopanib free base (GW786034X) as the hydrochloride salt (GW786034B). Pazopanib is a new molecular entity and is submitted for review pursuant to Section 505(b)(1) of the Food, Drug and Cosmetic Act. Reference is made to one active Investigational New Drug application, IND 65,747.</div>
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Quality by Design (QbD) approach and risk management to increase their understanding of the process and drug substance properties. A number of Critical Quality Attributes (CQAs) were identified. These are: Identity by IR, Chloride Identity, Crystalline Form, Content by HPLC, Drug-related Impurities (including named impurities and genotoxic (b) (4) (b) (4) (b) (4) (b) (4) Executive Summary Section CMC Review #1 Page 9 of 262 CMC REVIEW OF NDA 22-465 impurities content), Residue on Ignition, Particle Size, Residual Solvents, Water Content by Karl Fischer, Description, Pd Content, and Heavy Metals.</div>
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CQA are mainly controlled by controlling starting material attributes, intermediate attributes (e.g. specifications of GW786034 quality process parameters, and by following the manufacturing process. A risk based method (e.g. failure mode and effects analysis (FMEA)) was used to identify the Quality Critical Process Parameters (QCPPs), Quality Process Parameters (QPPs), CQAs and Quality Attributes (QAs) for the pazopanib hydrochloride manufacturing process. The inputs to the FMEA were knowledge gained through the work to develop the impurity fate map, spiking and purging studies, the Design of Experiments (DOE) work to establish potential QCPPs/QPPs, one factor at a time experiments to establish parameter proven acceptable ranges, and 6 years of plant experience preparing over batches of pazopanib hydrochloride in 3 plants throughout the GSK network. It was concluded from this risk assessment that there are no QCPP but a few QPP in the drug substance (DS) manufacturing process. Stages 1 and 2 had no QPP, the few were only present in stages 3 and 4. All the QPP were scale invariant. A combination of multivariate DOE and univariate experimentation was used to determine the Proven acceptable Ranges (PAR) for the variables. The risks for combining univariate and multivariate experimentation were found to be minimal, on the basis of outcome from the robustness study. For this study, all the process parameters were all set at the lower limit of the PARs to create a worst-case scenario for impurity purging. Neither new impurities nor elevated levels of known impurities were detected. This data demonstrated that multivariate interactions will not lead to elevated levels of impurities.</div>
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Drug Product Pazopanib Tablets, 200 mg and 400 mg are film-coated IR oral tablets. The two strengths contain 216.7 mg and 433.4 mg pazopanib hydrochloride, respectively, which are equivalent to 200 mg and 400 mg pazopanib (free base), respectively. Excipients in the tablet core are: microcrystalline cellulose, sodium starch glycolate, povidone, and magnesium stearate. Pazopanib Tablets, 200 mg are modified capsule-shaped, gray film-coated tablets, one side plain and the opposite side debossed with an identifying code of ‘GS JT’. Pazopanib Tablets, 400 mg are modified capsule-shaped, yellow film-coated tablets, one side plain and the opposite side debossed with an identifying code of ‘GS UHL’. The tablets are manufactured at Glaxo Operations UK Limited, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom. Primary packaging of tablets will be performed by either Glaxo Operations UK Limited, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom or GlaxoSmithKline Inc, 1011 North Arendell Avenue, Zebulon, North Carolina 27597, USA.</div>
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Pazopanib hydrochloride is a new molecular entity of Biopharmaceutics Classification System (BCS) Class 2 (poor solubility, high permeability) and a crystalline solid. Its solubility in pH 1.1 is 0.65 mg/mL. The conjugate acids of the basic nitrogens have the following acidity constants: pKa - pK1 = 2.1 (indazole), pK2 = 6.4 (pyrimidine), pK3 = 10.2 (sulfonamide).</div>
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"Synthetic approaches to the 2009 new drugs"<br />Kevin K.-C. Liua, Subas M. Sakyab, Christopher J. O’Donnellb, Andrew C. Flickb, Jin Lic,<br />Bioorganic & Medicinal Chemistry, Volume 19, Issue 3, Pages 1136–1154</div>
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"An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals"., Beilstein J. Org. Chem., 2011, 7, 442–495.</div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/WO2015068175A2?cl=en" href="https://www.google.com/patents/WO2015068175A2?cl=en">https://www.google.com/patents/WO2015068175A2?cl=en</a></div>
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Pazopanib is marketed as hydrochloride salt by Glaxoshiithkline under the trade name VOTRIENT<sup>®</sup> is tyrosine kinase inhibitor and indicated for the treatment of patients with advanced renal cell carcinoma (RCC) and treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.</div>
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U.S. Patent No (s). US 7105530 ("the '530 patent"), US7262203 ("the '203 patent") and US8114885 ("the '885 patent") discloses a variety of pyrimidineamines and their derivatives such as Pazopanib, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof.</div>
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The process disclosed in the '530 patent is schematically represented as follows:</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-34.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-34.jpg" rel="attachment wp-att-8180"><img alt="STR1" class="alignnone size-full wp-image-8180" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-34.jpg" height="538" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-34.jpg" style="height: auto; max-width: 100%;" width="815" /></a></div>
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Patent publication No. WO 2011/050159 ("the Ί59 publication") disclosed process for preparation of Pazopanib hydrochloride, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dicMoropyrimidine of Formula B in a solvent like industrial methylated sprit and specific reaction conditions like, in presence of a base, sodium bicarbonate having a particle size distribution of > 250μηι or 50 to 150μηι selected to ensure that the pH of the reaction mixture is less than 7 for the reaction time period not more than 300 min to obtain N-(2-c oropyrimidin-4-yl)- 2,3-dimethyl-2H-indazol-6-amine of Formula II. The compound of Formula Π was methylated in presence of a methylating agent in an organic solvent like dimethylformamide by using specific reaction conditions like, in presence of a base i.e. Potassium carbonate having a particle size distribution D99 of > 300μηι or D99 of < 200μηι selected to ensure that the reaction time needs to reduce the starting material to less than 2% in less than 8 his to obtain N-(2-cMoropyrimidin-4-yl)-N-2,3-trimemyl-2H-mdazol-6-amine of Formula III. The resultant methylated compound was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of 4M HC1 and methanol to yield Pazopanib hydrochloride.</div>
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WO Ί59 publication disclosed that use of sodium bicarbonate with specific particle size distribution of > 250μπι or 50 to 150μηι is key element in condensation of compound of Formula A and Formula B to niinimize the formation of Impurity of Formula 1 within</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000712@@@id00000062487058@@@7809216@@@imgf000005_0001.gif" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000712@@@id00000062487058@@@7809216@@@imgf000005_0001.gif" style="height: auto; max-width: 100%;" /></div>
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WO Ί59 publication also disclosed that use of potassium carbonate with specific particle size distribution D99 of > 300μπι or D99 of < 200μηι is key element in methylation of compound of Formula II to reduce the formation of Impurities of Formula 2, Formula 3 and Formula 4 within the range of about 0.05-3%.</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000712@@@id00000062487058@@@7809216@@@imgf000005_0002.gif" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000712@@@id00000062487058@@@7809216@@@imgf000005_0002.gif" style="height: auto; max-width: 100%;" /></div>
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Patent publication No. WO 2012/073254 ("the '254 publication") disclosed a process for preparation of pazopanib hydrochloride, which involves condensation of 2,4-dicMoropyrimidine of Formula B with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of a base like sodium bicarbonate and a solvent like ethanol to yield 5-(4-chloropyrimidm-2-yl-ammo)-2-memylbenzenesulfonamide The resultant compound was condensed with N-2,3-1rimethyl-2H-indazole-6-amine of Formula D in an alcoholic solvent like ethanol. WO '254 publication also discloses process for purification of pazopanib hydrochloride from alcoholic solvent and water. The process disclosed in the '254 publication is schematically represented as follows: <img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000712@@@id00000062487058@@@7809216@@@imgf000006_0001.gif" src="https://patentscope.wipo.int/search/docservice_image/WO@@@IN2014000712@@@id00000062487058@@@7809216@@@imgf000006_0001.gif" style="height: auto; max-width: 100%;" /></div>
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Patent publication No. IN 2505/CHE/2011 disclosed a process for preparation of pazopanib, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dichloropyrimidine of Formula B in presence of sodium bicarbonate and a phase transfer catalyst like tetrabutyl ammonium bromide in a solvent like methanol to obtain N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine of Formula II. The resultant compound was methylated in presence of methyl iodide, potassium carbonate in a solvent like dimethylformamide to obtain compound of Formula III. The obtained Formula III was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of dimethylformamide and concentrated HC1 to yield pazopanib hydrochloride.</div>
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Patent publication No. CN 103373989 ("the '989 publication") disclosed a process for preparation of Pazopanib intermediate of Formula III by condensation of N-2,3-trimethyl-2H-indazole-6-amine of Formula D with 2,4-dicWoropyrimidine of Formula B in</div>
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Patent publication No. WO 2014/97152 ("the Ί52 publication") disclosed a process for preparation of Pazopanib hydrochloride starting from 2,3-dimethyl-6-nitro-2H-indazole.</div>
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The processes for preparation of pazopanib described in the above literature have certain drawbacks as it involves: a) use of specific predefined particles of bases like sodium bicarbonate and potassium carbonate, which involves additional process steps like milling, grinding etc, b) use of expensive phase transfer catalysts and c) multiple steps making the process quite expensive, particularly on large scale.</div>
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European Medicines Agency (EMA) public assessment report disclosed that pazopanib hydrochloride is a white to slightly yellow, non-hygroscopic, crystalline substance and the manufacturing process consistently produces pazopanib hydrochloride Form 1. However, the EMEA does not describe any particular characterization data for the disclosed polymorph Form 1.</div>
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PCT Publication No. WO 2011/058179 ("the Ί79 publication") discloses pazopanib base crystalline Forms such as Form-I and Form-II and a process for its preparation; also disclosed characterization data of Form-I and Form-II by XRD, IR and melting point. -</div>
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PCT Publication No. WO 2011/069053 ("the '053 publication") discloses crystalline pazopanib base and crystalline pazopanib hydrochloride Forms such as Form-II, Form-Ill, Form-TV, Form-V, Form- VI, Form- VIII, Form-IX, Form-X, Form-XI, Form-XII, Form-XIII, Form-A, Form-G and also discloses crystalline Pazopanib dihydrochloride Forms such as Form-I, Form-XIV, Form-XV. The crystalline Forms reported in the PCT publication characterized by its XRD pattern.</div>
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IN Publication No. 3023/CHE/2010 discloses crystalline pazopanib dihydrochloride Form-I and crystalline pazopanib mono hydrochloride, process for it preparation and characterization by XRD of the same.</div>
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IN Publication No. 1535/CHE/2012 discloses crystalline pazopanib hydrochloride Form-SP and a process for its preparation; also disclosed characterization data, of Form-SP by XRD, DSC and TR.</div>
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PCT Publication No (s): WO 2007/143483, WO 2007/064753, WO 2006/20564 and WO 2005/105094 as well as US Publication No. US 2008/0293691 disclose anhydrous and hydrated Forms of pazopanib hydrochloride and their process for preparation thereof. '</div>
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IP. Com journal disclosure Number IPCOM000207426D discloses crystalline Form of pazopanib hydrochloride Form-R, which is characterized by XRD pattern.</div>
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Further, IP.Com journal disclosure Number IPCOM000193076D discloses crystalline Forms of N-(2-cUoropyrirnidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine of</div>
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Formula III such as Form I and Form II along with characteristic data of XRD pattern</div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/WO2012073254A1?cl=en" href="https://www.google.com/patents/WO2012073254A1?cl=en">https://www.google.com/patents/WO2012073254A1?cl=en</a></div>
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Examples</div>
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Example 1:</div>
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Preparation of 5-(4-chloropyrimidin-2ylamino)-2-methyIbenzenesulfonamide</div>
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To a mixture of 5-amino-2-methylbenzenesulfonamide (20 gm) in ethanol (208 ml) and tetrahydrofuran (52 ml) was added 2,4-dichloropryrimidine (44 gm) and sodium bicarbonate (36 gm) at room temperature. The contents were heated to 70 to 75°C and maintained for 13 hours. The reaction mass was then cooled to 10°C and maintained for 2 hours. The reaction mass was filtered and the solvent was distilled off under vacuum at below 50 to 55°C to obtain a residual mass. To the residual mass was added ethyl acetate (100 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 15.5 gm of 5-(4-chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide. Example 2:</div>
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Preparation of N,2,3-trimethyI-2H-indazol-6-amine</div>
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Sodium methoxide (19 gm) was dissolved in methanol (610 ml) and then added 2,3-dimethyl-2H-indazol-6-amine (13 gm). The reaction mixture was stirred for 15 minutes and then added paraformaldehyde (3.9 gm). The contents were heated to 60°C and stirred for 10 hours. The reaction mass was then cooled to room temperature and maintained for 4 hours 30 minutes. Sodium borohydride (2.8 gm) was added to the reaction mass slowly at room temperature and then heated to reflux. The reaction mass was maintained for 2 hours at reflux and then cooled to room temperature. The reaction mass was stirred for 14 hours at room temperature and then added sodium hydroxide solution (1M, 100 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with hydrochloric acid solution (40 ml) and then added ethyl acetate (400 ml). Then the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and treated with carbon. The combined organic layers were washed with sodium chloride solution and dried with sodium sulfate. The organic layer was treated with carbon and filtered through hi-flow bed. The solvent was distilled off under vacuum at below 50°C to obtain a residual mass. To the residual mass was added diisopropyl ether (75 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 10 gm of N,2,3-trimethyl-2H-indazol-6-amine.</div>
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Example 3:</div>
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Preparation of pazopanib hydrochloride</div>
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5-(4-Chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide (17 gm) as obtained in example 1, N,2,3-trimethyl-2H-indazol-6-amine (10 gm) as obtained in example 2 and ethanol (166 ml) were added at room temperature and then heated to reflux. The reaction mass was maintained for 3 hours at reflux and then added concentrated hydrochloric acid (1 ml). The reaction mass was maintained for 10 hours at reflux and then cooled to room temperature. The separated solid was filtered and dried to obtain 17 gm of pazopanib hydrochloride (HPLC Purity: 97.5%). Example 4:</div>
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Purification of pazopanib hydrochloride</div>
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Pazopanib hydrochloride (5 gm; HPLC Purity: 97.5%) as obtained in example 3 was dissolved in a mixture of methanol (100 ml) and water (10 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 30 minutes at reflux and filtered. The filtrate obtained was cooled to room temperature and maintained for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 3.5 gm of pazopanib hydrochloride (HPLC Purity: 99.9%). Example 5:</div>
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Purification of pazopanib hydrochloride</div>
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Pazopanib hydrochloride (22 gm; HPLC Purity: 98%), methanol (528 ml), water (55 ml) and concentrated hydrochloric acid (0.2 ml) were added at room temperature. The contents were heated to reflux and maintained for 30 minutes, filtered. Take the filtrate and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was then cooled to room temperature and stirred for 30 minutes at room temperature. The contents were further cooled to 0 to 5°C, stirred for 1 hour and filtered. The solid obtained was dried to give 19 gm of pazopanib hydrochloride (HPLC Purity: 99.85%).</div>
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Example 6:</div>
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Purification of pazopanib hydrochloride</div>
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Pazopanib hydrochloride (10 gm; HPLC Purity: 96%), methanol (250 ml), water (25 ml) and concentrated hydrochloric acid (0.1 ml) were added at room temperature. The contents were heated to reflux and maintained for 30 minutes, filtered. The filtrate obtained was then cooled to room temperature and stirred for 30 minutes at room temperature. The contents further cooled to 0 to 10°C and stirred for 1 hour. The separated solid was filtered and dried to obtain 6.6 gm of pazopanib hydrochloride (HPLC Purity: 99.8%).</div>
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Example 7: Purification of pazopanib hydrochloride</div>
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Pazopanib hydrochloride (22 gm; HPLC Purity: 97%) was dissolved in a mixture of isopropanol (132 ml) and water (20 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 1 hour at reflux and then cooled to room temperature. The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried to give 18 gm of pazopanib hydrochloride (HPLC Purity: 99.8%).</div>
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Paper</div>
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<a data-mce-href="http://pubs.acs.org/doi/full/10.1021/op400139z" href="http://pubs.acs.org/doi/full/10.1021/op400139z">http://pubs.acs.org/doi/full/10.1021/op400139z</a></div>
<h1 class="articleTitle" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="hlFld-Title">Assessment of Predictivity of Semiquantitative Risk Assessment Tool: Pazopanib Hydrochloride Genotoxic Impurities</span></h1>
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<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Elder%2C+David+P" href="http://pubs.acs.org/author/Elder%2C+David+P" id="authors">David P. Elder</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op400139z#cor1" href="http://pubs.acs.org/doi/full/10.1021/op400139z#cor1">*</a><span class="NLM_xref-aff">†</span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Okafo%2C+George" href="http://pubs.acs.org/author/Okafo%2C+George" id="authors">George Okafo</a></span><span class="NLM_xref-aff">†</span><span class="NLM_x">, and </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/McGuire%2C+Michael" href="http://pubs.acs.org/author/McGuire%2C+Michael" id="authors">Michael McGuire</a></span><span class="NLM_xref-aff">‡</span></span></div>
<div class="affiliations">
<div id="aff1">
<sup>†</sup> <span class="institution">GlaxoSmithKline</span>, Park Road, Ware, Hertfordshire, United Kingdom SG12 0DP</div>
<div id="aff2">
<sup>‡</sup> <span class="institution">GlaxoSmithKline</span>, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States</div>
</div>
<div id="citation">
<cite>Org. Process Res. Dev.</cite>, <span class="citation_year">2013</span>, <span class="citation_volume">17</span> (8), pp 1036–1041</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op400139z</div>
<div id="pubDate">
Publication Date (Web): July 02, 2013</div>
<div id="artCopyright">
Copyright © 2013 American Chemical Society</div>
<div id="correspondence">
*E-mail: <a data-mce-href="mailto:david.p.elder@gsk.com" href="mailto:david.p.elder@gsk.com">david.p.elder@gsk.com</a></div>
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<div class="hlFld-Abstract">
<h2 id="Abstract">
Abstract</h2>
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<div class="figure" id="f_null">
<a class="showFiguresEvent" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op400139z#" href="http://pubs.acs.org/doi/full/10.1021/op400139z#" id="absImg" title="Open Figure Viewer"><img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2013/oprdfk.2013.17.issue-8/op400139z/production/images/medium/op-2013-00139z_0005.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2013/oprdfk.2013.17.issue-8/op400139z/production/images/medium/op-2013-00139z_0005.gif" style="height: auto; max-width: 100%;" /></a></div>
<div class="articleBody_abstractText">
The recently developed semiquantitative assessment tool for the evaluation of carryover potential of mutagenic impurities (MIs) into the final API was applied to the five identified MIs within pazopanib hydrochloride (dimethyl sulfate (DMS) and compounds II, III, VI, and VIII). The theoretical and predicted purge factors were compared. The tool accurately predicted the purging capacity for the most reactive MI, DMS, giving a theoretical purge factor of 30000 versus an actual value of 29411 (for spiking at stage 1). For the other less reactive MIs, both measured and predicted values agreed reasonably well, and the high values for the purging factors were indicative of an effective process capability that could significantly reduce observed MI levels. The only exception was for compound VI, where although the measured and theoretical purge factors were in agreement, they were significantly lower (<200) than for the other MIs. In this case, a strategy was implemented including a requirement for control of this MI on API specification. The purge-factor assessment tool has the potential to play a key role in GRA (genotoxic risk assessment) processes and subsequent regulatory submissions. This tool could provide regulators with additional confidence to accept these purging arguments without resorting to testing. This could potentially significantly reduce the analytical testing burden for early clinical candidates.</div>
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PATENT</div>
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WO 2011058179</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The compound 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N-methylamino)pyrimidine-2- ylamino)-2-methylbenzenesulfonamide, also known as Pazopanib, is useful in the treatment of disorders associated with inappropriate or pathological angiogenesis, such as cancer, in mammals. Pazopanib has the following formula (I):</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
H CH,</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2011058179A1/imgf000002_0001.png" href="https://patentimages.storage.googleapis.com/WO2011058179A1/imgf000002_0001.png"><img alt="Figure imgf000002_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2011058179A1/imgf000002_0001.png" height="112" id="imgf000002_0001" src="https://patentimages.storage.googleapis.com/WO2011058179A1/imgf000002_0001.png" style="height: auto; max-width: 100%;" width="436" /></a></div>
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NH<sub>2</sub></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
In WO 02/059110 the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride as well as the uses of this compound have been disclosed. In particular, this compound is an inhibitor of tyrosine kinase enzymes, namely vascular endothelial growth factor receptors, and can be used for the treatment and/or prevention of diseases which are associated with tyrosine kinase enzymes such as vascular endothelial growth factor receptors, such as cancer, particularly breast cancer and colon cancer.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Alternative methods for the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride are disclosed in WO 03/106416.</div>
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In WO 2007/064752 the use of Pazopanib for the treatment of age related macula degeneration is disclosed. WO 2007/064753 further discloses Pazopanib for the treatment of various types of cancer, e.g. brain cancer, glioblastoma multiforme, neuroendocrine cancer, prostate cancer, myeloma, lung cancer, liver cancer, gallbladder cancer or skin cancer.</div>
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Typically Pazopanib is administered orally, as this route provides great comfort and convenience of dosing. Although the hydrochloride form of Pazopanib is known in the art, as described above, this form is not optimal in regard to bioavailability, inter-patient variability, and safety. Further, the known form of Pazopanib hydrochloride is not optimal with regard to mechanical and chemical stability, which is in particular necessary for manufacturing tablets, as well as not optimal in regard to flow properties, compressibility, dissolution rate. Additionally, it is at least to some extent hygroscopic and shows electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions</div>
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<a class="cLink" data-mce-href="http://www.sciencedirect.com/science/journal/0960894X" href="http://www.sciencedirect.com/science/journal/0960894X" title="Go to Bioorganic & Medicinal Chemistry Letters on ScienceDirect">Bioorganic & Medicinal Chemistry Letters</a></div>
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<a class="S_C_volIss" data-mce-href="http://www.sciencedirect.com/science/journal/0960894X/24/4" href="http://www.sciencedirect.com/science/journal/0960894X/24/4" title="Go to table of contents for this volume/issue">Volume 24, Issue 4</a>, 15 February 2014, Pages 1108–1110</div>
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<h1 class="svTitle" id="tm005">
Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents</h1>
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<li class="smh5"><a class="authorName svAuthor" data-fn="Haofei" data-ln="Qi" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" data-orcid="" data-pos="1" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" id="authname_N492e5dc0N49279cac">Haofei Qi</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af005" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af005" id="baf005" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-fn="Ligong" data-ln="Chen" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" data-orcid="" data-pos="2" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" id="authname_N492e5dc0N49279d60">Ligong Chen</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af005" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af005" id="baf005" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-fn="Bingni" data-ln="Liu" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" data-orcid="" data-pos="3" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" id="authname_N492e5dc0N49279e14">Bingni Liu</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af010" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af010" id="baf010" title="Affiliation: b"><sup>b</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-fn="Xinran" data-ln="Wang" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" data-orcid="" data-pos="4" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" id="authname_N492e5dc0N49279ec8">Xinran Wang</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af005" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af005" id="baf005" title="Affiliation: a"><sup>a</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-fn="Li" data-ln="Long" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" data-orcid="" data-pos="5" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" id="authname_N492e5dc0N49279f7c">Li Long</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af015" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af015" id="baf015" title="Affiliation: c"><sup>c</sup></a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-fn="Dengke" data-ln="Liu" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" data-orcid="" data-pos="6" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#" id="authname_N492e5dc0N4927a030">Dengke Liu</a><a class="intra_ref auth_aff" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af010" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#af010" id="baf010" title="Affiliation: b"><sup>b</sup></a><sup>, </sup><a class="intra_ref auth_corr" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#cor1" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#cor1" id="bcor1" title="Corresponding author contact information"></a><sup>,</sup></li>
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<dl class="extLinks nonEmpty"><dd class="doiLink"></dd><dd class="doi"><a class="S_C_ddDoi" data-mce-href="http://dx.doi.org/10.1016/j.bmcl.2014.01.003" href="http://dx.doi.org/10.1016/j.bmcl.2014.01.003" id="ddDoi" target="doilink">doi:10.1016/j.bmcl.2014.01.003</a></dd><dd class="rightsLink"></dd></dl>
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<div class="abstract svAbstract " data-etype="ab">
<h2 class="secHeading" id="authorab0151">
Abstract</h2>
<div id="sp0045">
A series of novel pazopanib derivatives, <strong class="boldFont">7a</strong>–<strong class="boldFont">m</strong>, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by <sup>1</sup>H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound <strong class="boldFont">7l</strong> was most potent with IC<sub>50</sub> values of 12 nM against VEGFR-2. Furthermore, compounds <strong class="boldFont">7c</strong>, <strong class="boldFont">7d</strong> and <strong class="boldFont">7m</strong>demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound <strong class="boldFont">7f</strong> showed superior inhibitory effects than that of pazopanib.</div>
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<a class="figureLink" data-mce-href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#gr1" href="http://www.sciencedirect.com/science/article/pii/S0960894X14000225#gr1" title="Chemical structure of pazopanib."><img alt="Chemical structure of pazopanib." border="0" class="imgLazyJSB figure large nrmImg" data-fulleid="1-s2.0-S0960894X14000225-gr1.jpg" data-fullheight="85" data-fullwidth="281" data-imgeids="1-s2.0-S0960894X14000225-gr1.jpg" data-loaded="true" data-mce-src="http://ars.els-cdn.com/content/image/1-s2.0-S0960894X14000225-gr1.jpg" data-thumbeid="1-s2.0-S0960894X14000225-gr1.sml" data-thumbheight="66" data-thumbwidth="219" height="85" src="http://ars.els-cdn.com/content/image/1-s2.0-S0960894X14000225-gr1.jpg" style="height: auto; max-width: 100%;" width="281" /></a></div>
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Figure 1.<br />
<div id="sp0020">
Chemical structure of pazopanib.</div>
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Patent</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.co.in/patents/WO2002059110A1?cl=en" href="https://www.google.co.in/patents/WO2002059110A1?cl=en">https://www.google.co.in/patents/WO2002059110A1?cl=en</a></div>
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Example 69</div>
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5-({4-[(2,3-dimethyl-2r/-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2- methylbenzenesulfonamide</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000096_0002.png" href="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000096_0002.png"><img alt="Figure imgf000096_0002" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000096_0002.png" height="148" id="imgf000096_0002" src="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000096_0002.png" style="height: auto; max-width: 100%;" width="272" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a solution of Intermediate Example 13 (200 mg, 0.695 mmol) and 5-amino-2- ethylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. HCI salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2- yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. Y\ NMR (400 MHz, deDMSO+NaHCOa) δ 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).</div>
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Example 13</div>
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Preparation of Λ/-(2-chloropyrimidin-4-yl)-Λ/,2,3-trimethyl-2r/-indazol-6-amine</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000061_0001.png" href="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000061_0001.png"><img alt="Figure imgf000061_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000061_0001.png" height="156" id="imgf000061_0001" src="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000061_0001.png" style="height: auto; max-width: 100%;" width="200" /></a></div>
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To a stirred solution of the Intermediate 12 (7.37 g) in DMF (50 ml) was added CS2CO3 (7.44 g, 2 eqv.) and Mel (1.84 ml, 1.1 eqv.) at room temperature. Mixture was stirred at rt for overnight The reaction mixture was poured into ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air- dried to afford Λ/-(2-chloropyrimidin-4-yl)-Λ/,2,3-trimethyl-2r/-indazol-6-amine as an off-white solid (6.43 g, 83%). 'H NMR (400 MHz, dsDMSO) δ 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).</div>
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Intermediate Example 12 Preparation of Λ/-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000060_0001.png" href="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000060_0001.png"><img alt="Figure imgf000060_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000060_0001.png" height="156" id="imgf000060_0001" src="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000060_0001.png" style="height: auto; max-width: 100%;" width="204" /></a></div>
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to a stirred solution of Intermediate Example 11 (2.97 g, .015 mol) and NaHCOs (5.05 g, .06 mol) in THF (15 mL) and ethanol (60 mL) was added 2,4-dichloropyrimidine (6.70 g, .045 mol) at room temperature. After the reaction was stirred for four hours at 85 °C, the suspension was cooled to rt, filtered and washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting solid was triturated with ethyl acetate to yield 3.84 g (89 % yield) of Λ/-(2-chloropyrimidin-4-yl)- 2,3-dimethyl-2tf-indazol-6-amine. <sup>1</sup>H NMR (400 MHz, deDMSO) δ 7.28 (d, J = 9.0 Hz, 1 H), 6.42 (d, J = 8.8 Hz, 1 H), 6.37 (s, 1 H), 5.18 (br s, 1 H), 3.84 (s, 3H), 2.43 (s, 3H). MS (ES+, m/z) 274 (M+H).</div>
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Intermediate Example 11</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Preparation of 2,3-dimethyl-2r/-indazol-6-amine</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000059_0002.png" href="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000059_0002.png"><img alt="Figure imgf000059_0002" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000059_0002.png" height="88" id="imgf000059_0002" src="https://patentimages.storage.googleapis.com/WO2002059110A1/imgf000059_0002.png" style="height: auto; max-width: 100%;" width="172" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro- 7W-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHC03 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 ml) and the combined organic phase was dried (Na2S0<sub>4</sub>). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2r/-indazole as a yellow solid (15.85 g, 73 o/o). <sup>1</sup>H NMR (300 MHz, dβDMSO) δ 8.51 (s, I H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).</div>
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To a stirred solution of 2,3-dimethyl-6-nitro-2V-indazole (1.13 g) in 2- methoxyethyl ether (12 ml), at 0 °C, was added a solution of 4.48 g of tin(ll) chloride in 8.9 ml of concentrated HCI dropwise over 5 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 40 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (1.1 g, 95 %), the HCI salt 2,3-dimethyl-2/7-indazol-6- amine. <sup>1</sup>H NMR (300 MHz, deDMSO) δ 7.77 (d, J = 8.9 Hz, 1 H), 7.18 (s, 1 H), 7.88 (m, 1 H), 4.04 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 162 (M+H).</div>
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NMR, MASS</div>
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<a data-mce-href="https://ayurajan.blogspot.in/" href="https://ayurajan.blogspot.in/">ayurajan</a></h1>
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Let's Research !!!!!</div>
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<a data-mce-href="https://ayurajan.blogspot.in/2014/12/pazopanib.html" href="https://ayurajan.blogspot.in/2014/12/pazopanib.html">https://ayurajan.blogspot.in/2014/12/pazopanib.html</a></div>
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<b>WO2003106416A2</b> <b>(</b>same appears in <b>Drug Future</b> <b>2006, <i>31</i>, <i>7</i>, 585-589)</b></div>
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<b>Pazopanib synthesis: J Med Chem 2008, </b><i>51</i><b>, 4632-4640 (</b>same appears in<b> </b><b>Beilstein J Org Chem 2011, <i>7</i>, 442–495)</b></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-28.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-28.jpg" rel="attachment wp-att-8164"><img alt="STR1" class="alignnone wp-image-8164" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-28.jpg" height="430" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-28.jpg" style="height: auto; max-width: 100%;" width="876" /></a> <a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-4.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-4.jpg" rel="attachment wp-att-8165"><img alt="STR2" class="alignnone wp-image-8165" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-4.jpg" height="782" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR2-4.jpg" style="height: auto; max-width: 100%;" width="904" /></a> <a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR3-3.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR3-3.jpg" rel="attachment wp-att-8166"><img alt="STR3" class="alignnone wp-image-8166" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR3-3.jpg" height="832" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR3-3.jpg" style="height: auto; max-width: 100%;" width="867" /></a></div>
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PAPER</div>
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<a data-mce-href="http://www.eurekaselect.com/97375" href="http://www.eurekaselect.com/97375">http://www.eurekaselect.com/97375</a></div>
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<a class="doi" data-mce-href="http://www.eurekaselect.com/97375#" href="http://www.eurekaselect.com/97375#">10.2174/157017812800233714</a></div>
<h4 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A Novel Practical Synthesis of Pazopanib: An Anticancer Drug</h4>
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<strong>Author(s):</strong> YiCheng Mei, BaoWei Yang, Wei Chen, DanDan Huang, Ying Li, Xin Deng, BaoMing Liu, JingJie Wang, Hai Qian and WenLong Huang</div>
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<strong>Affiliation: </strong>Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, P.R. China.</div>
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<h4>
Abstract:</h4>
This paper reports a novel approach to synthesize pazopanib. In our synthetic route, the potently mutagenic alkylating agents such as dimethyl sulfate and methyl iodide are avoided. A novel regioselective methylation of the 2- position of 3-methyl-6-nitro-1H-indazole was reported. This novel route is one step shorter than the previously reported route.</div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/WO2014097152A1?cl=en" href="https://www.google.com/patents/WO2014097152A1?cl=en">https://www.google.com/patents/WO2014097152A1?cl=en</a></div>
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Pazopanib is a tyrosine kinase inhibitor of Formula la.</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000002_0001.png" href="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000002_0001.png"><img alt="Figure imgf000002_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000002_0001.png" height="116" id="imgf000002_0001" src="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000002_0001.png" style="height: auto; max-width: 100%;" width="400" /></a></div>
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Formula la</div>
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Pazopanib is marketed as the hydrochloride salt, with the chemical name 5-[[4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride, having the structure as depicted in Formula I:</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000002_0002.png" href="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000002_0002.png"><img alt="Figure imgf000002_0002" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000002_0002.png" height="116" id="imgf000002_0002" src="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000002_0002.png" style="height: auto; max-width: 100%;" width="412" /></a></div>
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Formula I</div>
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U.S. Patent No. 7,105,530 provides a process for the preparation of a hydrochloride salt of a compound of Formula II</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000003_0001.png" href="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000003_0001.png"><img alt="Figure imgf000003_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000003_0001.png" height="88" id="imgf000003_0001" src="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000003_0001.png" style="height: auto; max-width: 100%;" width="184" /></a></div>
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Formula II involving the reduction of 2,3-dimethyl-6-nitro-2H-indazole with tin (II) chloride in concentrated hydrochloric acid in the presence of 2-methoxyethyl ether at 0°C. It also describes the preparation of a compound of Formula III</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000003_0002.png" href="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000003_0002.png"><img alt="Figure imgf000003_0002" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000003_0002.png" height="88" id="imgf000003_0002" src="https://patentimages.storage.googleapis.com/WO2014097152A1/imgf000003_0002.png" style="height: auto; max-width: 100%;" width="248" /></a></div>
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Formula III involving the reaction of a hydrochloride salt of compound of Formula II with 2,4- dichloropyrimidine in the presence of a base and solvent mixture of</div>
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tetrahydrofuran/ethanol followed by stirring for 4 hours at 85°C.</div>
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PCT Publication No. WO 2007/064752 provides a process for the preparation of a compound of Formula II comprising reducing 2,3-dimethyl-6-nitro-2H-indazole with 10% Palladium-carbon (50% wet) in the presence of methanol, followed by the addition of ammonium formate at a rate that ensures the reaction temperature is maintained at or between 25°C and 30°C. It also discloses the preparation of a compound of Formula III comprising heating the compound of Formula II with sodium bicarbonate in presence of tetrahydrofuran and ethanol at or between 75°C and 80°C followed by cooling to 20°C to</div>
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25°C.</div>
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The present invention provides a process for the preparation of a compound of Formula II which offers recycling of the Raney nickel catalyst used in the process, and an easy filtration work-up procedure. Further, the present invention offers selective reduction under mild conditions that is economical to use at an industrial scale.</div>
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The present invention also provides a process for the preparation of compound of Formula III which avoids the use of two or more solvents, and additionally, also circumvents heating and cooling procedures during the reaction. The aforesaid advantages yield a compound of Formula III with a lesser amount of N-(4-chloropyrimidin-2-yl)-2,3- dimethyl-2H-indazol-6-amine (CPDMI) impurity.</div>
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The compounds of Formula II and Formula III prepared by the present invention yield a compound of Formula la or its salts in comparable yield and suitable purity required for medicinal preparations.</div>
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EXAMPLES</div>
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Step 1: Synthesis of 2,3-dimcthyl-6-nitro-2H-indazole</div>
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Example 1 :</div>
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Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred suspension of 3-methyl-6-nitro-indazole (100 g, 0.56 mol) in ethyl acetate (2000 mL) over a period of 4 hours in four equal lots at 1 hour time intervals. The reaction mixture was stirred at 25 °C to 30°C for 16 hours. The solvent was recovered under reduced pressure. A saturated sodium bicarbonate solution (3240 mL) was added to the mixture slowly, and the reaction mixture was extracted with 4: 1 mixture of dichloromethane:isopropyl alcohol (1080 mL x 5). The solvent was recovered under reduced pressure. Methyl fert-butyl ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30 minutes at 45 °C to 50°C. The reaction mixture was cooled to 25 °C to 30°C and was stirred at this temperature for 30 minutes. The solid was filtered, washed with methyl tert- butyl ether (100 mL x 2), and dried in an air oven at 50°C for 12 hours to afford 2,3- dimethyl-6-nitro-2H-indazole as a yellow solid.</div>
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Yield: 82.4% w/w</div>
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Step 2: Synthesis of 2,3-dimethyl-2H-indazol-6-amine</div>
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Example 2a:</div>
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Raney nickel ( 12.50 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (50 g, 0.26 mol) in methanol (500 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm<sup>2</sup> - 4.0 kg/cm<sup>2</sup> at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (100 mL x 2). The filtrates were combined, and the solvent was recovered completely. «-Heptane (250 mL) and dichloromethane (50 mL) were added to the residue, and the reaction mixture was stirred for 1 hour at 25°C to 30°C. The solid was collected by filtration, washed with n-heptane (50 mL x 2), and dried under vacuum at 40°C to 45 °C to afford 2,3-dimethyl-2H-indazol-6-amine as a light brown solid.</div>
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Yield: 95% w/w</div>
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Example 2b:</div>
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Raney nickel (21.25 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (85 g, 0.45 mol) in methanol (850 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm<sup>2</sup> - 4.0 kg/cm<sup>2</sup> at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (85 mL x 3). The filtrates were combined, and the solvent was recovered up to the volume of 850 mL. The 2,3-dimethyl-2H-indazol-6-amine in methanol was used as such in the next step. Step 3: Synthesis of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine</div>
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Example 3 :</div>
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Sodium bicarbonate ( 112 g, 1.34 mol) was added to a stirred solution of 2,3- dimethyl-2H-indazol-6-amine (as obtained from step 2; Examples 2a and 2b) in methanol. 2,4-Dichloropyrimidine (99.35 g, 0.67 mol) was added to the reaction mixture followed by stirring of the reaction mixture for 24 hours at 25°C to 30°C. De-ionized water (850 mL) was added to the reaction mixture followed by stirring of the reaction mixture at 25 °C to 30°C for 1 hour. The solid was filtered. The wet solid was washed with de-ionized water (170 mL x 2) to obtain a wet material. De-ionized water (850 mL) was added to the wet material to obtain a slurry, and the slurry was stirred at 25°C to 30°C for 30 minutes. The solid was filtered, then washed with de-ionized water (170 mL x 2). The wet material obtained was treated with ethyl acetate (340 mL) to obtain a slurry. The slurry was stirred at 35°C to 40°C for 30 minutes and then cooled to 0°C to 5°C. The slurry was further stirred at 0°C to 5°C for 30 minutes. The solid was collected by filtration, then washed with cold ethyl acetate (170 mL x 2). The solid was dried in an air oven at 50°C for 16 hours to afford N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine as an off- white solid.</div>
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Yield: 86.7% w/w</div>
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Step 4: Synthesis of pazopanib hydrochloride</div>
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Example 4a: Synthesis of N-(2-Chloropyrimidin-4-yl)-N.2.3-trimethyl-2H-indazol-6- amine</div>
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Cesium carbonate (238 g, 0.73 mol) and iodomethane (57 g, 0.40 mol) were added to a stirred suspension of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (lOOg, 0.37 mol) in N,N-dimethylformamide (300 mL) at 25°C to 30°C. The reaction mixture was further stirred at 25 °C to 30°C for 6 hours followed by cooling of the reaction mixture to 0°C to 5°C. De-ionized water (300 mL) was added drop-wise to the reaction mixture, then the reaction mixture was stirred at 5°C to 10°C for 30 minutes. The solid was collected by filtration, and washed with de-ionized water (100 mL x 2). The wet material so obtained was dried in an air oven at 50°C for 12 hours to obtain the title compound.</div>
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Yield: 90.4% w/w Example 4b: Synthesis of pazopanib hydrochloride</div>
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To a suspension of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6- amine (90 g, 0.312 mol) and 5-amino-2-methyl benzene sulfonamide (64.07 g, 0.344 mol) in isopropyl alcohol (900 mL) was added 4M hydrochloric acid solution in isopropyl alcohol (1.56 mL, 6.25 mol). The reaction mixture was heated to reflux temperature for 10 hours to 12 hours. The reaction mixture was cooled to 25°C. The reaction mixture was further stirred at 25°C to 30°C for 30 minutes, then the solid was filtered. The wet solid was washed with isopropyl alcohol (180 mL x 2), and then dried under vacuum at 45 °C to 50°C for 12 hours to afford the hydrochloride salt of 5-({4-[(2,3-dimethyl-21-I-indazol-6- yl)(methyl) amino] pyrimidin-2-yl} amino-Z-methylbenzene sulfonamide as a light brown solid.</div>
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Yield: 97% w/w</div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/CN104557881A?cl=en" href="https://www.google.com/patents/CN104557881A?cl=en">https://www.google.com/patents/CN104557881A?cl=en</a></div>
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<span class="notranslate">pazopanib hydrochloride monohydrate prepared:</span></div>
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<span class="notranslate">(1) chemical reaction formula</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104557881A/CN104557881AD00051.png" href="https://patentimages.storage.googleapis.com/CN104557881A/CN104557881AD00051.png"><img alt="Figure CN104557881AD00051" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104557881A/CN104557881AD00051.png" id="idf0004" src="https://patentimages.storage.googleapis.com/CN104557881A/CN104557881AD00051.png" style="height: auto; max-width: 100%;" /></a></div>
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<span class="notranslate">(2) Operation process</span></div>
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<span class="notranslate">In the reaction flask pazopanib hydrochloride crude 100g, 700ml of acetonitrile was added under stirring and purified water 200ml, feeding is completed, begin heating to 75~80 ° C, until clear solvent filtration system, slowly dropped 10~20 ° C, keep stirring lh, filtered, and the filter cake washed with purified water and acetonitrile respectively, drained and the filter cake was dried at 60 ° C blast 5h, have pazopanib hydrochloride monohydrate solid 84g, yield 80.9%.</span> <span class="notranslate">For example, crystalline form pazopanib hydrochloride prepared the following examples.</span></div>
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<span class="notranslate">pazopanib hydrochloride polymorph of preparation:</span></div>
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<span class="notranslate">Example 1:</span></div>
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<span class="notranslate"> In the reaction flask pazopanib hydrochloride monohydrate 8. 0g, ethanol 50ml and purified water 0.Iml (the volume of water accounted for a mixed solution of 2% of the total volume of the square, ethanol - water mixture total volume was 6.26 times pazopanib hydrochloride monohydrate quality), heated to 75 ° C, stirred at reflux for about 5h, after cooling to 10~20 ° C, keep stirring lh, the filter cake washed with ethanol, then blast drying at 105 ° C 5h, to obtain ultrafine powder solid 6. 8g, yield of 81. 9%, HPLC purity was 99.8%, as measured crystal X- ray powder diffraction pattern of FIG. 1 the basic consistent, as measured with a DSC thermogram consistent FIG. 2, the particle size distribution measurement is basically the same as Fig 3 (D90 <10ym).</span></div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">CLIP</span></em></strong></div>
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Pazopanib is a highly bio-available, multi- tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-l, -2, -3, platelet-derived factor receptor (PDGFR) -α, -β, cytokine receptor (cKit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). Pazopanib was recently approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma; thus adding to the other FDA-approved VEGF pathway inhibitors, sunitinib, bevacizumab (in combination with interferon) and sorafinib for this same indication.</div>
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Processes by which pazopanib and its intermediates can be synthesized have been described in US Patent No. 7,105,530 as well as in the published PCT application WO03/106416.</div>
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U.S. patent no. 7,105,530 disclosed pyrimidineamines and their derivatives thereof. These compounds are antineoplastic agents, and are useful in the treatment of various cancers and renal cell carcinoma. Among them pazopanib hydrochloride, chemically 5-[4-[N-(2,3-Dimethyl-2H-indazol-6-yl)-N-methylamino]pyrimidin-2- ylamino]-2-methylbenzenesulfonamide hydrochloride. Pazopanib hydrochloride is represented by the following structure:<br />Pazopanib hydrochloride is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR (Vascular endothelial growth factor receptors)- 1, VEGFR-2, VEGFR-3, PDGFR (Platelet-derived growth factor receptors )-a/p, and c-kit that blocks tumor growth and inhibits angiogenesis. It has been approved for renal cell carcinoma by the U.S. Food and Drug Administration. Pazopanib hydrochloride may also be active in ovarian cancer and soft tissue sarcoma. Pazopanib hydrochloride also appears effective in the treatment of non-small cell lung carcinoma. Pazopanib hydrochloride is marketed under the brand name Votrient® by Glaxosmithkline in the form of tablet.</div>
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Processes for the preparation of pazopanib hydrochloride and related compounds were disclosed in U.S. patent no. 7,105,530 and U.S. patent no. 7,262,203.</div>
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According to U.S. patent no. 7,105,530, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine with 5- amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in isopropanol and ether.</div>
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U.S. patent application publication no. 2006/0252943 disclosed a process for the preparation of pazopanib hydrochloride. According to this patent, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3- trimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in ethanol or methanol or tetrahydrofuran or acetonitrile and dioxane.</div>
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<br /></div>
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<img alt="" class="" data-mce-src="http://journals.prous.com/journals/dof/20063107/html/df310585/images/scheme1.gif" height="478" src="http://journals.prous.com/journals/dof/20063107/html/df310585/images/scheme1.gif" style="height: auto; max-width: 100%;" width="792" /></div>
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Drugs of the Future, 2006, 31 (7): 585-589<br />WO0306416</div>
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CLIP</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-57#S50" href="http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-57#S50">An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals</a></div>
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<div>
Marcus Baumann<a data-mce-href="mailto:theitc@cam.ac.uk" href="mailto:theitc@cam.ac.uk"><img alt="Email of corresponding author" data-mce-src="http://beilstein-journals.org/bjoc/images/env_red.gif" src="http://beilstein-journals.org/bjoc/images/env_red.gif" style="height: auto; max-width: 100%;" /></a>, Ian R. Baxendale<a data-mce-href="mailto:theitc@cam.ac.uk" href="mailto:theitc@cam.ac.uk"><img alt="Email of corresponding author" data-mce-src="http://beilstein-journals.org/bjoc/images/env_red.gif" src="http://beilstein-journals.org/bjoc/images/env_red.gif" style="height: auto; max-width: 100%;" /></a>, Steven V. Ley<a data-mce-href="mailto:theitc@cam.ac.uk" href="mailto:theitc@cam.ac.uk"><img alt="Email of corresponding author" data-mce-src="http://beilstein-journals.org/bjoc/images/env_red.gif" src="http://beilstein-journals.org/bjoc/images/env_red.gif" style="height: auto; max-width: 100%;" /></a> and Nikzad Nikbin<a data-mce-href="mailto:theitc@cam.ac.uk" href="mailto:theitc@cam.ac.uk"><img alt="Email of corresponding author" data-mce-src="http://beilstein-journals.org/bjoc/images/env_red.gif" src="http://beilstein-journals.org/bjoc/images/env_red.gif" style="height: auto; max-width: 100%;" /></a></div>
<div>
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK</div>
<div>
<img alt="Email of corresponding author" data-mce-src="http://beilstein-journals.org/bjoc/images/env_red.gif" src="http://beilstein-journals.org/bjoc/images/env_red.gif" style="height: auto; max-width: 100%;" /> Corresponding author email</div>
<div>
Editor-in-Chief: J. Clayden</div>
<div>
<i>Beilstein J. Org. Chem.</i> <b>2011,</b> <i>7,</i> 442–495.</div>
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Pazopanib (<b>246</b>, Votrient) is a new potent multi-target tyrosine kinase inhibitor for various human cancer cell lines. Pazopanib is considered a promising replacement treatment to imatinib and sunitinib and was approved for renal cell carcinoma by the FDA in late 2009. The indazole system is built up via diazotisation and spontaneous cyclisation of 2-ethyl-5-nitroaniline (<b>247</b>) using <i>tert</i>-butyl nitrite. The resulting indazole structure <b>249</b> can be methylated entirely regioselectively with either Meerwein’s salt, trimethyl orthoformate or dimethyl sulfate. A tin-mediated reduction of the nitro group unmasks the aniline which undergoes nucleophilic aromatic substitution to introduce the pyrimidine system with the formation of <b>253</b>. Methylation of the secondary amine function with methyl iodide prior to a second S<sub>N</sub>Ar reaction with a sulfonamide-derived aniline affords pazopanib .</div>
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Synthesis of pazopanib.</div>
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<ol>
<li>Pandite, A. N.; Whitehead, B. F.; Ho, P. T. C.; Suttle, A. B. Cancer Treatment Method. WO Patent 2007/064753, June 7, 2007.</li>
<li>Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.; Epperly, A. H.; Hinkle, K. W.; Hunter, R. N., III; Johnson, J. H.; Knick, V. B.; Laudeman, C. P.; Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.; Veal, J. M.; Wang, L.; Stafford, J. A. <i>J. Med. Chem.</i><b>2008,</b><i>51,</i>4632–4640. <a data-mce-href="http://dx.doi.org/10.1021%2Fjm800566m" href="http://dx.doi.org/10.1021%2Fjm800566m" target="_blank">doi:10.1021/jm800566m</a></li>
</ol>
CLIP</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-29.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-29.jpg" rel="attachment wp-att-8168"><img alt="STR1" class="alignnone size-full wp-image-8168" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-29.jpg" height="408" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-29.jpg" style="height: auto; max-width: 100%;" width="691" /></a></div>
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<br /></div>
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Pazopanib hydrochloride (Votrient )<br />Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/b, and c-kit that blocks tumor growth and inhibits angiogenesis. It was approved for renal cell carcinoma by the U.S. Food<br />and Drug Administration in 2009 and is marketed under the trade name Votrient by the drug’s manufacturer, GlaxoSmithKline. The<br />synthesis of pazopanib begins with methylation of 3-methyl-6-nitroindazole (82) with trimethyl orthoformate in the presence of BF3 OEt to give indazole 83 in 65% yield (Scheme 14).65 Reduction of the nitro group was achieved via transfer hydrogenation to give 84 in 97% yield, and this was followed by coupling the aniline with 2,4-dichloropyrimidine in a THF-ethanol mixture at elevated<br />temperature to provide diarylamine 85 in 90% yield. The aniline nitrogen was then methylated using methyl iodide to give 86 in<br />83% yield prior to coupling with 5-amino-2-methylbenzenesulfonamide (87) and salt formation using an alcoholic solution of<br />HCl to furnish pazopanib hydrochloride (XIV) in 81% yield.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR4-1.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR4-1.jpg" rel="attachment wp-att-8169"><img alt="STR4" class="alignnone size-full wp-image-8169" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR4-1.jpg" height="164" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR4-1.jpg" style="height: auto; max-width: 100%;" width="457" /></a></h3>
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FDA Orange Book Patents<button class="toggle-btn helptip-btn"></button><button class="fullscreen-btn"></button></h3>
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<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">FDA Orange Book Patents: 1 of 3</th></tr>
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<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=7262203.PN.&OS=PN/7262203&RS=PN/7262203" href="http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=7262203.PN.&OS=PN/7262203&RS=PN/7262203" rel="nofollow" title="More information...">7262203</a></td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Expiration</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 19, 2021</td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">NOVARTIS PHARMS CORP</td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Drug Application</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ol>
<li><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_DISC" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_DISC">N022465</a> (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)</li>
<li><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_RX" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_RX">N022465</a> (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)</li>
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<div class="reference" data-ref-number="1">
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<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">FDA Orange Book Patents: 2 of 3</th></tr>
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<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=8114885.PN.&OS=PN/8114885&RS=PN/8114885" href="http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=8114885.PN.&OS=PN/8114885&RS=PN/8114885" rel="nofollow" title="More information...">8114885</a></td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Expiration</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 19, 2021</td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">NOVARTIS PHARMS CORP</td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Drug Application</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ol>
<li><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_DISC" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_DISC">N022465</a> (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)</li>
<li><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_RX" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_RX">N022465</a> (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)</li>
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<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">FDA Orange Book Patents: 3 of 3</th></tr>
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<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=7105530.PN.&OS=PN/7105530&RS=PN/7105530" href="http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=7105530.PN.&OS=PN/7105530&RS=PN/7105530" rel="nofollow" title="More information...">7105530</a></td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Expiration</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oct 19, 2023</td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">NOVARTIS PHARMS CORP</td></tr>
<tr><td class="limited" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Drug Application</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ol>
<li><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_DISC" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_DISC">N022465</a> (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)</li>
<li><a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_RX" href="http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=022465&TABLE1=OB_RX">N022465</a> (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)</li>
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<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
VOTRIENT (pazopanib) is a <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=22836" href="http://www.rxlist.com/script/main/art.asp?articlekey=22836" rel="dict">tyrosine</a> kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C<sub>21</sub>H<sub>23</sub>N<sub>7</sub>O<sub>2</sub>S•HCl and a molecular weight of 473.99. Pazopanib hydrochloride has the following chemical structure:</div>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><img alt="VOTRIENT (pazopanib) Structural Formula Illustration" data-mce-src="http://images.rxlist.com/images/rxlist/votrient1.gif" height="153" src="http://images.rxlist.com/images/rxlist/votrient1.gif" style="height: auto; max-width: 100%;" width="247" /></td></tr>
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Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.</div>
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Tablets of VOTRIENT are for oral administration. Each 200 mg tablet of VOTRIENT contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base. The inactive ingredients of VOTRIENT are:<b>Tablet Core:</b> Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. <b>Coating:</b> Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.</div>
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<li id="cite_note-FierceBiotech-4">FierceBiotech. 2008-09-15. Retrieved 2010-08-10.</li>
</ol>
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<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Country</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent Number</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Approved</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Expires (estimated)</th></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">United States</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7105530</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2009-10-19</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2023-10-19</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">United States</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7262203</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2009-10-19</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2021-12-19</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">United States</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8114885</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2009-10-19</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2021-12-19</td></tr>
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JUNE 4 2013 old article cut paste</div>
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GlaxoSmithKline’s (GSK) Votrient (pazopanib) has met the primary objective of a statistically significant improvement in the time to disease progression or death that is the progression-free survival (PFS) against placebo in Phase III ovarian cancer..</div>
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<a data-mce-href="http://clinicaltrials.pharmaceutical-business-review.com/news/gsks-votrient-meets-primary-objective-in-phase-iii-ovarian-cancer-trial-030613" href="http://clinicaltrials.pharmaceutical-business-review.com/news/gsks-votrient-meets-primary-objective-in-phase-iii-ovarian-cancer-trial-030613">http://clinicaltrials.pharmaceutical-business-review.com/news/gsks-votrient-meets-primary-objective-in-phase-iii-ovarian-cancer-trial-030613</a></div>
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<img alt="" data-mce-src="http://medicineworld.org/images/blogs/9-2008/chemotherapy-546340.jpg" src="http://medicineworld.org/images/blogs/9-2008/chemotherapy-546340.jpg" style="height: auto; max-width: 100%;" /></div>
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Pazopanib shrinks lung cancers before surgery</div>
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Formulation</h2>
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<a data-mce-href="https://www.google.co.in/patents/US20140255505" href="https://www.google.co.in/patents/US20140255505">https://www.google.co.in/patents/US20140255505</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Pazopanib is an angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors (PDGFR)-α/-β, and c-Kit. The hydrochloride salt of pazopanib (5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide) is marketed by GlaxoSmithKline as Votrient®, which is approved in the United States and other countries for the treatment of renal cell carcinoma (RCC).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Votrient® is currently prescribed to adults in the form of 200 mg tablets for oral administration, with each 200 mg tablet containing an amount of pazopanib hydrochloride equivalent to 200 mg of pazopanib free base.</div>
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Though the current tablets are acceptable of use in adults, the tablets are not preferred for use in potential future use for administering pazopanib to children. In pediatric populations, it is often desired that drug be available as a powder for reconstitution to an oral suspension. Manufacture of such a powder requires dry blending of various excipients with the active substance to provide good flow properties and content uniformity of the powder blend.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Several additional challenges exist concerning the use of pazopanib in a pediatric formulation. For instance, the nature of the drug substance favors conversion from the hydrochloride salt to the free base and hydrate forms in an aqueous environment such that standard formulations fail to provide adequate suspension stability at long term storage conditions of 25° C./65% RH or room temperature. Further, the drug has been found to have a bitter taste and, therefore, taste masking is critical.It is desired to invent a pediatric formulation of pazopanib hydrochloride suitable for administration to a pediatric population</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist columns references-column-count references-column-count-2" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<ol class="references">
<li id="cite_note-MSR-1"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://reference.medscape.com/drug/votrient-pazopanib-999306#showall" href="http://reference.medscape.com/drug/votrient-pazopanib-999306#showall" rel="nofollow">"Votrient (pazopanib) dosing, indications, interactions, adverse effects, and more"</a>. <i>Medscape Reference</i>. WebMD<span class="reference-accessdate">. Retrieved <span class="nowrap">27 January</span> 2014</span>.</cite></span></li>
<li id="cite_note-DM-2"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=f5b7b3a4-c3a4-4722-8ca5-8f6a5c622553&type=pdf&name=f5b7b3a4-c3a4-4722-8ca5-8f6a5c622553" href="http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=f5b7b3a4-c3a4-4722-8ca5-8f6a5c622553&type=pdf&name=f5b7b3a4-c3a4-4722-8ca5-8f6a5c622553" rel="nofollow">"VOTRIENT (pazopanib hydrochloride) tablet, film coated [GlaxoSmithKline LLC]"</a>(PDF). <i>DailyMed</i>. GlaxoSmithKline LLC. November 2013<span class="reference-accessdate">. Retrieved <span class="nowrap">27 January</span> 2014</span>.</cite></span></li>
<li id="cite_note-EMA-3"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001141/WC500094272.pdf" href="http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001141/WC500094272.pdf" rel="nofollow">"Votrient : EPAR - Product Information"</a> (PDF). <i>European Medicines Agency</i>. Glaxo Group Ltd. 23 January 2014<span class="reference-accessdate">. Retrieved <span class="nowrap">27 January</span> 2014</span>.</cite></span></li>
<li id="cite_note-EMC-4"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.medicines.org.uk/emc/medicine/23148/SPC/Votrient+200+mg+and+400+mg+film+coated+tablets/" href="http://www.medicines.org.uk/emc/medicine/23148/SPC/Votrient+200+mg+and+400+mg+film+coated+tablets/" rel="nofollow">"Votrient 200 mg and 400 mg film coated tablets - Summary of Product Characteristics (SPC)"</a>. <i>electronic Medicines Compendium</i>. GlaxoSmithKline UK. 20 December 2013<span class="reference-accessdate">. Retrieved <span class="nowrap">27 January</span> 2014</span>.</cite></span></li>
<li id="cite_note-TGA-5"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-07077-3" href="https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-07077-3" rel="nofollow">"PRODUCT INFORMATION VOTRIENT® TABLETS"</a> (PDF). <i>TGA eBusiness Services</i>. GlaxoSmithKline Australia Pty Ltd. 25 March 2013<span class="reference-accessdate">. Retrieved <span class="nowrap">27 January</span> 2014</span>.</cite></span></li>
<li id="cite_note-PBS-6"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.pbs.gov.au/medicine/item/2232L" href="http://www.pbs.gov.au/medicine/item/2232L" rel="nofollow">"Pharmaceutical Benefits Scheme (PBS) - Pazopanib"</a>. <i>Pharmaceutical Benefits Scheme</i>. Australian Government<span class="reference-accessdate">. Retrieved <span class="nowrap">27 January</span> 2014</span>.</cite></span></li>
<li id="cite_note-7"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.pharmac.govt.nz/Schedule?osq=Pazopanib" href="http://www.pharmac.govt.nz/Schedule?osq=Pazopanib" rel="nofollow">"Pazopanib - Online Pharmaceutical Schedule"</a>. Pharmaceutical Management Agency<span class="reference-accessdate">. Retrieved <span class="nowrap">9 June</span> 2015</span>.</cite></span></li>
<li id="cite_note-FierceBiotech-8"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_ref-FierceBiotech_8-0" href="https://en.wikipedia.org/wiki/Pazopanib#cite_ref-FierceBiotech_8-0">^</a></b></span> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.fiercebiotech.com/press-releases/pazopanib-shows-encouraging-activity-several-tumour-types-including-soft-tissue-sarco" href="http://www.fiercebiotech.com/press-releases/pazopanib-shows-encouraging-activity-several-tumour-types-including-soft-tissue-sarco" rel="nofollow">"Pazopanib shows encouraging activity in several tumour types, including soft tissue sarcoma and ovarian cancer"</a>. FierceBiotech. 2008-09-15<span class="reference-accessdate">. Retrieved <span class="nowrap">2010-08-10</span></span>.</cite></span></li>
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<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">LUO G. ET AL.: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Microwave-assisted+synthesis+of+aminopyrimidines%22" href="http://scholar.google.com/scholar?q=%22Microwave-assisted+synthesis+of+aminopyrimidines%22">Microwave-assisted synthesis of aminopyrimidines</a>", TETRAHEDRON LETTERS, vol. 43, no. 33, 2002, pages 5739 - 5742, XP004372432</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">See also references of <a data-mce-href="http://www.google.com/patents/EP2646431A4#npl-citations" href="http://www.google.com/patents/EP2646431A4#npl-citations">EP2646431A4</a></td></tr>
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<tr class="patent-data-table"><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Citing Patent</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Filing date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Publication date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title</th></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2014085373A1?cl=en" href="https://www.google.com/patents/WO2014085373A1?cl=en">WO2014085373A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 26, 2013</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 5, 2014</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Glaxosmithkline Llc</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Combination</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/CN103232443A?cl=en" href="https://www.google.com/patents/CN103232443A?cl=en">CN103232443A</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feb 1, 2013</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 7, 2013</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">天津药物研究院</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Indazole derivative crystal and its preparation method and use</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/CN104557881A?cl=en" href="https://www.google.com/patents/CN104557881A?cl=en">CN104557881A</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 30, 2014</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 29, 2015</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">山东博迈康药物研究有限公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Preparation method of pazopanib hydrochloride crystal form</td></tr>
</tbody></table>
</div>
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Boloor, A.; <i>et. al.</i> Pyrimidineamines as angiogenesis modulators. <b>US7105530B2</b></div>
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2. Boloor, A.; Harris, P. A.; <i>et. al.</i> Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor. J Med Chem <b>2008</b>, <i>51(15)</i>, 4632–4640.</div>
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3. Bhanushali, D. S.; <i>et. al.</i> Compositions and processes. <b>WO2011050159A1</b></div>
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4. Boloor, A.; <i>et. al. </i> Chemical Process. <b>WO2003106416A2</b></div>
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5. Pandite, A. M.; <i>et. al.</i> Cancer treatment method.<b> WO2007064753A2</b></div>
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<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">European Medicines Agency, "<a data-mce-href="http://scholar.google.com/scholar?q=%22CHMP+assessment+report%3A+Votrient%22" href="http://scholar.google.com/scholar?q=%22CHMP+assessment+report%3A+Votrient%22">CHMP assessment report: Votrient</a>", pages 1, 5, 6 (2010).</td></tr>
</tbody></table>
<a data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022465s000_ChemR.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022465s000_ChemR.pdf">http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022465s000_ChemR.pdf</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="http://peggyrcc.com/wp-content/uploads/2012/07/8-pazopanib1.jpg" src="http://peggyrcc.com/wp-content/uploads/2012/07/8-pazopanib1.jpg" style="height: auto; max-width: 100%;" /></div>
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Pazopanib">Pazopanib</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Pazopanib.svg" href="https://en.wikipedia.org/wiki/File:Pazopanib.svg"><img alt="Pazopanib.svg" data-file-height="486" data-file-width="677" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/7a/Pazopanib.svg/200px-Pazopanib.svg.png" height="144" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/7a/Pazopanib.svg/200px-Pazopanib.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/7/7a/Pazopanib.svg/300px-Pazopanib.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/7/7a/Pazopanib.svg/400px-Pazopanib.svg.png 2x" style="height: auto; max-width: 100%;" width="200" /></a></td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Pazopanib3Dan.gif" href="https://en.wikipedia.org/wiki/File:Pazopanib3Dan.gif"><img alt="Pazopanib3Dan.gif" data-file-height="256" data-file-width="256" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/77/Pazopanib3Dan.gif/200px-Pazopanib3Dan.gif" height="200" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/77/Pazopanib3Dan.gif/200px-Pazopanib3Dan.gif" srcset="//upload.wikimedia.org/wikipedia/commons/7/77/Pazopanib3Dan.gif 1.5x" style="height: auto; max-width: 100%;" width="200" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Votrient</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/monograph/pazopanib-hydrochloride.html" href="https://www.drugs.com/monograph/pazopanib-hydrochloride.html" rel="nofollow">Monograph</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/MedlinePlus" href="https://en.wikipedia.org/wiki/MedlinePlus" title="MedlinePlus">MedlinePlus</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.nlm.nih.gov"><a class="external text" data-mce-href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a610013.html" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a610013.html" rel="nofollow">a610013</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">License data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small>EU</small> <a data-mce-href="https://en.wikipedia.org/wiki/European_Medicines_Agency" href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency">EMA</a>: <span title="www.ema.europa.eu"><a class="external text" data-mce-href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Votrient" href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Votrient" rel="nofollow">Votrient</a></span></li>
<li><small>US</small> <span title="www.accessdata.fda.gov"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" title="U.S. Food and Drug Administration">FDA</a>: <a class="external text" data-mce-href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Pazopanib&SearchType=BasicSearch" href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Pazopanib&SearchType=BasicSearch" rel="nofollow">Pazopanib</a></span></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="Australia">AU</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#Australia" href="https://en.wikipedia.org/wiki/Pregnancy_category#Australia" title="Pregnancy category">D</a></li>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" title="Pregnancy category">D</a> (Evidence of risk)</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oral</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="Australia">AU</abbr>:</small> <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" href="https://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" title="Standard for the Uniform Scheduling of Drugs and Poisons">S4</a> (Prescription only)</li>
<li><small>CA</small>: <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
<li><small><abbr title="United Kingdom">UK</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">POM</a> (Prescription only)</li>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Plasma_protein_binding" href="https://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">>99%<sup class="reference" id="cite_ref-MSR_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1">[1]</a></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_metabolism" href="https://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Liver" href="https://en.wikipedia.org/wiki/Liver" title="Liver">Hepatic</a> (<a data-mce-href="https://en.wikipedia.org/wiki/CYP3A4" href="https://en.wikipedia.org/wiki/CYP3A4" title="CYP3A4">CYP3A4</a>, <a data-mce-href="https://en.wikipedia.org/wiki/CYP1A2" href="https://en.wikipedia.org/wiki/CYP1A2" title="CYP1A2">1A2</a> and<a data-mce-href="https://en.wikipedia.org/wiki/CYP2C8" href="https://en.wikipedia.org/wiki/CYP2C8" title="CYP2C8">2C8</a>-mediated)<sup class="reference" id="cite_ref-MSR_1-1"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1">[1]</a></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Biological_half-life" href="https://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">31.9 hours<sup class="reference" id="cite_ref-MSR_1-2"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1">[1]</a></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Excretion" href="https://en.wikipedia.org/wiki/Excretion" title="Excretion">Excretion</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Faeces (primary), urine (<4%)<sup class="reference" id="cite_ref-MSR_1-3"><a data-mce-href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1" href="https://en.wikipedia.org/wiki/Pazopanib#cite_note-MSR-1">[1]</a></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=444731-52-6" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=444731-52-6" rel="nofollow">444731-52-6</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_L01" href="https://en.wikipedia.org/wiki/ATC_code_L01" title="ATC code L01">L01XE11</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=L01XE11" href="http://www.whocc.no/atc_ddd_index/?code=L01XE11" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11525740" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11525740" rel="nofollow">11525740</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.9700526.html" href="http://www.chemspider.com/Chemical-Structure.9700526.html" rel="nofollow">9700526</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=7RN5DR86CK" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=7RN5DR86CK" rel="nofollow">7RN5DR86CK</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEMBL" href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL477772" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL477772" rel="nofollow">CHEMBL477772</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>21</sub><span title="Hydrogen">H</span><sub>23</sub><span title="Nitrogen">N</span><sub>7</sub><span title="Oxygen">O</span><sub>2</sub><span title="Sulfur">S</span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">437.517 g/mol</td></tr>
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////////////PAZOPANIB, <span class="">GW786034, Votrient, A<wbr></wbr>rmala, GW 786034, GW-<wbr></wbr>786034, </span><span class="">GW786034GW786034, V<wbr></wbr>OTRIENT, Pazopanib hydrochloride, FDA 2009, Antineoplastic, Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors, Renal Cell Carcinoma Therpay, Soft Tissue Sarcoma Therapy, パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид</span></div>
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O=S(=O)(N)c1c(ccc(c1)Nc2nccc(n2)N(c4ccc3c(nn(c3C)C)c4)C)C</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com4tag:blogger.com,1999:blog-1346483141860457136.post-11980479569568868002016-08-05T01:07:00.001-07:002016-08-05T01:07:52.894-07:00VELPATASVIR (GS-5816), GILEAD SCIENCES, велпатасвир, فالباتاسفير , 维帕他韦 ,<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="" class="" data-mce-src="http://drugspider.com/web/chemicalstructure/Velpatasvir.png" height="317" src="http://drugspider.com/web/chemicalstructure/Velpatasvir.png" style="height: auto; max-width: 100%;" width="755" /></div>
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<img alt="img" class="chemical-structure" data-mce-src="http://www.medkoo.com/uploads/product/Velpatasvir/image/Velpatasvir.gif" src="http://www.medkoo.com/uploads/product/Velpatasvir/image/Velpatasvir.gif" style="height: auto; max-width: 100%;" /></div>
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VELPATASVIR (GS-5816), GILEAD SCIENCES</div>
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CAS 1377049-84-7</div>
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<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Formula:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C49H54N8O8&sort=mw&sort_dir=asc" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C49H54N8O8&sort=mw&sort_dir=asc" title="Find all compounds with formula C49H54N8O8">C<sub>49</sub>H<sub>54</sub>N<sub>8</sub>O<sub>8</sub></a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Weight:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">883.00186 g/mol</td></tr>
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Hepatitis C virus NS 5 protein inhibitors</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">KEEP WATCHING AS I ADD MORE DATA, SYNTHESIS...............</span></h1>
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<span class="patent-bibdata-value-list"><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Gilead+Sciences,+Inc.%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Gilead+Sciences,+Inc.%22">Gilead Sciences, Inc.</a></span></span> INNOVATOR</div>
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<span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Elizabeth+M.+Bacon%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Elizabeth+M.+Bacon%22">Elizabeth M. Bacon</a>, </span><span class="patent-bibdata-value-list"><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Jeromy+J.+Cottell%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Jeromy+J.+Cottell%22">Jeromy J. Cottell</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Ashley+Anne+Katana%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Ashley+Anne+Katana%22">Ashley Anne Katana</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Darryl+Kato%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Darryl+Kato%22">Darryl Kato</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Evan+S.+Krygowski%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Evan+S.+Krygowski%22">Evan S. Krygowski</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22John+O.+Link%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22John+O.+Link%22">John O. Link</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22James+Taylor%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22James+Taylor%22">James Taylor</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Chinh+Viet+Tran%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Chinh+Viet+Tran%22">Chinh Viet Tran</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Martin+Teresa+Alejandra+Trejo%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Martin+Teresa+Alejandra+Trejo%22">Martin Teresa Alejandra Trejo</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Zheng-Yu+Yang%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Zheng-Yu+Yang%22">Zheng-Yu Yang</a>, </span><span class="patent-bibdata-value"><a data-mce-href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Sheila+Zipfel%22" href="https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Sheila+Zipfel%22">Sheila Zipfel</a></span>,</span></div>
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<img alt="Elizabeth Bacon" data-mce-src="https://media.licdn.com/media/AAEAAQAAAAAAAAOsAAAAJGFiMjc1MWYxLWU2OGYtNDY1OC05ZWZlLTc5YmY4MGVhMzMxZA.jpg" src="https://media.licdn.com/media/AAEAAQAAAAAAAAOsAAAAJGFiMjc1MWYxLWU2OGYtNDY1OC05ZWZlLTc5YmY4MGVhMzMxZA.jpg" style="height: auto; max-width: 100%;" /></div>
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<a data-mce-href="https://www.linkedin.com/in/elizabeth-bacon-174975111" href="https://www.linkedin.com/in/elizabeth-bacon-174975111"><span class="fn"><span class="full-name" dir="auto">Elizabeth Bacon</span></span></a></h1>
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Senior Research Associate II at Gilead Sciences</div>
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Methyl {(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-1 ,1 1 dihydroisochromeno[4',3':6,7]naphtho[1 ,2-d]imidazol-9-yl}-1 H-imidazol-2-yl)-5- methylpyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate</div>
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<span class="searchhit">methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate</span></div>
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methyl {(2S)-1 - [(2S,5S)-2-(5-{2-[(2S,4S)-l- {(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl) pyrrolidin-2-yl]-l,l 1 dihydroisochromeno [4',3':6,7]naphtho[l,2-d]imidazol-9-yl}-lH-imidazol-2-yl)- 5-methylpyrrolidin-l-yl]-3-methyl-l -oxobutan-2-yl}carbamate</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-60.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-60.jpg" rel="attachment wp-att-8007"><img alt="str1" class="alignnone wp-image-8007" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-60.jpg" height="261" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-60.jpg" style="height: auto; max-width: 100%;" width="147" /></a></div>
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<span class="fn"><span class="full-name" dir="auto"><a data-mce-href="https://www.linkedin.com/in/sheila-zipfel-88477b2" href="https://www.linkedin.com/in/sheila-zipfel-88477b2">Sheila Zipfel</a></span></span></h1>
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Research Scientist I at Gilead Sciences</div>
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<strong>{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(Méthoxycarbonyl)amino]-2-phénylacétyl}-4-(méthoxyméthyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-1,11-dihydroisochroméno[4',3':6,7]naphto[1,2-d]imidazol-2-yl)-5 -méthyl-1-pyrrolidinyl]-3-méthyl-1-oxo-2-butanyl}carbamate de méthyle</strong></div>
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<strong>Carbamic acid, N-[(1R)-2-[(2S,4S)-2-[4-[1,11-dihydro-2-[(2S,5S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-5-methyl-2-pyrrolidinyl][2]benzopyrano[4',3':6,7]naphth[1,2-d]imidazol-9-yl]-1H- imidazol-2-yl]-4-(methoxymethyl)-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-, methyl ester</strong></div>
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Methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-4-yl}-1,11-dihydro[2]benzopyrano[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-54.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-54.jpg" rel="attachment wp-att-7989"><img alt="str1" class="alignnone size-full wp-image-7989" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-54.jpg" height="304" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-54.jpg" style="height: auto; max-width: 100%;" width="834" /></a></div>
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<img alt="" class="" data-mce-src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcSDR64sNrJoEZuXWbUoNp2sntti6gJgNmxpIkr1O6ThSBchp7XY2Q" height="416" src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcSDR64sNrJoEZuXWbUoNp2sntti6gJgNmxpIkr1O6ThSBchp7XY2Q" style="height: auto; max-width: 100%;" width="796" /><img alt="Velpatasvir.png" class="structure-img" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=67683363&t=l" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=67683363&t=l" style="height: auto; max-width: 100%;" title="A structure of Velpatasvir" /></div>
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<img alt="" class="irc_mi iND22qLvZ4hc-pQOPx8XEepE" data-mce-src="https://newdrugapprovals.files.wordpress.com/2016/07/9257f-i-series.jpg" height="320" src="https://newdrugapprovals.files.wordpress.com/2016/07/9257f-i-series.jpg" style="height: auto; max-width: 100%;" width="610" /></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-61.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-61.jpg" rel="attachment wp-att-8010"><img alt="str1" class="alignnone size-full wp-image-8010" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-61.jpg" height="567" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-61.jpg" style="height: auto; max-width: 100%;" width="1001" /></a></div>
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<table border="1" cellpadding="10" cellspacing="0" class="generalInfo gvTables" id="MainContent_PublicProductProfileControl_dvGeneralInformationMain" rules="all"><tbody>
<tr><td style="font-family: inherit; font-size: inherit;">Description</td><td style="font-family: inherit; font-size: inherit;">Pan-genotypic HCV NS5A inhibitor</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Molecular Target</td><td style="font-family: inherit; font-size: inherit;"><a class="company_link" data-mce-href="http://www.biocentury.com/targets/hcv_ns5a_protein" href="http://www.biocentury.com/targets/hcv_ns5a_protein" id="MainContent_PublicProductProfileControl_dvGeneralInformationMain_hlMolecularTarget1" title="HCV NS5A protein">HCV NS5A protein</a> <a class="company_link mce-item-anchor" href="https://www.blogger.com/null" id="MainContent_PublicProductProfileControl_dvGeneralInformationMain_hlMolecularTarget2" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;"></a></td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Mechanism of Action</td><td style="font-family: inherit; font-size: inherit;">HCV non-structural protein 5A inhibitor</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Therapeutic Modality</td><td style="font-family: inherit; font-size: inherit;">Small molecule</td></tr>
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<tr><td style="font-family: inherit; font-size: inherit;">Latest Stage of Development</td><td style="font-family: inherit; font-size: inherit;">Phase II</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Standard Indication</td><td style="font-family: inherit; font-size: inherit;"><a class="company_link" data-mce-href="http://www.biocentury.com/diseases/infectious_hepatitis_c_virus_%28hcv%29" href="http://www.biocentury.com/diseases/infectious_hepatitis_c_virus_%28hcv%29" target="_blank" title="Hepatitis C virus (HCV)">Hepatitis C virus (HCV)</a></td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Indication Details</td><td style="font-family: inherit; font-size: inherit;">Treat HCV genotype 1 infection; Treat HCV infection</td></tr>
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<ul style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li class="data-list__property" id="at-a-glance_origniator"><span class="data-list__property-value">Gilead Sciences</span></li>
<li class="data-list__property" id="at-a-glance_class"><strong class="data-list__property-key">Class </strong><span class="data-list__property-value">Antivirals; Carbamates; Chromans; Imidazoles; Naphthols; Phenylacetates; Phosphoric acid esters; Pyrimidine nucleotides; Pyrrolidines; Small molecules</span></li>
<li class="data-list__property" id="at-a-glance_mechanismOfAction"><strong class="data-list__property-key">Mechanism of Action </strong><span class="data-list__property-value">Hepatitis C virus NS 5 protein inhibitors</span></li>
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<ul class="data-list__content data-list__content--highest-dev-phases" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li class="data-list__property"><strong class="data-list__property-key">Registered </strong><span class="data-list__property-value">Hepatitis C</span></li>
</ul>
<h3 class="data-list__heading" id="at-a-glance_mostRecentEvents" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Most Recent Events</h3>
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<li class="data-list__property"><strong class="data-list__property-key">14 Jul 2016</strong> <span class="data-list__property-value property-value--event-details">Registered for Hepatitis C in Canada (PO)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">08 Jul 2016</strong> <span class="data-list__property-value property-value--event-details">Registered for Hepatitis C in Liechtenstein, Iceland, Norway, European Union (PO)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">30 Jun 2016</strong> <span class="data-list__property-value property-value--event-details">Gilead Sciences plans a phase III trial for Hepatitis C (Combination therapy, Treatment-experienced) in Japan (PO (NCT02822794)</span></li>
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<img alt="" class="irc_mi ijHRuNmEQruk-pQOPx8XEepE" data-mce-src="http://www.trbimg.com/img-532cc3f0/turbine/la-15768901-h983208-jpg-20140321/2048/2048x1363" height="393" src="http://www.trbimg.com/img-532cc3f0/turbine/la-15768901-h983208-jpg-20140321/2048/2048x1363" style="height: auto; max-width: 100%;" width="591" /></div>
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<span class="irc_su" dir="ltr"><strong><em><span data-mce-style="color: #ff0000;" style="color: red;">Darryl Kato works on a hepatitis treatment at Gilead Sciences Inc.'s lab</span> </em></strong></span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Velpatasvir, also known as GS-5816, is a potent and selective Hepatitis C virus NS5A inhibitor. GS-5816 has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.</div>
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WO 2013/075029. Compound I has the formula:</div>
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<span class="searchhit"><br /><img alt="" class="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/US@@@US153621930@@@id00000064021122@@@7259270@@@us20150361085a1-20151217-c00002.png" height="161" src="https://patentscope.wipo.int/search/docservice_image/US@@@US153621930@@@id00000064021122@@@7259270@@@us20150361085a1-20151217-c00002.png" style="height: auto; max-width: 100%;" width="422" /></span></div>
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<span class="searchhit">methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate</span></div>
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<img alt="" class="irc_mi iEaKxo63dR8c-pQOPx8XEepE" data-mce-src="https://newdrugapprovals.files.wordpress.com/2016/07/584d0-shutterstock_89792167.jpg" height="393" src="https://newdrugapprovals.files.wordpress.com/2016/07/584d0-shutterstock_89792167.jpg" style="height: auto; max-width: 100%;" width="749" />.</div>
<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
PAPER</h1>
<h1 class="articleTitle" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="hlFld-Title">Patent Highlights: Recently Approved HCV NS5a Drugs</span></h1>
<div id="articleMeta" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Hughes%2C+David+L" href="http://pubs.acs.org/author/Hughes%2C+David+L" id="authors">David L. Hughes</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00241#cor1" href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00241#cor1"><sup>*</sup></a></span></div>
<div class="affiliations">
<div id="aff1">
<span class="institution">Cidara Therapeutics</span>, 6310 Nancy Ridge Dr., Suite 101, San Diego, California 92121, <span class="country">United States</span></div>
</div>
<div id="citation">
<cite>Org. Process Res. Dev.</cite>, Article ASAP</div>
<div id="doi">
<strong>DOI: </strong>10.1021/acs.oprd.6b00241, <a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00241" href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00241">http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00241</a></div>
<div id="pubDate">
</div>
<div id="correspondence">
*E-mail: <a data-mce-href="mailto:dhughes@cidara.com" href="mailto:dhughes@cidara.com">dhughes@cidara.com</a>.</div>
<div class="articleNote">
</div>
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<div class="hlFld-Abstract">
<h2 id="Abstract">
Abstract</h2>
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<div class="articleBody_abstractText">
Five inhibitors of the NS5a enzyme have been approved as part of oral regimens for the treatment of hepatitis C virus, including daclatasvir (Bristol-Myers Squibb), ledipasvir (Gilead Sciences), ombitasvir (AbbVie), elbasvir (Merck), and velpatasvir (Gilead Sciences). This article reviews worldwide patents and patent applications that have been published on synthetic routes and final forms for these five drugs.</div>
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<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<em><span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></em></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://google.com/patents/WO2013075029A1?cl=en" href="https://google.com/patents/WO2013075029A1?cl=en">https://google.com/patents/WO2013075029A1?cl=en</a></div>
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Example NP</div>
<div class="patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentimages.storage.googleapis.com/WO2013075029A1/imgf000136_0001.png" href="https://patentimages.storage.googleapis.com/WO2013075029A1/imgf000136_0001.png"><img alt="Figure imgf000136_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2013075029A1/imgf000136_0001.png" height="616" id="imgf000136_0001" src="https://patentimages.storage.googleapis.com/WO2013075029A1/imgf000136_0001.png" style="height: auto; max-width: 100%;" width="604" /></a></div>
<div class="patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Methyl {(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-1 ,1 1 dihydroisochromeno[4',3':6,7]naphtho[1 ,2-d]imidazol-9-yl}-1 H-imidazol-2-yl)-5- methylpyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Methyl {(2S)-l-[(2S,5S)-2-(5-{2-[(2S,4S)-l-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-l,ll dihydroisochromeno [4',3':6,7]naphtho[l,2-d]imidazol-9- yl}-lH-imidazol-2-yl)-5-methylpyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The synthesis of this compound was prepared according to the procedure of example LR-1 with the following modification. During the Suzuki coupling, (2S)-l-[(2S,5S)-2-(5-iodo-lH-imidazol- 2-yl)-5-methylpyrrolidin-l-yl]-2-[(l-meth^ was used in lieu of</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(2S)-l -[(2S)-2-(5-bromo-lH-imidazol-2-yl)pyrrolidin-l-yl]-2-[(l-methoxyethenyl)amino]-3- methylbutan-l-one. The crade material was purified by preparative HPLC to provide methyl {(2S)-1 - [(2S,5S)-2-(5-{2-[(2S,4S)-l- {(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl) pyrrolidin-2-yl]-l,l 1 dihydroisochromeno [4',3':6,7]naphtho[l,2-d]imidazol-9-yl}-lH-imidazol-2-yl)- 5-methylpyrrolidin-l-yl]-3-methyl-l -oxobutan-2-yl}carbamate as a white solid (17 mg, 0.019 mmol, 17%). <sup>l</sup>U NMR (400 MHz, cd<sub>3</sub>od) δ 8.63 (s, 1H), 8.19 (d, 1H), 8.04 (m, 1H), 7.87 (m, 2H), 7.66 (m, 2H), 7.52 - 7.39 (m, 6H), 5.50 (m, 2H), 5.32 (s, 2H), 5.16 (m, 1H), 4.12 (m, 1H), 3.80 (m, 4H), 3.66 (s, 6H), 3.43 (m, 4H), 3.23 (s, 3H), 2.72-1.99 (m, 9H), 1.56 (d, 3H), 1.29 (m, 1H), 0.99 (d, 3H), 0.88 (d, 3H).</div>
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<img alt="" class="irc_mut iEaKxo63dR8c-HwpH6ZlgJaI" data-mce-src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcRN2qpu_9uCFi2j3aWSNONgsHpSOnky479r16F0KcMwy_0Cp8nvRg" height="393" src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcRN2qpu_9uCFi2j3aWSNONgsHpSOnky479r16F0KcMwy_0Cp8nvRg" style="height: auto; max-width: 100%;" width="524" /></div>
<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<em><span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></em></h1>
<div class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=EA9081FA756B61CF36CAB52B75C92C1F.wapp1nA?docId=WO2015191437&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription" href="https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=EA9081FA756B61CF36CAB52B75C92C1F.wapp1nA?docId=WO2015191437&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription">US 20150361073 A1</a></div>
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Scheme 1</div>
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Compound (J)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000036_0001.gif" height="94" id="imgf000036_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000036_0001.gif" style="height: auto; max-width: 100%;" width="473" /> Compound (I) H CO- Com pound (G)</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000036_0002.gif" height="514" id="imgf000036_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000036_0002.gif" style="height: auto; max-width: 100%;" width="388" /></div>
<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000122_0001.gif" height="606" id="imgf000122_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000122_0001.gif" style="height: auto; max-width: 100%;" width="486" /></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sup>st</sup> alkylation: Conversion of Compound (I-a) to Compound (G-a)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000123_0001.gif" height="108" id="imgf000123_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000123_0001.gif" style="height: auto; max-width: 100%;" width="488" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound (I-a) (45 g, 1.0 equiv.), Compound (J-a) (26.7g, 1.03 equiv.) and potassium carbonate (20.7g, 1.5 equiv.) in dichloromethane (450 mL) were stirred at about 20 °C for approximately 3-4 hours. After the completion of the reaction, water (450 mL) was charged into the reactor and the mixture was stirred. Layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with 2 wt% NaH<sub>2</sub>PO4/10wt% NaCl solution (450 mL). The organic layer was then concentrated and the solvent was swapped from dichloromethane into tetrahydrofuran. A purified sample of Compound (G-a) has the following spectrum: ¾ NMR (400 MHz,</div>
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CDC1<sub>3</sub>) δ 7.90-7.94 (m, 1H), 7.81-7.85 (m, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 5.19-5.56 (2dd, 2H), 5.17 (s, 2H), 4.73 (t, 1H), 4.39-4.48 (m, 1H), 3.70-3.77 (m, 1H), 3.37-3.45 (m, 2H), 3.33-3.35 (d, 3H), 3.28-3.32 (m, 1H), 3.20-3.25 (dd, 1H), 2.92-2.96 (dt, 1H), 2.44-2.59 (m, 4H), 1.97-2.09 (m, 1H), 1.44 (d, 9H).</div>
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Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative starting material may be Compound (I) where X may be -CI, -Br, -OTs, -OS0<sub>2</sub>Ph, -OS0<sub>2</sub>Me, -OS0<sub>2</sub>CF<sub>3</sub>, -OS0<sub>2</sub>R, , and -OP(0)(OR)<sub>2</sub> and Y may be -CI, -Br, -OTs, -OS0<sub>2</sub>Ph, -OS0<sub>2</sub>Me, -OS0<sub>2</sub>CF<sub>3</sub>, -OS0<sub>2</sub>R, and -OP(0)(OR)<sub>2</sub>. R may be alkyl, haloalkyl, or an optionally substituted aryl.</div>
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Various bases may also be employed, such as phosphate salts (including but not limited to KH<sub>2</sub>P0<sub>4</sub>, K<sub>3</sub>P0<sub>4</sub>, Na<sub>2</sub>HP0<sub>4</sub>, and Na<sub>3</sub>P0<sub>4</sub>) and carbonate salts (including but not limited to Na<sub>2</sub>C0<sub>3</sub>,Cs<sub>2</sub>C0<sub>3</sub>, and NaHC0<sub>3</sub>). Where the starting material is Compound (J), KHC0<sub>3</sub> or preformed potassium, sodium, and cesium salts of Compound (J) may also be used.</div>
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Alternative solvents can include 2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, dimethylformamide, acetone, MEK, and MIBK.</div>
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The reaction temperature may range from about 10 °C to about 60 °C.</div>
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" alkylation: Conversion of Compound (G-a) to Compound (B-a):</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000124_0001.gif" height="111" id="imgf000124_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000124_0001.gif" style="height: auto; max-width: 100%;" width="489" /></div>
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A solution of Compound (G-a) (prepared as described earlier starting from 45 g of Compound (I-a)) was mixed with Compound (H) (42.9g, 1.5 equiv.), and cesium carbonate (26. lg, 0.8 equiv.). The reaction mixture was stirred at about 40-45 °C until reaction was complete and then cooled to about 20 °C. Water (450 mL) and ethyl acetate (225 mL) were added and the mixture was agitated. Layers were separated, and the aqueous layer was extracted with ethyl acetate (150 mL). Combined organic phase was concentrated and solvent was swapped to toluene. A purified sample of Compound (B-a) has the following spectrum: ¾ NMR (400 MHz, CDC1<sub>3</sub>) 57.90-7.93 (m, 1H), 7.81-7.83 (m, 1H), 7.73 (s, 1H), 7.63-7.64 (d, 1H), 7.59-7.60 (d, 1H), 5.52-5.63 (m, 1H), 5.30-5.43 (q, 1H), 5.13-5.23 (s+m, 3H), 4.56-4.64 (m, 2H), 4.39-4.48 (m, 1H), 4.20-4.27 (m, 1H), 3.62-3.79 (m, 2H), 3.66 (s, 2H), 3.36-3.45 (m, 2H), 3.34-3.35 (d, 3H), 3.07-3.25 (m, 3H), 2.59-2.37 (m, 5H), 1.97-2.16 (m, 3H), 1.60 (s, 3H), 1.38-1.45 (m, 12H), 0.91-1.03 (m, 6H).</div>
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Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative starting material may include Compound (G) where Y may be -CI, -Br, -OTs, -OS0<sub>2</sub>Ph, -OS0<sub>2</sub>Me, -OS0<sub>2</sub>CF<sub>3</sub>, -OS0<sub>2</sub>R, , or -OP(0)(OR)<sub>2</sub>. where R is alkyl, aryl, or substituted aryl. In some embodiments, the substituted aryl may be an aryl having one or more substituents, such as alkyl, alkoxy, hydroxyl, nitro, halogen, and others as discussed above.</div>
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Various bases may be employed. Non-limiting examples can include phosphate salts (including but not limited to KH<sub>2</sub>P0<sub>4</sub>, K<sub>3</sub>P0<sub>4</sub>, Na<sub>2</sub>HP0<sub>4</sub>, and Na<sub>3</sub>P0<sub>4</sub>) and carbonate salts (including but not limited to K<sub>2</sub>C0<sub>3</sub> or Na<sub>2</sub>C0<sub>3</sub>). If Compound (H) is used as the starting material, Li<sub>2</sub>C0<sub>3</sub> or preformed potassium, sodium, and cesium salt of Compound (H) may be employed.</div>
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Alternative solvents may include 2-methyltetrahydrofuran, dichloromethane, toluene, mixtures of THF/Toluene, isopropyl acetate, ethyl acetate, l-methyl-2-pyrrolidinone, Ν,Ν-dimethylacetamide, acetone, MEK,and MIBK. An alternative additive may be</div>
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potassium iodide, and the reaction temperature may range from about 40 °C to about 60 °C or about 40 °C to about 50 °C.</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000125_0001.gif" height="110" id="imgf000125_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000125_0001.gif" style="height: auto; max-width: 100%;" width="519" /></div>
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A toluene solution of Compound (B-a) (604 g solution from 45 g of Compound (I-a)) was charged to a reaction vessel containing ammonium acetate (185.2 g) and isopropanol (91.0 g). The contents of the reactor were agitated at about 90 °C until the reaction was complete (about 16 to 24 hours). The reaction mixture was cooled to about 45 °C, and then allowed to settle for layer separation. Water (226 g) was added to the organic phase, and the resulting mixture was separated at about 30 °C. Methanol (274 g), Celite (26.9 g) and an aqueous solution of sodium hydroxide (67.5 g, 50%) and sodium chloride (54.0 g) in water (608 g) were added to the organic phase, and the resulting mixture was agitated for a minimum of 30 minutes. The mixture was then filtered through Celite and rinsed forward with a mixture of toluene (250 g) and isopropanol (1 1 g). The biphasic filtrate was separated and water (223 g) was added to the organic phase, and the resulting mixture was agitated at about 30 °C for at least 15 minutes. The mixture was filtered through Celite and rinsed forward with toluene (91 g). The organic layer was concentrated by vacuum distillation to 355 g and was added over 30 minutes to another reactor containing w-heptane (578 g). The resulting slurry is filtered, with the wetcake was washed with w-heptane (450 mL) and dried in a vacuum oven to afford Compound (C-a). A purified sample of Compound (C-a) has the following spectrum: *H NMR (400 MHz, CDC1<sub>3</sub>) δ 12.27-11.60 (m, 1 H), 1 1.18-10.69 (m, 1 H), 7.83 - 7.44 (m, 4 H), 7.36 (d, J = 7.9 Hz, 1 H), 7.28 - 7.05 (m, 1 H), 5.65 - 5.25 (m, 1H), 5.25 - 4.83 (m, 4 H), 4.34 - 4.03 (m, 2 H), 3.93 - 3.63 (m, 4 H), 3.52 (s, 1 H), 3.35 (d, J = 2.4 Hz, 4 H), 3.19 - 2.94 (m, 4 H), 2.88 (dd, J = 12.0, 7.9 Hz, 3 H), 2.66 - 1.85 (m, 5 H), 1.79 (s, 5 H), 1.37 - 1.12 (m, 6H), 1.04-0.98 (m, 6 H), 0.82 (t, J = 7.7 Hz, 2 H).</div>
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Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative reagents, in lieu of ammonium acetate, can include hexamethyldisilazane, ammonia, ammonium formate, ammonium propionate, ammonium hexanoate, and ammonium octanoate. Various solvents, such as toluene, xylene, an alcohol</div>
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(including but not limited to isopropanol, 1-propanol, 1-butanol, 2-butanol, 2-methoxyethanol, and glycols, such as ethylene glycol and propylene glycol) may be employed. Alternative catalyst/additives may include magnesium stearate, acetic acid, propionic acid, and acetic anhydride. The reaction temperature may range from about 60 °C to about 110 °C or about 85 °C to about 95 °C.</div>
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D</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000126_0001.gif" height="91" id="imgf000126_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000126_0001.gif" style="height: auto; max-width: 100%;" width="514" /></div>
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Preparation of Compound (D-a) using DDQ as oxidant:</div>
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A solution of Compound (C-a) (255.84 g) in 2-methyltetrahydrofuran (1535 mL) was cooled to about 0 °C and acetic acid (0.92 mL) was added. To this mixture was added a solution of DDQ (76.98 g) in 2-methyltetrahydrofuran (385 mL) over about 30 minutes. Upon reaction completion, a 10 wt% aqueous potassium hydroxide solution (1275 mL) was added over about 30 minutes and the mixture was warmed to about 20 °C. Celite (101.5 g) was added and the slurry was filtered through Celite (50.0 g) and the filter cake was rinsed with 2-methyltetrahydrofuran (765 mL). The phases of the filtrate were separated. The organic phase was washed successively aqueous potassium hydroxide solution (1020 mL, 10 wt%), aqueous sodium bisulfite solution (1020 mL, 10 wt%), aqueous sodium bicarbonate solution (1020 mL, 5 wt%) and aqueous sodium chloride solution (1020 mL, 5 wt%). The organic phase was then concentrated to a volume of about 650 mL. Cyclopentyl methyl ether (1530 mL) was added and the resulting solution was concentrated to a volume of about 710 mL. The temperature was adjusted to about 40 °C and Compound (D-a) seed (1.0 g) was added. The mixture was agitated until a slurry forms, then methyl tert-butyl ether (2300 mL) was added over about 3 hours. The slurry was cooled to about 20 °C over about 2 hours and filtered. The filter cake was rinsed with methyl tert-butyl ether (1275 mL) and dried in a vacuum oven at about 40 °C to provide Compound (D-a). A purified sample of Compound (D-a) has the following spectrum: ¾ NMR (400 MHz, CDC1<sub>3</sub>) δ 13.05-10.50 (comp m, 2H), 8.65-6.95 (comp m, 8H), 5.50-5.35 (m, 2H), 5.25^1.60 (comp m, 3H), 4.35-4.20 (m, 1H), 4.00-3.65 (comp m, 4H), 3.60-3.45 (m, 1H), 3.45-3.25 (comp m, 4H), 3.25-3.00 (comp m, 2H), 2.95-1.65 (comp m, 6H), 1.47 (br s, 9H), 1.40-1.25 (comp m, 2H), 1.20-0.70 (comp m, 9H).</div>
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Alternative Preparation of Compound (D-a) using Mn02 as oxidant:</div>
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A mixture of Compound (C-a) (50.0 g), manganese (IV) oxide (152.8 g) and dichloromethane (500 mL) is stirred at about 20 °C. Upon completion of the reaction, Celite (15 g) was added. The resulting slurry was filtered through Celite (20 g) and the filter cake was rinsed with dichloromethane (500 mL). The filtrate was concentrated and solvent exchanged into cyclopentyl methyl ether (250 mL). The resulting solution was warmed to about 60 °C and treated with an aqueous potassium hydroxide solution (250 mL, 10wt%). The biphasic mixture is stirred at about 45 °C for about 12 hours. The phases are then separated and the organic phase is concentrated to a volume of about 150 mL. The concentrate is filtered, seeded with Compound (D-a) seed and agitated at about 40 °C to obtain a slurry. Methyl tert-butyl ether (450 mL) was added to the slurry over 30 minutes and the resulting mixture was cooled to about 20 °C. The precipitated solid was filtered, rinsed with methyl tert-butyl ether (250 mL) and dried in a vacuum oven at about 40 °C to obtain Compound (D-a).</div>
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Alternative Preparation of Compound (D-a) through catalytic dehydrogenation</div>
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A mixture of Compound (C-a) (2.5 g, 2.7 mmol, 1 equiv), 5% Pd/Al<sub>2</sub>0<sub>3</sub> (2.5 g) and 1-propanol (25 mL, degassed) was stirred at reflux under inert environment for about 5.5 hours. The reaction mixture was then cooled to ambient temperature and filtered through Celite, and the residue rinsed with 1-propanol (2 x 5 mL) to obtain a solution of Compound (D-a).</div>
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Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in a reaction scheme employing stoichiometric oxidants, alternative oxidants may include manganese(IV) oxide, copper(II) acetate, copper(II) trifluoroacetate, copper(II) chloride, copper(II) bromide, bromine (Br<sub>2</sub>), iodine (I<sub>2</sub>), N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1 ,4-benzoquinone, tetrachloro-l,4-benzoquinone (chloranil), eerie ammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide, άϊ-tert-butyl peroxide, benzoyl peroxide, oxygen ((¾), sodium hypochlorite, sodium hypobromite, tert-butyl hypochlorite, Oxone, diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene. Various additives may be employed, and non-limiting examples may be carbonate bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and the like), amines (e.g., triethylamine, diisopropylethylamine and the like), and acids (e.g., trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, ara-toluenesulfonic acid, methanesulfonic acid), sodium acetate, potassium acetate, and the like). The reaction temperature may range from about -10°C to 80 °C. The reaction may take place in solvents, such as halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), aromatic solvents (e.g., toluene, xylenes, etc.), ethereal solvents (tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 1 ,2-dimethoxyethane, diglyme, triglyme, etc.), alcoholic solvents (e.g., methanol, ethanol, w-propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, propylene glycol, etc.), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, etc.), ketone solvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), polar aprotic solvents (e.g., acetonitrile, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethyl sulfoxide, etc.), amine solvents (e.g., triethylamine, morpholine, etc.), acetic acid, and water.</div>
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In reaction schemes employing catalytic oxidants, alternative catalysts may include palladium catalysts (e.g., palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) chloride, palladium(II) bromide, palladium(II) iodide, palladium(II) benzoate, palladium(II) sulfate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-iert-butylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride, bis(benzonitrile)palladium(II) chloride, palladium on carbon, palladium on alumina, palladium on hydroxyapatite, palladium on calcium carbonate, palladium on barium sulfate, palladium(II) hydroxide on carbon), platinum catalysts (e.g., platinum on carbon, platinum(IV) oxide, chloroplatinic acid, potassium chloroplatinate), rhodium catalysts (e.g., rhodium on carbon, rhodium on alumina,</div>
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bis(styrene)bis(triphenylphosphine)rhodium(0)), ruthenium catalysts (e.g., ruthenium(II) salen, dichloro(para-cymene)ruthenium(II) dimer), iridium catalysts (e.g., iridium(III) chloride, (l,5-cyclooctadiene)diiridium(I) dichloride, bis(l,5-cyclooctadiene)iridium(I) tetrafluoroborate, bis(triphenylphosphine)(l,5-cyclooctadiene)iridium(I) carbonyl chloride, bis(triphenylphosphine)(l,5-cyclooctadiene)iridium(I) tetrafluoroborate), copper catalysts (e.g., copper(I) chloride, copper(II) chloride, copper(I) bromide, copper(II) bromide, copper(I) iodide, copper(II) iodide, copper(II) acetate, copper(II) trifluoroacetate, copper(I) trifluoromethanesulfonate, copper(II) trifluoromethanesulfonate, copper(II) sulfate), iron catalysts (e.g., iron(II) sulfate, iron(II) chloride, iron(III) chloride), vanadium catalysts (e.g., dichloro(ethoxy)oxovanadium, dichloro(isopropoxy)oxovanadium), manganese catalysts (e.g., manganese(rV) oxide, manganese(III) (salen) chloride), cobalt catalysts (e.g., cobalt(II) acetate, cobalt(II) chloride, cobalt(II) salen), indium(III) chloride, silver(I) oxide, sodium tungstate, quinone catalysts (e.g., 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, 1,4-benzoquinone, and tetrachloro-l,4-benzoquinone (chloranil)).</div>
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Alternative co-oxidants can include, but are not limited to, sodium nitrite, copper(II) acetate, sodium persulfate, potassium persulfate, ammonium persulfate, sodium perborate, nitrobenzenesulfonate, 2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPO), pyridine-N-oxide, hydrogen peroxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, benzoyl peroxide, oxygen (0<sub>2</sub>), sodium hypochlorite, sodium hypobromite, tert-butyl hypochlorite, oxone, diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene.</div>
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Varoius hydrogen acceptors may be employed. Non-limiting examples can include unsaturated hydrocarbons (e.g., tert-butylethylene, tert-butyl acetylene, 2-hexyne, cyclohexene, and the like), acrylate esters (e.g., methyl acrylate, ethyl acrylate, isopropyl acrylate, tert-butyl acrylate, and the like), maleate esters (e.g., dimethyl maleate, diethyl maleate, diisopropyl maleate, dibutyl maleate, and the like), fumarate esters (e.g., dimethyl fumarate, diethyl fumarate, diisopropyl fumarate, dibutyl fumarate, and the like), and quinones (e.g. chloranil, 1 ,4-benzoquinone, etc.).</div>
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Alternative additives may be employed, such as carbonate bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, etc.), amine bases (e.g., triethylamine, diisopropylethylamine, etc.), phosphines (e.g., triphenylphosphine, tri(ort zotolyl)phosphine, tricyclohexylphosphine, tri-w-butylphosphine, tri-tert-butylphosphine, etc.), acids (e.g., trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, ara-toluenesulfonic acid, methanesulfonic acid, etc.), sodium acetate, N-hydroxyphthalimide, salen, 2,2 '-bipyri dine, 9,10-phenanthroline, and quinine.</div>
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The reaction can proceed at temperatures ranging from about 10 °C to about 120 °C. Various solvents can be employed, including but not limited to halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, and the like), aromatic solvents (e.g., toluene, xylenes, and the like), ethereal solvents (tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme, triglyme, and the like), alcoholic solvents (e.g., methanol, ethanol, w-propanol, isopropanol, w-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, propylene glyco, and the like), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, and the like), ketone solvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, and the like), polar aprotic solvents (e.g., acetonitrile, Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethyl sulfoxide, and the like), amine solvents (e.g., triethylamine, morpholine, and the like), acetic acid, and water.</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000130_0001.gif" height="93" id="imgf000130_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000130_0001.gif" style="height: auto; max-width: 100%;" width="497" /></div>
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Acetyl chloride (135 mL, 5 equiv.) was added slowly to methanol (750 mL) under external cooling maintaining reaction temperature below 30 °C. The resulting methanolic hydrogen chloride solution was cooled to about 20 °C, and added slowly over about 1 hour to a solution of Compound (D-a) (300 g, 1 equiv.) in methanol (750 mL) held at about 60 °C, and rinsed forward with methanol (300 mL). The reaction mixture was agitated at about 60 °C until reaction was complete (about 1 hour), and then cooled to about 5 °C. The reaction mixture was adjusted to pH 7-8 by addition of sodium methoxide (25 wt. % solution in methanol, 370 mL) over about 20 minutes while maintaining reaction temperature below about 20 °C. Phosphoric acid (85 wt. %, 26 mL, 1 equiv.) and Celite (120 g) were added to the reaction mixture, which was then adjusted to about 20 °C, filtered, and the filter cake was rinsed with methanol (1050 mL). The combined filtrate was polish filtered and treated with phosphoric acid (85 wt. %, 104 mL, 4 equiv.). The mixture was was adjusted to about 60 °C, seeded with Compound (E-a) seed crystals (1.5 g), aged at about 60 °C for 4 hours and cooled slowly to about 20 °C over about 7.5 hours. The precipitated product was filtered, washed with methanol (2 x 600 mL), and dried in a vacuum oven at about 45 °C to provide</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound (E-a). <sup>!</sup>H NMR (400 MHz, D<sub>2</sub>0) δ 7.53-6.77 (comp m, 8H), 5.24-4.80 (comp m, 3H), 4.59-4.38 (comp m, 2H), 4.15-3.90 (m, 1H), 3.65-3.38 (comp m, 5H), 3.36-3.14 (comp m, 4H), 2.75 (s, 1H), 2.87-2.66 (m, 1H), 2.29-1.60 (comp m, 6H), 1.27 (d, 3H), 0.76 (m, 6H).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Alternative reagents and reaction conditions to those disclosed above may also be employed. Various deprotection agents are well known to those skilled in the art and include those disclosed in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (4th edition) J. Wiley & Sons, 2007, hereby incorporated by reference in its entirety. For example, a wide range of acids may be used, including but not limited to phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, thionyl chloride,and trimethylsilyl chloride. A wide range of solvents may be employed, including but not limited to water, ethanol, acetonitrile, acetone, tetrahydrofuran, 1 ,4-dioxane, and toluene. Deprotection may proceed at temperatures ranging from about 20 °C to about 110 °C or from about 55 °C to about 65 °C.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A wide range of bases may be employed as a neutralization reagent. Non-limiting examples can include sodium phosphate dibasic, potassium phosphate dibasic, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, N, N-diisopropylethylamine, and 4-methylmorpholine. Various solvents may be used for neutralization, such as water, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, acetonitrile, 2-butanone, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, dichloromethane, and dichloroethane.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Neutralization may proceed at temperatures ranging from about -20 °C to about 60 °C or about 5 °C to about 15 °C.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Various crystallization reagents can be employed. Non-limiting examples may be hydrochloric acid, hydrobromic acid, sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid, oxalic acid, and glucuronic acid. Solvents for crystallization can include, but is not limited to, water, ethanol, 1-propanol, 2-propanol, and acetonitrile. Crystallization may proceed at temperatures ranging from about -20 °C to about 100 °C.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Free-Basing of Compound (E-a) to Prepare Compound (E)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000131_0001.gif" height="57" id="imgf000131_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000131_0001.gif" style="height: auto; max-width: 100%;" width="496" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
ompound (E-a) OCH, H3CO- Compound (E)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound (E-a) (10.0 g, 10.1 mmol) was dissolved in water (100 g) and then dichloromethane (132 g) and 28% ammonium hydroxide (7.2 g) were added sequentially. The biphasic mixture was stirred for 45 minutes. Celite (2.2 g) was added, the mixture was filtered through a bed of additional Celite (5.1 g), and the phases were then separated. The lower organic phase was washed with water (50 g), filtered, and then concentrated by rotary evaporation to produce Compound (E). 'H NMR (400 MHz, CD<sub>3</sub>OD) δ 8.35-7.17 (m, 8H), 5.6^1.68 (m, 3H), 4.41-3.96 (m, 2H), 3.96-3.72 (br s, 1H), 3.74-3.48 (m, 2H), 3.42 (d, 2H), 3.33 (s, 3H), 3.28 (s, 1H), 3.19-3.01 (m, 1H), 3.00-2.79 (m, 1H), 2.69-1.82 (m, 6H), 1.80-1.45 (m, 3H), 1.21-0.73 (m, 8H).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, tris-hydrochloride salts of Compound (E) may be used. Various bases may be employed, such as sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Various solvents, such as 2-methyltetrahydrofuran and ethyl acetate, may be employed. The temperature may range from about 15 °C to about 25 °C.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Alternative Free-Basing of Compound (E-b) to Prepare Compound (E)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000132_0001.gif" height="69" id="imgf000132_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000132_0001.gif" style="height: auto; max-width: 100%;" width="494" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound (E-b) (15.2 g) was dissolved in water (100 g) and then dichloromethane</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(132 g) and 28% ammonium hydroxide (7.4 g) were added sequentially. The biphasic mixture was stirred for about 45 minutes. Celite (2.1 g) was added, the mixture was filtered through a bed of additional Celite (5.2 g), and the phases were then separated. The lower organic phase was washed with water (50 g), filtered, and then concentrated by rotary evaporation to produce Compound (E). *H NMR (400 MHz, CD<sub>3</sub>OD) δ 7.92-6.73 (m, 8H), 5.51-4.90 (m, 2H), 4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Salt Conversion of Compound (E-a) to Compound (E-b)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000132_0002.gif" height="68" id="imgf000132_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000132_0002.gif" style="height: auto; max-width: 100%;" width="496" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A solution of Compound (E-a) (10.0 g, 10.1 mmol), a solution of 37% HCI (10 g) in water (20 g), and acetonitrile (30 g)was warmed to about 50 °C and agitated for about lh. The solution was cooled to about 20 °C and acetonitrile (58 g) was charged to the reactor during which time a slurry formed. The slurry was stirred for about 21 h and then additional acetonitrile (39 g) was added. The slurry was cooled to about 0 °C, held for about 60 min and the solids were then isolated by filtration, rinsed with 7% (w/w) water in acetonitrile (22 g) previously cooled to about 5 °C. The wet cake was partially deliquored to afford</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound (E-b). *H NMR (400 MHz, D<sub>2</sub>0) δ 7.92-6.73 (m, 8H), 5.51^1.90 (m, 2H),</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).</div>
<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
</h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000133_0001.gif" height="120" id="imgf000133_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000133_0001.gif" style="height: auto; max-width: 100%;" width="492" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A flask was charged sequentially with 2-chloro-4,6-bis[3-(perfluorohexyl)propyloxy]-1,3,5-triazine ("CDMT") (2.2 giv) and methanol (8.9 g) and the slurry was cooled to about 0 °C. To the mixture was added NMM (1.3 g) over about 5 minutes, maintaining an internal temperature of less than 20 °C. The solution was stirred for about 20 minutes to produce a solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride in methanol.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
To a solution of Compound (E) (7.1 g) in dichloromethane (170 g) was added</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound (Γ) (2.8 g). The solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride in methanol was added over 2 minutes followed by a rinse of methanol (1.1 g). After about 2.5 h, the completed reaction solution was washed sequentially with aqueous 10% potassium bicarbonate solution (40 mL), 3% hydrochloric acid (40 mL), and aqueous 10% potassium bicarbonate solution (40 mL). The lower organic phase was washed with water (40 mL), filtered, and then concentrated by rotary evaporation to produce Compound (A). ¾ NMR (400 MHz, CD<sub>3</sub>OD) δ 8.56-6.67 (m, 13H), 5.76^1.94 (m, 4H), 4.86-4.67 (m, 1H), 4.47-3.98 (m, 1H), 3.98-2.72 (m, 15H), 2.74-1.77 (m, 7H), 1.77-1.40 (m, 2H), 1.39-0.53 (m, 8H).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, tris-phosphate salts or tris-hydrochloride salts of Compound (G) may be used as alternative starting material. The reaction may take place at a temperature range of from about 10 °C to about 20 °C. Alternative coupling agents include, but are not limited to, EDC/HOBt, HATU, HBTU, TBTU, BOP, PyClOP, PyBOP, DCC/HOBt, COMU, EDCLOxyma, T3P, and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate. An alternative bases that may be employed can be diisopropylethylamine. The reaction may proceed in DMF and at temperatures ranging from about -20 °C to about 30 °C.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Salt Formation and Crystallization of Compound (A)</div>
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Crystallization of Compound (A-a)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000134_0001.gif" height="68" id="imgf000134_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000134_0001.gif" style="height: auto; max-width: 100%;" width="493" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A flask was charged with Compound (A) (10 g) and ethanol (125 mL) and was then warmed to about 45 °C. Concentrated hydrochloric acid (2.3 mL) was added followed by Compound (A-a) seed crystals (5 mg). The mixture was cooled to about 20 °C over about 5 h and held for about an additional 1 1 h. The solids were isolated by filtration, washed with ethanol (2 x 20 mL), and deliquored to produce Compound (A-a). <sup>!</sup>H NMR (400 MHz, CD<sub>3</sub>OD) δ 8.94-7.22 (m, 14H), 5.78-5.1 1 (m, 5H), 4.53-4.04 (m, 1H), 3.99-3.57 (m, 10H), 3.57-3.41 (m, 2H), 2.99-2.24 (m, 5H), 2.24-1.85 (m, 3H), 1.80-1.50 (m, 2H), 1.39-0.73 (m, 8H).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Alternative Crystallization of Compound (A-b)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000134_0002.gif" height="68" id="imgf000134_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000134_0002.gif" style="height: auto; max-width: 100%;" width="491" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A reaction vessel was charged with Compound (A) (25.0 g) followed by ethanol (125 mL) and 10% H<sub>3</sub>PO<sub>4</sub> (250 mL). The solution was seeded with Compound (A-b) (100 mg) and stirred for about 17.5 h. The solids were isolated by filtration, washed with ethanol (2 x 5 mL), deliquored, and dried in a vacuum oven to produce Compound (A-b). <sup>J</sup>H NMR (400 MHz, D<sub>2</sub>0) δ 7.76-6.48 (m, 13H), 5.53^1.90 (m, 3H), 4.60-4.32 (m, 2H), 4.29-3.76 (m, 1H), 3.70-2.75 (m, 14H), 2.66-1.51 (m, 8H), 1.51-1.09 (m, 3H), 1.05-0.45 (m, 7H).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative acids may be hydrochloric acid, hydrobromic acid, L-tartaric acid. Various solvents may be employed, such as methanol, ethanol, water, and isopropanol. The reaction may proceed at temperatures ranging from about 5 °C to about 60 °C.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Free-Basing of Compound (A)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Free-Basing of Compound (A-a) to Prepare Compound (A)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000135_0001.gif" height="68" id="imgf000135_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000135_0001.gif" style="height: auto; max-width: 100%;" width="493" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A reaction vessel was charged with Compound (A-a) (18.2 g) followed by ethyl acetate (188 g) and 10% potassium bicarbonate (188 g) and the mixture was stirred for about 25 minutes. The phases were separated and the upper organic phase was then washed with water (188 mL). The resulting organic solution was concentrated, ethanol (188 g) was added, and the solution was evaporated to produce a concentrate (75 g). The resulting concentrate added into water (376 g) to produce a slurry. The solids were isolated by filtration, washed with water (38 g), de liquored and dried in a vacuum oven at about 50 °C to produce</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Compound (A).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Alternative Free-Basing of Compound (A-b) to Prepare Compound (A)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000135_0002.gif" height="58" id="imgf000135_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2015034655@@@id00000062733096@@@8029192@@@imgf000135_0002.gif" style="height: auto; max-width: 100%;" width="492" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
om poun -</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A reaction vessel was charged with Compound (A-b) (3.0 g) followed by EtOAc (15 mL) and 10% KHCO<sub>3</sub> (15 mL) and agitation was initiated. After about 5 h, the phases were separated and the organic phase was washed with water (15 mL) and then concentrated by rotary evaporation under vacuum. The residue was taken up in EtOH (4.5 mL) and then added to water (30 mL) to produce a slurry. After about 15 min, the solids were isolated by filtration rinsing forward water (3 x 3 mL). The solids were dried at about 50 to 60 °C vacuum oven for about 15 h to produce Compound (A).</div>
<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<img alt="" class="irc_mut iEaKxo63dR8c-HwpH6ZlgJaI" data-mce-src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcSHf6fp1PwH2oowisNwGLtT58hZ2V2cLGB_5Et9snGqpBm0PWwPtw" height="200" src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcSHf6fp1PwH2oowisNwGLtT58hZ2V2cLGB_5Et9snGqpBm0PWwPtw" style="height: auto; max-width: 100%;" width="132" /></h1>
<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
</h1>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<strong><em><span data-mce-style="color: #800000;" style="color: maroon;">CLIP AND ITS REFERENCES</span></em></strong></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="title2" id="d314170e1317">Synthetic Route—Final Steps</span></div>
<div class="NLM_p" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The final steps to velpatasvir from backbone dibromide <b>62</b> (Scheme 14) are described and claimed in a process chemistry patent application.<a class="ref" href="https://www.blogger.com/null">(43)</a> The bond disconnections are the same as described in the composition of matter patents.<a class="ref" href="https://www.blogger.com/null">(44)</a></div>
<div class="NLM_p" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The phenacyl bromide of <b>62</b> is selectively alkylated with the chiral methoxylmethyl proline <b>63</b> using K<sub>2</sub>CO<sub>3</sub> in CH<sub>2</sub>Cl<sub>2</sub> to provide intermediate<b>64</b>. After aqueous workup, the solvent is switched into THF for the alkylation of the secondary bromide with the 2-methylproline-Moc-<span class="smallcaps">l</span>-valine dipeptide <b>65</b> using Cs<sub>2</sub>CO<sub>3</sub> to afford bis-ester <b>66</b>.</div>
<div class="NLM_p" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Formation of the bis-imidazole <b>67</b> is conducted using NH<sub>4</sub>OAc in toluene/<i>i</i>-PrOH, conditions similar to those originally described for daclatasvir and also used for ledipasvir except that <i>i</i>-PrOH is added as cosolvent, likely for increased solubility. Dehydrogenation to the aromatic core <b>68</b> is accomplished with DDQ and HOAc in 2-MeTHF solvent.</div>
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Deprotection of the Boc group with HCl/MeOH affords the bis-amine <b>69</b> which is crystallized as a triphosphate salt.</div>
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The final amide coupling with the chiral phenylglycine carbamate fragment <b>70</b> mediated by CDMT affords velpatasvir. No yields are provided in the experimental section of the patent and characterization is limited to generalized <sup>1</sup>H NMR data, ie, the aromatic region of velpatasvir is reported as δ 8.56–6.67 (m, 13H).<a class="ref" href="https://www.blogger.com/null">(43)</a></div>
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</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-151.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-151.jpg" rel="attachment wp-att-7963"><img alt="STR1" class="alignnone wp-image-7963" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-151.jpg" height="794" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-151.jpg" style="height: auto; max-width: 100%;" width="534" /></a></div>
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</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-152.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-152.jpg" rel="attachment wp-att-7964"><img alt="STR1" class="alignnone wp-image-7964" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-152.jpg" height="454" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-152.jpg" style="height: auto; max-width: 100%;" width="508" /></a></div>
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</div>
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Synthetic RouteEarly Steps. Multiple routes to intermediates 62, 63, and 65 are described in the process<br />patent application but are not claimed.43 The route to 2-methylproline-Moc-valine fragment 65 is outlined in Scheme 15.45</div>
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</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-55.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-55.jpg" rel="attachment wp-att-7993"><img alt="str1" class="alignnone size-full wp-image-7993" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-55.jpg" height="331" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-55.jpg" style="height: auto; max-width: 100%;" width="461" /></a></div>
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N-Boc (S)-pyroglutamic acid ethyl ester is ring-opened with methylmagnesium bromide to form Boc-amine 71. Deprotection with TFA and reductive amination with NaBH(OAc)3 are conducted in a one-pot reaction. Hydride transfer to the intermediate imine occurs on the face opposite to the ethoxycarbonyl group to afford cis-pyrrolidine<br />72, which is isolated as the tosylate salt. Amide coupling with Moc-L-valine followed by hydrolysis affords the dipeptide 65.<br />Three routes are described for the synthesis of fragment 63. The first route, and the only chemistry in the patent that is<br />described on a multikilo scale, is outlined in Scheme 16.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-56.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-56.jpg" rel="attachment wp-att-7994"><img alt="str1" class="alignnone size-full wp-image-7994" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-56.jpg" height="434" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-56.jpg" style="height: auto; max-width: 100%;" width="461" /></a></div>
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</div>
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Dimethyl N-Boc-L-glutamate is formylated at low temperature with acetic formic anhydride, which is cyclized to the enamine 73 with TFA. The patent scheme shows both Boc groups present in structure 73, so it is not clear if this is an error or if the Boc groups remain intact upon TFA treatment and whether imine formation can occur with the Boc-protected amine.</div>
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Hydrogenation of the double bond is carried out with Pd/C;then the ester is reduced to the primary alcohol 74 with<br />NaBH4. Deprotection of both Boc groups is followed by reprotection of the nitrogen to afford 75. After methylation, the dicyclohexylamine salt of 63 is crystallized, presumably to remove the trans-diastereomer formed during the hydrogenation. After salt break, 63 free acid is crystallized from hexane/CH2Cl2.<br />The second approach to 63 starts with N-Boc-cis-4-cyano-Lproline methyl ester and converts the cyano group to the<br />methoxymethyl group in 4−5 steps (Scheme 17).</div>
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</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-57.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-57.jpg" rel="attachment wp-att-7995"><img alt="str1" class="alignnone size-full wp-image-7995" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-57.jpg" height="233" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-57.jpg" style="height: auto; max-width: 100%;" width="456" /></a></div>
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The stereochemistry appears to be maintained at both chiral centers through the sequence. Methanolysis of the cyano group to the methyl ester occurs with concomitant deprotection of the Boc group, so reprotection is necessary. The ester at the 4-position is then selectively hydrolyzed with 1.4 equiv of NaOH in THF at −1 °C to afford ester-acid 76. No yield is provided so no information is available for the selectivity of hydrolysis at the 4-position vs the more hindered 2-position, except that hydrolysis later in the sequence requires a temperature of 20 °C.<br />Reduction of the carboxylic acid to the primary alcohol is accomplished with borane−dimethyl sulfide followed by<br />hydrolysis of the methyl ester, then alkylation of the primary alcohol with MeI to afford 63, which is purified by<br />crystallization from i-PrOH/water. Alternatively, hydrolysis of the ester and alkylation can be carried out in a single pot reaction with 63 crystallized from toluene/heptane.<br />A number of routes to backbone 62 are described, but all rely on an alkylation/C−H activation sequence as outlined in<br />Scheme 18.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-58.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-58.jpg" rel="attachment wp-att-7996"><img alt="str1" class="alignnone size-full wp-image-7996" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-58.jpg" height="311" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-58.jpg" style="height: auto; max-width: 100%;" width="459" /></a></div>
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</div>
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An alternate bond disconnection for the synthesis of velpatasvir is described in a Chinese patent application in which left (77) and right-hand (78) fragments are more fully elaborated and then the tetracyclic backbone is constructed at a stereochemistry appears to be maintained at both chiral centers through the sequence. Methanolysis of the cyano group to the methyl ester occurs with concomitant deprotection of the Bocgroup, so reprotection is necessary. The ester at the 4-position is then selectively hydrolyzed with 1.4 equiv of NaOH in THF<br />at −1 °C to afford ester-acid 76. No yield is provided so no information is available for the selectivity of hydrolysis at the 4-position vs the more hindered 2-position, except that hydrolysis later in the sequence requires a temperature of 20 °C.<br />Reduction of the carboxylic acid to the primary alcohol is accomplished with borane−dimethyl sulfide followed by<br />hydrolysis of the methyl ester, then alkylation of the primary alcohol with MeI to afford 63, which is purified by<br />crystallization from i-PrOH/water. Alternatively, hydrolysis of the ester and alkylation can be carried out in a single pot reaction with 63 crystallized from toluene/heptane.<br />A number of routes to backbone 62 are described, but all rely on an alkylation/C−H activation sequence as outlined in<br />Scheme 18. An alternate bond disconnection for the synthesis of velpatasvir is described in a Chinese patent application in which left (77) and right-hand (78) fragments are more fully elaborated and then the tetracyclic backbone is constructed at a late stage.46 This route is more convergent than the Gilead route but overall requires a similar number of steps (Scheme19).</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-59.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-59.jpg" rel="attachment wp-att-7997"><img alt="str1" class="alignnone size-full wp-image-7997" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-59.jpg" height="197" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-59.jpg" style="height: auto; max-width: 100%;" width="466" /></a></div>
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Final Form.</div>
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A patent application describes and claims 19 crystal forms of velpatasvir, including free base (1 form), bis-HCl salt (5 forms), phosphate salt (9 forms), bis-HBr salt (1form), L-tartrate salt (2 forms), and D-tartrate salt (1 form).47</div>
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</div>
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Two patent applications describe solid dispersion formulations of velpitasvir alone and as a combination with sofosbuvir,48 suggesting that velpitasvir is rendered amorphous during the formulation process. According to the patent applications,several forms of velpitasvir API are suitable for use in the solid dispersion process although a specific claim is made for a spraydried process of free base in ethanol.48</div>
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(43) Allan, K. M.; Fujimori, S.; Heumann, L. V.; Huynh, G. M.;Keaton, K. A.; Levins, C. M.; Pamulapati, G. R.; Roberts, B. J.; Sarma,K.; Teresk, M. G.; Wang, X.; Wolckenhauer, S. A. Processes for Preparing Antiviral Compounds. U.S. Patent Application 2015/0361073 A1, December 17, 2015.<br />(44) (a) Bacon, E. M.; Cottrell, J. J.; Katana, A. A.; Kato, D.;Krygowski, E. S.; Link, J. O.; Taylor, J.; Tran, C. V.; Martin, T. A. T.;Yang, Z.-Y.; Zipfel, S. Antiviral Compounds. U.S. Patent 8,575,135 B2,November 5, 2013. (b) Bacon, E. M.; Cottrell, J. J.; Katana, A. A.;Kato, D.; Krygowski, E. S.; Link, J. O.; Taylor, J.; Tran, C. V.; Martin, T. A. T.; Yang, Z.-Y.; Zipfel, S. Antiviral Compounds. U.S. Patent 8,921,341 B2, December 30, 2014.<br />(45) The process patent43 appears to contain an error in structure Va,which should not contain a Boc group.</div>
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(46) Mu, X.; Liu, N. Velpatasvir Intermediate and PreparationMethod Thereof. Chinese Patent Application CN 105294713 A,February 3, 2016.<br />(47) Lapina, O. V.; Shi, B.; Wang, F.; Wolckenhauer, S. A. SolidForms of an Antiviral Compound. U.S. Patent Application 2015/0361085 A1, December 17, 2015.<br />(48) (a) Gorman, E.; Mogalian, E.; Oliyai, R.; Stefanidis, D.; Zia, V.Solid Dispersion Formulation of an Antiviral Compound. U.S. PatentApplication 2015/0064252 A1, March 5, 2015. (b) Gorman, E.;Mogalian, E.; Oliyai, R.; Stefanidis, D.; Wiser, L.; Zia, V. CombinationFormulation of Two Antiviral Compounds.</div>
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<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<em><span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></em></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
US 2015/0361085</div>
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<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=US153621930&redirectedID=true" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=US153621930&redirectedID=true">https://patentscope.wipo.int/search/en/detail.jsf?docId=US153621930&redirectedID=true</a></div>
<div class="para_text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" rules="none" style="border: 1px dashed rgb(187, 187, 187); width: 95%px;"><tbody>
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Compound I Form I</div>
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<table border="0" class="mce-item-table" rules="none" style="border: 1px dashed rgb(187, 187, 187); width: 95%px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><div class="para_text">
<a class="mce-item-anchor" href="https://www.blogger.com/null" name="0153" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;" title="Paragraph [0153]"></a> An additional stable form screen was performed using the same procedure as described above but included a crystalline intermediate (Compound II shown below) as seeds.</div>
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<span class="searchhit"><br /><img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/US@@@US153621930@@@id00000064021122@@@7259270@@@us20150361085a1-20151217-c00014.png" src="https://patentscope.wipo.int/search/docservice_image/US@@@US153621930@@@id00000064021122@@@7259270@@@us20150361085a1-20151217-c00014.png" style="height: auto; max-width: 100%;" /></span></div>
<div class="para_text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" data-mce-style="height: 148px;" rules="none" style="border: 1px dashed rgb(187, 187, 187); height: 148px; width: 679px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><div class="para_text">
<a class="mce-item-anchor" href="https://www.blogger.com/null" name="0154" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;" title="Paragraph [0154]"></a> Compound II can be synthesized according to the methods described in WO 2013/075029 or U.S. Provisional Application No. 62/010,813. Needle-like particles were formed in butyronitrile, propionitrile, MEK/toluene, MEK/IPE and 2-pentanone/toluene. XRPD patterns of the wet solids were mostly consistent with each other with minor shifting in the peaks. The new form is named Compound I Form I, which is believed to be isostructural channel solvates with the respective solvents. After air drying all solids afforded amorphous XRPD patterns.</div>
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</div>
<div class="para_text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" data-mce-style="height: 152px;" rules="none" style="border: 1px dashed rgb(187, 187, 187); height: 152px; width: 673px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><div class="para_text">
<a class="mce-item-anchor" href="https://www.blogger.com/null" name="0155" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;" title="Paragraph [0155]"></a> Another stable form screen was performed using carbon (Darco G-60) treated Compound I, solvents, antisolvent (diisopropyl ether (IPE)), and seeds of Compound I Form I. This screen afforded crystalline solids from additional solvents as summarized in Table 1. The XRPD patterns of all of these solvates are consistent with Form I. The solvates were observed to convert to amorphous solids after drying. The XRPD patterns of Compound I were obtained in the experimental setting as follows: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 2-40°, step size 0.0167°, counting time: 15.875 s.</div>
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[TABLE-US-00002]<br />
<table border="1" cellpadding="0" cellspacing="0" style="width: 100%px;"><tbody>
<tr><td style="font-family: inherit; font-size: inherit;"><table border="0" cellpadding="5" cellspacing="0" class="mce-item-table" data-mce-style="height: 90px;" rules="none" style="border: 1px dashed rgb(187, 187, 187); height: 90px; width: 672px;"><colgroup><col align="center" width="781.2"></col></colgroup><thead>
<tr><td class="table_data" colspan=" > 1" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">TABLE 1</td></tr>
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<tr><td align="center" class="table_data" colspan=" > 1" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Stable form screen of carbon treated Compound I</td></tr>
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<table border="0" cellpadding="5" cellspacing="0" class="mce-item-table" data-mce-style="height: 789px;" rules="none" style="border: 1px dashed rgb(187, 187, 187); height: 789px; width: 670px;"><colgroup><col align="center" width="277.2"></col><col align="center" width="151.20000000000002"></col><col align="center" width="352.8"></col></colgroup><thead></thead><tbody valign="top">
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Solvents</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">PLM</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Comments</td></tr>
<tr><td align="center" class="table_data" colspan=" > 3" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Water</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Amorphous</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Slurry</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Water/EtOH</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Amorphous</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sticky phase coating</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ACN/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Birefringent</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Slurry of needles</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">MeOH/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Solution</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Seeds dissolved</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">EtOH/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Solution</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Seeds dissolved</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Acetone/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Birefringent</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Thick slurry of</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">needles</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">IPA/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Amorphous</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sticky coating</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">MEK/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Birefringent</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Thick slurry of</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">needles</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">MIBK/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Birefringent</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">White paste</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DCM/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Birefringent</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Thick slurry of small</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">needles</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">THF/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Solution</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Seeds dissolved</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2-MeTHF/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Amorphous</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">slurry</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">EtOAc/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Birefringent</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Thick slurry of</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">needles</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">IPAc/IPE</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Amorphous</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">slurry</td></tr>
<tr><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Toluene</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Amorphous</td><td class="table_data" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sticky coating</td></tr>
<tr><td align="center" class="table_data" colspan=" > 3" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
</tbody></table>
</td></tr>
</tbody></table>
</div>
<div class="para_text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" rules="none" style="border: 1px dashed rgb(187, 187, 187); width: 95%px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><div class="para_text">
<a class="mce-item-anchor" href="https://www.blogger.com/null" name="0156" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;" title="Paragraph [0156]"></a> The crystallinity of Compound I Form I can be improved by using a butyronitrile/butyl ether (BN/BE) mixture according to the following procedure.</div>
</td></tr>
</tbody></table>
</div>
<div class="para_text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" rules="none" style="border: 1px dashed rgb(187, 187, 187); width: 95%px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><div class="para_text">
<a class="mce-item-anchor" href="https://www.blogger.com/null" name="0157" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;" title="Paragraph [0157]"></a> The crystallization experiment was started with 40 to 75 mg Compound I in 1.1 to 3.0 mL of a BN/BE in a ratio of 7:4 (anhydrous solvents). The sample was held at RT over P<sub>2</sub>O<sub>5 </sub>for 23 days without agitation, and crystals formed in the solution. Afterwards, the liquid phase was replaced with butyl ether and the solids were obtained by centrifuge. These solids, corresponding to Compound I Form I, were used for the subsequent step as seed.</div>
</td></tr>
</tbody></table>
</div>
<div class="para_text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" rules="none" style="border: 1px dashed rgb(187, 187, 187); width: 95%px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><div class="para_text">
<a class="mce-item-anchor" href="https://www.blogger.com/null" name="0158" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;" title="Paragraph [0158]"></a> Purified Compound I (709.8 mg) was prepared from reflux of ethanol solution with Darco G-60 and was added to a new vial via a filter. While stirring, 7 mL of anhydrous butyronitrile (BN) was added. A clear orange solution was obtained. While stirring, 4 mL of anhydrous butyl ether (BE) was added slowly. To the solution was added 7.7 mg of Compound I Form I (from previous BN:BE crystallization experiment) as seed. The solution became cloudy and the seeds did not dissolve. The sample was stirred for ˜10 minutes before the agitation was stopped. The vial was capped and placed into a jar with some P<sub>2</sub>O<sub>5 </sub>solids at room temperature. After 6 days, a thin layer of bright yellow precipitate was observed on the wall and the bottom of the vial. The liquid phase was withdrawn and 3 mL of anhydrous butyl ether was added. Solids were scraped down with a spatula from the vial. The suspension was heated to about 30° C. for over half hour period and was held for ˜1 hour before cooling to 20° C. at about 0.1° C./min (without agitation). The sample was stored in ajar with P<sub>2</sub>O<sub>5 </sub>solids for 5 days. The sample was vacuum filtered using 0.22 μm nylon filter, washed with 2×200 μL of anhydrous butyl ether, and air dried under reduced pressure for about 5 minutes.</div>
</td></tr>
</tbody></table>
</div>
<div class="para_text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" data-mce-style="height: 197px;" rules="none" style="border: 1px dashed rgb(187, 187, 187); height: 197px; width: 670px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><div class="para_text">
<a class="mce-item-anchor" href="https://www.blogger.com/null" name="0159" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;" title="Paragraph [0159]"></a> XRPD analysis of the sample showed good very sharp peaks as shown in <b>FIG. 1</b>. The XRPD analysis setting was as follows: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 1-40°, step size 0.0167°, counting time: 36.83 s. The characteristic peaks of crystalline Compound I Form I include: 2.9, 3.6, 4.8, 5.2, 6.0° 2θ (<b>FIG. 1</b>). The XRPD pattern of Form I was successfully indexed, indicating that Form I is composed primarily of a single crystalline phase. Extremely large unit cell volume containing up to ˜60 API molecules in the unit cell was observed. The amorphous halo observed in the XRPD pattern could be a result of the size of the unit cell. Butyl ether stoichiometry could not be estimated. Two alternative indexing solutions were found: monoclinic and orthorhombic.</div>
</td></tr>
</tbody></table>
</div>
<div class="para_text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table border="0" class="mce-item-table" data-mce-style="height: 64px;" rules="none" style="border: 1px dashed rgb(187, 187, 187); height: 64px; width: 674px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" valign="top"><div class="para_text">
<a class="mce-item-anchor" href="https://www.blogger.com/null" name="0160" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;" title="Paragraph [0160]"></a> DSC and TGA data confirmed that Form I is a solvated form. DSC shows a broad endotherm with onset at 109° C. and small endotherm with onset at 177° C. (<b>FIG. 2</b>). TGA shows 22% weight loss below 150° C. (<b>FIG. 3</b>).</div>
</td></tr>
</tbody></table>
</div>
<h1 class="citation" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<em><span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></em></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
CN 105294713</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/CN105294713A?cl=en" href="https://www.google.com/patents/CN105294713A?cl=en">https://www.google.com/patents/CN105294713A?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentimages.storage.googleapis.com/pdfs/2601c633c50937ffb780/CN105294713A.pdf" href="https://patentimages.storage.googleapis.com/pdfs/2601c633c50937ffb780/CN105294713A.pdf">https://patentimages.storage.googleapis.com/pdfs/2601c633c50937ffb780/CN105294713A.pdf</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-40.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-40.jpg" rel="attachment wp-att-7968"><img alt="str1" class="alignnone size-full wp-image-7968" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-40.jpg" height="530" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-40.jpg" style="height: auto; max-width: 100%;" width="780" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-41.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-41.jpg" rel="attachment wp-att-7969"><img alt="str1" class="alignnone size-full wp-image-7969" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-41.jpg" height="505" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-41.jpg" style="height: auto; max-width: 100%;" width="767" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Example 12</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-39.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-39.jpg" rel="attachment wp-att-7967"><img alt="str1" class="alignnone size-full wp-image-7967" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-39.jpg" height="217" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-39.jpg" style="height: auto; max-width: 100%;" width="831" /></a></div>
<div class="patent-image small-patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Under nitrogen, was added l〇2g1 said, adding methylene burn 500 blood dissolved, 4mol / L fertilizer 1 1,4-dioxane SOOmL, football for 1 hour at room temperature, of the C (already burned: ethyl acetate 1: 1) point in the control board, the starting material spot disappeared, the reaction was stopped, the solvent was concentrated, was added (R & lt) -2- (methoxy several yl) -2-phenylacetic acid 29g, COMU60g, DMF blood 500, diisopropylethylamine 223M1,25 ° C reaction I h, ethyl acetate was added IL diluted, purified water is added IL painted twice, dried over anhydrous sulfate instrument, and concentrated, methanol was added SOOmL temperature 60 ° C dissolved, 250mL of purified water was slowly added dropwise, to precipitate a solid, the addition was completed, cooled to 50 ° C for 1 hour, cooled to room temperature, filtered, and concentrated to give Velpatasvir (GS-5816) product 90. 5g, 78. 2〇 yield / billion.</span> <span class="notranslate">H-NMR (400MHz, CDs isolated) 5 7. 94 - 7.67 (m, 4H), 7.59 of J = 9.1 Hz, 1H), 7. 52 (S, 1H), 7.48 - 7. 33 (m, 4H) , 7.11 of J = 18. 7Hz, 1H), 5.68 of J = 6.3Hz, 1H), 5.48 - 5.33 (m, 1H), 5.23 (dd, J = 24.1, 15.7Hz, 1H), 5.17 -5.03 (m, 3H), 4.22 (dd, J = 17.0, 9.6Hz, 1H), 4.16 - 4.01 (m, 1H), 3.91 (d, J = 24. 1 Hz, 1H), 3 83 -. 3. 68 (m, 1H), 3 68 -. 3. 59 (m, 3H), 3 59 -. 3. 49 (m, 3H), 3.38 (ddd, J = 15.9, 9.6, 5.7Hz, 2H), 3.28 - 3.14 (m, 5H), 3.10 (dd, J = 14.0, 8.2 Hz, 1H), 3.00 (dd, J = 17.8, 9.6Hz, 1H), 2.92 (dd, J = 14.5, 6.7 Hz, 1H), 2.73 - 2.41 (m, 2H), 2.40 - 2.11 (m, 2H), 2. 11 - 1.83 (m, 2H), 1.54 deduction J = 9. 7 Hz, 2H), 1.24 of J = 6.2Hz, 1H), 1.06 (t, J = 8.0 Hz, 1H), 0.99 of J = 6.8 Hz, 1H), 0. 94 (d, J = 6. 6Hz, 2H), 0. 85 (d, J = 6. 7Hz, 2H ).</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-54.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-54.jpg" rel="attachment wp-att-7989"><img alt="str1" class="alignnone size-full wp-image-7989" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-54.jpg" height="304" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-54.jpg" style="height: auto; max-width: 100%;" width="834" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Construction</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-42.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-42.jpg" rel="attachment wp-att-7977"><img alt="str1" class="alignnone size-full wp-image-7977" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-42.jpg" height="169" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-42.jpg" style="height: auto; max-width: 100%;" width="457" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-43.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-43.jpg" rel="attachment wp-att-7978"><img alt="str1" class="alignnone size-full wp-image-7978" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-43.jpg" height="223" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-43.jpg" style="height: auto; max-width: 100%;" width="720" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-44.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-44.jpg" rel="attachment wp-att-7979"><img alt="str1" class="alignnone size-full wp-image-7979" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-44.jpg" height="161" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-44.jpg" style="height: auto; max-width: 100%;" width="788" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-45.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-45.jpg" rel="attachment wp-att-7980"><img alt="str1" class="alignnone size-full wp-image-7980" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-45.jpg" height="127" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-45.jpg" style="height: auto; max-width: 100%;" width="768" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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<em><span data-mce-style="color: #ff0000;" style="color: red;">Clip and foot notes</span></em></h1>
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Velpatasvir only got its name last year and was previously known as GS-5816. That compound was only announced back in 2013 when Gilead showed the initial <i>in vitro</i>studies on a handful of posters. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#tPSVN" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#tPSVN" id="cite-tPSVN">[1]</a> <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#kzZZS" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#kzZZS" id="cite-kzZZS">[2]</a> Very little information is available on this follow-up compound. The following was pretty much the summary of their poster presentation.</div>
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<img alt="" class="portrait qtext_image zoomable_in zoomable_in_feed lazy_loaded lazy_loading" data-mce-src="https://qph.ec.quoracdn.net/main-qimg-991c62bade705db2f58ec09a97d4a2b8?convert_to_webp=true" height="890" src="https://qph.ec.quoracdn.net/main-qimg-991c62bade705db2f58ec09a97d4a2b8?convert_to_webp=true" style="height: auto; max-width: 100%;" width="776" /></div>
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To understand the medical significance of this study, Sofosbuvir is the best-in-class NS5B inhibitor from Gilead (see link for more information). <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#qotyF" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#qotyF" id="cite-qotyF">[3]</a> These inhibitors work the fastest when paired with a NS5A inhibitor like Daclatasvir or Ledipasvir (making up the Sofosbuvir+Ledipasvir = Harvoni combination) or the Viekira Pak combo. <i>Disclosure: I am an employee of Bristol-Myers Squibb which produces Daclatasvir</i>. However, HCV comprises of 7 different genotypes. Harvoni and Viekira Pak are approved against genotypes 1a, 1b. Harvoni is indicated for genotypes 4, 5, and 6. For the treatment of genotypes 2 and 3, sofosbuvir is generally combined with ribavirin or interferon which has notable side effects. While 70% of patients have genotype 1, for the remainder of patients with the other variants, they are still stuck with the more risky (and more expensive and longer) therapy.</div>
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I think this is the structure of GS-5816. It's not yet published in any journal. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#ULKDW" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#ULKDW" id="cite-ULKDW">[4]</a></div>
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For comparison, here is the structure of Ledipasvir, the first generation NS5A inhibitor used in Harvoni. Structurally speaking, they are pretty similar so it seems like GS-5816 is the product of good old fashioned medchem.<img alt="" class="landscape qtext_image zoomable_in_feed lazy_loaded lazy_loading" data-mce-src="https://qph.ec.quoracdn.net/main-qimg-3f10aa1b3226e76b88a6fca2974b5469?convert_to_webp=true" src="https://qph.ec.quoracdn.net/main-qimg-3f10aa1b3226e76b88a6fca2974b5469?convert_to_webp=true" style="height: auto; max-width: 100%;" /></div>
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The clearest summary of the 4 Phase III trials can be found on Gilead's website. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cLmHU" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cLmHU" id="cite-cLmHU">[5]</a>ASTRAL-1 was run on genotypes 1, 2, 4, 5, 6. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#BvlqF" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#BvlqF" id="cite-BvlqF">[6]</a> ASTRAL-2 focused on genotype 2. ASTRAL-3 focused on genotype 3. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#TtLcu" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#TtLcu" id="cite-TtLcu">[7]</a> ASTRAL-4 focused on HCV patients with Child-Pugh cirrhosis. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#DcNxW" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#DcNxW" id="cite-DcNxW">[8]</a> These patients previously had interferon treatment but had a poor response and are generally very sick.<img alt="" class="portrait qtext_image zoomable_in_feed lazy_loaded lazy_loading" data-mce-src="https://qph.ec.quoracdn.net/main-qimg-1a49b03b09b63e1f3b1e5edc05435ad9?convert_to_webp=true" src="https://qph.ec.quoracdn.net/main-qimg-1a49b03b09b63e1f3b1e5edc05435ad9?convert_to_webp=true" style="height: auto; max-width: 100%;" /></div>
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I think that a few interesting things stand out. ASTRAL-1 occurred from July 2014 to December 2014 but upon a request from the FDA, ASTRAL-2 and 3 were started in September 2014-July 2015 in order to have an isolated study on genotypes 2 and 3. For a 24 week study that's incredibly fast. As discussed elsewhere, clinical trials are often limited by the speed of patient enrollment and these studies can take years. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#jZBKG" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#jZBKG" id="cite-jZBKG">[9]</a> Here, they were able to find volunteers for a 1000 patient study within weeks. An interesting note about the clinical trial design, the ASTRAL-1 team knew that the historical cure rate was 85% and were able to correctly power the trial to get a statistically significant study on the first try. Also, deep sequencing was used to identify and stratify the HCV genotypes. In ASTRAL-1, 42% of the patients had NS5A resistance and 9% had NS5B resistance.</div>
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The market impact may be significant to Achillion which was a former partner of Gilead and a potential acquisition target. Achillion was working with Janssen on its own second generation NS5A inhibitor, odalasvir. This announcement may kill the market for a competing product as well as remove the acquisition hype.</div>
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How did Gilead come up with Velpatasvir? It really sounds like good solid science. Ledipasvir was developed to be a best-in-class NS5A inhibitor and it was recognized that it worked well with NS5B inhibitors. It was also understood that most of the NS5A inhibitors specific only towards certain N5SA genotypes and that there was a clear unmet need for patients with HCV genotypes 2 and 3. With the help of some computational modeling <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#LTIuk" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#LTIuk" id="cite-LTIuk">[10]</a>Gilead developed assays for all of the HCV genotypes to screen for a pan-genotype NS5A inhibitor to follow up to their 2014 Ledipasvir trials and leveraging their strategic advantage in the HCV market, were able to quickly ramp up 4 major clinical trials to demonstrate the clinical efficacy of their next gen drug combination.</div>
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That's really good science. Not long ago, Gilead stated that it was planning on eradicating HCV. This compound is a part of the Gilead license with Indian generic manufacturers but it seems like MSF is contesting that decision. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#dQjIv" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#dQjIv" id="cite-dQjIv">[11]</a> <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#mjhVh" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#mjhVh" id="cite-mjhVh">[12]</a> With this drug Gilead is now another step closer towards that goal. <a class="citation_link" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#WEyqD" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#WEyqD" id="cite-WEyqD">[13]</a></div>
<div class="qtext_citation_lead" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Footnotes</div>
<div class="citation" id="tPSVN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="citation_index" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-tPSVN" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-tPSVN">[1] </a><span class="qlink_container"><a class="external_link" data-mce-href="http://www.natap.org/2013/EASL/EASL_34.htm" href="http://www.natap.org/2013/EASL/EASL_34.htm" rel="noopener nofollow" target="_blank">GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier</a></span></div>
<div class="citation" id="kzZZS" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="citation_index" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-kzZZS" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-kzZZS">[2] </a><span class="qlink_container"><a class="external_link" data-mce-href="http://www.journal-of-hepatology.eu/article/S0168-8278(13)61192-7/pdf" href="http://www.journal-of-hepatology.eu/article/S0168-8278(13)61192-7/pdf" rel="noopener nofollow" target="_blank">Page on journal-of-hepatology.eu</a></span></div>
<div class="citation" id="qotyF" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="citation_index" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-qotyF" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-qotyF">[3] </a><span class="qlink_container"><a data-mce-href="https://www.quora.com/How-was-Sovaldi-the-drug-now-being-marketed-by-Gilead-first-discovered-by-Pharmasset/answer/Christopher-VanLang" href="https://www.quora.com/How-was-Sovaldi-the-drug-now-being-marketed-by-Gilead-first-discovered-by-Pharmasset/answer/Christopher-VanLang" target="_blank">Christopher VanLang's answer to How was Sovaldi (the drug now being marketed by Gilead), first discovered by Pharmasset?</a></span></div>
<div class="citation" id="ULKDW" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="citation_index" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-ULKDW" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-ULKDW">[4] </a><span class="qlink_container"><a class="external_link" data-mce-href="http://www.chemblink.com/products/1377049-84-7.htm" href="http://www.chemblink.com/products/1377049-84-7.htm" rel="noopener nofollow" target="_blank">CAS # 1377049-84-7, Velpatasvir, GS 5816, Methyl [(2S)-1-[(2S,5S)-2-[9-[2-[(2S,4S)-1-[(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate</a></span></div>
<div class="citation" id="cLmHU" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="citation_index" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-cLmHU" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-cLmHU">[5] </a><span class="qlink_container"><a class="external_link" data-mce-href="http://www.gilead.com/news/press-releases/2015/9/gilead-announces-svr12-rates-from-four-phase-3-studies-evaluating-a-oncedaily-fixeddose-combination-of-sofosbuvir-sof-and-velpatasvir-vel-gs5816-for-the-treatment-of-all-six-hepatitis-c-genotypes" href="http://www.gilead.com/news/press-releases/2015/9/gilead-announces-svr12-rates-from-four-phase-3-studies-evaluating-a-oncedaily-fixeddose-combination-of-sofosbuvir-sof-and-velpatasvir-vel-gs5816-for-the-treatment-of-all-six-hepatitis-c-genotypes" rel="noopener nofollow" target="_blank">Page on gilead.com</a></span></div>
<div class="citation" id="BvlqF" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="citation_index" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-BvlqF" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-BvlqF">[6] </a><span class="qlink_container"><a class="external_link" data-mce-href="http://www.nejm.org/doi/full/10.1056/NEJMoa1512610" href="http://www.nejm.org/doi/full/10.1056/NEJMoa1512610" rel="noopener" target="_blank">Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection — NEJM</a></span></div>
<div class="citation" id="TtLcu" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="citation_index" data-mce-href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-TtLcu" href="https://www.quora.com/How-did-the-drug-Velpatasvir-make-such-a-miracle#cite-TtLcu">[7] </a><span class="qlink_container"><a class="external_link" data-mce-href="http://www.nejm.org/doi/full/10.1056/NEJMoa1512612" href="http://www.nejm.org/doi/full/10.1056/NEJMoa1512612" rel="noopener" target="_blank">Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection — NEJM</a></span></div>
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<img alt="09338-acsnews1-gileadcxd" class="cq-dd-image" data-mce-src="http://cen.acs.org/content/cen/articles/93/i38/Heroes-Chemistry/_jcr_content/articlebody/subpar/articlemedia_7.img.jpg/1466568442912.jpg" height="365" src="http://cen.acs.org/content/cen/articles/93/i38/Heroes-Chemistry/_jcr_content/articlebody/subpar/articlemedia_7.img.jpg/1466568442912.jpg" style="height: auto; max-width: 100%;" title="09338-acsnews1-gileadcxd" width="706" /></div>
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<div class="title">
SAVING LIVES</div>
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The Gilead team responsible for Harvoni: Front row, from left: John Link, Chris Yang, Rowchanak Pakdaman, Bob Scott, and Benjamin Graetz. Back row, from left: Erik Mogalian and Bruce Ross. Not pictured: Michael Sofia.</div>
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Credit: Gilead Sciences</div>
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<a data-mce-href="http://www.gilead.com/" href="http://www.gilead.com/" title="Gilead">Gilead's</a> Harvoni is a combination of two antiviral agents, sofosbuvir and ledipasvir. “In hepatitis C, the virus mutates so rapidly that to overcome resistance, we use a combination of drugs, and each one pulls their own weight in the process,” says John Link, who discovered ledipasvir.</div>
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Link says that the amount of interdisciplinary collaboration on the drug was unprecedented for the company. “Once ledipasvir was discovered, the process chemists were right there with us understanding the kinds of things we were doing, and medicinal chemists and process chemists worked on making material to scale for preclinical studies,” he says. “We all realized this was our moment to make a difference for patients with hepatitis C.”</div>
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Harvoni is the first once-a-day pill for treatment of chronic hepatitis C, and it has a cure rate in the U.S. of 94-99%. The drug is an alternative to injected interferon treatment, which has been associated with significant side effects.</div>
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“The high cure rates that we saw in our clinical trials are really amazing,” Link says. “Before we had these compounds, I had only hoped that we could equal something like interferon-type regimens in cure rates, without all the horrible side effects. To dramatically exceed them is important for patients.”</div>
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Harvoni patients can attest to the drug’s effectiveness. Mark Melancon, who had contracted hepatitis C 25 years ago, says that after taking Harvoni, he now has no trace of the virus in his body, and his liver is beginning to repair itself. “Four weeks into it, and the virus was gone. Not detectable,” he says. “To have this virus hanging over my head for 25 years and then it was just gone, I can’t explain the feeling. The people who worked hard on this medication, they need to know that I appreciate it.”</div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">REFERENCES</span></em></strong></h1>
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<a data-mce-href="https://www.eiseverywhere.com/file_uploads/c2a2b5664a374fe807c0b95bb546321d_JordanFeld.pdf" href="https://www.eiseverywhere.com/file_uploads/c2a2b5664a374fe807c0b95bb546321d_JordanFeld.pdf">https://www.eiseverywhere.com/file_uploads/c2a2b5664a374fe807c0b95bb546321d_JordanFeld.pdf</a></div>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://google.com/patents/WO2013075029A1?cl=en" href="https://google.com/patents/WO2013075029A1?cl=en">WO2013075029A1</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 16, 2012</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 23, 2013</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Gilead Sciences, Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Condensed imidazolylimidazoles as antiviral compounds</td></tr>
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<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent ID</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Date</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent Title</th></tr>
</thead><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20130309196.PGNR.&OS=DN/20130309196&RS=DN/20130309196" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20130309196.PGNR.&OS=DN/20130309196&RS=DN/20130309196">US2013309196</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2013-11-21</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8575135.PN.&OS=PN/8575135&RS=PN/8575135" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8575135.PN.&OS=PN/8575135&RS=PN/8575135">US8575135</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2013-11-05</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Antiviral compounds</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20130164260.PGNR.&OS=DN/20130164260&RS=DN/20130164260" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20130164260.PGNR.&OS=DN/20130164260&RS=DN/20130164260">US2013164260</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2013-06-27</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
</tbody></table>
<table class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><thead>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent ID</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Date</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent Title</th></tr>
</thead><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150064252.PGNR.&OS=DN/20150064252&RS=DN/20150064252" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150064252.PGNR.&OS=DN/20150064252&RS=DN/20150064252">US2015064252</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-03-05</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">SOLID DISPERSION FORMULATION OF AN ANTIVIRAL COMPOUND</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150064253.PGNR.&OS=DN/20150064253&RS=DN/20150064253" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150064253.PGNR.&OS=DN/20150064253&RS=DN/20150064253">US2015064253</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-03-05</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8940718.PN.&OS=PN/8940718&RS=PN/8940718" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8940718.PN.&OS=PN/8940718&RS=PN/8940718">US8940718</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-01-27</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Antiviral compounds</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8921341.PN.&OS=PN/8921341&RS=PN/8921341" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8921341.PN.&OS=PN/8921341&RS=PN/8921341">US8921341</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-12-30</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Antiviral compounds</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140357595.PGNR.&OS=DN/20140357595&RS=DN/20140357595" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140357595.PGNR.&OS=DN/20140357595&RS=DN/20140357595">US2014357595</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-12-04</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">METHODS OF PREVENTING AND TREATING RECURRENCE OF A HEPATITIS C VIRUS INFECTION IN A SUBJECT AFTER THE SUBJECT HAS RECEIVED A LIVER TRANSPLANT</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140343008.PGNR.&OS=DN/20140343008&RS=DN/20140343008" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140343008.PGNR.&OS=DN/20140343008&RS=DN/20140343008">US2014343008</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-11-20</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HEPATITIS C TREATMENT</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140316144.PGNR.&OS=DN/20140316144&RS=DN/20140316144" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140316144.PGNR.&OS=DN/20140316144&RS=DN/20140316144">US2014316144</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-10-23</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140309432.PGNR.&OS=DN/20140309432&RS=DN/20140309432" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140309432.PGNR.&OS=DN/20140309432&RS=DN/20140309432">US2014309432</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-10-16</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140212491.PGNR.&OS=DN/20140212491&RS=DN/20140212491" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140212491.PGNR.&OS=DN/20140212491&RS=DN/20140212491">US2014212491</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-07-31</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140018313.PGNR.&OS=DN/20140018313&RS=DN/20140018313" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140018313.PGNR.&OS=DN/20140018313&RS=DN/20140018313">US2014018313</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-01-16</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
</tbody></table>
<table class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><thead>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent ID</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Date</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent Title</th></tr>
</thead><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20160083394.PGNR.&OS=DN/20160083394&RS=DN/20160083394" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20160083394.PGNR.&OS=DN/20160083394&RS=DN/20160083394">US2016083394</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2016-03-24</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=9221833.PN.&OS=PN/9221833&RS=PN/9221833" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=9221833.PN.&OS=PN/9221833&RS=PN/9221833">US9221833</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-12-29</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Antiviral compounds</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150361073.PGNR.&OS=DN/20150361073&RS=DN/20150361073" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150361073.PGNR.&OS=DN/20150361073&RS=DN/20150361073">US2015361073</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-12-17</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">PROCESSES FOR PREPARING ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150361085.PGNR.&OS=DN/20150361085&RS=DN/20150361085" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150361085.PGNR.&OS=DN/20150361085&RS=DN/20150361085">US2015361085</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-12-17</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">SOLID FORMS OF AN ANTIVIRAL COMPOUND</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150361087.PGNR.&OS=DN/20150361087&RS=DN/20150361087" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150361087.PGNR.&OS=DN/20150361087&RS=DN/20150361087">US2015361087</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-12-17</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150353529.PGNR.&OS=DN/20150353529&RS=DN/20150353529" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150353529.PGNR.&OS=DN/20150353529&RS=DN/20150353529">US2015353529</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-12-10</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150299213.PGNR.&OS=DN/20150299213&RS=DN/20150299213" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150299213.PGNR.&OS=DN/20150299213&RS=DN/20150299213">US2015299213</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-10-22</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150175646.PGNR.&OS=DN/20150175646&RS=DN/20150175646" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150175646.PGNR.&OS=DN/20150175646&RS=DN/20150175646">US2015175646</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-06-25</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">SOLID FORMS OF AN ANTIVIRAL COMPOUND</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150150897.PGNR.&OS=DN/20150150897&RS=DN/20150150897" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150150897.PGNR.&OS=DN/20150150897&RS=DN/20150150897">US2015150897</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-06-04</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">METHODS OF TREATING HEPATITIS C VIRUS INFECTION IN SUBJECTS WITH CIRRHOSIS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150141326.PGNR.&OS=DN/20150141326&RS=DN/20150141326" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150141326.PGNR.&OS=DN/20150141326&RS=DN/20150141326">US2015141326</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-05-21</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">ANTIVIRAL COMPOUNDS</td></tr>
</tbody></table>
<table class="infobox mce-item-table" data-mce-style="height: 519px;" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: 519px; line-height: 24px; width: 744px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Velpatasvir">Velpatasvir</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Velpatasvir_structure.svg" href="https://en.wikipedia.org/wiki/File:Velpatasvir_structure.svg"><img alt="Velpatasvir structure.svg" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/92/Velpatasvir_structure.svg/220px-Velpatasvir_structure.svg.png" height="156" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/92/Velpatasvir_structure.svg/220px-Velpatasvir_structure.svg.png" style="height: auto; max-width: 100%;" width="220" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">(2<i>S</i>)-2-{[hydroxy(methoxy)methylidene]amino}-1-[(2<i>S</i>,5<i>S</i>)-2-(17-{2-[(2<i>S</i>,4<i>S</i>)-1-[(2<i>R</i>)-2-{[hydroxy(methoxy)methylidene]amino}-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1<i>H</i>-imidazol-5-yl}-21-oxa-5,7-diazapentacyclo[11.8.0.0³,¹¹.0⁴,⁸.0¹⁴,¹⁹]henicosa-1(13),2,4(8),6,9,11,14(19),15,17-nonaen-6-yl)-5-methylpyrrolidin-1-yl]-3-methylbutan-1-one</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=1377049-84-7" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=1377049-84-7" rel="nofollow">1377049-84-7</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=67683363" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=67683363" rel="nofollow">67683363</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.34501056.html" href="http://www.chemspider.com/Chemical-Structure.34501056.html" rel="nofollow">34501056</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=KCU0C7RS7Z" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=KCU0C7RS7Z" rel="nofollow">KCU0C7RS7Z</a></span><sup> <img alt="Yes" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>49</sub><span title="Hydrogen">H</span><sub>54</sub><span title="Nitrogen">N</span><sub>8</sub><span title="Oxygen">O</span><sub>8</sub></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">883.02 g·mol<sup>−1</sup></td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
//////////////VELPATASVIR, GS-5816, GILEAD SCIENCES, Epclusa , FDA 2016, <strong>велпатасвир,</strong><strong>فالباتاسفير , </strong><strong>维帕他韦</strong> , велпатасвир, فالباتاسفير , 维帕他韦 , <a data-mce-href="https://www.linkedin.com/in/elizabeth-bacon-174975111" href="https://www.linkedin.com/in/elizabeth-bacon-174975111"><span class="fn"><span class="full-name" dir="auto">Elizabeth Bacon, </span></span></a><span class="fn"><span class="full-name" dir="auto"><a data-mce-href="https://www.linkedin.com/in/sheila-zipfel-88477b2" href="https://www.linkedin.com/in/sheila-zipfel-88477b2">Sheila Zipfel</a></span></span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<div id="syn_hid_0">
<div class="syn">
<span class="">UNII:KCU0C7RS7Z</span></div>
</div>
</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
C[C@H]1CC[C@H](N1C(=O)[C@H](C(C)C)NC(=O)OC)C2=NC3=C(N2)C=CC4=CC5=C(C=C43)OCC6=C5C=CC(=C6)C7=CN=C(N7)[C@@H]8C[C@@H](CN8C(=O)[C@@H](C9=CC=CC=C9)NC(=O)OC)COC</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="irc_mut iQhjClB8LWRc-HwpH6ZlgJaI" data-mce-src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcRP-k-Hx0g9pu3ocGSw4w94z4BOC7-JZ_xIIN8Ul_rOESCYkSxK" height="362" src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcRP-k-Hx0g9pu3ocGSw4w94z4BOC7-JZ_xIIN8Ul_rOESCYkSxK" style="height: auto; max-width: 100%;" width="512" /></div>
<table class="nowraplinks collapsible autocollapse navbox-inner mce-item-table" data-mce-style="height: 1887px;" id="collapsibleTable0" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: 1887px; line-height: 24px; width: 702px;"><tbody>
<tr><th class="navbox-title" colspan="2" scope="col" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/RNA_virus" href="https://en.wikipedia.org/wiki/RNA_virus" title="RNA virus">RNA virus</a> <a data-mce-href="https://en.wikipedia.org/wiki/Antiviral_drug" href="https://en.wikipedia.org/wiki/Antiviral_drug" title="Antiviral drug">antivirals</a> (primarily <a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_J05" href="https://en.wikipedia.org/wiki/ATC_code_J05" title="ATC code J05">J05</a>, also <a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_S01#S01AD" href="https://en.wikipedia.org/wiki/ATC_code_S01#S01AD" title="ATC code S01">S01AD</a> and <a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_D06#D06BB" href="https://en.wikipedia.org/wiki/ATC_code_D06#D06BB" title="ATC code D06">D06BB</a>)</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Hepatitis_C" href="https://en.wikipedia.org/wiki/Hepatitis_C" title="Hepatitis C">Hepatitis C</a></th><td class="navbox-list navbox-odd hlist" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div>
</div>
<table class="nowraplinks navbox-subgroup mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/NS3_%28HCV%29" href="https://en.wikipedia.org/wiki/NS3_%28HCV%29" title="NS3 (HCV)">NS3</a>/<a data-mce-href="https://en.wikipedia.org/wiki/NS4A" href="https://en.wikipedia.org/wiki/NS4A" title="NS4A">4A</a> protease inhibitors (–previr)</th><td class="navbox-list navbox-odd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ul>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Asunaprevir" href="https://en.wikipedia.org/wiki/Asunaprevir" title="Asunaprevir">Asunaprevir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Boceprevir" href="https://en.wikipedia.org/wiki/Boceprevir" title="Boceprevir">Boceprevir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Faldaprevir" href="https://en.wikipedia.org/wiki/Faldaprevir" title="Faldaprevir">Faldaprevir</a><sup><b>‡</b></sup></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Grazoprevir" href="https://en.wikipedia.org/wiki/Grazoprevir" title="Grazoprevir">Grazoprevir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Paritaprevir" href="https://en.wikipedia.org/wiki/Paritaprevir" title="Paritaprevir">Paritaprevir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Simeprevir" href="https://en.wikipedia.org/wiki/Simeprevir" title="Simeprevir">Simeprevir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Telaprevir" href="https://en.wikipedia.org/wiki/Telaprevir" title="Telaprevir">Telaprevir</a></li>
</ul>
</td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/NS5A" href="https://en.wikipedia.org/wiki/NS5A" title="NS5A">NS5A</a> inhibitors (–asvir)</th><td class="navbox-list navbox-even" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ul>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Daclatasvir" href="https://en.wikipedia.org/wiki/Daclatasvir" title="Daclatasvir">Daclatasvir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Elbasvir" href="https://en.wikipedia.org/wiki/Elbasvir" title="Elbasvir">Elbasvir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Ledipasvir" href="https://en.wikipedia.org/wiki/Ledipasvir" title="Ledipasvir">Ledipasvir</a></li>
<li><a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=MK-3682&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=MK-3682&action=edit&redlink=1" title="MK-3682 (page does not exist)">MK-3682</a></li>
<li><a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=MK-8408&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=MK-8408&action=edit&redlink=1" title="MK-8408 (page does not exist)">MK-8408</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Odalasvir" href="https://en.wikipedia.org/wiki/Odalasvir" title="Odalasvir">Odalasvir</a><sup><b>†</b></sup></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Ombitasvir" href="https://en.wikipedia.org/wiki/Ombitasvir" title="Ombitasvir">Ombitasvir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Ravidasvir" href="https://en.wikipedia.org/wiki/Ravidasvir" title="Ravidasvir">Ravidasvir</a><sup><b>†</b></sup></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Samatasvir" href="https://en.wikipedia.org/wiki/Samatasvir" title="Samatasvir">Samatasvir</a><sup><b>†</b></sup></li>
<li><strong class="selflink">Velpatasvir</strong></li>
</ul>
</td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/NS5B" href="https://en.wikipedia.org/wiki/NS5B" title="NS5B">NS5B</a> <a data-mce-href="https://en.wikipedia.org/wiki/RNA_polymerase" href="https://en.wikipedia.org/wiki/RNA_polymerase" title="RNA polymerase">RNA polymerase</a> inhibitors (–buvir)</th><td class="navbox-list navbox-odd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ul>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Beclabuvir" href="https://en.wikipedia.org/wiki/Beclabuvir" title="Beclabuvir">Beclabuvir</a><sup><b>†</b></sup></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Dasabuvir" href="https://en.wikipedia.org/wiki/Dasabuvir" title="Dasabuvir">Dasabuvir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Deleobuvir" href="https://en.wikipedia.org/wiki/Deleobuvir" title="Deleobuvir">Deleobuvir</a><sup><b>§</b></sup></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Filibuvir" href="https://en.wikipedia.org/wiki/Filibuvir" title="Filibuvir">Filibuvir</a><sup><b>§</b></sup></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Setrobuvir" href="https://en.wikipedia.org/wiki/Setrobuvir" title="Setrobuvir">Setrobuvir</a><sup><b>§</b></sup></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Sofosbuvir" href="https://en.wikipedia.org/wiki/Sofosbuvir" title="Sofosbuvir">Sofosbuvir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Radalbuvir" href="https://en.wikipedia.org/wiki/Radalbuvir" title="Radalbuvir">Radalbuvir</a><sup><b>†</b></sup></li>
</ul>
</td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Combination drugs</th><td class="navbox-list navbox-even" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ul>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Elbasvir/grazoprevir" href="https://en.wikipedia.org/wiki/Elbasvir/grazoprevir" title="Elbasvir/grazoprevir">Elbasvir/grazoprevir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Ledipasvir/sofosbuvir" href="https://en.wikipedia.org/wiki/Ledipasvir/sofosbuvir" title="Ledipasvir/sofosbuvir">Ledipasvir/sofosbuvir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Ombitasvir/paritaprevir/ritonavir" href="https://en.wikipedia.org/wiki/Ombitasvir/paritaprevir/ritonavir" title="Ombitasvir/paritaprevir/ritonavir">Ombitasvir/paritaprevir/ritonavir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Velpatasvir/sofosbuvir" href="https://en.wikipedia.org/wiki/Velpatasvir/sofosbuvir" title="Velpatasvir/sofosbuvir">Velpatasvir/sofosbuvir</a></li>
</ul>
</td></tr>
</tbody></table>
</td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Picornavirus" href="https://en.wikipedia.org/wiki/Picornavirus" title="Picornavirus">Picornavirus</a></th><td class="navbox-list navbox-even hlist" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ul>
<li><i><a data-mce-href="https://en.wikipedia.org/wiki/Viral_entry" href="https://en.wikipedia.org/wiki/Viral_entry" title="Viral entry">viral entry</a>:</i> <a data-mce-href="https://en.wikipedia.org/wiki/Pleconaril" href="https://en.wikipedia.org/wiki/Pleconaril" title="Pleconaril">Pleconaril</a><sup><b>†</b></sup></li>
</ul>
</td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Anti-<a data-mce-href="https://en.wikipedia.org/wiki/Influenza" href="https://en.wikipedia.org/wiki/Influenza" title="Influenza">influenza</a> agents</th><td class="navbox-list navbox-odd hlist" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ul>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Umifenovir" href="https://en.wikipedia.org/wiki/Umifenovir" title="Umifenovir">Umifenovir</a></li>
</ul>
<ul>
<li><i><a data-mce-href="https://en.wikipedia.org/wiki/Adamantane" href="https://en.wikipedia.org/wiki/Adamantane" title="Adamantane">adamantane derivatives</a>/<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/M2_protein" href="https://en.wikipedia.org/wiki/M2_protein" title="M2 protein">M2 inhibitors</a></i> (<a data-mce-href="https://en.wikipedia.org/wiki/Adapromine" href="https://en.wikipedia.org/wiki/Adapromine" title="Adapromine">Adapromine</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Amantadine" href="https://en.wikipedia.org/wiki/Amantadine" title="Amantadine">Amantadine</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Rimantadine" href="https://en.wikipedia.org/wiki/Rimantadine" title="Rimantadine">Rimantadine</a>)</li>
</ul>
<ul>
<li><i><a data-mce-href="https://en.wikipedia.org/wiki/Neuraminidase_inhibitor" href="https://en.wikipedia.org/wiki/Neuraminidase_inhibitor" title="Neuraminidase inhibitor">neuraminidase inhibitors</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Antiviral_drug#Release_phase" href="https://en.wikipedia.org/wiki/Antiviral_drug#Release_phase" title="Antiviral drug">release phase</a></i> (<a data-mce-href="https://en.wikipedia.org/wiki/Oseltamivir" href="https://en.wikipedia.org/wiki/Oseltamivir" title="Oseltamivir">Oseltamivir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Zanamivir" href="https://en.wikipedia.org/wiki/Zanamivir" title="Zanamivir">Zanamivir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Peramivir" href="https://en.wikipedia.org/wiki/Peramivir" title="Peramivir">Peramivir</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Laninamivir" href="https://en.wikipedia.org/wiki/Laninamivir" title="Laninamivir">Laninamivir</a><sup><b>†</b></sup>)</li>
</ul>
</td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Multiple/general</th><td class="navbox-list navbox-even hlist" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div>
</div>
<table class="nowraplinks navbox-subgroup mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Interferon" href="https://en.wikipedia.org/wiki/Interferon" title="Interferon">Interferon</a></th><td class="navbox-list navbox-odd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ul>
<li><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Interferon_alfa_2b" href="https://en.wikipedia.org/wiki/Interferon_alfa_2b" title="Interferon alfa 2b">Interferon alfa 2b</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Peginterferon_alfa-2a" href="https://en.wikipedia.org/wiki/Peginterferon_alfa-2a" title="Peginterferon alfa-2a">Peginterferon alfa-2a</a><sup><b>#</b></sup></li>
</ul>
</td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><th class="navbox-group" scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Multiple/unknown</th><td class="navbox-list navbox-even" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><ul>
<li><a data-mce-href="https://en.wikipedia.org/wiki/BCX4430" href="https://en.wikipedia.org/wiki/BCX4430" title="BCX4430">BCX4430</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Favipiravir" href="https://en.wikipedia.org/wiki/Favipiravir" title="Favipiravir">Favipiravir</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Moroxydine" href="https://en.wikipedia.org/wiki/Moroxydine" title="Moroxydine">Moroxydine</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Ribavirin" href="https://en.wikipedia.org/wiki/Ribavirin" title="Ribavirin">Ribavirin</a><sup><b>#</b></sup>/<a data-mce-href="https://en.wikipedia.org/wiki/Taribavirin" href="https://en.wikipedia.org/wiki/Taribavirin" title="Taribavirin">Taribavirin</a><sup><b>†</b></sup></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Triazavirin" href="https://en.wikipedia.org/wiki/Triazavirin" title="Triazavirin">Triazavirin</a></li>
</ul>
</td></tr>
</tbody></table>
</td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
<tr><td class="navbox-abovebelow" colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="hlist">
<ul>
<li><sup>#</sup><a data-mce-href="https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Medicines" href="https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Medicines" title="WHO Model List of Essential Medicines">WHO-EM</a></li>
<li><sup>‡</sup><a data-mce-href="https://en.wikipedia.org/wiki/List_of_withdrawn_drugs" href="https://en.wikipedia.org/wiki/List_of_withdrawn_drugs" title="List of withdrawn drugs">Withdrawn</a> from market</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Clinical_trial" href="https://en.wikipedia.org/wiki/Clinical_trial" title="Clinical trial">Clinical trials</a>:<ul>
<li><sup>†</sup><a data-mce-href="https://en.wikipedia.org/wiki/Clinical_trial#Phase_III" href="https://en.wikipedia.org/wiki/Clinical_trial#Phase_III" title="Clinical trial">Phase III</a></li>
<li><sup>§</sup><a data-mce-href="https://en.wikipedia.org/wiki/Clinical_trial#Phase_II" href="https://en.wikipedia.org/wiki/Clinical_trial#Phase_II" title="Clinical trial">Never to phase III</a></li>
</ul>
</li>
</ul>
</div>
</td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
/////</div>
</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-1346483141860457136.post-64793949171017589192016-08-03T21:02:00.001-07:002016-08-03T21:08:52.595-07:00Arformoterol, (R,R)-Formoterol For Chronic obstructive pulmonary disease (COPD)<div dir="ltr" style="text-align: left;" trbidi="on">
<img src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/57/Arformoterol.svg/250px-Arformoterol.svg.png" /><br />
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<h1 class="h4">
<span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_WrapTitle">Arformoterol</span></h1>
<ul class="struct-props">
<li><span class="prop_title">MF </span><span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_prop_MF">C<sub>19</sub>H<sub>24</sub>N<sub>2</sub>O<sub>4</sub></span></li>
<li><span class="prop_title">MW </span>344.405</li>
</ul>
</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>(R,R)-Formoterol</strong></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>Cas 67346-49-0</strong></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Chronic obstructive pulmonary disease (COPD)</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<ul class="old_db">
<li>Sunovion/Sepracor (Originator)</li>
<li>Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists</li>
<li>LAUNCHED 2007 , Phase III ASTHMA</li>
</ul>
</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>Formamide, N-[2-hyd<wbr></wbr>roxy-5-[(1R)-1-hydr<wbr></wbr>oxy-2-[[(1R)-2-(4-m<wbr></wbr>ethoxyphenyl)-1-met<wbr></wbr>hylethyl]amino]ethy<wbr></wbr>l]phenyl]-</strong></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="http://www.medzilla.com/images/sepracor.gif" src="http://www.medzilla.com/images/sepracor.gif" style="height: auto; max-width: 100%;" /><img alt="" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/img3d.cgi?cid=3083544" src="https://pubchem.ncbi.nlm.nih.gov/image/img3d.cgi?cid=3083544" style="height: auto; max-width: 100%;" />3D STRUCTURE</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b>Arformoterol</b> is a <a data-mce-href="https://en.wikipedia.org/wiki/Long-acting_beta-adrenoceptor_agonist" href="https://en.wikipedia.org/wiki/Long-acting_beta-adrenoceptor_agonist" title="Long-acting beta-adrenoceptor agonist">long-acting β<sub>2</sub> adrenoreceptor agonist</a> (LABA) indicated for the treatment of <a data-mce-href="https://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_disease" href="https://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_disease" title="Chronic obstructive pulmonary disease">chronic obstructive pulmonary disease</a>(COPD). It is sold by <a data-mce-href="https://en.wikipedia.org/wiki/Sunovion" href="https://en.wikipedia.org/wiki/Sunovion" title="Sunovion">Sunovion</a>, under the trade name <b>Brovana</b>, as a solution of arformoterol tartrate to be administered twice daily (morning and evening) by <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Nebuliser" href="https://en.wikipedia.org/wiki/Nebuliser" title="Nebuliser">nebulization</a>.<sup class="reference" id="cite_ref-1"><a data-mce-href="https://en.wikipedia.org/wiki/Arformoterol#cite_note-1" href="https://en.wikipedia.org/wiki/Arformoterol#cite_note-1">[1]</a></sup></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Arformoterol inhalation solution, a long-acting beta2-adrenoceptor agonist, was launched in the U.S. in 2007 for the long-term twice-daily (morning and evening) treatment of bronchospasm in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. The product, known as Brovana(TM), for use by nebulization only, is the first long-acting beta2-agonist to be approved as an inhalation solution for use with a nebulizer. The product was developed and is being commercialized by Sunovion Pharmaceuticals (formerly Sepracor)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9a/Arformoterol_ball-and-stick_model.png/250px-Arformoterol_ball-and-stick_model.png" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9a/Arformoterol_ball-and-stick_model.png/250px-Arformoterol_ball-and-stick_model.png" style="height: auto; max-width: 100%;" />Arformoterol ball-and-stick model</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Bronchodilators, in particular β<sub>2</sub>-adrenoceptor agonists, are recognized as very effective drugs to treat asthma and other bronchospastic conditions. Important characteristics for these drugs are activity, selectivity, duration of action, and onset. While the first-generation drugs (e.g., isoprenaline or terbutaline) were relatively unselective and short-acting, the current drugs have either a fast onset but only a short duration of action of about 4 h (albuterol) or a slow onset (20 min) with a longer duration of action (salmeterol). Formoterol (IUPAC name: 3-formamido-4-hydroxy-α-[[<i>N</i>-(<i>p</i>-methoxy-α-methylphenethyl)amino]methyl]benzyl alcohol) is unique in that it not only is extremely potent and selective but also has a duration of up to 12 h and a rapid onset of 1−5 min. Most β<sub>2</sub>-adrenoceptor agonists are currently marketed as racemates despite regulatory preference and different biological activity of pure enantiomers. In the case of formoterol it has been shown that the (<i>R,R</i>)-isomer is 1000 times more active than the (<i>S,S</i>)-isomer</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="Arformoterol.png" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=3083544&t=l" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=3083544&t=l" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
It is the active (<i>R</i>,<i>R</i>)-(−)-<a data-mce-href="https://en.wikipedia.org/wiki/Enantiomer" href="https://en.wikipedia.org/wiki/Enantiomer" title="Enantiomer">enantiomer</a> of <a data-mce-href="https://en.wikipedia.org/wiki/Formoterol" href="https://en.wikipedia.org/wiki/Formoterol" title="Formoterol">formoterol</a> and was approved by the <a data-mce-href="https://en.wikipedia.org/wiki/United_States" href="https://en.wikipedia.org/wiki/United_States" title="United States">United States</a> <a data-mce-href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> (FDA) on October 6, 2006 for the treatment of COPD.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Arformoterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. Arformoterol inhalation is used to prevent bronchoconstriction in people with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. The use of arformoterol is pending revision due to safety concerns in regards to an increased risk of severe exacerbation of asthma symptoms, leading to hospitalization as well as death in some patients using long acting beta agonists for the treatment of asthma.</div>
<div class="summary-description-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Arformoterol is an ADRENERGIC BETA-2 RECEPTOR AGONIST with a prolonged duration of action. It is used to manage ASTHMA and in the treatment of CHRONIC OBSTRUCTIVE PULMONARY DISEASE.<br />
<div class="reference" data-ref-number="46">
<span class="btn-text"> <img alt="" data-mce-src="http://www.pharmacology2000.com/Autonomics/Adrenergics1/arformoterol1u3d.JPG" src="http://www.pharmacology2000.com/Autonomics/Adrenergics1/arformoterol1u3d.JPG" style="height: auto; max-width: 100%;" />Arformoterol (Brovana)</span></div>
<div class="reference" data-ref-number="46">
</div>
</div>
<div class="summary-description-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Arformoterol is a beta2-Adrenergic Agonist. The mechanism of action of arformoterol is as an Adrenergic beta2-Agonist.</div>
<div class="summary-description-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</div>
<div class="summary-description-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Arformoterol is a long-acting <a class="pubchem-internal-link CID-71465" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/beta-2" href="https://pubchem.ncbi.nlm.nih.gov/compound/beta-2">beta-2</a> adrenergic agonist and isomer of <a class="pubchem-internal-link CID-3410" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/formoterol" href="https://pubchem.ncbi.nlm.nih.gov/compound/formoterol">formoterol</a> with bronchodilator activity. Arformoterol selectively binds to and activates <a class="pubchem-internal-link CID-71465" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/beta-2" href="https://pubchem.ncbi.nlm.nih.gov/compound/beta-2">beta-2</a> adrenergic receptors in bronchiolar smooth muscle, thereby causing stimulation of adenyl cyclase, the enzyme that catalyzes the conversion of <a class="pubchem-internal-link CID-5957" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/adenosine%20triphosphate" href="https://pubchem.ncbi.nlm.nih.gov/compound/adenosine%20triphosphate">adenosine triphosphate</a> (<a class="pubchem-internal-link CID-5957" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/ATP" href="https://pubchem.ncbi.nlm.nih.gov/compound/ATP">ATP</a>) to cyclic-3',5'-adenosine monophosphate (<a class="pubchem-internal-link CID-6076" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/cAMP" href="https://pubchem.ncbi.nlm.nih.gov/compound/cAMP">cAMP</a>). Increased intracellular <a class="pubchem-internal-link CID-6076" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/compound/cAMP" href="https://pubchem.ncbi.nlm.nih.gov/compound/cAMP">cAMP</a> levels cause relaxation of bronchial smooth muscle and lead to a reduced release of inflammatory mediators from mast cells. This may eventually lead to an improvement of airway function.</div>
<div class="summary-description-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Formoterol (Foradil) is a long acting β<sub>2</sub>-agonist used as a bronchodilator in the therapy of asthma and chronic bronchitis. The (<i>R</i>,<i>R</i>)-enantiomer has been shown to be more active than the other stereoisomers (<i>R</i>,<i>S</i>;<i> S</i>,<i>R; </i>and<i> S</i>,<i>S</i>) of formoterol. (<i>R</i>,<i>R</i>)-Formoterol is extremely potent and selective, having rapid onset (1−5 min) and long duration, and is 1000 times more active than the (<i>S</i>,<i>S</i>) isomer</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<img alt="" data-mce-src="http://medicaldice.com/medicines-a-z/wp-content/uploads/2015/08/a133-Arformoterol-Tartrate-Inhalation.jpg" src="http://medicaldice.com/medicines-a-z/wp-content/uploads/2015/08/a133-Arformoterol-Tartrate-Inhalation.jpg" style="height: auto; max-width: 100%;" /></h2>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<img alt="" data-mce-src="http://images.rxlist.com/images/rxlist/brovana1.gif" src="http://images.rxlist.com/images/rxlist/brovana1.gif" style="height: auto; max-width: 100%;" /></h2>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
</h2>
<h1 class="h4" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_WrapTitle">Arformoterol tartrate</span></h1>
<ul class="struct-props" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li><span class="prop_title">Molecular Formula</span><span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_prop_MF">C<sub>23</sub>H<sub>30</sub>N<sub>2</sub>O<sub>10</sub></span></li>
<li><span class="prop_title">Average mass</span>494.492</li>
<li> cas 200815-49-2</li>
<li>183-185°C</li>
</ul>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>Butanedioic acid, 2<wbr></wbr>,3-dihydroxy-, (2R,<wbr></wbr>3R)-, compd. with f<wbr></wbr>ormamide, N-[2-hydr<wbr></wbr>oxy-5-[(1R)-1-hydro<wbr></wbr>xy-2-[[(1R)-2-(4-me<wbr></wbr>thoxyphenyl)-1-meth<wbr></wbr>ylethyl]amino]ethyl<wbr></wbr>]phenyl]- (1:1)</strong> <span class="synonym_ref" title="">[ACD/Index Name]</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>N-{2-hydroxy-5-[(1R<wbr></wbr>)-1-hydroxy-2-{[(1R<wbr></wbr>)-2-(4-methoxypheny<wbr></wbr>l)-1-methylethyl]am<wbr></wbr>ino}ethyl]phenyl}fo<wbr></wbr>rmamide 2,3-dihydro<wbr></wbr>xybutanedioate (sal<wbr></wbr>t)</strong></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table class="shop_table custom-table fixed_layout mce-item-table" data-mce-style="height: 71px;" style="border: 1px dashed rgb(187, 187, 187); height: 71px; width: 732px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">N-[2-Hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino] ethyl]phenyl]formamide (+)-(2R,3R)-Tartaric Acid; (-)-Formoterol 1,2-Dihydroxyethane-1,2-dicarboxylic Acid; (R,R)-Formoterol Threaric Acid; Arformoterol d-Tartaric Acid; Arformoterol d-α,β-Dihydroxysuccinic Acid</td></tr>
</tbody></table>
</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">(R,R)-Formoterol-L-<wbr></wbr>(+)-tartrate</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">200815-49-2</span> CAS</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<div id="syn_hid_0">
<div class="syn">
<span class="">Arformoterol tartrate (USAN)</span></div>
<div class="syn">
<span class="">Brovana</span></div>
<div class="syn">
<span class="">UNII:5P8VJ2I235</span></div>
<div class="syn">
<img alt="" class="" data-mce-src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcQg50qk1GX310J7SkuTKWQPUUsudMmYU_hsfI4B-O8bOm9d9PsQ0Q" height="471" src="https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcQg50qk1GX310J7SkuTKWQPUUsudMmYU_hsfI4B-O8bOm9d9PsQ0Q" style="height: auto; max-width: 100%;" width="471" /></div>
</div>
</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcSdJkt7bmd0RABqYeHsyuxb25SdjYWHguEwhwz7L8q2kKrcCR4X3A" height="778" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcSdJkt7bmd0RABqYeHsyuxb25SdjYWHguEwhwz7L8q2kKrcCR4X3A" style="height: auto; max-width: 100%;" width="389" /></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Arformoterol Tartrate, can be used in the synthesis of Omeprazole (O635000), which is a proton pump inhibitor, that inhibits gasteric secretion, also used in the treatment of dyspepsia, peptic ulcer disease, etc. Itis also the impurity of Esomeprazole Magnesium (E668300), which is the S-form of Omeprazole, and is a gastric proton-pump inhibitor. Also, It can be used for the preparation of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy.</div>
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<img alt="" data-mce-src="https://www.researchgate.net/profile/A_Guerrero/publication/230801677/figure/fig1/AS:349523776950276@1460344370222/Figure-1.png" src="https://www.researchgate.net/profile/A_Guerrero/publication/230801677/figure/fig1/AS:349523776950276@1460344370222/Figure-1.png" style="height: auto; max-width: 100%;" /></div>
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<img alt="Figure" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2002/oprdfk.2002.6.issue-6/op025531h/production/images/medium/op025531hf00001.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2002/oprdfk.2002.6.issue-6/op025531h/production/images/medium/op025531hf00001.gif" style="height: auto; max-width: 100%;" /></h1>
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<span data-mce-style="color: #ff0000;" style="color: red;">SYNTHESIS</span></h1>
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PATENT</div>
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US-9309186</div>
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Example 1</div>
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Synthesis of (R,R)-Formoterol-L-tartrate Form D</div>
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A solution containing 3.9 g (26 mmol) of L-tartaric acid and 36 mL of methanol was added to a solution of 9 g (26 mmol) of arformoterol base and 144 mL methanol at 23.degree. C. Afterwards, the resulting mixture was seeded with form D and stirred at 23.degree. C. for 1 hour. It was then further cooled to 0-5.degree. C. for 1 hour and the product collected by filtration and dried under inlet air (atmospheric pressure) for 16 hours to provide 11.1 g (86% yield) (99.7% chemical purity, containing 0.14% of the degradation impurity (R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy- l]amino]ethanol) of (R,R)-formoterol L-tartrate form D, as an off white powder. .sup.1H-NMR (200 MHz, d.sub.6-DMSO) .delta.: 1.03 (d, 3H); 2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H); 6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH). No residual solvent was detected (.sup.1H-NMR).</div>
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PSD: d.sub.50=2.3 .mu.m.</div>
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<br /></div>
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<span data-mce-style="color: #ff0000;" style="color: red;"><em> PAPER</em></span></h1>
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</div>
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Tetrahedron Letters, Vol. 38, No. 7, pp. 1125-1128, 1997</div>
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Enantio- and Diastereoselective Synthesis of all Four Stereoisomers of Formoterol</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-26.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-26.jpg" rel="attachment wp-att-8135"><img alt="STR1" class="alignnone size-full wp-image-8135" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-26.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-26.jpg" height="240" style="height: auto; max-width: 100%;" width="843" /></a></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-27.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-27.jpg" rel="attachment wp-att-8136"><img alt="STR1" class="alignnone size-full wp-image-8136" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-27.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-27.jpg" height="385" style="height: auto; max-width: 100%;" width="831" /></a></div>
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<span data-mce-style="color: #ff0000;" style="color: red;"> </span></h1>
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<span data-mce-style="color: #ff0000;" style="color: red;">PAPER</span></h1>
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<h1 class="articleTitle">
<span class="hlFld-Title">Taking Advantage of Polymorphism To Effect an Impurity Removal: Development of a Thermodynamic Crystal Form of (<i><span class="single_highlight_class">R</span>,<span class="single_highlight_class">R</span></i>)-<span class="single_highlight_class">Formoterol</span>Tartrate</span></h1>
<div id="articleMeta">
<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Tanoury%2C+Gerald+J" href="http://pubs.acs.org/author/Tanoury%2C+Gerald+J" id="authors">Gerald J. Tanoury</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op025531h#op025531hAF1" href="http://pubs.acs.org/doi/abs/10.1021/op025531h#op025531hAF1">*</a><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op025531h#op025531hAF2" href="http://pubs.acs.org/doi/abs/10.1021/op025531h#op025531hAF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Hett%2C+Robert" href="http://pubs.acs.org/author/Hett%2C+Robert" id="authors">Robert Hett</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kessler%2C+Donald+W" href="http://pubs.acs.org/author/Kessler%2C+Donald+W" id="authors">Donald W. Kessler</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Wald%2C+Stephen+A" href="http://pubs.acs.org/author/Wald%2C+Stephen+A" id="authors">Stephen A. Wald</a> , and</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Senanayake%2C+Chris+H" href="http://pubs.acs.org/author/Senanayake%2C+Chris+H" id="authors">Chris H. Senanayake</a> <a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op025531h#op025531hAF1" href="http://pubs.acs.org/doi/abs/10.1021/op025531h#op025531hAF1">*</a><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op025531h#op025531hAF3" href="http://pubs.acs.org/doi/abs/10.1021/op025531h#op025531hAF3"><sup>‡</sup></a></span></span></div>
<div class="affiliations">
Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.</div>
<div id="citation">
<cite>Org. Proc. Res. Dev.</cite>, <span class="citation_year">2002</span>, <span class="citation_volume">6</span> (6), pp 855–862</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op025531h</div>
<div id="pubDate">
</div>
<div id="correspondence">
<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op025531h" href="http://pubs.acs.org/doi/abs/10.1021/op025531h">http://pubs.acs.org/doi/abs/10.1021/op025531h</a></div>
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<div id="articleBody">
<div class="hlFld-Abstract">
<h2 id="Abstract">
Abstract</h2>
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<img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2002/oprdfk.2002.6.issue-6/op025531h/production/images/medium/op025531hn00001.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2002/oprdfk.2002.6.issue-6/op025531h/production/images/medium/op025531hn00001.gif" style="height: auto; max-width: 100%;" /></div>
<div class="articleBody_abstractText">
The development and large-scale implementation of a novel technology utilizing polymorphic interconversion and crystalline intermediate formation of (<i>R</i>,<i>R</i>)-<span class="single_highlight_class">formoterol</span> <span class="smallcaps">l</span>-tartrate ((<i>R</i>,<i>R</i>)-FmTA, <b>1</b>) as a tool for the removal of impurities from the final product and generation of the most thermodynamically stable crystal form is reported. The crude product was generated by precipitation of the free base as the <span class="smallcaps">l</span>-tartrate salt in a unique polymorphic form, form B. Warming the resultant slurry effected the formation of a partially hydrated stable crystalline intermediate, form C, with a concomitant decrease in the impurity levels in the solid. Isolation and recrystallization of form C provided <b>1</b> in the thermodynamically most stable polymorph, form A.</div>
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SYN1</div>
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SYN 2</div>
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<img alt="" data-mce-src="http://www.brovana.com/img/12-hours.png" src="http://www.brovana.com/img/12-hours.png" style="height: auto; max-width: 100%;" /></div>
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SYN 3</div>
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<img alt="" data-mce-src="http://www.brovana.com/img/brovana-how-to-use.jpg" src="http://www.brovana.com/img/brovana-how-to-use.jpg" style="height: auto; max-width: 100%;" /></div>
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SYN 4</div>
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SYN 5</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<a data-mce-href="http://www.google.co.in/patents/EP2348013A1?cl=en" href="http://www.google.co.in/patents/EP2348013A1?cl=en">http://www.google.co.in/patents/EP2348013A1?cl=en</a></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Formoterol, (+/-)N-[2-hydroxy-5-[1-hydroxy-2-[[2-(p-methoxyphenyl)-2-propylamino]ethyl]phenyl]-formamide, is a highly potent and β<sub>2</sub>-selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. Its chemical structure is depicted below:</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP2348013A1/imgb0001.png" href="http://patentimages.storage.googleapis.com/EP2348013A1/imgb0001.png"><img alt="Figure imgb0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP2348013A1/imgb0001.png" src="http://patentimages.storage.googleapis.com/EP2348013A1/imgb0001.png" height="148" id="ib0001" style="height: auto; max-width: 100%;" width="224" /></a></div>
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Formoterol has two chiral centres, each of which can exist into two different configurations. This results into four different combinations, (R,R), (S,S), (S,R) and (R,S). Formoterol is commercially available as a racemic mixture of 2 diasteromers (R,R) and (S,S) in a 1:1 ratio. The generic name Formoterol always refers to its racemic mixture. <i>Trofast et al.</i> (Chirality, 1, 443, 1991) reported on the potency of these isomers, showing a decrease in the order of (R,R)>(R,S)≥(S,R)>(S,S). The (R,R) isomer, also known as Arformoterol, being 1000 fold more potent than the (S,S) isomer. Arformoterol is commercialised by Sepracor as Brovana</div>
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Formoterol was first disclosed in Japanese patent application (Application N° 13121 ) whereby Formoterol is synthesised by N-alkylation using a phenacyl bromide as described in the scheme below:</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/EP2348013A1/imgb0002.png" href="http://patentimages.storage.googleapis.com/EP2348013A1/imgb0002.png"><img alt="Figure imgb0002" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/EP2348013A1/imgb0002.png" src="http://patentimages.storage.googleapis.com/EP2348013A1/imgb0002.png" height="332" id="ib0002" style="height: auto; max-width: 100%;" width="660" /></a></div>
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Afterwards, a small number of methods have been reported so far, regarding the synthesis of the (R,R) isomer, also referred as (R,R)-Formoterol and Arformoterol.</div>
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<span class="inline-nplcit" id="ncit0001">Murase et al. [Chem. Pharm. Bull. 26(4) 1123-1129(1978</span>)] reported the preparation of (R,R)-Formoterol from a racemic mixture of the (R,R) and (S,S) isomers by optical resolution using optically active tartaric acid. Trofast <i>et al.</i> described a method in which 4-benzyloxy-3-nitrostyrene oxide was coupled with a optically pure (R,R)- or (S,S)-N-phenylethyl-N-(1-p-methoxyphenyl)-2-(propyl)amine to give a diastereomeric mixture of Formoterol precursors. These precursors were further separated by HPLC in order to obtain pure Formoterol isomers. Both synthetic processes undergo long synthetic procedures and low yields.</div>
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Patent publication <a class="patcit" data-mce-href="http://www.google.co.in/patents/EP0938467" href="http://www.google.co.in/patents/EP0938467" id="pcit0002">EP0938467 </a>describes a method in which Arformoterol is prepared <i>via</i> the reaction of the optically pure (R) N-benzyl-2-(4-methoxyphenyl)-1-(methylethylamine) with an optically pure (R)-4-benzyloxy-3-nitrostyrene oxide or (R)-4-benzyloxy-3-formamidostyrene oxide followed by formylation of the amino group. This method requires relatively severe reaction conditions, 24 h at a temperature of from 110 up to 130 °C as well as a further purification step using tartaric acid in order to eliminate diastereomer impurities formed during the process.</div>
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<a class="patcit" data-mce-href="http://www.google.co.in/patents/WO2009147383" href="http://www.google.co.in/patents/WO2009147383" id="pcit0003">WO2009/147383 </a>discloses a process for the preparation of intermediates of Formoterol and Arformoterol which comprises a reduction of a ketone intermediate of formula:</div>
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Using chiral reductive agent with an enantiomeric excess of about 98% which requires further purification steps to obtain a product of desired optical purity.</div>
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R,R)-Formoterol (Arformoterol) or a salt thereof from optically pure and stable intermediate (R)-2-(4-Benzyloxy-3-nitro-phenyl)-oxirane (compound II), suitable for industrial use, in combination with optically pure amine in higher yields, as depicted in the scheme below:</div>
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Compound (R, R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methylethyl]-(1-phenyl-ethyl)-amino]-ethanol (compound VI), having the configuration represented by the following formula:<br />
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<b>Examples</b><b>(R)-2-(4-Benzyloxy-3-nitro-phenyl)-oxirane (II)</b><br />
A solution of 90 g (0.25 mol) of (R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-bromo-ethanol (compound I) in 320 mL of toluene and 50 mL of MeOH was added to a stirred suspension of 46 g (0.33 mol) of K<sub>2</sub>CO<sub>3</sub> in 130 mL of toluene and 130 mL of MeOH. The mixture was stirred at 40°C for 20 h and washed with water (400 mL). The organic phase was concentrated under reduced pressure to a volume of 100 mL and stirred at 25 °C for 30 min. It was then further cooled to 0-5°C for 30 min. and the product collected by filtration and dried at 40 °C to provide 67.1 g (97% yield) (98% chemical purity, 100% e.e.) of compound II as an off-white solid. <sup>1</sup> <b>H-NMR (200 MHz, CDCl<sub>3</sub>) δ:</b> 2.80-2.90 (m, 2H); 3.11-3.20 (m, 2H), 3.80-3.90 (m, 1H); 5.23 (s, 2H); 7.11 (d, 2H); 7.41 (m, 5H), 7.76 (d, 2H).<br />
<b>Preparation of (R,R)-[2-(4-Methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amine (III)</b><br />
A solution of 13 g (78.6 mmol) of 1-(4-Methoxy-phenyl)-propan-2-one and 8.3 g (78.6 mmol) of (R)-1-Phenylethylamine in 60 mL MeOH was hydrogenated in the presence of 1.7 g of Pt/C 5% at 10 atm. and 30 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and concentrated under reduced pressure to give compound III as an oil. The obtained oil was dissolved in 175 mL of acetone, followed by addition of 6.7 mL (80.9 mmol) of a 12M HCl solution. The mixture was stirred at 23 °C for 30 min and at 0-5 °C for 30 min. The product collected by filtration and dried at 40 °C to provide 13.8 g of the hydrochloride derivate as a white solid. The obtained solid was stirred in 100 mL of acetone at 23 °C for 1h and at 0-5 °C for 30 min, collected by filtration and dried at 40 °C to provide 13.2 g of the hydrochloride derivate as a white solid. This compound was dissolved in 100 mL of water and 100 mL of toluene followed by addition of 54 mL (54 mmol) of 1N NaOH solution. The organic phase was concentrated to give 11.7 g (55% yield) (99% chemical purity and 100% e.e) of compound III as an oil.<b><sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>) δ:</b> 0.88 (d, 3H); 1.31 (d, 3H), 2.40-2.50 (m, 1H); 2.60-2.80 (m, 2H); 3.74 (s, 3H); 3.90-4.10 (m, 1H); 6.77- 6.98 (m, 4H), 7.31 (s, 5H).<br />
<b>Synthesis of (R,R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (IV)</b><br />
A 1-liter flask was charged with 50g (0.18 mol) of <b>II</b> and 50g (0.18 mol) of <b>III</b> and stirred under nitrogen atmosphere at 140 °C for 20 h. To the hot mixture was added 200 mL of toluene to obtain a solution, which was washed with 200 mL of 1N HCl and 200 mL of water. The organic phase was concentrated under reduced pressure to give 99 g (99% yield) (88% chemical purity) of compound IV as an oil. Enantiomeric purity 100%. <b><sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>) δ:</b> 0.98 (d, 3H); 1.41 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.74 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.19 (s, 2H); 6.69-7.42 (m, 16H); 7.77 (s, 1H).<br />
<b>Synthesis of (R, R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (V)</b><br />
A solution of 99 g (0.18 mol) of <b>IV</b> in 270 mL IPA and 270 mL toluene was hydrogenated in the presence of 10 g of Ni-Raney at 18 atm and 40 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 87 g (92% yield) (83% chemical purity, 100 % e.e.) of compound <b>V</b> as an oil. <b><sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>) δ</b>: 0.97 (d, 3H); 1.44 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.74 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.07 (s, 2H); 6.67-6.84 (m, 7H); 7.25-7.42 (m, 10H).<br />
<b>Synthesis of (R,R)-N-(2-Benzyloxy-5-{1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethyl)-phenyl)-formamide (VI)</b><br />
24 mL (0.63 mol) of formic acid was added to 27 mL (0.28 mol) of acetic anhydride and stirred at 50 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with 100 mL of CH<sub>2</sub>Cl<sub>2</sub> and cooled to 0 °C. A solution of 78 g (0.15 mol) of <b>V</b> in 300 mL de CH<sub>2</sub>Cl<sub>2</sub> was slowly added and stirred for 1h at 0 °C. Then, 150 mL of 10% K<sub>2</sub>CO<sub>3</sub> aqueous solution were added and stirred at 0 °C for 15 min. The organic phase was washed twice with 400 mL of 10% K<sub>2</sub>CO<sub>3</sub> aqueous solution and concentrated under reduced pressure to give 80 g (97% yield, 100% e.e.) (75% chemical purity) of compound <b>VI</b> as an oil. <b><sup>1</sup>H-NMR (200 MHz, CDCl<sub>3</sub>) δ</b>: 0.98 (d, 3H); 1.42 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.75 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.09 (s, 2H); 6.67-7.41 (m, 17H); 8.4 (d, 1H).<br />
<b>Synthesis (R,R)-N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (VII)</b><br />
A solution of 8.5 g (16 mmol) of <b>VI</b>, previous purified by column chromatography on silica gel (AcOEt/heptane, 2:3), in 60 mL ethanol was hydrogenated in the presence of 0.14 g of Pd/C 5% at 10 atm. and 40 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and concentrated under reduced pressure to give 5 g (93% yield) (91% chemical purity, 100% e.e.) of compound <b>VII</b> as foam. m. p.= 58-60 °C. <b><sup>1</sup>H-NMR (200 MHz, d<sub>6</sub>-DMSO) δ</b>: 0.98 (d, 3H); 2.42-2.65 (m, 5H); 3.20-3.40 (m, 1H); 3.71 (s, 3H); 4.43-4.45 (m, 1H); 6.77-7.05 (m, 5H); 8.02 (s, 1H), 8.26 (s, 1H).<br />
<b>Synthesis (R,R)-N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (VII)</b><br />
A solution of 46 g (0.08 mol) of VI, crude product, was dissolved in 460 mL ethanol and hydrogenated in the presence of 0.74 g of Pd/C 5% at 10 atm. and 40 ° C for 28 h. The mixture was filtered though a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 24 g (83% yield) (77% chemical purity, 100% e.e.) of compound VII as a foam. m. p. = 58-60 °C. <b><sup>1</sup>H-NMR (200 MHz, d<sub>6</sub>-DMSO) δ:</b> 0.98 (d, 3H); 2.42-2.65 (m, 5H); 3.20-3.40 (m, 1H); 3.71 (s, 3H); 4.43-4.45 (m, 1H); 6.77-7.05 (m, 5H); 8.02 (s, 1H), 8.26 (s, 1H).<br />
The HPLC conditions used for the determination of the Chemical purity % are described in the table below:<br />
<ul class="description" lang="EN">
<li><div class="description-line" id="p0047">
<table class="description-table mce-item-table" frame="all" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr class="description-tr"><td align="left" class="description-td" colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HPLC Column</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Kromasil 100 C-18</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dimensions</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.15 m x 4.6 mm x 5 µm</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Buffer</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2.8 ml TEA (triethylamine) pH=3.00 H<sub>3</sub>PO<sub>4</sub> (85%) in 1 L of H<sub>2</sub>O</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Phase B</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Acetonitrile</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Flow rate</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1.5 ml miN<sup>-1</sup></td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Temperature</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">40 °C</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Wavelength</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">230 nm<br />
The HPLC conditions used for the determination of the enantiomeric purity % are described in the table below:</td></tr>
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<div class="description-line" id="p0048">
<table class="description-table mce-item-table" frame="all" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr class="description-tr"><td align="left" class="description-td" colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HPLC Column</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chiralpak AD-H</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dimensions</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.25 m x 4.6 mm</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Buffer</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">n-hexane : IPA : DEA (diethyl amine) : H<sub>2</sub>O 85:15:0.1:0.1</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Flow rate</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.8 ml min<sup>-1</sup></td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Temperature</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">25 °C</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Wavelength</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">228 nm</td></tr>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<a data-mce-href="https://www.google.com/patents/CN101921201A?cl=en" href="https://www.google.com/patents/CN101921201A?cl=en">https://www.google.com/patents/CN101921201A?cl=en</a></div>
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<span class="notranslate">Example 1</span><br />
<span class="notranslate">(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxy- phenyl) -N - [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral Intermediate (III) (17. 3g, yield 88%).</span> <span class="notranslate">HPLC: de values of> 90%; MS (ESI) m / z: 541 3 (M ++ 1); 1H-NMR (CDCl3):.. Δ 0. 96 (d, 3H), 1 49 (d, 3H ), 2 · 15 (q, 1Η), 2 · 67 (dq, 2H), 2. 99 (dq, 2H), 3. 74 (s, 3H), 4. 09 (d, 1H), 4. 56 (q, 1H), 5. 24 (s, 2H), 6. 77 (dd, 4H), 7. 10 (d, 1H), 7. 25-7. 5 (m, 11H), 7. 84 ( s, 1H).</span><br />
<span class="notranslate"> Example 2</span><br />
<span class="notranslate"> (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N - [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) and toluene 100ml, 110 ° C0-flow reactor 36 hours, the solvent was distilled off succeeded intermediates (III) (16. 8g, yield 85%).</span><br />
<span class="notranslate">Example 3</span><br />
<span class="notranslate">(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene After [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) and dichloromethane 100ml, 30 ° C for 48 hours, and the solvent was distilled off - yl) -N succeeded intermediates (III) (15. Sg, yield 80%).</span><br />
<span class="notranslate">Example 4</span><br />
<span class="notranslate"> (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N - [(R) -I- phenyl-ethyl] -2-amino-propane (II) (8. 75g, 32mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral intermediate form (III) (16. 3g, 83% yield).</span><br />
<span class="notranslate">Example 5</span><br />
<span class="notranslate"> (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N - [(R) -I- phenyl-ethyl] -2-amino-propane (II) (14. 6g, 54mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral intermediate form (III) (17. 5g, 89% yield).</span><br />
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<span data-mce-style="color: #ff0000;" style="color: red;">Scheme</span></h1>
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chirality 1991, 3, 443-50</div>
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Fumaric acid (0.138 mmol, 16 mg) was added to the residue dissolved in methanol. Evaporation of the solvent gave the<br />
product (SS) W semifumarate (109 mg) characterized by 'HNMR (4-D MSO) 6 (ppm) 1.00 (d, 3H, CHCH,), 4.624.70 (m, lH,<br />
CHOH), 3.73 (s, 3H, OCH,), 6.M.9 (m, 3H, aromatic), 7.00 (dd,4H, aromatic), 6.49 (s, 1@ CH = CH fumarate). MS of disilylated<br />
(SS) W: 473 (M +<H3,7%); 367 (M '<8H90, 45%); 310 61%). The (RSS) fraction was treated in the same manner<br />
giving the product (R;S) W semifumarate, which was characterized by 'H-NMR (4-DMSO) 6 (ppm) 1.01 (d, 3H, CHCH,),<br />
3.76 (s, 3H, OC&), 6.49 (s, lH, CH=CH, fumarate) 6.M.9 (m, 3H, aromatic), 7.0 (dd, 4H, aromatic). MS of disilylated (R;S)<br />
(M'X~~HIGNO1,7 %); 178 ( C I ~H~ ~N95O%,) ; 121 (CsH90, W. 473 (M'4H3, 5%); 367 (M'4gH90, 48%); 310<br />
(M +--CI~HIGNO18, %); 178 (CIIHIGNO, 95%); 121 (CsH90, 52%). The structural data for the (RR) and (S;R) enantiomers<br />
were in accordance with the proposed structures. The enantiomeric purity obtained for the enantiomers in each batch is<br />
shown in Table 1.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-17.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-17.jpg" rel="attachment wp-att-8124"><img alt="STR1" class="alignnone size-full wp-image-8124" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-17.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-17.jpg" height="496" style="height: auto; max-width: 100%;" width="807" /></a></div>
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Scheme</div>
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The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).</div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">Org Process Res Dev1998,2,(2):96</span></em></strong></div>
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<h1 class="articleTitle">
<span class="hlFld-Title">Large-Scale Synthesis of Enantio- and Diastereomerically Pure (<i>R</i>,<i>R</i>)-Formoterol<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op970116o#op970116oAF2" href="http://pubs.acs.org/doi/abs/10.1021/op970116o#op970116oAF2"><sup>†</sup></a></span></h1>
<div id="articleMeta">
<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Hett%2C+Robert" href="http://pubs.acs.org/author/Hett%2C+Robert" id="authors">Robert Hett</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op970116o#op970116oAF1" href="http://pubs.acs.org/doi/abs/10.1021/op970116o#op970116oAF1">*</a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Fang%2C+Qun+K" href="http://pubs.acs.org/author/Fang%2C+Qun+K" id="authors">Qun K. Fang</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Gao%2C+Yun" href="http://pubs.acs.org/author/Gao%2C+Yun" id="authors">Yun Gao</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op970116o#op970116oAF1" href="http://pubs.acs.org/doi/abs/10.1021/op970116o#op970116oAF1">*</a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Wald%2C+Stephen+A" href="http://pubs.acs.org/author/Wald%2C+Stephen+A" id="authors">Stephen A. Wald</a> , and</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Senanayake%2C+Chris+H" href="http://pubs.acs.org/author/Senanayake%2C+Chris+H" id="authors">Chris H. Senanayake</a></span></span></div>
<div class="affiliations">
Process Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752</div>
<div id="citation">
<cite>Org. Proc. Res. Dev.</cite>, <span class="citation_year">1998</span>, <span class="citation_volume">2</span> (2), pp 96–99</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op970116o</div>
<div id="pubDate">
</div>
<div id="correspondence">
<span data-mce-style="color: #ff0000;" style="color: red;"><a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op970116o" href="http://pubs.acs.org/doi/abs/10.1021/op970116o">http://pubs.acs.org/doi/abs/10.1021/op970116o</a></span></div>
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<div id="articleBody">
<div class="hlFld-Abstract">
<h2 id="Abstract">
Abstract</h2>
<div id="abstractBox">
<div class="articleBody_abstractText">
(<i>R</i>,<i>R</i>)-Formoterol (<b>1</b>) is a long-acting, very potent β<sub>2</sub>-agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure (<i>R</i>,<i>R</i>)-formoterol fumarate is achieved by a chromatography-free process with an overall yield of 44%. Asymmetric catalytic reduction of bromoketone <b>4</b> using as catalyst oxazaborolidine derived from (1<i>R</i>, 2<i>S</i>)-1-amino-2-indanol and resolution of chiral amine <b>3 </b>are the origins of chirality in this process. Further enrichment of enantio- and diastereomeric purity is accomplished by crystallizations of the isolated intermediates throughout the process to give (<i>R</i>,<i>R</i>)-formoterol (<b>1) </b>as the pure stereoisomer (ee, de >99.5%).</div>
</div>
<h2 class="syn">
<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">(R,R)-formoterol fumarate</span></em></strong> (53.5 g, 70%) as white crystals: mp = 139 °C dec; [α]<sup>20</sup><sub>D</sub> = −45.5 (<i>c</i> = 1, H<sub>2</sub>O); ee, de > 99.5%; <sup>1</sup>H NMR (300 MHz, DMSO-<i>d</i><sub>6</sub>) δ (ppm) 9.64 (s), 9.35 (d), 8.55 (d), 8.29 (s), 8.15 (s), 7.14 (d, 2 H), 7.0 (m), 6.95 (d, 2 H), 6.51 (s, 1 H), 4.82 (m, 1 H), 3.72 (s, 3 H), 3.35 (m, 1 H), 3.10 (m, 3 H), 2.58 (m, 1 H), 2.50 (br s, 2 H), 1.06 (d, 3 H).</h2>
<div class="syn">
Anal. Calcd for C<sub>42</sub>H<sub>52</sub>N<sub>4</sub>O<sub>12</sub>: C, 62.67; H, 6.51; N, 6.96. Found: C, 62.34; H, 6.57; N, 6.85.</div>
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Scheme</div>
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<img alt="" data-mce-src="http://www.chemdrug.com/file/upload/SYNTHESIS/SYN/23/23603402a.gif" src="http://www.chemdrug.com/file/upload/SYNTHESIS/SYN/23/23603402a.gif" style="height: auto; max-width: 100%;" /></div>
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The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture, which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV). The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI), which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF, yielding the chiral bromoethanol derivative (VIII). The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX), which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X). The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI), which is acylated with formic acid to afford the formamide compound (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, providing the target compound.</div>
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The synthesis of the chiral borolidine catalyst (II) starting from indoline (I), as well as the enantioselective reduction of 4'-(benzyloxy)-3'-nitrophenacyl bromide (III), catalyzed by borolidine (II), and using various borane complexes (borane/dimethylsulfide, borane/THF and borane/diethylaniline), has been studied in order to solve the problems presented in large-scale synthesis. The conclusions of the study are that the complex borane/diethylaniline (DEANB) is the most suitable reagent for large-scale reduction of phenacyl bromide (III) since the chemical hazards and inconsistent reagent quality of the borane/THF and borane/dimethylsulfide complexes disqualified their use in large-scale processes. The best reaction conditions of the reduction with this complex are presented.</div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/EP2285770A1?cl=en" href="https://www.google.com/patents/EP2285770A1?cl=en">https://www.google.com/patents/EP2285770A1?cl=en</a></div>
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Formoterol is a long-acting β<sub>2</sub>-adrenoceptor agonist and has a long duration of action of up to 12 hours. Chemically it is termed as Λ/-[2-hydroxy-5-[1-hydroxy-2-[[2-(4- methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]-formamide. The structure of formoterol is as shown below.<br />
<div class="patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/WO2009147383A1/imgf000003_0001.png" href="https://patentimages.storage.googleapis.com/WO2009147383A1/imgf000003_0001.png"><img alt="Figure imgf000003_0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/WO2009147383A1/imgf000003_0001.png" height="136" id="imgf000003_0001" src="https://patentimages.storage.googleapis.com/WO2009147383A1/imgf000003_0001.png" style="height: auto; max-width: 100%;" width="348" /></a></div>
The asterisks indicate that formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four diastereomers which have the following configurations: (R,R), (S<sub>1</sub>S), (S<sub>1</sub>R) and (R<sub>1</sub>S).<br />
(R<sub>1</sub>R) and (S<sub>1</sub>S) are mirror images of each other and are therefore enantiomers. Similarly (S<sub>1</sub>R) and (R<sub>1</sub>S) form other enatiomeric pair.<br />
The commercially-available formoterol is a 50:50 mixture of the (R<sub>1</sub>R)- and (S<sub>1</sub>S)- enantiomers. (R,R)-formoterol is an extremely potent full agonist at the β<sub>2-</sub>adrenoceptor and is responsible for bronchodilation and has anti-inflammatory properties. On the other hand (S,S)-enantiomer, has no bronchodilatory activity and is proinflammatory.<br />
Murase et al. [Chem.Pharm.Bull., .26(4)1123-1129(1978)] synthesized all four isomers of formoterol and examined for β-stimulant activity. In the process, racemic formoterol was subjected to optical resolution with tartaric acid.<br />
In another attempt by Trofast et al. [Chirality, 3:443-450(1991 )], racemic 4-benzyloxy-3- nitrostryrene oxide was coupled with optically pure N-[(R)-1-phenylethyl]-2-(4- methoxyphenyl)-(R)1-methylethylamine to give diastereomeric mixtures of intermediates, which were separated by column chromatography and converted to the optically pure formoterol.<br />
In yet another attempt, racemic formoterol was subjected to separation by using a chiral compound [International publication WO 1995/018094].<br />
WO 98/21175 discloses a process for preparing optically pure formoterol using optically pure intermediates (R)-N-benzyl-2-(4-methoxyphenyl)-1-methylethyl amine and (R)-4- benzyloxy-3-formamidostyrene oxide.<br />
Preparation of optically pure formoterol is also disclosed in IE 000138 and GB2380996.</div>
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<img alt="" data-mce-src="http://patentimages.storage.googleapis.com/WO2009147383A1/imgf000024_0001.png" src="http://patentimages.storage.googleapis.com/WO2009147383A1/imgf000024_0001.png" style="height: auto; max-width: 100%;" /></div>
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Example 7<br />
Preparation of Arformoterol<br />
4-benzyloxy-3-formylamino-α-[N-benzyl-N-(1-methyl-2-p- methoxyphenylethyl)aminomethyl]benzyl alcohol (120gms, 0.23M), 10% Pd/C (12 gms) and denatured spirit (0.6 lit) were introduced in an autoclave. The reaction mass was hydrogenated by applying 4 kg hydrogen pressure at 25-30<sup>0</sup>C for 3 hrs. The catalyst was removed by filtration and the, clear filtrate concentrated under reduced pressure below 40<sup>0</sup>C to yield the title compound. (63 gms, 80%).<br />
Example 8<br />
Preparation of Arformoterol Tartrate<br />
Arformoterol base (60 gms, 0.17M), 480 ml IPA , 120 ml toluene and a solution of l_(+)- tartaric acid (25.6 gms, 0.17M) in 60 ml distilled water were stirred at 25-30<sup>0</sup>C for 2 hrs and further at 40°- 45°C for 3 hrs. The reaction mass was cooled to 25-30<sup>0</sup>C and further chilled to 20<sup>0</sup>C for 30 mins. The solid obtained was isolated by filtration to yield the title compound. (60 gms, 70%),<br />
The tartrate salt was dissolved in hot 50% IPA-water (0.3 lit), cooled as before and filtered to provide arformoterol tartrate. (30 gms, 50 % w/w). having enantiomeric purity greater than 99%.</div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">PAPER</span></em></strong></h1>
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Organic Process Research & Development 2000, 4, 567-570</div>
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Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a Functionalized Nitroarene: Preparation of a Key Intermediate in the Synthesis of (R,R)-Formoterol Tartrate...........<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op000287k" href="http://pubs.acs.org/doi/abs/10.1021/op000287k">http://pubs.acs.org/doi/abs/10.1021/op000287k</a></div>
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<h1 class="articleTitle">
<span class="hlFld-Title">Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a Functionalized Nitroarene: Preparation of a Key Intermediate in the Synthesis of (<i>R</i>,<i>R</i>)-Formoterol Tartrate</span></h1>
<div id="articleMeta">
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<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Wilkinson%2C+H+Scott" href="http://pubs.acs.org/author/Wilkinson%2C+H+Scott" id="authors">H. Scott Wilkinson</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Hett%2C+Robert" href="http://pubs.acs.org/author/Hett%2C+Robert" id="authors">Robert Hett</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Tanoury%2C+Gerald+J" href="http://pubs.acs.org/author/Tanoury%2C+Gerald+J" id="authors">Gerald J. Tanoury</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op000287k#op000287kAF1" href="http://pubs.acs.org/doi/abs/10.1021/op000287k#op000287kAF1">*</a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Senanayake%2C+Chris+H" href="http://pubs.acs.org/author/Senanayake%2C+Chris+H" id="authors">Chris H. Senanayake</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op000287k#op000287kAF1" href="http://pubs.acs.org/doi/abs/10.1021/op000287k#op000287kAF1">*</a> and</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Wald%2C+Stephen+A" href="http://pubs.acs.org/author/Wald%2C+Stephen+A" id="authors">Stephen A. Wald</a></span></span></div>
<div class="affiliations">
Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.</div>
<div id="citation">
<cite>Org. Proc. Res. Dev.</cite>, <span class="citation_year">2000</span>, <span class="citation_volume">4</span> (6), pp 567–570</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op000287k</div>
</div>
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In the synthesis of the β<sub>2</sub>-adrenoceptor agonist (<i>R,R</i>)-formterol, a key step in the synthesis was the development of a highly chemoselective reduction of (1<i>R</i>)-2-bromo-1-[3-nitro-4-(phenylmethoxy)phenyl]ethan-1-ol to give (1<i>R</i>)-1-[3-amino-4-(phenylmethoxy)phenyl]-2-bromoethan-1-ol. The aniline product was isolated as the corresponding formamide. The reaction required reduction of the nitro moiety in the presence of a phenyl benzyl ether, a secondary benzylic hydroxyl group, and a primary bromide, and with no racemization at the stereogenic carbinol carbon atom. The development of a synthetic methodology using heterogeneous catalytic hydrogenation to perform the required reduction was successful when a sulfur-based poison was added. The chemistry of sulfur-based poisons to temper the reacitivty of catalyst was studied in depth. The data show that the type of hydrogenation catalyst, the oxidation state of the poison, and the substituents on the sulfur atom had a dramatic effect on the chemoselectivity of the reaction. Dimethyl sulfide was the poison of choice, possessing all of the required characteristics for providing a highly chemoselective and high yielding reaction. The practicality and robustness of the process was demonstrated by preparing the final formamide product with high chemoselectivity, chemical yield, and product purity on a multi-kilogram scale.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;"> PAPER</span></h1>
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Tetrahedron: Asymmetry 11 (2000) 2705±2717</div>
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An ecient enantioselective synthesis of (R,R)-formoterol, a potent bronchodilator, using lipases<br />
Francisco Campos, M. Pilar Bosch and Angel Guerrero*</div>
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formoterol (R,R)-1 as amorphous solid. Rf: 0.27 (SiO2, AcOEt:MeOH, 1:1). 20D=-41.5 (CHCl3, c 0.53).</div>
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IR, : 3383, 2967, 2923, 1674, 1668, 1610, 1514, 1442, 1247, 1033,815 cm^1.</div>
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1H NMR (300 MHz, CDCl3), : 8.11 (b, 1H), 7.46 (b, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.9±6.7 (c, 4H), 4.46 (m, 1H), 4.34 (b, 3H interchangeable), 3.74 (s, 3H), 2.90±2.45 (c, 5H), 1.02 (d,J=5.7 Hz, 3H) ppm.</div>
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13C NMR (75 MHz, CDCl3), : 160.2, 158.3, 147.7, 133.4, 130.6, 130.2 (2C),125.7, 123.7, 119.5, 117.8, 114.0 (2C), 71.3, 55.3, 54.7, 53.6, 42.0, 19.4 ppm.</div>
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CI (positive, LC-MS)(m/z, %) 435 (M+1, 100).</div>
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The tartrate salt was prepared by dissolving 13.8 mg (0.04 mmol) of(R,R)-1 and 6.0 mg (0.04 mmol) of (l)-(+)-tartaric acid in 150 mL of 85% aqueous isopropanol.<br />
The solution was left standing overnight and the resulting crystalline solid (7.6 mg) puri®ed on areverse-phase column (1 g, Isolute SPE C18) using mixtures of MeOH±H2O as eluent. The solventwas removed under vacuum and the aqueous solution lyophilized (^35 C, 0.6 bar) overnight. The(l)-(+)-tartrate salt of (R,R)-1 showed an 20D=-29.4 (H2O, c 0.61) (>99% ee based on the<br />
reported value 34). 34=Hett, R.; Senanayake, C. H.; Wald, S. A. Tetrahedron Lett. 1998, 39, 1705.</div>
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PAPER</div>
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<h1 class="articleTitle">
<span class="hlFld-Title">Diethylanilineborane: A Practical, Safe, and Consistent-Quality Borane Source for the Large-Scale Enantioselective Reduction of a Ketone Intermediate in the Synthesis of (<i>R</i>,<i>R</i>)-Formoterol</span></h1>
<div id="articleMeta">
<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Wilkinson%2C+H+Scott" href="http://pubs.acs.org/author/Wilkinson%2C+H+Scott" id="authors">H. Scott Wilkinson</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Tanoury%2C+Gerald+J" href="http://pubs.acs.org/author/Tanoury%2C+Gerald+J" id="authors">Gerald J. Tanoury</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op015504b#op015504bAF1" href="http://pubs.acs.org/doi/abs/10.1021/op015504b#op015504bAF1">*</a><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op015504b#op015504bAF2" href="http://pubs.acs.org/doi/abs/10.1021/op015504b#op015504bAF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Wald%2C+Stephen+A" href="http://pubs.acs.org/author/Wald%2C+Stephen+A" id="authors">Stephen A. Wald</a> , and</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Senanayake%2C+Chris+H" href="http://pubs.acs.org/author/Senanayake%2C+Chris+H" id="authors">Chris H. Senanayake</a> <a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op015504b#op015504bAF1" href="http://pubs.acs.org/doi/abs/10.1021/op015504b#op015504bAF1">*</a></span></span></div>
<div class="affiliations">
Chemical Research and Development, Sepracor Incorporated, 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.</div>
<div id="citation">
<cite>Org. Proc. Res. Dev.</cite>, <span class="citation_year">2002</span>, <span class="citation_volume">6</span> (2), pp 146–148</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op015504b</div>
<div id="pubDate">
</div>
<div id="correspondence">
<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op015504b" href="http://pubs.acs.org/doi/abs/10.1021/op015504b">http://pubs.acs.org/doi/abs/10.1021/op015504b</a></div>
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<div id="articleBody">
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<h2 id="Abstract">
Abstract</h2>
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<img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2002/oprdfk.2002.6.issue-2/op015504b/production/images/medium/op015504bn00001.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2002/oprdfk.2002.6.issue-2/op015504b/production/images/medium/op015504bn00001.gif" style="height: auto; max-width: 100%;" /></div>
<div class="articleBody_abstractText">
The development of a process for the use of <i>N</i>,<i>N</i>-diethylaniline−borane (DEANB) as a borane source for the enantioselective preparation of a key intermediate in the synthesis of (<i>R</i>,<i>R</i>)-formoterol <span class="smallcaps">l</span>-tartrate, bromohydrin <b>2</b>, from ketone <b>3</b> on kilogram scale is described. DEANB was found to be a more practical, safer, and higher-quality reagent when compared to other more conventional borane sources: borane−THF and borane−DMS.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PAPER</span></h1>
<a data-mce-href="http://nopr.niscair.res.in/bitstream/123456789/8917/1/IJCB%2044B(1)%20167-169.pdf" href="http://nopr.niscair.res.in/bitstream/123456789/8917/1/IJCB%2044B(1)%20167-169.pdf">http://nopr.niscair.res.in/bitstream/123456789/8917/1/IJCB%2044B(1)%20167-169.pdf</a><br />
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<a data-mce-href="http://www.bioorg.org/down/Hetetorcycles_07_2243.pdf?ckattempt=1" href="http://www.bioorg.org/down/Hetetorcycles_07_2243.pdf?ckattempt=1">http://www.bioorg.org/down/Hetetorcycles_07_2243.pdf?ckattempt=1</a></div>
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PAPER</div>
<div class="cit" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/14725487#" href="http://www.ncbi.nlm.nih.gov/pubmed/14725487#" title="Drugs in R&D.">Drugs R D.</a> 2004;5(1):25-7.</div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol.</h1>
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<h3>
Abstract</h3>
<div class="">
Sepracor in the US is developing arformoterol [R,R-formoterol], a single isomer form of the beta(2)-adrenoceptor agonist formoterol [eformoterol]. This isomer contains two chiral centres and is being developed as an inhaled preparation for the treatment of respiratory disorders. Sepracor believes that arformoterol has the potential to be a once-daily therapy with a rapid onset of action and a duration of effect exceeding 12 hours. In 1995, Sepracor acquired New England Pharmaceuticals, a manufacturer of metered-dose and dry powder inhalers, for the purpose of preparing formulations of levosalbutamol and arformoterol. Phase II dose-ranging clinical studies of arformoterol as a longer-acting, complementary bronchodilator were completed successfully in the fourth quarter of 2000. Phase III trials of arformoterol began in September 2001. The indications for the drug appeared to be asthma and chronic obstructive pulmonary disease (COPD). However, an update of the pharmaceutical product information on the Sepracor website in September 2003 listed COPD maintenance therapy as the only indication for arformoterol. In October 2002, Sepracor stated that two pivotal phase III studies were ongoing in 1600 patients. Sepracor estimates that its NDA submission for arformoterol, which is projected for the first half of 2004, will include approximately 3000 adult subjects. Sepracor stated in July 2003 that it had completed more than 100 preclinical studies and initiated or completed 15 clinical studies for arformoterol inhalation solution for the treatment of bronchospasm in patients with COPD. In addition, Sepracor stated that the two pivotal phase III studies in 1600 patients were still progressing. In 1995, European patents were granted to Sepracor for the use of arformoterol in the treatment of asthma, and the US patent application was pending.</div>
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CLIP</div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">PAPER</span></em></strong></h1>
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<a class="S_C_ddDoi" data-mce-href="http://dx.doi.org/10.1016/j.cclet.2008.01.012" href="http://dx.doi.org/10.1016/j.cclet.2008.01.012" id="ddDoi" target="doilink">doi:10.1016/j.cclet.2008.01.012</a></div>
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<a data-mce-href="http://www.sciencedirect.com/science/article/pii/S1001841708000132" href="http://www.sciencedirect.com/science/article/pii/S1001841708000132">http://www.sciencedirect.com/science/article/pii/S1001841708000132</a></div>
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<a class="cLink" data-mce-href="http://www.sciencedirect.com/science/journal/10018417" href="http://www.sciencedirect.com/science/journal/10018417" title="Go to Chinese Chemical Letters on ScienceDirect">Chinese Chemical Letters</a></div>
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<a class="S_C_volIss" data-mce-href="http://www.sciencedirect.com/science/journal/10018417/19/3" href="http://www.sciencedirect.com/science/journal/10018417/19/3" title="Go to table of contents for this volume/issue">Volume 19, Issue 3</a>, March 2008, Pages 279–280</div>
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<h1 class="svTitle" id="">
New method in synthesizing an optical active intermediate for (<em>R</em>,<em>R</em>)-formoterol</h1>
<ul class="authorGroup noCollab svAuthor">
<li class="smh5"><a class="authorName svAuthor" data-fn="Wei" data-ln="Fan" data-mce-href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#" data-orcid="" data-pos="1" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#" id="authname_N84de03c0N42f75dd0">Wei Fan</a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-fn="Lei" data-ln="Chen" data-mce-href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#" data-orcid="" data-pos="2" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#" id="authname_N84de03c0N42f75e60">Lei Chen</a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-fn="Li" data-ln="Hai" data-mce-href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#" data-orcid="" data-pos="3" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#" id="authname_N84de03c0N42f75ef0">Li Hai</a>,</li>
<li class="smh5"><a class="authorName svAuthor" data-fn="Yong" data-ln="Wu" data-mce-href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#" data-orcid="" data-pos="4" data-t="a" data-tb="" href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#" id="authname_N84de03c0N42f75f80">Yong Wu</a><a class="intra_ref auth_corr" data-mce-href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#cor1" href="http://www.sciencedirect.com/science/article/pii/S1001841708000132#cor1" id="bcor1" title="Corresponding author contact information"></a><sup>,</sup></li>
</ul>
<ul class="affiliation authAffil smh">
<li class="smh5plus"><span id="">Key Laboratory of Drug Targeting Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China\</span></li>
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Abstract</h2>
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(<em>R</em>)-1-(4-Methoxyphenyl)propan-2-amine <strong class="boldFont">2a</strong>, an optical active intermediate for (<em>R</em>,<em>R</em>)-formoterol, was synthesized from <span class="smallcaps">d</span>-alanine in 65% overall yield by using a simple route, which contained protecting amino group, cyclization, coupling with Grignard reagent, reduction and deprotection.</div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;"> IR spectra of (a) (R,R)-formoterol tartrate/form A, (b) (R,R)-formoterol tartrate/form B, (c) (R,R)-formoterol tartrate/form C.</span></em></strong></h2>
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<span class="mw-headline" id="References">References</span></h2>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Muller, P., et al.: Arzneimittel-Forsch., 33, 1685 (1983); Wallmark, B., et al.: Biochim. Biophys. Acta., 778, 549 (1984); Morii, M., et al.: J. Biol. chem., 268, 21553 (1993); Ritter, M., et al.: Br. J. Pharmacol., 124, 627 (1998); Stenhoff, H., et al.: J. Chromatogr., 734, 191 (1999), Johnson, D.A., et al.: Expert Opin. Pharmacother., 4, 253 (2003); Bouyssou, T., et al.: Bio. Med. Chem. Lett. 20, 1410, (2010);</td></tr>
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<div class="reflist" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<ol class="references">
<li id="cite_note-1"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.rxlist.com/cgi/generic/brovana_ids.htm" href="http://www.rxlist.com/cgi/generic/brovana_ids.htm" rel="nofollow">"Brovana Prescribing information, Dosage and Administration section"</a>. <a class="external text" data-mce-href="http://web.archive.org/web/20080213040930/http://www.rxlist.com/cgi/generic/brovana_ids.htm" href="http://web.archive.org/web/20080213040930/http://www.rxlist.com/cgi/generic/brovana_ids.htm" rel="nofollow">Archived</a> from the original on 13 February 2008<span class="reference-accessdate">. Retrieved<span class="nowrap">2008-03-14</span></span>.</cite></span></li>
<li>SEE <a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm5013227" href="http://pubs.acs.org/doi/abs/10.1021/jm5013227">http://pubs.acs.org/doi/abs/10.1021/jm5013227</a></li>
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<span class="mw-headline" id="External_links">External links</span></h2>
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<li><a class="external text" data-mce-href="http://www.brovana.com/" href="http://www.brovana.com/" rel="nofollow">Brovana</a> website</li>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/EP0390762A1?cl=en" href="http://www.google.co.in/patents/EP0390762A1?cl=en">EP0390762A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">23 Mar 1990</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3 Oct 1990</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aktiebolaget Draco</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">New bronchospasmolytic compounds and process for their preparation</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/EP0938467A1?cl=en" href="http://www.google.co.in/patents/EP0938467A1?cl=en">EP0938467A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7 Nov 1997</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1 Sep 1999</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sepracor, Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of optically pure isomers of formoterol</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/EP1082293A2?cl=en" href="http://www.google.co.in/patents/EP1082293A2?cl=en">EP1082293A2</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20 May 1999</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">14 Mar 2001</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sepracor Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Formoterol polymorphs</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO2009147383A1?cl=en" href="http://www.google.co.in/patents/WO2009147383A1?cl=en">WO2009147383A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2 Jun 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10 Dec 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cipla Limited</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the synthesis of arformoterol</td></tr>
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<tr class="patent-data-table"><th class="patent-data-table-th" colspan="3" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Reference</th></tr>
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<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HETT R ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Enantio-+and+Diastereoselective+Synthesis+of+all+Four+Stereoisomers+of+Formoterol%22" href="http://scholar.google.com/scholar?q=%22Enantio-+and+Diastereoselective+Synthesis+of+all+Four+Stereoisomers+of+Formoterol%22">Enantio- and Diastereoselective Synthesis of all Four Stereoisomers of Formoterol</a>" TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL LNKD- DOI:10.1016/S0040-4039(97)00088-9, vol. 38, no. 7, 17 February 1997 (1997-02-17), pages 1125-1128, XP004034214 ISSN: 0040-4039</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">LING HUANG ET AL.: "<a data-mce-href="http://scholar.google.com/scholar?q=%22The+Asymmetric+Synthesis+of+%28R%2CR%29-Formoterol+via+Transfer+Hydrogenation+with+Polyethylene+Glycol+Bound+Rh+Catalyst+in+PEG2000+and+Water%22" href="http://scholar.google.com/scholar?q=%22The+Asymmetric+Synthesis+of+%28R%2CR%29-Formoterol+via+Transfer+Hydrogenation+with+Polyethylene+Glycol+Bound+Rh+Catalyst+in+PEG2000+and+Water%22">The Asymmetric Synthesis of (R,R)-Formoterol via Transfer Hydrogenation with Polyethylene Glycol Bound Rh Catalyst in PEG2000 and Water</a>" CHIRALITY, vol. 22, 30 April 2009 (2009-04-30), pages 206-211, XP002592699</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">MURASE ET AL. CHEM. PHARM. BULL. vol. 26, no. 4, 1978, pages 1123 - 1129</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">4</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">TROFAST ET AL. CHIRALITY vol. 1, 1991, page 443</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">TROFAST J ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22STERIC+ASPECTS+OF+AGONISM+AND+ANTAGONISM+AT+BETA-ADRENICEPTORS%3A+SYNTHESIS+OF+AND+PHARMACOLOGICAL+EXPERIMENTS+WITH+THE+ENANTIOMERS+OF+FORMOTEROL+AND+THEIR+DIASTEREOMERS%22" href="http://scholar.google.com/scholar?q=%22STERIC+ASPECTS+OF+AGONISM+AND+ANTAGONISM+AT+BETA-ADRENICEPTORS%3A+SYNTHESIS+OF+AND+PHARMACOLOGICAL+EXPERIMENTS+WITH+THE+ENANTIOMERS+OF+FORMOTEROL+AND+THEIR+DIASTEREOMERS%22">STERIC ASPECTS OF AGONISM AND ANTAGONISM AT BETA-ADRENICEPTORS: SYNTHESIS OF AND PHARMACOLOGICAL EXPERIMENTS WITH THE ENANTIOMERS OF FORMOTEROL AND THEIR DIASTEREOMERS</a>" CHIRALITY, WILEY-LISS, NEW YORK, US LNKD- DOI:10.1002/CHIR.530030606, vol. 3, no. 6, 1 January 1991 (1991-01-01) , pages 443-450, XP002057060 ISSN: 0899-0042</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">WILKINSON, H.S ET AL. ORGANIC PROCESS RESEARCH AND DEVELOPMENT vol. 6, 2002, pages 146 - 148</td></tr>
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<h3 class="r">
<a data-href="https://core.ac.uk/download/pdf/6115604.pdf" data-mce-href="https://www.google.co.in/url?sa=t&rct=j&q=&esrc=s&source=web&cd=19&ved=0ahUKEwi0qbzdrqXOAhVDvY8KHdxPDuM4ChAWCEswCA&url=https%3A%2F%2Fcore.ac.uk%2Fdownload%2Fpdf%2F6115604.pdf&usg=AFQjCNHEWD8NTnQzqC9UhJT1zDOHp5iREQ&sig2=wi7oTDa20GOMJ7u-7HiUGQ" href="https://www.google.co.in/url?sa=t&rct=j&q=&esrc=s&source=web&cd=19&ved=0ahUKEwi0qbzdrqXOAhVDvY8KHdxPDuM4ChAWCEswCA&url=https%3A%2F%2Fcore.ac.uk%2Fdownload%2Fpdf%2F6115604.pdf&usg=AFQjCNHEWD8NTnQzqC9UhJT1zDOHp5iREQ&sig2=wi7oTDa20GOMJ7u-7HiUGQ" target="_blank">Durham E-Theses A Solid-state NMR Study of Formoterol Fumarate</a></h3>
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<div class="f kv _SWb">
<cite class="_Rm">https://core.ac.uk/download/pdf/6115604.pdf</cite><br />
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<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Arformoterol">Arformoterol</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Arformoterol.svg" href="https://en.wikipedia.org/wiki/File:Arformoterol.svg"><img alt="Arformoterol.svg" data-file-height="217" data-file-width="512" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/57/Arformoterol.svg/250px-Arformoterol.svg.png" height="106" src="https://upload.wikimedia.org/wikipedia/commons/thumb/5/57/Arformoterol.svg/250px-Arformoterol.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/5/57/Arformoterol.svg/375px-Arformoterol.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/5/57/Arformoterol.svg/500px-Arformoterol.svg.png 2x" style="height: auto; max-width: 100%;" width="250" /></a></td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Arformoterol_ball-and-stick_model.png" href="https://en.wikipedia.org/wiki/File:Arformoterol_ball-and-stick_model.png"><img alt="Arformoterol ball-and-stick model.png" data-file-height="1225" data-file-width="2238" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9a/Arformoterol_ball-and-stick_model.png/250px-Arformoterol_ball-and-stick_model.png" height="137" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9a/Arformoterol_ball-and-stick_model.png/250px-Arformoterol_ball-and-stick_model.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/9/9a/Arformoterol_ball-and-stick_model.png/375px-Arformoterol_ball-and-stick_model.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/9/9a/Arformoterol_ball-and-stick_model.png/500px-Arformoterol_ball-and-stick_model.png 2x" style="height: auto; max-width: 100%;" width="250" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><i>N</i>-[2-hydroxy-5-[(1<i>R</i>)-1-hydroxy-2-[[(2<i>R</i>)-1-(4-methoxyphenyl) propan-2-yl]amino]ethyl] phenyl]formamide</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Brovana</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/monograph/arformoterol-tartrate.html" href="https://www.drugs.com/monograph/arformoterol-tartrate.html" rel="nofollow">Monograph</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/MedlinePlus" href="https://en.wikipedia.org/wiki/MedlinePlus" title="MedlinePlus">MedlinePlus</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.nlm.nih.gov"><a class="external text" data-mce-href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a602023.html" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a602023.html" rel="nofollow">a602023</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">License data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small>US</small> <span title="www.accessdata.fda.gov"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" title="U.S. Food and Drug Administration">FDA</a>: <a class="external text" data-mce-href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Arformoterol&SearchType=BasicSearch" href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Arformoterol&SearchType=BasicSearch" rel="nofollow">Arformoterol</a></span></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" title="Pregnancy category">C</a> (Risk not ruled out)</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Inhalation solution for<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Nebuliser" href="https://en.wikipedia.org/wiki/Nebuliser" title="Nebuliser">nebuliser</a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Plasma_protein_binding" href="https://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">52–65%</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Biological_half-life" href="https://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26 hours</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=67346-49-0" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=67346-49-0" rel="nofollow">67346-49-0</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">none</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3083544" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3083544" rel="nofollow">3083544</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/IUPHAR/BPS" href="https://en.wikipedia.org/wiki/IUPHAR/BPS" title="IUPHAR/BPS">IUPHAR/BPS</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.guidetopharmacology.org"><a class="external text" data-mce-href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7479" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7479" rel="nofollow">7479</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/DrugBank" href="https://en.wikipedia.org/wiki/DrugBank" title="DrugBank">DrugBank</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugbank.ca"><a class="external text" data-mce-href="http://www.drugbank.ca/drugs/DB01274" href="http://www.drugbank.ca/drugs/DB01274" rel="nofollow">DB01274</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.2340731.html" href="http://www.chemspider.com/Chemical-Structure.2340731.html" rel="nofollow">2340731</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=F91H02EBWT" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=F91H02EBWT" rel="nofollow">F91H02EBWT</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEBI" href="https://en.wikipedia.org/wiki/ChEBI" title="ChEBI">ChEBI</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:408174" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:408174" rel="nofollow">CHEBI:408174</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEMBL" href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1201137" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1201137" rel="nofollow">CHEMBL1201137</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>19</sub><span title="Hydrogen">H</span><sub>24</sub><span title="Nitrogen">N</span><sub>2</sub><span title="Oxygen">O</span><sub>4</sub></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">344.405 g/mol</td></tr>
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<img alt="Formoterol" data-mce-src="http://www.druglead.com/cds/structure/Formoterol.gif" src="http://www.druglead.com/cds/structure/Formoterol.gif" style="height: auto; max-width: 100%;" /></div>
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<b></b>Formoterol</div>
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<b>CAS Registry Number:</b> 73573-87-2</div>
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<b>CAS Name:</b> <i>rel</i>-<i>N-</i>[2-Hydroxy-5-[(1<i>R</i>)-1-hydroxy-2-[[(1<i>R</i>)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide</div>
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<b>Additional Names:</b> 3-formylamino-4-hydroxy-a-[<i>N-</i>[1-methyl-2-(<i>p-</i>methoxyphenyl)ethyl]aminomethyl]benzyl alcohol; (±)-2¢-hydroxy-5¢-[<i>(RS)-</i>1-hydroxy-2-[[(<i>RS</i>)-<i>p</i>-methoxy-a-methylphenethyl]amino]ethyl]formanilide</div>
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<b>Molecular Formula:</b> C19H24N2O4</div>
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<b>Molecular Weight:</b> 344.40</div>
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<b>Percent Composition:</b> C 66.26%, H 7.02%, N 8.13%, O 18.58%</div>
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<b>Literature References:</b> Selective b2-adrenergic receptor agonist. Mixture of <i>R,R </i>(-) and <i>S,S</i> (+) enantiomers. Prepn: M. Murakami<i>et al.,</i> <b>DE</b> <b>2305092</b>; <i>eidem,</i> <b>US</b> <b>3994974</b> (1973, 1976 both to Yamanouchi); K. Murase <i>et al.,</i> <i>Chem. Pharm. Bull.</i> <b>25,</b> 1368 (1977). Absolute configuration and activity of isomers: <i>eidem,</i> <i>ibid.</i> <b>26,</b> 1123 (1978). Toxicity studies: T. Yoshida <i>et al.,</i> <i>Pharmacometrics</i><b>26,</b> 811 (1983). HPLC determn in plasma: J. Campestrini <i>et al.,</i> <i>J. Chromatogr. B</i> <b>704,</b> 221 (1997). Review of pharmacology: G. P. Anderson, <i>Life Sci.</i> <b>52,</b> 2145-2160 (1993); and clinical efficacy: R. A. Bartow, R. N. Brogden, <i>Drugs</i> <b>55,</b> 303-322 (1998).</div>
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<b>Derivative Type:</b> Fumarate dihydrate</div>
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<b>CAS Registry Number:</b> 43229-80-7</div>
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<b>Manufacturers' Codes:</b> BD-40A</div>
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<b>Trademarks:</b> Atock (Yamanouchi); Foradil (Novartis); Oxeze (AstraZeneca)</div>
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<b>Molecular Formula:</b> (C19H24N2O4)2.C4H4O4.2H2O</div>
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<b>Molecular Weight:</b> 840.91</div>
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<b>Percent Composition:</b> C 59.99%, H 6.71%, N 6.66%, O 26.64%</div>
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<b>Properties:</b> Crystals from 95% isopropyl alcohol, mp 138-140°. pKa1 7.9; pKa2 9.2. Log P (octanol/water): 0.4 (pH 7.4). Freely sol in glacial acetic acid; sol in methanol; sparingly sol in ethanol, isopropanol; slightly sol in water. Practically insol in acetone, ethyl acetate, diethyl ether. LD50 in male, female, rats, mice (mg/kg): 3130, 5580, 6700, 8310 orally; 98, 100, 72, 71 i.v.; 1000, 1100, 640, 670 s.c.; 170, 210, 240, 210 i.p. (Yoshida).</div>
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<b>Melting point:</b> mp 138-140°</div>
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<b>pKa:</b> pKa1 7.9; pKa2 9.2</div>
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<b>Log P:</b> Log P (octanol/water): 0.4 (pH 7.4)</div>
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<b>Toxicity data:</b> LD50 in male, female, rats, mice (mg/kg): 3130, 5580, 6700, 8310 orally; 98, 100, 72, 71 i.v.; 1000, 1100, 640, 670 s.c.; 170, 210, 240, 210 i.p. (Yoshida)</div>
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<b>Derivative Type:</b> <i>R,R</i>-Form</div>
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<b>CAS Registry Number:</b> 67346-49-0</div>
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<b>Additional Names:</b> <span data-mce-style="color: #ff0000;" style="color: red;">Arformoterol</span></div>
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<b>Derivative Type:</b> <i>R,R</i>-Form L-tartrate</div>
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<b>CAS Registry Number:</b> 200815-49-2</div>
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<b>Additional Names:</b> <span data-mce-style="color: #ff0000;" style="color: red;">Arformoterol tartrate</span></div>
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<b>Molecular Formula:</b> C19H24N2O4.C4H6O6</div>
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<b>Molecular Weight:</b> 494.49</div>
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<b>Percent Composition:</b> C 55.86%, H 6.12%, N 5.67%, O 32.36%</div>
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<b>Literature References:</b> Prepn: Y. Gao <i>et al.,</i> <b>WO</b> <b>9821175</b>; <i>eidem,</i> <b>US</b> <b>6040344</b> (1998, 2000 both to Sepracor). Pharmacology: D. A. Handley <i>et al.,</i> <i>Pulm. Pharmacol. Ther.</i> <b>15</b>, 135 (2002).</div>
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<b>Properties:</b> Off-white powder, mp 184°.</div>
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<b>Melting point:</b> mp 184°</div>
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<b>Therap-Cat:</b> Antiasthmatic.</div>
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<b>Keywords:</b> ?Adrenergic Agonist; Bronchodilator; Ephedrine Derivatives.</div>
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//////Arformoterol, (R,R)-Formoterol, <span class="">(R,R)-Formoterol-L-<wbr></wbr>(+)-tartrate, </span><span class="">200815-49-2, </span>Arformoterol tartrate , Brovana, UNII:5P8VJ2I235, Sepracor, Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases, COPD , RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists, Phase III, 2007, Sunovion</div>
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COC1=CC=C(C[C@@H](C)NC[C@H](O)C2=CC(NC=O)=C(O)C=C2)C=C1</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-1346483141860457136.post-67708918974798454682016-08-01T01:51:00.001-07:002016-08-01T01:51:51.765-07:00New Antiarthritic Drug Candidate S-2474<div dir="ltr" style="text-align: left;" trbidi="on">
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-3.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-3.jpg" rel="attachment wp-att-8064"><img alt="STR1" class="alignnone wp-image-8064" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-3.jpg" height="534" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-3.jpg" style="height: auto; max-width: 100%;" width="549" /></a></div>
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<img alt="" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800008w/production/images/medium/op-2008-00008w_0011.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800008w/production/images/medium/op-2008-00008w_0011.gif" style="height: auto; max-width: 100%;" /></div>
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S-2474</div>
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(<i>E</i>)-(5)-(3,5-Di-<i>tert</i>-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide</div>
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Shionogi Research Laboratories</div>
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cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO)</div>
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<a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/op800008w" href="http://pubs.acs.org/doi/suppl/10.1021/op800008w">mp 135−137 °C.</a></div>
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S-2474,158089-95-3, 158089-96-4 ((Z)-isomer),C20-H31-N-O3-S,</div>
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E)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethylisothiazolidine 1,1-dioxide</div>
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<li>Phenol, 2,6-bis(1,1-dimethylethyl)-4-[(2-ethyl-5-isothiazolidinylidene)methyl]-, S,S-dioxide, (E)-</li>
<li class="alt">2,6-Bis(1,1-dimethylethyl)-4-[(E)-(2-ethyl-1,1-dioxido-5-isothiazolidinylidene)methyl]phenol</li>
<li>Phenol, 2,6-bis(1,1-dimethylethyl)-4-[(2-ethyl-1,1-dioxido-5-isothiazolidinylidene)methyl]-, (E)-</li>
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(<i>E</i>)-(5)-(3,5-Di-<i>tert</i>-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474, ), which was discovered at Shionogi Research Laboratories, shows potent inhibitory effects on both cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) and is anticipated to be promising as an antiarthritic drug</div>
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<img alt="" class="" data-mce-src="http://www.shionogi.co.jp/ssp/img/logo.gif" height="146" src="http://www.shionogi.co.jp/ssp/img/logo.gif" style="height: auto; max-width: 100%;" width="874" /></div>
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synthesis of novel γ-sultam derivatives containing the di-<i>tert</i>-butylphenol antioxidant moiety. Several compounds with lower alkyl groups at the 2-position of the γ-sultam skeleton showed potent inhibitory activities against PGE<sub>2</sub> production via the COX pathway and LTB<sub>4</sub> production via the 5-LO pathway, as well as production of IL-1 in in vitro assays. Extensive pharmacological characterizations revealed that 2-ethyl-γ-sultam derivative <b>10b</b> displays multiple inhibition of COX, 5-LO, and IL-1 production similar to tenidap and also good selective COX-2 inhibition like NS-398 and celecoxib. It exerted excellent antiinflammatory activity without any ulcerogenic effects and was designated as S-2474 an agent having both NSAID and cytokine modulating properties. S-2474 is now being developed as a promising alternative antiarthritic drug candidate</div>
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SYNTHESIS</div>
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17th Symp Med Chem (Nov 19 1997 , Tsukuba), EP 0595546; JP 1994211819; US 5418230</div>
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The intermediate gamma-sultam (III) was prepared by condensation of 3-chloropropylsulfonyl chloride (I) with ethylamine, followed by cyclization of the resulting chloro sulfonamide (II) under basic conditions. Condensation of 3,5-di- tert-butyl-4- (methoxymethoxy) benzaldehyde (IV) with sultam (III) in the presence of LDA produced the aldol addition compound (V). Then, acid-promoted dehydration and simultaneous methoxymethyl group deprotection gave rise to a mixture of the desired E-benzylidene sultam and the corresponding Z-isomer (VII), which were separated by column chromatography.</div>
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<img alt="" data-mce-src="http://www.chemdrug.com/file/upload/SYNTHESIS/SYN/21/21013401a.gif" src="http://www.chemdrug.com/file/upload/SYNTHESIS/SYN/21/21013401a.gif" style="height: auto; max-width: 100%;" /></div>
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PAPER</div>
<h1 class="articleTitle" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="hlFld-Title">Novel Antiarthritic Agents with 1,2-Isothiazolidine-1,1-dioxide (γ-Sultam) Skeleton: Cytokine Suppressive Dual Inhibitors of Cyclooxygenase-2 and 5-Lipoxygenase</span></h1>
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<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Inagaki%2C+Masanao" href="http://pubs.acs.org/author/Inagaki%2C+Masanao" id="authors">Masanao Inagaki</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Tsuri%2C+Tatsuo" href="http://pubs.acs.org/author/Tsuri%2C+Tatsuo" id="authors">Tatsuo Tsuri</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF1" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF1">*</a><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Jyoyama%2C+Hirokuni" href="http://pubs.acs.org/author/Jyoyama%2C+Hirokuni" id="authors">Hirokuni Jyoyama</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Ono%2C+Takashi" href="http://pubs.acs.org/author/Ono%2C+Takashi" id="authors">Takashi Ono</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Yamada%2C+Katsutoshi" href="http://pubs.acs.org/author/Yamada%2C+Katsutoshi" id="authors">Katsutoshi Yamada</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kobayashi%2C+Mika" href="http://pubs.acs.org/author/Kobayashi%2C+Mika" id="authors">Mika Kobayashi</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Hori%2C+Yozo" href="http://pubs.acs.org/author/Hori%2C+Yozo" id="authors">Yozo Hori</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Arimura%2C+Akinori" href="http://pubs.acs.org/author/Arimura%2C+Akinori" id="authors">Akinori Arimura</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Yasui%2C+Kiyoshi" href="http://pubs.acs.org/author/Yasui%2C+Kiyoshi" id="authors">Kiyoshi Yasui</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Ohno%2C+Kouji" href="http://pubs.acs.org/author/Ohno%2C+Kouji" id="authors">Kouji Ohno</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kakudo%2C+Shinji" href="http://pubs.acs.org/author/Kakudo%2C+Shinji" id="authors">Shinji Kakudo</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Koizumi%2C+Kenzo" href="http://pubs.acs.org/author/Koizumi%2C+Kenzo" id="authors">Kenzo Koizumi</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Suzuki%2C+Ryuji" href="http://pubs.acs.org/author/Suzuki%2C+Ryuji" id="authors">Ryuji Suzuki</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kato%2C+Miyako" href="http://pubs.acs.org/author/Kato%2C+Miyako" id="authors">Miyako Kato</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF3" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF3"><sup>‡</sup></a></span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kawai%2C+Shinichi" href="http://pubs.acs.org/author/Kawai%2C+Shinichi" id="authors">Shinichi Kawai</a> ,<a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF3" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF3"><sup>‡</sup></a> and</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Matsumoto%2C+Saichi" href="http://pubs.acs.org/author/Matsumoto%2C+Saichi" id="authors">Saichi Matsumoto</a> <a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF1" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF1">*</a><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015#jm9906015AF2"><sup>†</sup></a></span></span></div>
<div class="affiliations">
Shionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, Japan, and Institute of Medical Science, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki 216-8512, Japan</div>
<div id="citation">
<cite>J. Med. Chem.</cite>, <span class="citation_year">2000</span>, <span class="citation_volume">43</span> (10), pp 2040–2048</div>
<div id="doi">
<strong>DOI: </strong>10.1021/jm9906015</div>
</div>
<div class="casTitle" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<div id="absImg">
<img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2000/jmcmar.2000.43.issue-10/jm9906015/production/images/medium/jm9906015n00001.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2000/jmcmar.2000.43.issue-10/jm9906015/production/images/medium/jm9906015n00001.gif" style="height: auto; max-width: 100%;" /></div>
<div class="articleBody_abstractText">
Various 1,2-isothiazolidine-1,1-dioxide (γ-sultam) derivatives containing an antioxidant moiety, 2,6-di-<i>tert</i>-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the γ-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (<i>E</i>)-(5)-(3,5-di-<i>tert</i>-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure−activity relationships (SAR) examined and some pharmacological evaluations are described.</div>
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<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm9906015" href="http://pubs.acs.org/doi/abs/10.1021/jm9906015">http://pubs.acs.org/doi/abs/10.1021/jm9906015</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PAPER</div>
<h1 class="articleTitle" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="hlFld-Title">Highly <i>E</i>-Selective and Effective Synthesis of Antiarthritic Drug Candidate S-2474 Using Quinone Methide Derivatives</span></h1>
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<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Inagaki%2C+Masanao" href="http://pubs.acs.org/author/Inagaki%2C+Masanao" id="authors">Masanao Inagaki</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Haga%2C+Nobuhiro" href="http://pubs.acs.org/author/Haga%2C+Nobuhiro" id="authors">Nobuhiro Haga</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kobayashi%2C+Makoto" href="http://pubs.acs.org/author/Kobayashi%2C+Makoto" id="authors">Makoto Kobayashi</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Ohta%2C+Naoki" href="http://pubs.acs.org/author/Ohta%2C+Naoki" id="authors">Naoki Ohta</a> ,</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Kamata%2C+Susumu" href="http://pubs.acs.org/author/Kamata%2C+Susumu" id="authors">Susumu Kamata</a> , and</span> </span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Tsuri%2C+Tatsuo" href="http://pubs.acs.org/author/Tsuri%2C+Tatsuo" id="authors">Tatsuo Tsuri</a> <a class="ref" data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/jo0106795#jo0106795AF1" href="http://pubs.acs.org/doi/suppl/10.1021/jo0106795#jo0106795AF1">*</a></span></span></div>
<div class="affiliations">
Shionogi Research Laboratories, Shionogi & Company, Ltd., Fukushima-ku, Osaka 553-0002, Japan</div>
<div id="citation">
<cite>J. Org. Chem.</cite>, <span class="citation_year">2002</span>, <span class="citation_volume">67</span> (1), pp 125–128</div>
<div id="doi">
<strong>DOI: </strong>10.1021/jo0106795</div>
<div id="pubDate">
<strong><a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/jo0106795" href="http://pubs.acs.org/doi/suppl/10.1021/jo0106795">http://pubs.acs.org/doi/suppl/10.1021/jo0106795</a></strong></div>
<div>
<br data-mce-bogus="1" /></div>
</div>
<div class="casAbstract" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/joceah/2002/joceah.2002.67.issue-1/jo0106795/production/images/medium/jo0106795n00001.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/joceah/2002/joceah.2002.67.issue-1/jo0106795/production/images/medium/jo0106795n00001.gif" style="height: auto; max-width: 100%;" /></div>
<div class="casAbstract" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
We have developed an efficient and E-selective synthesis of an antiarthritic drug candidate (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474), in which α-methoxy-p-quinone methide is used as a key intermediate. α-Methoxy-p-quinone methide was revealed to be an equiv. to a p-hydroxy protected benzaldehyde. It reacts smoothly with α-sulfonyl carbanion to give 1,6-addn. intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.</div>
<div class="casAbstract" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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<div class="casAbstract" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
An improved synthesis has been reported. Acid -catalyzed ketalization of aldehyde (VIII) with trimethyl orthoformate provided the dimethyl acetal (IX) which, upon thermal decomposition in refluxing xylene, gave rise to the alpha-methoxy methylenequinone derivative (X ). This was then condensed with the lithio derivative of sultam (III) to form selectively the desired E-adduct. in an analogous procedure, aldehyde (VIII) was converted to the chloromethylene compound (XI) with methanesulfonyl chloride and triethylamine in refluxing CH2Cl2 . Condensation of (XI) with the lithiated sultam (III) furnished the desired E-benzylidene sultam.</div>
<div class="casAbstract" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="http://www.chemdrug.com/file/upload/SYNTHESIS/SYN/21/21013402a.gif" src="http://www.chemdrug.com/file/upload/SYNTHESIS/SYN/21/21013402a.gif" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PAPER</div>
<h1 class="articleTitle" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="hlFld-Title">Development of One-Pot Synthesis of New Antiarthritic Drug Candidate S-2474 with High <i>E</i>-Selectivity</span></h1>
<div id="articleMeta" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Oda%2C+Katsuo" href="http://pubs.acs.org/author/Oda%2C+Katsuo" id="authors">Katsuo Oda</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn1" href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn1"><sup>†</sup></a><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Hida%2C+Takemasa" href="http://pubs.acs.org/author/Hida%2C+Takemasa" id="authors">Takemasa Hida</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#cor1" href="http://pubs.acs.org/doi/full/10.1021/op800008w#cor1">*</a><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn1" href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn1"><sup>†</sup></a><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Sakata%2C+Teruo" href="http://pubs.acs.org/author/Sakata%2C+Teruo" id="authors">Teruo Sakata</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn2" href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn2"><sup>‡</sup></a><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Nagai%2C+Masahiko" href="http://pubs.acs.org/author/Nagai%2C+Masahiko" id="authors">Masahiko Nagai</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn2" href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn2"><sup>‡</sup></a><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Sugata%2C+Yoshihide" href="http://pubs.acs.org/author/Sugata%2C+Yoshihide" id="authors">Yoshihide Sugata</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn2" href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn2"><sup>‡</sup></a><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Masui%2C+Toshiaki" href="http://pubs.acs.org/author/Masui%2C+Toshiaki" id="authors">Toshiaki Masui</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn1" href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn1"><sup>†</sup></a><span class="NLM_x"> and </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Nogusa%2C+Hideo" href="http://pubs.acs.org/author/Nogusa%2C+Hideo" id="authors">Hideo Nogusa</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn1" href="http://pubs.acs.org/doi/full/10.1021/op800008w#at-fn1"><sup>†</sup></a></span></div>
<div class="affiliations">
Chemical Development Department, CMC Development Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan, and Shionogi Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan</div>
<div id="citation">
<cite>Org. Process Res. Dev.</cite>, <span class="citation_year">2008</span>, <span class="citation_volume">12</span> (3), pp 442–446</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op800008w</div>
<div id="pubDate">
</div>
<div id="correspondence">
<a data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w" href="http://pubs.acs.org/doi/full/10.1021/op800008w">http://pubs.acs.org/doi/full/10.1021/op800008w</a></div>
<div>
* To whom correspondence should be addressed. Telephone: <span class="phone">+81-6-6401-8198</span> . Fax: <span class="fax">+81-6-6401-1371</span>. E-mail:<a data-mce-href="mailto:takemasa.hida@shionogi.co.jp" href="mailto:takemasa.hida@shionogi.co.jp">takemasa.hida@shionogi.co.jp</a>., †<br />
<div class="last">
Chemical Development Department, CMC Development Laboratories.</div>
, ‡Shionogi Research Laboratories.</div>
</div>
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<a class="showFiguresEvent" data-mce-href="http://pubs.acs.org/doi/full/10.1021/op800008w#" href="http://pubs.acs.org/doi/full/10.1021/op800008w#" id="absImg" title="Open Figure Viewer"><img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800008w/production/images/medium/op-2008-00008w_0010.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800008w/production/images/medium/op-2008-00008w_0010.gif" style="height: auto; max-width: 100%;" /></a></div>
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A one-pot synthesis of S-2474 was developed to overcome the problems of a large number of steps, low stereoselectivity, low yield, a large amount of waste, and severe reaction conditions. Aldol-type condensation of 3,5-di-<i>tert</i>-butyl-4-hydroxybenzaldehyde and <i>N</i>-ethyl-γ-sultam was carried out with LDA and then quenched with water. Dehydration proceeded under basic conditions, providing S-2474 directly as a single isomer on the benzylidene double bond. The reaction mechanism appears to involve a quinone methide intermediate. Environmental assessment of the development of this compound is also discussed in this paper.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-1.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-1.jpg" rel="attachment wp-att-8060"><img alt="STR1" class="alignnone size-full wp-image-8060" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-1.jpg" height="523" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-1.jpg" style="height: auto; max-width: 100%;" width="776" /></a></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-2.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-2.jpg" rel="attachment wp-att-8061"><img alt="STR1" class="alignnone size-full wp-image-8061" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-2.jpg" height="480" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-2.jpg" style="height: auto; max-width: 100%;" width="789" /></a></div>
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///////<span class="hlFld-Title">New, Antiarthritic , Drug Candidate, S-2474, </span>Shionogi Research Laboratories, cyclooxygenase-2, (COX-2), 5-lipoxygenase , (5-LO), PHASE 2, 158089-95-3, 158089-96-4, S2474, S 2474</div>
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<li><a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/op800008w" href="http://pubs.acs.org/doi/suppl/10.1021/op800008w">Supporting Info</a></li>
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CCN2CC\C(=C/c1cc(c(O)c(c1)C(C)(C)C)C(C)(C)C)S2(=O)=O</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-1346483141860457136.post-20289546636895397882016-07-28T00:50:00.001-07:002016-07-28T00:50:52.655-07:00Varenicline (Chantix™) バレニクリン酒石酸塩<div dir="ltr" style="text-align: left;" trbidi="on">
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<a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Varenicline.svg" href="https://en.wikipedia.org/wiki/File:Varenicline.svg" style="background-color: white;"><img alt="Varenicline.svg" data-file-height="97" data-file-width="249" data-mce-selected="1" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/49/Varenicline.svg/190px-Varenicline.svg.png" height="74" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/49/Varenicline.svg/190px-Varenicline.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/4/49/Varenicline.svg/285px-Varenicline.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/4/49/Varenicline.svg/380px-Varenicline.svg.png 2x" style="height: auto; max-width: 100%; outline: rgb(119, 119, 119) solid 1px; resize: none;" width="190" /></a></div>
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Varenicline (Chantix™)</div>
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<span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_WrapTitle">Varenicline</span></h1>
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<li><span class="prop_title">MF </span><span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_prop_MF">C<sub>13</sub>H<sub>13</sub>N<sub>3</sub></span></li>
<li><span class="prop_title">MW </span>211.26</li>
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<strong>(1R,12S)-5,8,14-Tri<wbr></wbr>azatétracyclo[10.3.<wbr></wbr>1.0<sup>2,11</sup><wbr></wbr>.0<sup>4,9</sup><wbr></wbr>]hexadéca-2,4,6,8,1<wbr></wbr>0-pentaène</strong> <span class="synonym_language">[French]</span> <span class="synonym_ref" title="">[ACD/IUPAC Name]</span></div>
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<strong>6,10-Methano-6H-aze<wbr></wbr>pino[4,5-g]quinoxal<wbr></wbr>ine, 7,8,9,10-tetra<wbr></wbr>hydro-, (6R,10S)-</strong> <span class="synonym_ref" title="">[ACD/Index Name]</span></div>
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<strong>Champix</strong></div>
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<span class="">(1R,12S)-5,8,14-tri<wbr></wbr>azatetracyclo[10.3.<wbr></wbr>1.02,11.04,9]hexade<wbr></wbr>ca-2(11),3,5,7,9-pe<wbr></wbr>ntaene</span></div>
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<span class="">CP-526,555</span></div>
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<span class="">MFCD08460603</span></div>
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<span class="">MFCD10001497</span></div>
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<span class="">UNII:W6HS99O8ZO</span></div>
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APPROVALS</div>
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FDA MAY 10, 2006</div>
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EMA SEPT 2006</div>
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PMDA JAPAN JAN 25 2008</div>
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<b>Varenicline</b> (trade name <b>Chantix</b> and <b>Champix</b> usually in the form of varenicline <a data-mce-href="https://en.wikipedia.org/wiki/Tartrate" href="https://en.wikipedia.org/wiki/Tartrate" title="Tartrate">tartrate</a>), is a prescription medication used to treat<a data-mce-href="https://en.wikipedia.org/wiki/Nicotine" href="https://en.wikipedia.org/wiki/Nicotine" title="Nicotine">nicotine</a> addiction. Varenicline is a <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Nicotinic_receptor" href="https://en.wikipedia.org/wiki/Nicotinic_receptor" title="Nicotinic receptor">nicotinic receptor</a> <a data-mce-href="https://en.wikipedia.org/wiki/Partial_agonist" href="https://en.wikipedia.org/wiki/Partial_agonist" title="Partial agonist">partial agonist</a>—it stimulates nicotine receptors more weakly than <a data-mce-href="https://en.wikipedia.org/wiki/Nicotine" href="https://en.wikipedia.org/wiki/Nicotine" title="Nicotine">nicotine</a> itself does. In this respect it is similar to <a data-mce-href="https://en.wikipedia.org/wiki/Cytisine" href="https://en.wikipedia.org/wiki/Cytisine" title="Cytisine">cytisine</a> and different from the <a data-mce-href="https://en.wikipedia.org/wiki/Receptor_antagonist" href="https://en.wikipedia.org/wiki/Receptor_antagonist" title="Receptor antagonist">nicotinic antagonist</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Bupropion" href="https://en.wikipedia.org/wiki/Bupropion" title="Bupropion">bupropion</a>, and <a data-mce-href="https://en.wikipedia.org/wiki/Nicotine_replacement_therapy" href="https://en.wikipedia.org/wiki/Nicotine_replacement_therapy" title="Nicotine replacement therapy">nicotine replacement therapies</a>(NRTs) like <a data-mce-href="https://en.wikipedia.org/wiki/Nicotine_patch" href="https://en.wikipedia.org/wiki/Nicotine_patch" title="Nicotine patch">nicotine patches</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Nicotine_gum" href="https://en.wikipedia.org/wiki/Nicotine_gum" title="Nicotine gum">nicotine gum</a>. As a partial agonist it both reduces cravings for and decreases the pleasurable effects of cigarettes and other tobacco products. Through these mechanisms it can assist some patients to quit smoking.</div>
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<img alt="" data-mce-src="https://www.drugs.com/pro/images/f0ff4f27-5185-4881-a749-c6b7a0ca5696/chantix-11.jpg" src="https://www.drugs.com/pro/images/f0ff4f27-5185-4881-a749-c6b7a0ca5696/chantix-11.jpg" style="height: auto; max-width: 100%;" /></div>
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<img alt="Varenicline" data-mce-src="http://www.druglead.com/cds/structure/Varenicline.gif" src="http://www.druglead.com/cds/structure/Varenicline.gif" style="height: auto; max-width: 100%;" /></h2>
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Varenicline</div>
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<b>CAS Registry Number:</b> 249296-44-4</div>
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<b>CAS Name:</b> 7,8,9,10-Tetrahydro-6,10-methano-6<i>H</i>-pyrazino[2,3-<i>h</i>][3]benzazepine</div>
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<b>Additional Names:</b> 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11)-3,5,7,9-pentaene</div>
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<b>Manufacturers' Codes:</b> CP-526555</div>
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<b>Molecular Formula:</b> C13H13N3</div>
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<b>Molecular Weight:</b> 211.26</div>
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<b>Percent Composition:</b> C 73.91%, H 6.20%, N 19.89%</div>
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<b>Literature References:</b> Nicotinic a4b2 acetylcholine receptor partial agonist. Prepn: P. R. P. Brooks, J. W. Coe, <b>WO</b> <b>0162736</b>(2001 to Pfizer). Synthesis, receptor binding studies, and <i>in vivo</i> dopaminergic acitvity: J. W. Coe <i>et al.,</i> <i>J. Med. Chem.</i> <b>48</b>, 3474 (2005). Metabolism: R. S. Obach <i>et al.,</i> <i>Drug Metab. Dispos.</i> <b>34</b>, 121 (2006).</div>
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<img alt="" data-mce-src="https://dailymed.nlm.nih.gov/dailymed/archives/image.cfm?archiveid=8935&type=img&name=chantix-01.jpg" src="https://dailymed.nlm.nih.gov/dailymed/archives/image.cfm?archiveid=8935&type=img&name=chantix-01.jpg" style="height: auto; max-width: 100%;" /></div>
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<b>Derivative Type:</b> Tartrate</div>
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<b>CAS Registry Number:</b> 375815-87-5</div>
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<b>Trademarks:</b> Champix (Pfizer)</div>
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<b>Molecular Formula:</b> C13H13N3.C4H6O6</div>
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<b>Molecular Weight:</b> 361.35</div>
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<b>Percent Composition:</b> C 56.51%, H 5.30%, N 11.63%, O 26.57%</div>
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<b>Therap-Cat:</b> Aid in smoking cessation.</div>
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バレニクリン酒石酸塩<br />Varenicline Tartrate<br /><a data-mce-href="http://jpdb.nihs.go.jp/jan/chemdraw5/Varenicline_Tartrate.cdx" href="http://jpdb.nihs.go.jp/jan/chemdraw5/Varenicline_Tartrate.cdx"><img alt="" data-mce-src="http://jpdb.nihs.go.jp/jan/gif/Varenicline_Tartrate.png" src="http://jpdb.nihs.go.jp/jan/gif/Varenicline_Tartrate.png" style="height: auto; max-width: 100%;" /></a><br />C<sub>1</sub><sub>3</sub>H<sub>1</sub><sub>3</sub>N<sub>3</sub><img alt="▪" class="emoji" data-mce-placeholder="1" data-mce-resize="false" data-wp-emoji="1" draggable="false" src="https://s.w.org/images/core/emoji/72x72/25aa.png" style="background-attachment: initial !important; background-clip: initial !important; background-image: none !important; background-origin: initial !important; background-position: initial !important; background-repeat: initial !important; background-size: initial !important; border-radius: 0px; border: none !important; box-shadow: none !important; display: inline !important; height: 1em !important; margin: 0px 0.07em !important; max-width: 100%; outline: 0px; padding: 0px; vertical-align: -0.1em !important; width: 1em !important;" />C<sub>4</sub>H<sub>6</sub>O<sub>6</sub> : 361.35<br />[375815-87-5]</div>
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<span class="mw-headline" id="Medical_uses">Medical uses</span></h2>
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Varenicline is used for <a data-mce-href="https://en.wikipedia.org/wiki/Smoking_cessation" href="https://en.wikipedia.org/wiki/Smoking_cessation" title="Smoking cessation">smoking cessation</a>. In a 2009 <a data-mce-href="https://en.wikipedia.org/wiki/Meta-analysis" href="https://en.wikipedia.org/wiki/Meta-analysis" title="Meta-analysis">meta-analysis</a> varenicline was found to be more effective than bupropion (<a data-mce-href="https://en.wikipedia.org/wiki/Odds_ratio" href="https://en.wikipedia.org/wiki/Odds_ratio" title="Odds ratio">odds ratio</a> 1.40) and NRTs (odds ratio 1.56).<sup class="reference" id="cite_ref-Mills2009_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Mills2009-1" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Mills2009-1">[1]</a></sup></div>
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A 2013 Cochrane overview and network <a data-mce-href="https://en.wikipedia.org/wiki/Meta-analysis" href="https://en.wikipedia.org/wiki/Meta-analysis" title="Meta-analysis">meta-analysis</a> concluded that varenicline is the most effective medication for tobacco cessation and that smokers were nearly three times more likely to quit on varenicline than with placebo treatment. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation.<sup class="reference" id="cite_ref-Cochrane2013_2-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Cochrane2013-2" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Cochrane2013-2">[2]</a></sup><sup class="reference" id="cite_ref-Elrashidi2014_3-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Elrashidi2014-3" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Elrashidi2014-3">[3]</a></sup></div>
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The United States' <a data-mce-href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> (US FDA) has approved the use of varenicline for up to twelve weeks. If smoking cessation has been achieved it may be continued for another twelve weeks.<sup class="reference" id="cite_ref-FDA2006_4-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-FDA2006-4" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-FDA2006-4">[4]</a></sup></div>
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Varenicline has not been tested in those under 18 years old or pregnant women and therefore is not recommended for use by these groups. Varenicline is considered a <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">class C</a> pregnancy drug, as animal studies have shown no increased risk of congenital anomalies, however, no data from human studies is available.<sup class="reference" id="cite_ref-5"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-5" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-5">[5]</a></sup> An observational study is currently being conducted assessing for malformations related to varenicline exposure, but has no results yet.<sup class="reference" id="cite_ref-6"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-6" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-6">[6]</a></sup> An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine.<sup class="reference" id="cite_ref-7"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-7" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-7">[7]</a></sup></div>
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<img alt="" data-mce-src="http://medications.li/static/fcae93cb3f956eb8be334d39e865fb18.jpg" src="http://medications.li/static/fcae93cb3f956eb8be334d39e865fb18.jpg" style="height: auto; max-width: 100%;" /></div>
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Varenicline L-tartrate (Compound I) is the international commonly accepted name for 7,8,9,10- tetrahydro-6, 10-methano-6i7-pyrazino [2, 3- h] [3 ] benzazepme, (2R, 3R) -2 , 3-dihydroxybutanedioate (1:1) (which is also known as 5,8,14- tπazatetracyclo [10.3.1. O<sup>2</sup>'<sup>11</sup>. O<sup>4</sup>'<sup>9</sup>] -hexadeca-2 (11) , 3, 5, 7, 9-pentaene, (2R, 3R)-2,3- dihydroxybutanedioate (1:1)) and has an empirical formula of C13H13N3 <sup>•</sup> C4H6O6 and a molecular weight of 361.35. Varenicline L-tartrate is a commercially marketed pharmaceutically active substance known to be useful for the treatment of smoking addiction.</div>
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(D</div>
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Varenicline L-tartrate is a partial agonist selective for (X<sub>4</sub>β<sub>2</sub> nicotinic acetylcholine receptor subtypes. In the United States, varenicline L-tartrate is marketed under the name Chantix™ for the treatment of smoking cessation. Varenicline base and its pharmaceutically acceptable acid addition salts are described in U.S. Patent No. 6,410,550. In particular, Example 26 of U.S. Patent No. 6,410,550 describes the preparation of varenicline hydrochloride salt using 1- (4 , 5-dinitro-10- aza-tπcyclo [6.3.1.O<sup>2</sup>'<sup>7</sup>] dodeca-2, 4, 6-trien-10-yl) -2,2,2- tπfluoroethanone (compound of formula (III)) as starting compound. On the other hand, Example HA) of U.S. Patent No. 6,410,550 illustrates the preparation of compound of formula (III) via nitration of compound of formula (II) using an excess of nitronium triflate (>4 equiv) as a nitrating agent. The process disclosed in U.S. Patent No. 6,410,550 is depicted in Scheme 1.</div>
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VareniclineΗCl</div>
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Scheme 1</div>
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However, Coe et al., J. Med. Chem., 48, 3474 (2005), describes the same process and examples as U.S. Patent No. 6,410,550, and it also reveals that this process affords intermediate ortho-4 , 5-dinitrocompound of formula (III) together with the meta-3, 5-dinitro- isomer (i.e. the meta-dinitrocompound) in a ratio 9:1. The presence of the meta-dinitrocompound may affect not only the purity of the intermediate compound of formula III but it may also have an effect on the purity of the final varenicline tartrate, given that it can be carried along the synthetic pathway and/or it can also give rise to other derivative impurities. Thereby, as well as in U.S. Patent No. 6,410,550, in order to isolate pure compound of formula (III) , the raw product is triturated with ethyl acetate/hexane to afford compound of formula (III) with 77% yield. Additionally, the mother liquor is purified by chromatography on silica gel to improve the yield to a total of 82.8%. However, this process is not desirable for industrial implementation since it requires extensive and complicated purification procedures, i.e. trituration of the solid product along with column chromatography purification of the mother liquor, which is not very efficient or suitable for industrial scale-up.</div>
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Several improved processes for the synthesis of varenicline or its salts have been reported in the literature (e.g. WO2006/090236) . However, none of these processes tackle the optimization of the purification step of compound of formula (III).</div>
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There is therefore the need for providing an improved process for the preparation of varenicline L- tartrate which involves simple experimental procedures well suited to industrial production, which avoids the use of column chromatography purifications, and which affords high pure varenicline L-tartrate which hence can be used directly as a starting product for the preparation of the marketed pharmaceutical speciality.</div>
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Additionally, it has been observed that varenicline L-tartrate is usually obtained as a yellow solid under - A -</div>
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standard synthetic conditions. In this regard, colour must be attributed to the presence of some specific impurities that may or may not be detectable by conventional methods such as HPLC. The presence of impurities may adversely affect the safety and shelf life of formulations. In this connection, International application No. WO2006/090236 describes the isolation of vareniclme L- tartrate as a white solid. However, in order to remove coloured impurities, the varenicline L-tartrate obtained in WO2006/090236 is treated with a particular activated carbon having a specific grade (i.e. Darco KB-B™) . In fact, Example 5 of WO2006/090236 describes a large reprocessing step which comprises: dissolving varenicline L-tartrate in water, adding toluene, basifying with NaOH aqueous solution, collecting the toluene phase containing varenicline free base, distilling, adding methanol, azeotropically distilling the mixture, and adding more methanol to obtain a methanolic solution containing varenicline free base, adding Darco KB-B™ (10% w/w) , stirring for one hour, filtering through a pad of celite, and treating with L-tartaric acid to give varenicline L- tartrate salt as a white solid. Further, WO2006/090236 provides the absorbance at 430 nm of a varenicline L- tartrate salt solution, either in dichloromethane or in toluene, with or without using Darco KB-B™ activated carbon. However, this measure cannot be used to corroborate the whiteness of the solid varenicline L- tartrate. In addition, Example 3 of International application No. WO2002/092089, also disclose the preparation of varenicline L-tartrate polymorphic form C (i.e. a hydrate polymorph) as a white precipitate. Therefore, there is also a need for a simple and efficient method for preparing varenicline L-tartrate with enhanced whiteness and having a high purity.</div>
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<span data-mce-style="color: #0000ff;" style="color: blue;">SYNTHESIS</span></h1>
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Synthesis of Intermediate VIII</div>
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<span data-mce-style="color: #0000ff;" style="color: blue;">Paper</span></h1>
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<i>J. Med. Chem.</i> <b>48</b>, 3474 (2005).</div>
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<a data-mce-href="http://pubs.acs.org/doi/pdf/10.1021/jm050069n" href="http://pubs.acs.org/doi/pdf/10.1021/jm050069n">http://pubs.acs.org/doi/pdf/10.1021/jm050069n</a></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<a data-mce-href="https://www.google.com/patents/WO2001062736A1?cl=en" href="https://www.google.com/patents/WO2001062736A1?cl=en">https://www.google.com/patents/WO2001062736A1?cl=en</a></div>
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Profiles of Drug Substances, Excipients and Related Methodology, Volume 37</h1>
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<span class="addmd">edited by Harry G. Brittain</span></div>
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<span data-mce-style="color: #0000ff;" style="color: blue;">SYNTHESIS</span></h1>
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DOI: 10.1021/jm00190a020</div>
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<tr><td class="fileinfo-paramfield" id="fileinfotpl_date" lang="en" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DOI: 10.1021/jm050069n</td><td lang="en" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
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CLIP</div>
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<span class="notranslate">Scheme (I) compound patent US6410550B1 is provided adjacent difluorobromobenzene as raw materials by DA reaction, oxidation, cyclization, debenzylation get varenicline intermediate (II).</span> <span class="notranslate">The synthesis route is as follows:</span></div>
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CLIP</div>
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<span class="notranslate">Patent CN101693712A mainly given varenicline intermediate (II) The preparation process is different from the compound patented.</span> <span class="notranslate">After the five-step method patents cited compounds.</span> <span class="notranslate">The entire route is longer, while using a large number of precious metal catalysts and reaction conditions need very strict control, inappropriate EVAL industry production.</span><br />
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CLIP</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/CN102827079A?cl=en" href="https://www.google.com/patents/CN102827079A?cl=en">CN 102827079</a></div>
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<span class="notranslate">A varenicline intermediate 2,3, 4, 5-tetrahydro-1,5-methylene bridge synthesis -1H-3- benzazepine hydrochloride, which comprises the following Step: (1) 2-indanone of formula 3 and the compound and paraformaldehyde under alkaline or acidic conditions Mannich reaction, as shown in general formula 2 intermediate; (2) the step (I) obtained through reaction of Formula 2 intermediate under basic or acidic conditions by reducing the role of the carbonyl group is reduced to a methylene group, and get varenicline intermediate (II) by debenzylation, the reaction is:</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AC00021.png" href="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AC00021.png"><img alt="Figure CN102827079AC00021" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AC00021.png" id="icf0001" src="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AC00021.png" style="height: auto; max-width: 100%;" /></a></div>
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<span class="notranslate">Wherein, R groups are selected from _H, _Me, _Et, _iPr> _t_Bu.</span></div>
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<span class="notranslate">Figure 2;</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AD00072.png" href="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AD00072.png"><img alt="Figure CN102827079AD00072" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AD00072.png" id="idf0006" src="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AD00072.png" style="height: auto; max-width: 100%;" /></a></div>
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<span class="notranslate">Wherein, R group is -H, -Me, -Et, -iPr or -t_Bu.</span></div>
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<span class="notranslate">(2) Step (I) obtained by the reaction intermediates of formula under basic or acidic conditions by reducing the role of the carbonyl group is reduced 2 methylene, and get by debenzylation cutting Lenk Lin intermediate (II);</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AD00073.png" href="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AD00073.png"><img alt="Figure CN102827079AD00073" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AD00073.png" id="idf0007" src="https://patentimages.storage.googleapis.com/CN102827079A/CN102827079AD00073.png" style="height: auto; max-width: 100%;" /></a></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-110.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-110.jpg" rel="attachment wp-att-7880"><img alt="STR1" class="alignnone size-full wp-image-7880" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-110.jpg" height="99" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-110.jpg" style="height: auto; max-width: 100%;" width="660" /></a></div>
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<span data-mce-style="color: #0000ff;" style="color: blue;">CLIP</span></h1>
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Varenicline, a nicotinic 42 partial agonist, was approved in the US for the treatment of smoking cessation in May of 2006. It was developed and marketed by Pfizer as a treatment for cigarette smokers who want to quit. Varenicline partially activates the nicotinic receptors and thus reduces the craving for cigarette that smokers feel when they try to quit smoking. By mitigating this craving and antagonizing nicotine activity without other symptoms, this novel drug helps quitting this dangerous addiction easier on the patients [6,52]. Several modifications [54,55] to the original synthesis [53,56] have been reported in the literature, including an improved process scale synthesis of the last few steps (Scheme 15) [57]. The Grignard reaction was initiated on a small scale by addition of 2-bromo fluorobenzene 113 to a slurry of Magnesium turnings and catalytic 1,2-dibromoethane in THF and heating the mixture until refluxing in maintained. To this refluxing mixture was added a mixture of the 2-bromo fluorobenzene 113 and cyclopentadiene 114 over a period of 1.5 h. After complete addition, the reaction was allowed to reflux for additional 1.5 h to give the Diels- Alder product 115 in 64% yield. Dihydroxylation of the olefin 115 by reacting with catalytic osmium tetraoxide in the presence of N-methylmorpholine N-oxide (NMO) in acetone: water mixture at room temperature provided the diol 116 in 89% yield. Oxidative cleavage of diol 116 with sodium periodate in biphasic mixture of water: DCE at 10ºC provided di-aldehyde 117 which was immediately reacted with benzyl amine in the presence of sodium acetoxyborohydride to give benzyl amine 118 in 85.7% yield. The removal of the benzyl group was effected by hydrogenation of the HCl salt in 40-50 psi hydrogen pressure with 20% Pd(OH)2 in methanol to give amine hydrochloride 119 in 88% yield. Treatment of amine 119 with trifluoroacetic anhydride and pyridine in dichloromethane at 0ºC gave trifluoroacetamide 120 in 94% yield. Dinitro compound 121 was prepared by addition of trifluoroacetamide 120 to a mixture of trifluoromethane sulfonic acid and nitric acid, which was premixed, in dichloromethane at 0ºC. Reduction of the dinitro compound 121 by hydrogenation at 40-50 psi hydrogen in the presence of catalytic 5%Pd/C in isopropanol:water mixture provided the diamine intermediate 122 which was quickly reacted with glyoxal in water at room temperature for 18h to give compound 123 in 85% overall yield. The trifluoroacetamide 123 was then hydrolyzed with 2 M sodium hydroxide in toluene at 37-40ºC for 2-3h followed by preparation of tartrate salt in methanol to furnish varenicline tartrate (XV).</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-107.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-107.jpg" rel="attachment wp-att-7876"><img alt="STR1" class="alignnone size-full wp-image-7876" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-107.jpg" height="526" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-107.jpg" style="height: auto; max-width: 100%;" width="906" /></a></div>
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[52]Keating, G.; Siddiqui, M. A. A. CNSdrugs, 2006, 11, 946.<br />[53] Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold,E. P. ; Huang, J.; Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox, C.<br />B.; Shrikhande, A.; Heym, J. H.; Schaeffer, E.; Rollema, H.; Lu,Y.; Mansbach, R. S.; Chambers, L. K.; Rovetti, C. C.; Schulz, D.<br />W.; Tingley, III, F. D.; O’Neill, B. T. J. Med. Chem., 2005, 48,3474.<br />[54] Brooks, P. R.; Caron, S.; Coe, J. W.; Ng, K. K.; Singer, R. A.;Vazquez, E.; Vetelino, M. G.; Watson, Jr. H. H.; Whritenour, D.<br />C.; Wirtz, M. C. Synthesis, 2004, 11, 1755.<br />[55] Singer, R. A.; McKinley, J. D.; Barbe, G.; Farlow, R. A. Org. Lett.,2004, 6, 2357.<br />[56] Coe, J. W.; Brooks, P. R. P. US-6410550 B1, 2002.<br />[57] Busch, F. R.; Hawkins, J. M.; Mustakis, L. G.; Sinay, T. G., Jr.;Watson, T. J. N.; Withbroe, G. J. WO-2006090236 A1, 2006.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
WO 2002085843</div>
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<a data-mce-href="https://google.com/patents/WO2002085843A2?cl=en" href="https://google.com/patents/WO2002085843A2?cl=en">https://google.com/patents/WO2002085843A2?cl=en</a></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-109.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-109.jpg" rel="attachment wp-att-7879"><img alt="STR1" class="alignnone size-full wp-image-7879" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-109.jpg" height="220" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-109.jpg" style="height: auto; max-width: 100%;" width="669" /></a></div>
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<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/EP2204369A1?cl=en" href="https://www.google.com/patents/EP2204369A1?cl=en">https://www.google.com/patents/EP2204369A1?cl=en</a></div>
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Varenicline (a compound I of formula I) is the international commonly accepted non-proprietary name for 7,8,9,10-tetrahydro-6,10-methano-6<i>H</i>-pyrazino[2,3-<i>h</i>][3]benzazepine (which is also known as 5,8,14-triazatetracyclo[10.3.1.0<sup>2,11</sup>.0<sup>4,9</sup>]-hexadeca-2(11),3,5,7,9-pentaene), and has an empirical formula of C<sub>13</sub>H<sub>13</sub>N<sub>3</sub> and a molecular weight of 211.26.</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/EP2204369A1/imgb0001.png" href="https://patentimages.storage.googleapis.com/EP2204369A1/imgb0001.png"><img alt="Figure imgb0001" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/EP2204369A1/imgb0001.png" height="96" id="ib0001" src="https://patentimages.storage.googleapis.com/EP2204369A1/imgb0001.png" style="height: auto; max-width: 100%;" width="224" /></a></div>
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The L-tartrate salt of varenicline is known to be therapeutically useful and is commercially marketed for the treatment of smoking addiction. Varenicline L-tartrate is a partial agonist selective for α<sub>4</sub>β<sub>2</sub> nicotinic acetylcholine receptor subtypes. In the United States, varenicline L-tartrate is marketed under the trade mark Chantix and is indicated as an aid to smoking cessation treatment.</div>
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Varenicline base and its pharmaceutically acceptable acid addition salts are described in <a class="patcit" data-mce-href="https://www.google.com/patents/US6410550" href="https://www.google.com/patents/US6410550" id="pcit0001">U.S. Patent No. 6,410,550 </a>. In particular, the preparation of varenicline provided in this reference makes use of 10-aza-tricyclo[6.3.1.0<sup>2,7</sup>]-dodeca-2(7),3,5-triene (a compound of Formula VI), as a key intermediate compound (see Scheme 1 below). Specifically, Example 1 of <a class="patcit" data-mce-href="https://www.google.com/patents/US6410550" href="https://www.google.com/patents/US6410550" id="pcit0002">U.S. Patent No. 6,410,550 </a>describes the synthetic preparation of key intermediate compound of Formula VI as depicted in Scheme 1.</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/EP2204369A1/imgb0002.png" href="https://patentimages.storage.googleapis.com/EP2204369A1/imgb0002.png"><img alt="Figure imgb0002" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/EP2204369A1/imgb0002.png" height="272" id="ib0002" src="https://patentimages.storage.googleapis.com/EP2204369A1/imgb0002.png" style="height: auto; max-width: 100%;" width="660" /></a></div>
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1,2,3,4-tetrahydro-1,4-methano-naphthalene-<i>cis</i>-2,3-diol (a compound of Formula III), and / or indane-1,3-dicarbaldehyde (a compound of Formula IV).</div>
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<u>Example 1: Preparation of 1,2,3,4-tetrahydro-1,4-methano-naphthalene-<i>cis</i>-2,3-diol (a compound of Formula III)</u></div>
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A 10mL round bottom flask was charged with a compound of formula II (142mg, 1mmol), <i>N</i>-methylmorpholine-<i>N</i>-oxide (120mg, 1.03mmol), <i>tert</i>-butanol (3mL) and water (1mL). FibreCat<sup>™</sup> 3003 (OsO<sub>4</sub> anchored onto a polymeric support) (11.6mg, 0.0025mmol) was added to this solution and the mixture was heated to reflux. Complete conversion to a compound of formula III was detected by GC, method A, after 48h.</div>
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<u>Example 2: Preparation of 1,2,3,4-tetrahydro-1,4-methano-naphthalene-<i>cis</i>-2,3-diol (a compound of Formula III)</u><u>Step A) Preparation of hexadecyl-trimethylammoniumpermanganate (HTAP):</u></div>
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HTAP was prepared from ion exchange reaction between hexadecyltrimethylammoniumbromide and potassium permanganate.</div>
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Potassium permanganate (17.38g, 0.11mol, 1equiv.) was dissolved in 500mL water. A solution of hexadecyltrimethylammoniumbromide (40.10g, 0.11mol, 1equiv) in 500mL water was added drop-wise over 45 min at 20-22°C, and the mixture stirred for 30 minutes at this temperature. The precipitated solid was collected by filtration, washed with water (3 x 100mL) and dried under vacuum at 35°C for 24 hours to give 34.38g of HTAP as a light purple solid.</div>
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<u>Step B) Preparation of a compound of formula III:</u></div>
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Compound II (3.52g, 24.8mmol, 1equiv.) was dissolved in anhydrous tetrahydrofuran (80mL) and a solution of HTAP (10g, 24.8mmol, 1.0equiv.) in anhydrous tetrahydrofuran (125mL) was added drop-wise at 23-30°C over 45min. The reaction was monitored by TLC (hexane-ethyl acetate = 1:1). After complete reaction the mixture was cooled to below 10°C, and methyl <i>tert</i>-butyl ether (50mL) and 5% aqueous NaOH solution (50mL) were added and the mixture stirred for 30min. The solid was removed by filtration, and washed with methyl <i>tert</i>-butyl ether (2 x 30mL). The combined layers of the filtrate were separated and the aqueous phase extracted with methyl <i>tert</i>-butyl ether (2 x 30mL). The organic layers were combined and washed with 5% aqueous NaOH solution (50mL), water (2 x 50mL), dried over MgSO<sub>4</sub>, filtered and concentrated to obtain a dark green solid. This residue was suspended in acetone (15mL) and collected by filtration, washing with additional acetone (3 x 5mL). The product was dried under vacuum at 40°C to give 2.215g (50.7% yield) as a white crystalline solid.</div>
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<i>Analytical data</i>: m.p. = 178.8-179.3°C; <sup>1</sup>H-NMR: See Figure 1; <sup>13</sup>C-NMR: See Figure 2.</div>
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<u>Example 3: Preparation of indane-1,3-dicarbaldehyde (a compound of Formula IV)</u></div>
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A 25 mL round bottom flask was charged with a compound of formula I (142mg, 1mmol), Ruthenium (III) chloride hydrate (Aldrich, Reagent Plus<sup>™</sup>) (7.2mg, 0.035mmol), acetonitrile (8.5mL) and water (1.1mL). The solution was heated to 45°C and sodium periodate (449mg, 2.1mmol) was added portionwise over 25 minutes. After 1h, the reaction was cooled to ambient temperature and filtered. The solids were washed with ethyl acetate (3 x 2mL) and water (3mL). The filtrate was concentrated under vacuum and 5mL of water were added to the obtained residue. The mixture was extracted with ethyl acetate (2 x 5mL) and the combination of the organic layers was washed with water (3 x 5mL), dried with MgSO<sub>4</sub> and concentrated under vacuum to obtain a compound of formula IV (118mg) in 68% yield, 70.9% purity (analyzed by GC, method A).</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
WO 199935131, WO 2002092089, US 2013030179</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-108.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-108.jpg" rel="attachment wp-att-7878"><img alt="STR1" class="alignnone size-full wp-image-7878" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-108.jpg" height="456" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-108.jpg" style="height: auto; max-width: 100%;" width="676" /></a></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/WO2009065872A2?cl=en" href="https://www.google.com/patents/WO2009065872A2?cl=en">https://www.google.com/patents/WO2009065872A2?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Example 1: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3] benzazepine L-tartrate (i.e. varenicline L-tartrate)</div>
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A) Preparation of compound of formula (III)</div>
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This example is based on U.S. Patent No. 6,410,550.</div>
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A 250 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with 10-aza-tricyclo [ 6.3.1. O<sup>2</sup>'<sup>7</sup>] dodeca-2, 4, 6- triene para-toluene sulfonic acid salt (12.4g, 37.5 mmol) and 44 mL of CH<sub>2</sub>Cl<sub>2</sub>. Triethylamine (8.3 g, 82.5 mmol) was added to the slurry and the resulting solution was cooled to 0-5 <sup>0</sup>C. The addition funnel was charged with a solution of (CF<sub>3</sub>CO)<sub>2</sub>O (8.1q, 41.25 mmol) in 19 mL of CH<sub>2</sub>Cl<sub>2</sub>. This solution was slowly added to the reaction mixture, maintaining the temperature < 15 <sup>0</sup>C. The resulting mixture was stirred for 1 hour, and the complete conversion was monitored by GC. The crude reaction mixture was washed with water (2 * 40 mL) and brine (40 mL) . The organic phase was used in the next step without further purification.</div>
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On the other hand, a 500 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with CF<sub>3</sub>SO<sub>3</sub>H (25.9 g, 172.5 mmol), CH<sub>2</sub>Cl<sub>2</sub> (110 mL) and cooled to 0-5 <sup>0</sup>C. At this temperature, fuming nitric acid (5.4 g, 86.25 mmol) was added slowly. To the resulting slurry at 0-5 <sup>0</sup>C, the solution obtained in the previous step was slowly added, maintaining the temperature < 15 <sup>0</sup>C. After the addition, the reaction mixture was stirred overnight. The complete dinitration was confirmed by GC. The crude reaction mixture was poured into water (60 mL) an ice (80 g) and stirred. The phases were separated and the aqueous phase was extracted with CH<sub>2</sub>Cl<sub>2</sub> (3 x 50 mL) . The mixture of the organic phases was washed with aqueous saturated NaHCO<sub>3</sub>, dried over Na<sub>2</sub>SO<sub>4</sub> and volatiles evaporated under vacuum to obtain 11.9 g of a solid that was suspended and stirred for 2 hours in AcOEt (12 mL) and hexanes (24 mL) . The solid was filtered and washed with hexanes to obtain the compound of formula (III), 9.1g with a purity of 88.9% by GC (9.8% of meta-dimtrocompound impurity) .</div>
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B) Preparation of compound of formula (IV)</div>
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This example is based on International Patent No. WO/2006/090236.</div>
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A 200 mL autoclave was charged with (III) (9.1 g, 26.3 mmol), damp 5% Pd/C 50% and 180 mL of a 2- propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 18 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered through Celite and washed with 2-propanol (40 mL) . To this solution, K<sub>2</sub>HPO<sub>4</sub>(458 mg, 2.63 mmol) was added. The mixture was cooled at 0-5 <sup>0</sup>C and a solution of 4.07 g of 40% aqueous glyoxal diluted with water (14.5 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 68 mL and water (128 mL) was added drop- wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water (20 mL) and dried m a oven at 50 <sup>0</sup>C to obtain the compound of formula (IV), 6.78 g.</div>
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C) Preparation of vareniclme L-tartrate (compound of formula (I) )</div>
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This example is based on International Patent No. WO/2006/090236.</div>
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A 250 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with compound of formula (IV) (6.78 g, 22 mmol) and toluene</div>
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(47 mL) . To this solution was added a solution of NaOH (2.7 g, 68.2 mmol) in water (34 mL) . The mixture was heated to 40<sup>0</sup>C and stirred for 4 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (68 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (30 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (90 mL) and evaporated again. The final residue was dissolved in 156 mL of MeOH. 1.3 g of activated carbon "Darco G-60 100 mesh" were added and the mixture was stirred for 30 min and filtered through Celite to obtain an intense yellow solution. The process with activated carbon was repeated without any improvement in the colour. This solution was added drop-wise over a solution of L- tartaric acid (3.63 g, 24.2 mmol) in MeOH (47 mL) . The slurry was stirred for 72 hours at room temperature, filtered, washed with MeOH and dried in an oven at 50 <sup>0</sup>C for 8 hours, to obtain 5.05 g of varenicline L-tartrate as a yellow solid with a 95.5% purity by HPLC (4.4% of unknown impurity A). Colour L: 92.75, a*: -7.19, b*:43.08.</div>
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Comparative Example 2: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazmo [2, 3-h] [3 ] benzazepine L-tartrate (i.e. varenicline L-tartrate) A) Preparation of compound of formula (IV)</div>
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This example is based on International Patent No. WO/2006/090236.</div>
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A 200 mL autoclave was charged with (III) prepared according to Comparative Example 1.A) (4.1 g) , 123 mg of damp 5% Pd/C 50% and 81 mL of a 2-propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 24 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered through Celite and washed with 2-propanol (16 mL) . To this solution, K<sub>2</sub>HPO<sub>4</sub> (207 mg, 1.19 mmol) was added. The mixture was cooled at 0-5 <sup>0</sup>C and a solution of 1.84 g of 40% aqueous glyoxal diluted with water (6.6 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 30 mL and water (56 mL) was added drop-wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water and dried in a oven at 50 <sup>0</sup>C to obtain 3.15 g of compound of formula (IV) .</div>
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B) Preparation of vareniclme L-tartrate (compound of formula (I) )</div>
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This example is based on International application No. WO/2006/090236. A 100 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with</div>
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7, 8, 9, 10-tetrahydro-8- (tπfluoroacetyl) -6, 10-methano-6H- pyrazino [2 , 3-h] [3] benzazepine, i.e. compound of formula</div>
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(IV) (3.14 g, 10.2 mmol) and toluene (22 mL) . To this solution was added a solution of NaOH (1.3 g, 31.6 mmol) in water (16 mL) . The mixture was heated to 40 <sup>0</sup>C and stirred for 2.5 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (30 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (15 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (45 mL) and evaporated again. The final residue was dissolved m 70 mL of MeOH. 314 mg of activated carbon "Darco G-60 100 mesh" were added and the mixture was stirred for 30 mm and filtered through Celite to obtain a yellow solution. This solution was added drop-wise over a solution of L- tartaπc acid (1.68 g, 11.22 mmol) m MeOH (22 mL) . The slurry was stirred for 1 hour at room temperature, filtered, washed with MeOH (2 x 5 mL) and dried under vacuum, to obtain vareniclme L-tartrate (2.48 g) as a yellow solid with a 95.6% purity by HPLC (4.4% of unknown impurity A). Colour L: 99.50, a*: -4.98, b*:43.02</div>
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Comparative Example 3: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3 ] benzazepine L-tartrate (i.e. vareniclme L-tartrate)</div>
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This example is based on International application No. WO/2002/092089.</div>
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2 g of vareniclme L-tartrate as obtained from Comparative Example 1 were dissolved in 3 mL of water.</div>
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To this solution, 100 mL of CH<sub>3</sub>CN were added, and the resulting slurry was stirred for 10 mm and filtered.</div>
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After drying the product was analysed to be a 98.2% purity by HPLC (1.7% of unknown impurity A) . Colour L: 91.44, a*: -3.24, b* : 33.47</div>
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Example 1: Preparation of 7, 8, 9, lO-tetrahydro-6, 10- methano-6H-pyrazmo [2, 3-h] [3] benzazepine L-tartrate</div>
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(i.e. vareniclme L-tartrate)</div>
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A) Preparation of compound of formula (III) This example is based on U.S. Patent No. 6,410,550, except for the purification step, which is the object of the present invention (i.e. crystallization in toluene) .</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A 500 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with 10-aza-tricyclo [ 6.3.1. O<sup>2</sup>'<sup>7</sup>] dodeca-2, 4, 6- tπene para-toluene sulfonic acid salt (32.5g, 98.2 mmol) and 115 mL of CH<sub>2</sub>Cl<sub>2</sub>. Triethylamine (21.8 g, 216 mmol) was added to the slurry and the resulting solution was cooled to 0-5 <sup>0</sup>C. The addition funnel was charged with a solution of (CF<sub>3</sub>CO)<sub>2</sub>O (22.7 g, 108 mmol) in 50 mL of CH<sub>2</sub>Cl<sub>2</sub>. This solution was slowly added to the reaction mixture, maintaining the temperature < 15 <sup>0</sup>C. The resulting mixture was stirred for 1 hour, and the complete conversion was monitored by GC. The crude reaction mixture was washed with water (2 x 100 mL) and brine (100 mL) . The organic phase was used in the next step without further purification.</div>
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A l L round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with CF<sub>3</sub>SO<sub>3</sub>H (67.8 g, 452 mmol), CH<sub>2</sub>Cl<sub>2</sub> (280 mL) and cooled to 0-5 <sup>0</sup>C. At this temperature, fuming nitric acid (14.2 g, 226 mmol) was slowly added. To the resulting slurry at 0-5 <sup>0</sup>C, the solution obtained in the previous step was slowly added, maintaining the temperature < 15 <sup>0</sup>C. After the addition, the reaction mixture was stirred overnight. The complete dinitration was confirmed by GC. The crude reaction mixture was poured into water (150 mL) an ice (200 g) and stirred. The phases were separated and the aqueous phase was extracted with CH<sub>2</sub>Cl<sub>2</sub> (100 mL) . The mixture of the organic phases was washed with aqueous saturated NaHCO<sub>3</sub> (2x100 mL) , water (100 mL) , dried over Na<sub>2</sub>SO<sub>4</sub> and volatiles evaporated under vacuum to obtain 30.5 g of a solid with a 83.6% purity by GC (12.5% of meta- dinitrocompound impurity) . 20 g of this solid were crystallized in toluene (100 mL) to obtain the compound of formula (III), 15 g of a pale brown solid with a 98.5 % purity by GC (meta-dinitrocompound impurity not detected) .</div>
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B) Preparation of compound of formula (IV) This example is based on International Patent No. WO/2006/090236.</div>
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A 200 mL autoclave was charged with (III) (9.1 g, 26.3 mmol, crystals from toluene), damp 5% Pd/C 50% and 180 mL of a 2-propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 18 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered over Celite and washed with 2- propanol (40 mL) . To this solution, K<sub>2</sub>HPO<sub>4</sub> (458 mg, 2.63 mmol) was added. The mixture was cooled at 0-5 <sup>0</sup>C and a solution of 4.07 g of 40% aqueous glyoxal diluted with water (14.5 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 68 mL and water (128 mL) was added drop-wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water (20 mL) and dried m a oven at 50 <sup>0</sup>C to obtain the product, 7.16 g of compound of formula (IV) with a 99.9% purity by HPLC. C) Preparation of varenicline L-tartrate (compound of formula ( I) )</div>
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Thrs example rs based on International Patent No. WO/2006/090236. A 250 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with a solution of NaOH (2.89 g, 72.23 mmol) in water (36 mL) , compound of formula (IV) (7.15 g, 23.3 mmol) and toluene (50 mL) . The mixture was heated to 40 <sup>0</sup>C and stirred for 4 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (71 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (36 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (110 mL) and evaporated again. The final residue was dissolved in 164 mL of MeOH. 750 mg of activated carbon "Darco G-60 100 mesh" were added and the mixture was stirred for 30 min and filtered through Celite to obtain a yellow solution. This solution was added drop- wise over a solution of L-tartaric acid (3.84 g, 25.6 mmol) in MeOH (50 mL) . The slurry was stirred for 14 hours at room temperature, filtered, washed with MeOH and dried under vacuum, to obtain varenicline L-tartrate</div>
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(7.04 g) as an off-white solid with a >99.9% purity by HPLC (unknown impurity A not detected) . Colour L: 94.39, a*: 2.27, b*:9.02.</div>
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<img alt="" class="" data-mce-src="http://patentimages.storage.googleapis.com/WO2009065872A2/imgf000003_0001.png" height="288" src="http://patentimages.storage.googleapis.com/WO2009065872A2/imgf000003_0001.png" style="height: auto; max-width: 100%;" width="826" /></div>
<h3 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Post-marketing_surveillance">Post-marketing surveillance</span></h3>
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No evidence for increased risks of cardiovascular events, depression, or self-harm with varenicline versus nicotine replacement therapy has been found in one post-marketing surveillance study.<sup class="reference" id="cite_ref-Kotz2015_23-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Kotz2015-23" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Kotz2015-23">[23]</a></sup></div>
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<span class="mw-headline" id="Mechanism_of_action">Mechanism of action</span></h2>
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Varenicline displays full <a data-mce-href="https://en.wikipedia.org/wiki/Agonist" href="https://en.wikipedia.org/wiki/Agonist" title="Agonist">agonism</a> on <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/%CE%917_nicotinic_acetylcholine_receptor" href="https://en.wikipedia.org/wiki/%CE%917_nicotinic_acetylcholine_receptor" title="Α7 nicotinic acetylcholine receptor">α<sub>7</sub></a> <a data-mce-href="https://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor" href="https://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor" title="Nicotinic acetylcholine receptor">nicotinic acetylcholine receptors</a>.<sup class="reference" id="cite_ref-pmid16766716_24-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid16766716-24" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid16766716-24">[24]</a></sup><sup class="reference" id="cite_ref-pmid20965579_25-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid20965579-25" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid20965579-25">[25]</a></sup> And it is a <a data-mce-href="https://en.wikipedia.org/wiki/Partial_agonist" href="https://en.wikipedia.org/wiki/Partial_agonist" title="Partial agonist">partial agonist</a> on the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/%CE%914%CE%B22_nicotinic" href="https://en.wikipedia.org/wiki/%CE%914%CE%B22_nicotinic" title="Α4β2 nicotinic">α<sub>4</sub>β<sub>2</sub></a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/%CE%913%CE%B24-nAChR" href="https://en.wikipedia.org/wiki/%CE%913%CE%B24-nAChR" title="Α3β4-nAChR">α<sub>3</sub>β<sub>4</sub></a>, and <a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=%CE%916%CE%B22&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=%CE%916%CE%B22&action=edit&redlink=1" title="Α6β2 (page does not exist)">α<sub>6</sub>β<sub>2</sub></a> subtypes.<sup class="reference" id="cite_ref-26"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-26" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-26">[26]</a></sup> In addition, it is a weak agonist on the <a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=%CE%913%CE%B22&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=%CE%913%CE%B22&action=edit&redlink=1" title="Α3β2 (page does not exist)">α<sub>3</sub>β<sub>2</sub></a> containing receptors.</div>
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Varenicline's partial agonism on the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/%CE%914%CE%B22-nicotinic" href="https://en.wikipedia.org/wiki/%CE%914%CE%B22-nicotinic" title="Α4β2-nicotinic">α<sub>4</sub>β<sub>2</sub></a> receptors rather than nicotine's full agonism produces less effect of <a data-mce-href="https://en.wikipedia.org/wiki/Dopamine" href="https://en.wikipedia.org/wiki/Dopamine" title="Dopamine">dopamine</a> release than nicotine's. This α<sub>4</sub>β<sub>2</sub> competitive binding, reduces the ability of nicotine to bind and stimulate the mesolimbic dopamine system - similar to the method of action of <a data-mce-href="https://en.wikipedia.org/wiki/Buprenorphine" href="https://en.wikipedia.org/wiki/Buprenorphine" title="Buprenorphine">buprenorphine</a> in the treatment of opioid addiction.<sup class="reference" id="cite_ref-Elrashidi2014_3-3"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Elrashidi2014-3" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-Elrashidi2014-3">[3]</a></sup></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Pharmacokinetics">Pharmacokinetics</span></h2>
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Most of the active compound is excreted by the <a data-mce-href="https://en.wikipedia.org/wiki/Kidney" href="https://en.wikipedia.org/wiki/Kidney" title="Kidney">kidneys</a> (92–93%). A small proportion is <a data-mce-href="https://en.wikipedia.org/wiki/Glucuronidation" href="https://en.wikipedia.org/wiki/Glucuronidation" title="Glucuronidation">glucuronidated</a>, oxidised, <i>N</i>-formylated or conjugated to a <a data-mce-href="https://en.wikipedia.org/wiki/Hexose" href="https://en.wikipedia.org/wiki/Hexose" title="Hexose">hexose</a>.<sup class="reference" id="cite_ref-27"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-27" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-27">[27]</a></sup> The elimination half-life is about 24 hours.</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="History">History</span></h2>
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Use of <a data-mce-href="https://en.wikipedia.org/wiki/Cytisus" href="https://en.wikipedia.org/wiki/Cytisus" title="Cytisus">Cytisus</a> plant as a smoking substitute during <a data-mce-href="https://en.wikipedia.org/wiki/World_War_II" href="https://en.wikipedia.org/wiki/World_War_II" title="World War II">World War II</a><sup class="reference" id="cite_ref-28"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-28" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-28">[28]</a></sup> led to use as a cessation aid in eastern Europe and extraction of cytisine.<sup class="reference" id="cite_ref-29"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-29" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-29">[29]</a></sup> <a data-mce-href="https://en.wikipedia.org/wiki/Cytisine" href="https://en.wikipedia.org/wiki/Cytisine" title="Cytisine">Cytisine</a> <a data-mce-href="https://en.wikipedia.org/wiki/Structural_analog" href="https://en.wikipedia.org/wiki/Structural_analog" title="Structural analog">analogs</a> led to varenicline at Pfizer.<sup class="reference" id="cite_ref-30"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-30" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-30">[30]</a></sup><sup class="reference" id="cite_ref-pmid515342_31-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid515342-31" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid515342-31">[31]</a></sup><sup class="reference" id="cite_ref-pmid16908787_32-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid16908787-32" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid16908787-32">[32]</a></sup></div>
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Varenicline received a "priority review" by the US FDA in February 2006, shortening the usual 10-month review period to 6 months because of its demonstrated effectiveness in<a data-mce-href="https://en.wikipedia.org/wiki/Clinical_trial" href="https://en.wikipedia.org/wiki/Clinical_trial" title="Clinical trial">clinical trials</a> and perceived lack of safety issues.<sup class="reference" id="cite_ref-pmid16467225_33-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid16467225-33" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-pmid16467225-33">[33]</a></sup> The agency's approval of the drug came on May 11, 2006.<sup class="reference" id="cite_ref-FDA2006_4-1"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-FDA2006-4" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-FDA2006-4">[4]</a></sup> On August 1, 2006, varenicline was made available for sale in the United States and on September 29, 2006, was approved for sale in the <a data-mce-href="https://en.wikipedia.org/wiki/European_Union" href="https://en.wikipedia.org/wiki/European_Union" title="European Union">European Union</a>.<sup class="reference" id="cite_ref-EMA2011_34-0"><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_note-EMA2011-34" href="https://en.wikipedia.org/wiki/Varenicline#cite_note-EMA2011-34">[34]</a></sup></div>
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SEE</div>
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<span class="mixed-citation"><a data-mce-href="http://www.emea.europa.eu/humandocs/PDFs/EPAR/champix/H-699-en6.pdf" href="http://www.emea.europa.eu/humandocs/PDFs/EPAR/champix/H-699-en6.pdf" target="pmc_ext">www.emea.europa.eu/humandocs/PDFs/EPAR/champix/H-699-en6.pdf</a>.</span></div>
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<span class="element-citation">Busch FR, Concannon PE, Handfield RE, McKinley JD, McMahon ME, Singer RA, Watson TJ, Withbroe GJ, Stivanello M, Leoni L, Bezze C. Synthesis of (1 (Aminomethyl)-2,3-dihydro-1H-inden-3-yl)methanol: Structural Confirmation of the Main Band Impurity Found in Varenicline® Starting Material.<span class="ref-journal">Synth Commun. </span>2008;<span class="ref-vol">38</span>:441–447. <a data-mce-href="http://dx.doi.org/10.1080/00397910701771231" href="http://dx.doi.org/10.1080/00397910701771231" target="pmc_ext">http://dx.doi.org/10.1080/00397910701771231</a>.</span></div>
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<span class="mixed-citation">Varenicline standards and impurity controls. <a data-mce-href="http://www.freepatentsonline.com/US2007/0224690.html" href="http://www.freepatentsonline.com/US2007/0224690.html" target="pmc_ext">www.freepatentsonline.com/US2007/0224690.html</a>.</span></div>
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<span class="mixed-citation">N-formyl and N-methyl degradation products. <a data-mce-href="http://www.freepatentsonline.com/y2004/0235850.html" href="http://www.freepatentsonline.com/y2004/0235850.html" target="pmc_ext">www.freepatentsonline.com/y2004/0235850.html</a>.</span></div>
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<span class="mixed-citation">Methods of reducing degradant formation in pharmaceutical compositions of Varenicline.<a data-mce-href="http://www.freepatentsonline.com/y2008/0026059.html" href="http://www.freepatentsonline.com/y2008/0026059.html" target="pmc_ext">www.freepatentsonline.com/y2008/0026059.html</a>.</span></div>
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<span class="mixed-citation">Varenicline standards and impurity controls. <a data-mce-href="http://www.freepatentsonline.com/EP2004186.html" href="http://www.freepatentsonline.com/EP2004186.html" target="pmc_ext">www.freepatentsonline.com/EP2004186.html</a>.</span></div>
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<span class="element-citation">Satheesh B, Kumarpulluru S, Raghavan V, Saravanan D. UHPLC Separation and Quantification of Related Substances of Varenicline Tartrate Tablet. <span class="ref-journal">Acta Chromatogr. </span>2010;<span class="ref-vol">22</span>:207–218.<a data-mce-href="http://dx.doi.org/10.1556/AChrom.22.2010.2.4" href="http://dx.doi.org/10.1556/AChrom.22.2010.2.4" target="pmc_ext">http://dx.doi.org/10.1556/AChrom.22.2010.2.4</a>.</span></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-120.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-120.jpg" rel="attachment wp-att-7893"><img alt="STR1" class="alignnone size-full wp-image-7893" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-120.jpg" height="130" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-120.jpg" style="height: auto; max-width: 100%;" width="521" /></a></div>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/US6410550" href="https://www.google.com/patents/US6410550">US6410550</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 13, 1998</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 25, 2002</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pfizer Inc</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aryl fused azapolycyclic compounds</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2009155403A2?cl=en" href="https://www.google.com/patents/WO2009155403A2?cl=en">WO2009155403A2</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 18, 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 23, 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Teva Pharmaceutical Industries Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Processes for the preparation of varenicline and intermediates thereof</td></tr>
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<tr class="patent-data-table"><th class="patent-data-table-th" colspan="3" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Reference</th></tr>
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<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">BHUSHAN, VIDYA; RATHORE, RAJENDRA; CHANDRASEKARAN, S.: "<a data-mce-href="http://scholar.google.com/scholar?q=%22A+Simple+and+Mild+Method+for+the+cis-Hydroxylation+of+Alkenes+with+Cetyltrimethylammonium+Permanganate%22" href="http://scholar.google.com/scholar?q=%22A+Simple+and+Mild+Method+for+the+cis-Hydroxylation+of+Alkenes+with+Cetyltrimethylammonium+Permanganate%22">A Simple and Mild Method for the cis-Hydroxylation of Alkenes with Cetyltrimethylammonium Permanganate</a>" SYNTHESIS, no. 5, 1984, pages 431-433, XP002581198</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">BROOKS P R ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Synthesis+of+2%2C3%2C4%2C5-tetrahydro-1%2C5-methano-1H-3-benzaz+epine+via+oxidative+cleavage+and+reductive+amination+strategies%22" href="http://scholar.google.com/scholar?q=%22Synthesis+of+2%2C3%2C4%2C5-tetrahydro-1%2C5-methano-1H-3-benzaz+epine+via+oxidative+cleavage+and+reductive+amination+strategies%22">Synthesis of 2,3,4,5-tetrahydro-1,5-methano-1H-3-benzaz epine via oxidative cleavage and reductive amination strategies</a>" SYNTHESIS 20040803 DE, no. 11, 3 August 2004 (2004-08-03), pages 1755-1758, XP002581197 ISSN: 0039-7881</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">SORBERA L A ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Varenicline+tartrate%3A+Aid+to+smoking+cessation+nicotinic+%5Balpha%5D4%5Bbeta%5D2+partial+agonist%22" href="http://scholar.google.com/scholar?q=%22Varenicline+tartrate%3A+Aid+to+smoking+cessation+nicotinic+%5Balpha%5D4%5Bbeta%5D2+partial+agonist%22">Varenicline tartrate: Aid to smoking cessation nicotinic [alpha]4[beta]2 partial agonist</a>" DRUGS OF THE FUTURE 200602 ES LNKD- DOI:10.1358/DOF.2006.031.02.964028, vol. 31, no. 2, February 2006 (2006-02), pages 117-122, XP002581199 ISSN: 0377-8282 DOI: 10.1358/dof.2006.031.02.964028</td></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2001062736A1?cl=en" href="https://www.google.com/patents/WO2001062736A1?cl=en">WO2001062736A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feb 8, 2001</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 30, 2001</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pfizer Products Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aryl fused azapolycyclic compounds</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2002085843A2?cl=en" href="https://www.google.com/patents/WO2002085843A2?cl=en">WO2002085843A2</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 4, 2002</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oct 31, 2002</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pfizer Products Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Process for the preparation of 1,3-substituted indenes and aryl-fused azapolycyclic compounds</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2006090236A1?cl=en" href="https://www.google.com/patents/WO2006090236A1?cl=en">WO2006090236A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feb 21, 2006</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 31, 2006</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pfizer Products Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Preparation of high purity substituted quinoxaline</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2008060487A2?cl=en" href="https://www.google.com/patents/WO2008060487A2?cl=en">WO2008060487A2</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 9, 2007</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 22, 2008</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pfizer Products Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Polymorphs of nicotinic intermediates</td></tr>
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<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">COE J W ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Varenicline%3A+an+alpha4beta2+Nicotinic+Receptor+Partial+Agonist+for+Smoking+Cessation%22" href="http://scholar.google.com/scholar?q=%22Varenicline%3A+an+alpha4beta2+Nicotinic+Receptor+Partial+Agonist+for+Smoking+Cessation%22">Varenicline: an alpha4beta2 Nicotinic Receptor Partial Agonist for Smoking Cessation</a>" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON., US, vol. 48, no. 10, 1 January 2005 (2005-01-01), pages 3474-3477, XP002474642 ISSN: 0022-2623 cited in the application</td></tr>
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<tr class="patent-data-table"><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Citing Patent</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Filing date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Publication date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title</th></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2010005643A1?cl=en" href="https://www.google.com/patents/WO2010005643A1?cl=en">WO2010005643A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 28, 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jan 14, 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Teva Pharmaceutical Industries Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Processes for purifying varenicline l-tartrate salt and preparing crystalline forms of varenicline l-tartrate salt</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2011110954A1?cl=en" href="https://www.google.com/patents/WO2011110954A1?cl=en">WO2011110954A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 8, 2011</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 15, 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Actavis Group Ptc Ehf</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Highly pure varenicline or a pharmaceutically acceptable salt thereof substantially free of methylvarenicline impurity</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2011154586A3?cl=en" href="https://www.google.com/patents/WO2011154586A3?cl=en">WO2011154586A3</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 13, 2011</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 22, 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Medichem, S. A.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Improved methods for the preparation of quinoxaline derivatives</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/EP2581375A2?cl=en" href="https://www.google.com/patents/EP2581375A2?cl=en">EP2581375A2</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 13, 2011</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 17, 2013</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Medichem, S.A.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Improved methods for the preparation of quinoxaline derivatives</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/US8039620" href="https://www.google.com/patents/US8039620">US8039620</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 21, 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oct 18, 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Teva Pharmaceutical Industries Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Varenicline tosylate, an intermediate in the preparation process of varenicline L-tartrate</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/US8178537" href="https://www.google.com/patents/US8178537">US8178537</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 22, 2010</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 15, 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Teva Pharmaceutical Industries Ltd.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Solid state forms of varenicline salts and processes for preparation thereof</td></tr>
</tbody></table>
</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist columns references-column-count references-column-count-2" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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<li id="cite_note-Mills2009-1"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Mills2009_1-0" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Mills2009_1-0"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Mills EJ, Wu P, Spurden D, Ebbert JO, Wilson K (2009). <a class="external text" data-mce-href="http://www.biomedcentral.com/content/pdf/1477-7517-6-25.pdf" href="http://www.biomedcentral.com/content/pdf/1477-7517-6-25.pdf" rel="nofollow">"Efficacy of pharmacotherapies for short-term smoking abstinance: a systematic review and meta-analysis"</a> (PDF). <i>Harm Reduct J</i> <b>6</b>: 25. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1186%2F1477-7517-6-25" href="https://dx.doi.org/10.1186%2F1477-7517-6-25" rel="nofollow">10.1186/1477-7517-6-25</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760513" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760513" rel="nofollow">2760513</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/19761618" href="https://www.ncbi.nlm.nih.gov/pubmed/19761618" rel="nofollow">19761618</a>.</cite></span></li>
<li id="cite_note-Cochrane2013-2"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Cochrane2013_2-0" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Cochrane2013_2-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Cochrane2013_2-1" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Cochrane2013_2-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Cahill K, Stevens S, Perera R, Lancaster T (May 2013). <a class="external text" data-mce-href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009329.pub2/full" href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009329.pub2/full" rel="nofollow">"Pharmacological interventions for smoking cessation: an overview and network meta-analysis"</a>. <i>Cochrane Database Syst Rev</i> (Systematic Review & Meta-Analysis) <b>5</b>: CD009329.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1002%2F14651858.CD009329.pub2" href="https://dx.doi.org/10.1002%2F14651858.CD009329.pub2" rel="nofollow">10.1002/14651858.CD009329.pub2</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/23728690" href="https://www.ncbi.nlm.nih.gov/pubmed/23728690" rel="nofollow">23728690</a>.</cite></span></li>
<li id="cite_note-Elrashidi2014-3"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Elrashidi2014_3-0" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Elrashidi2014_3-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Elrashidi2014_3-1" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Elrashidi2014_3-1"><sup><i><b>b</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Elrashidi2014_3-2" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Elrashidi2014_3-2"><sup><i><b>c</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Elrashidi2014_3-3" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Elrashidi2014_3-3"><sup><i><b>d</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Elrashidi MY, Ebbert JO (June 2014). "Emerging drugs for the treatment of tobacco dependence: 2014 update". <i>Expert Opin Emerg Drug</i> (Review) <b>19</b> (2): 243–60.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1517%2F14728214.2014.899580" href="https://dx.doi.org/10.1517%2F14728214.2014.899580" rel="nofollow">10.1517/14728214.2014.899580</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/24654737" href="https://www.ncbi.nlm.nih.gov/pubmed/24654737" rel="nofollow">24654737</a>.</cite></span></li>
<li id="cite_note-FDA2006-4"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-FDA2006_4-0" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-FDA2006_4-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-FDA2006_4-1" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-FDA2006_4-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text">U.S. Food and Drug Administration.<a class="external text" data-mce-href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108651.htm" href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108651.htm" rel="nofollow"><i>FDA Approves Novel Medication for Smoking Cessation</i></a>. Press release, 11 May 2006.</span></li>
<li id="cite_note-5"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-5" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-5"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Cressman, AM; Pupco, A; Kim, E; Koren, G; Bozzo, P (May 2012). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352787" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352787" rel="nofollow">"Smoking cessation therapy during pregnancy."</a>. <i>Canadian Family Physician</i> <b>58</b> (5): 525–7. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352787" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352787" rel="nofollow">3352787</a>.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/22586193" href="https://www.ncbi.nlm.nih.gov/pubmed/22586193" rel="nofollow">22586193</a>.</cite></span></li>
<li id="cite_note-6"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-6" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-6"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://clinicaltrials.gov/ct2/show/study/NCT01290445" href="http://clinicaltrials.gov/ct2/show/study/NCT01290445" rel="nofollow">"Varenicline Pregnancy Cohort Study"</a>. <i>clinicaltrials.gov</i>.</cite></span></li>
<li id="cite_note-7"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-7" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-7"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT" href="http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT" rel="nofollow">"LactMed"</a>. <i>nih.gov</i>.</cite></span></li>
<li id="cite_note-8"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-8" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-8"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Leung, LK; Patafio, FM; Rosser, WW (September 28, 2011). <a class="external text" data-mce-href="http://www.biomedcentral.com/1472-6904/11/15" href="http://www.biomedcentral.com/1472-6904/11/15" rel="nofollow">"Gastrointestinal adverse effects of varenicline at maintenance dose: a meta-analysis"</a>. <i>BMC clinical pharmacology</i><b>11</b> (1): 15. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1186%2F1472-6904-11-15" href="https://dx.doi.org/10.1186%2F1472-6904-11-15" rel="nofollow">10.1186/1472-6904-11-15</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192741" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192741" rel="nofollow">3192741</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/21955317" href="https://www.ncbi.nlm.nih.gov/pubmed/21955317" rel="nofollow">21955317</a>.</cite></span></li>
<li id="cite_note-9"> <span class="reference-text"><cite class="citation web">American Cancer Society. <a class="external text" data-mce-href="http://www.cancer.org/docroot/CDG/content/CDG_Varenicline.asp" href="http://www.cancer.org/docroot/CDG/content/CDG_Varenicline.asp" rel="nofollow">"Cancer Drug Guide: Varenicline"</a><span class="reference-accessdate">. Retrieved <span class="nowrap">2008-01-19</span></span>.</cite></span></li>
<li id="cite_note-10"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-10" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-10"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d52bc40b-db7b-4243-888c-9ee95bbc6545" href="http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d52bc40b-db7b-4243-888c-9ee95bbc6545" rel="nofollow">"DailyMed - CHANTIX- varenicline tartrate"</a>. <i>nih.gov</i>.</cite></span></li>
<li id="cite_note-aikenstandard-11"><span class="reference-text"><cite class="citation web">FDA. <a class="external text" data-mce-href="http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm" href="http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm169988.htm" rel="nofollow">"Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban"</a><span class="reference-accessdate">. Retrieved <span class="nowrap">2009-07-01</span></span>.</cite></span></li>
<li id="cite_note-www.accessdata.fda.gov-12"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-www.accessdata.fda.gov_12-0" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-www.accessdata.fda.gov_12-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-www.accessdata.fda.gov_12-1" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-www.accessdata.fda.gov_12-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021928s033s034s037lbl.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021928s033s034s037lbl.pdf" rel="nofollow">"www.accessdata.fda.gov"</a> (PDF).</cite></span></li>
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<li id="cite_note-FDA.org-14"> <span class="reference-text"><cite class="citation news"><a class="external text" data-mce-href="http://www.fda.gov/Drugs/DrugSafety/ucm259161.htm" href="http://www.fda.gov/Drugs/DrugSafety/ucm259161.htm" rel="nofollow">"FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease"</a>. 2011-06-16.</cite></span></li>
<li id="cite_note-15"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-15" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-15"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Singh, S; Loke, YK, Spangler, JG, Furberg, CD (Sep 6, 2011). <a class="external text" data-mce-href="http://www.cmaj.ca/content/early/2011/07/04/cmaj.110218.full.pdf+html" href="http://www.cmaj.ca/content/early/2011/07/04/cmaj.110218.full.pdf+html" rel="nofollow">"Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis"</a> (PDF). <i>CMAJ : Canadian Medical Association</i> <b>183</b> (12): 1359–66.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1503%2Fcmaj.110218" href="https://dx.doi.org/10.1503%2Fcmaj.110218" rel="nofollow">10.1503/cmaj.110218</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168618" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168618" rel="nofollow">3168618</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/21727225" href="https://www.ncbi.nlm.nih.gov/pubmed/21727225" rel="nofollow">21727225</a>.</cite></span></li>
<li id="cite_note-16"> <span class="reference-text"><cite class="citation journal">Takagi, H; Umemoto, T (Sep 6, 2011). <a class="external text" data-mce-href="http://www.cmaj.ca/content/183/12/1404.2.full" href="http://www.cmaj.ca/content/183/12/1404.2.full" rel="nofollow">"Varenicline: quantifying the risk"</a>. <i>CMAJ : Canadian Medical Association</i> <b>183</b> (12): 1404. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1503%2Fcmaj.111-2063" href="https://dx.doi.org/10.1503%2Fcmaj.111-2063" rel="nofollow">10.1503/cmaj.111-2063</a>.<a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168634" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168634" rel="nofollow">3168634</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/21896705" href="https://www.ncbi.nlm.nih.gov/pubmed/21896705" rel="nofollow">21896705</a>.</cite></span></li>
<li id="cite_note-17"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-17" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-17"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Samuels, L (Sep 6, 2011). <a class="external text" data-mce-href="http://www.cmaj.ca/content/183/12/1407.full" href="http://www.cmaj.ca/content/183/12/1407.full" rel="nofollow">"Varenicline: cardiovascular safety"</a>. <i>CMAJ : Canadian Medical Association</i> <b>183</b> (12): 1407–08. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1503%2Fcmaj.111-2073" href="https://dx.doi.org/10.1503%2Fcmaj.111-2073" rel="nofollow">10.1503/cmaj.111-2073</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168639" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168639" rel="nofollow">3168639</a>.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/21896709" href="https://www.ncbi.nlm.nih.gov/pubmed/21896709" rel="nofollow">21896709</a>.</cite></span></li>
<li id="cite_note-EMA.europa.eu-18"> <span class="reference-text"><cite class="citation news"><a class="external text" data-mce-href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/07/news_detail_001314.jsp&mid=WC0b01ac058004d5c1&murl=menus/news_and_events/news_and_events.jsp&jsenabled=true" href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/07/news_detail_001314.jsp&mid=WC0b01ac058004d5c1&murl=menus/news_and_events/news_and_events.jsp&jsenabled=true" rel="nofollow">"European Medicine Agency confirms positive benefit-risk balance for Champix."</a>. 2011-07-21.</cite></span></li>
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<li id="cite_note-Mills2014-20"> <span class="reference-text"><cite class="citation journal">Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ (January 2014). <a class="external text" data-mce-href="http://circ.ahajournals.org/content/129/1/28.long" href="http://circ.ahajournals.org/content/129/1/28.long" rel="nofollow">"Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis"</a>.<i>Circulation</i> (Network Meta-Analysis) <b>129</b> (1): 28–41.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1161%2FCIRCULATIONAHA.113.003961" href="https://dx.doi.org/10.1161%2FCIRCULATIONAHA.113.003961" rel="nofollow">10.1161/CIRCULATIONAHA.113.003961</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/24323793" href="https://www.ncbi.nlm.nih.gov/pubmed/24323793" rel="nofollow">24323793</a>.</cite></span></li>
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<li id="cite_note-Rowland2014-22"> <span class="reference-text"><cite class="citation journal">Rowland K (April 2014). "ACP Journal Club. Review: Nicotine replacement therapy increases CVD events; bupropion and varenicline do not". <i>Annals of Internal Medicine</i>(Review & Commentary) <b>160</b> (8): JC2. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.7326%2F0003-4819-160-8-201404150-02002" href="https://dx.doi.org/10.7326%2F0003-4819-160-8-201404150-02002" rel="nofollow">10.7326/0003-4819-160-8-201404150-02002</a>.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/24733219" href="https://www.ncbi.nlm.nih.gov/pubmed/24733219" rel="nofollow">24733219</a>.</cite></span></li>
<li id="cite_note-Kotz2015-23"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Kotz2015_23-0" href="https://en.wikipedia.org/wiki/Varenicline#cite_ref-Kotz2015_23-0"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Kotz D, Viechtbauer W, Simpson C, van Schayck OC, West R, Sheikh A (2015).<a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593936" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593936" rel="nofollow">"Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study"</a>.<i>Lancet Respir Med</i> (retrospective cohort) <b>3</b>: 761–768. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1016%2FS2213-2600%2815%2900320-3" href="https://dx.doi.org/10.1016%2FS2213-2600%2815%2900320-3" rel="nofollow">10.1016/S2213-2600(15)00320-3</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593936" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593936" rel="nofollow">4593936</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/26355008" href="https://www.ncbi.nlm.nih.gov/pubmed/26355008" rel="nofollow">26355008</a>.</cite></span></li>
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<li id="cite_note-pmid16908787-32"> <span class="reference-text"><cite class="citation journal">Etter JF (2006). <a class="external text" data-mce-href="http://archinte.ama-assn.org/cgi/content/full/166/15/1553" href="http://archinte.ama-assn.org/cgi/content/full/166/15/1553" rel="nofollow">"Cytisine for smoking cessation: a literature review and a meta-analysis"</a>. <i>Arch. Intern. Med.</i> <b>166</b> (15): 1553–1559. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1001%2Farchinte.166.15.1553" href="https://dx.doi.org/10.1001%2Farchinte.166.15.1553" rel="nofollow">10.1001/archinte.166.15.1553</a>.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/16908787" href="https://www.ncbi.nlm.nih.gov/pubmed/16908787" rel="nofollow">16908787</a>.</cite></span></li>
<li id="cite_note-pmid16467225-33"> <span class="reference-text"><cite class="citation journal">Kuehn BM (2006). "FDA speeds smoking cessation drug review". <i>JAMA</i> <b>295</b> (6): 614–614.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1001%2Fjama.295.6.614" href="https://dx.doi.org/10.1001%2Fjama.295.6.614" rel="nofollow">10.1001/jama.295.6.614</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/16467225" href="https://www.ncbi.nlm.nih.gov/pubmed/16467225" rel="nofollow">16467225</a>.</cite></span></li>
<li id="cite_note-EMA2011-34"> <span class="reference-text"><cite class="citation web">European Medicines Agency (2011-01-28). <a class="external text" data-mce-href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000699/human_med_000696.jsp" href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000699/human_med_000696.jsp" rel="nofollow">"EPAR summary for the public. Champix varenicline"</a>. London<span class="reference-accessdate">. Retrieved <span class="nowrap">2011-02-14</span></span>.</cite></span></li>
</ol>
</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="External_links">External links</span></h2>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<a class="external text" data-mce-href="http://www.chantix.com/" href="http://www.chantix.com/" rel="nofollow">Manufacturer's website USA</a></h2>
<ul style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li><a class="external text" data-mce-href="http://www.champix.org.uk/" href="http://www.champix.org.uk/" rel="nofollow">Manufacturer's website UK</a></li>
<li><a class="external text" data-mce-href="http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106540.htm" href="http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106540.htm" rel="nofollow">FDA Alert</a></li>
<li><a class="external text" data-mce-href="http://whatsthedose.com/spl/0069-0471.html" href="http://whatsthedose.com/spl/0069-0471.html" rel="nofollow">Package insert</a></li>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-121.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-121.jpg" rel="attachment wp-att-7894"><img alt="STR1" class="alignnone size-full wp-image-7894" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-121.jpg" height="316" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-121.jpg" style="height: auto; max-width: 100%;" width="500" /></a></div>
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Varenicline">Varenicline</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Varenicline.svg" href="https://en.wikipedia.org/wiki/File:Varenicline.svg"><img alt="Varenicline.svg" data-file-height="97" data-file-width="249" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/49/Varenicline.svg/190px-Varenicline.svg.png" height="74" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/49/Varenicline.svg/190px-Varenicline.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/4/49/Varenicline.svg/285px-Varenicline.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/4/49/Varenicline.svg/380px-Varenicline.svg.png 2x" style="height: auto; max-width: 100%;" width="190" /></a></td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Varenicline_ball-and-stick_model.png" href="https://en.wikipedia.org/wiki/File:Varenicline_ball-and-stick_model.png"><img alt="Varenicline ball-and-stick model.png" data-file-height="1145" data-file-width="1844" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/de/Varenicline_ball-and-stick_model.png/190px-Varenicline_ball-and-stick_model.png" height="118" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/de/Varenicline_ball-and-stick_model.png/190px-Varenicline_ball-and-stick_model.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/d/de/Varenicline_ball-and-stick_model.png/285px-Varenicline_ball-and-stick_model.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/d/de/Varenicline_ball-and-stick_model.png/380px-Varenicline_ball-and-stick_model.png 2x" style="height: auto; max-width: 100%;" width="190" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7,8,9,10-Tetrahydro-6,10-methano-6<i>H</i>-pyrazino[2,3-h] [3]benzazepine</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chantix</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/monograph/chantix.html" href="https://www.drugs.com/monograph/chantix.html" rel="nofollow">Monograph</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/MedlinePlus" href="https://en.wikipedia.org/wiki/MedlinePlus" title="MedlinePlus">MedlinePlus</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.nlm.nih.gov"><a class="external text" data-mce-href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a606024.html" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a606024.html" rel="nofollow">a606024</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">License data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small>EU</small> <a data-mce-href="https://en.wikipedia.org/wiki/European_Medicines_Agency" href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency">EMA</a>: <span title="www.ema.europa.eu"><a class="external text" data-mce-href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Champix" href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Champix" rel="nofollow">Champix</a></span></li>
<li><small>US</small> <span title="www.accessdata.fda.gov"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" title="U.S. Food and Drug Administration">FDA</a>: <a class="external text" data-mce-href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Varenicline&SearchType=BasicSearch" href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Varenicline&SearchType=BasicSearch" rel="nofollow">Varenicline</a></span></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="Australia">AU</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#Australia" href="https://en.wikipedia.org/wiki/Pregnancy_category#Australia" title="Pregnancy category">B3</a></li>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" title="Pregnancy category">C</a> (Risk not ruled out)</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oral</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="Australia">AU</abbr>:</small> <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" href="https://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" title="Standard for the Uniform Scheduling of Drugs and Poisons">S4</a> (Prescription only)</li>
<li><small>CA</small>: <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
<li><small><abbr title="United Kingdom">UK</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">POM</a> (Prescription only)</li>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Plasma_protein_binding" href="https://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><20%</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_metabolism" href="https://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Limited (<10%)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Biological_half-life" href="https://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">24 hours</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Excretion" href="https://en.wikipedia.org/wiki/Excretion" title="Excretion">Excretion</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Kidney" href="https://en.wikipedia.org/wiki/Kidney" title="Kidney">Renal</a> (81–92%)</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=249296-44-4" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=249296-44-4" rel="nofollow">249296-44-4</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup> 375815-87-5</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_N07" href="https://en.wikipedia.org/wiki/ATC_code_N07" title="ATC code N07">N07BA03</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=N07BA03" href="http://www.whocc.no/atc_ddd_index/?code=N07BA03" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5310966" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5310966" rel="nofollow">5310966</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/IUPHAR/BPS" href="https://en.wikipedia.org/wiki/IUPHAR/BPS" title="IUPHAR/BPS">IUPHAR/BPS</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.guidetopharmacology.org"><a class="external text" data-mce-href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5459" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5459" rel="nofollow">5459</a></span></td></tr>
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<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>13</sub><span title="Hydrogen">H</span><sub>13</sub><span title="Nitrogen">N</span><sub>3</sub></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">211.267 g/mol</td></tr>
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////////////Varenicline, Chantix™, FDA 2006, 249296-44-4, 375815-87-5, Champix , Pfizer, バレニクリン酒石酸塩</div>
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n1c2cc3c(cc2ncc1)[C@@H]4CNC[C@H]3C4</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com3tag:blogger.com,1999:blog-1346483141860457136.post-81609867119928161792016-07-27T21:01:00.001-07:002016-07-28T00:02:51.596-07:00SPIRONOLACTONE, спиронолактон , سبيرونولاكتون , 螺内酯 ,<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Skeletal formula of spironolactone" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/98/Spironolactone.svg/220px-Spironolactone.svg.png" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/98/Spironolactone.svg/220px-Spironolactone.svg.png" style="height: auto; max-width: 100%;" /></div>
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Spironolactone</div>
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Spironolactone, <strong>Supra-puren, </strong><strong>Suracton, </strong><strong>спиронолактон, </strong><strong>سبيرونولاكتون</strong> ,</div>
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<strong>螺内酯</strong> , <span class="synonym_confirmed">Abbolactone, </span><span class="synonym_confirmed">Aldactide, </span><span class="synonym_confirmed">SNL, </span><span class="synonym_confirmed">Spiroctanie, </span><span class="synonym_confirmed">Sprioderm, </span><span class="synonym_confirmed">Verospirone, Opianin</span></div>
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7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone</div>
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(1'S,2R,2'R,9'R,10'<wbr></wbr>R,11'S,15'S)-9'-(ac<wbr></wbr>etylsulfanyl)-2',15<wbr></wbr>'-dimethylspiro[oxo<wbr></wbr>lane-2,14'-tetracyc<wbr></wbr>lo[8.7.0.0<sup>2,7</sup>.0<sup>11,15</sup>]heptadecan]-6'-ene-5,5'-dione</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>(7a,17a)-7-(Acetylt<wbr></wbr>hio)-17-hydroxy-3-o<wbr></wbr>xopregn-4-ene-21-ca<wbr></wbr>rboxylic acid g-lac<wbr></wbr>tone</strong></div>
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<strong>17-Hydroxy-7a-merca<wbr></wbr>pto-3-oxo-17a-pregn<wbr></wbr>-4-ene-21-carboxyli<wbr></wbr>c Acid g-Lactone Ac<wbr></wbr>etate</strong></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>3-(3-Oxo-7a-acetylt<wbr></wbr>hio-17b-hydroxy-4-a<wbr></wbr>ndrosten-17a-yl)pro<wbr></wbr>pionic Acid g-Lacto<wbr></wbr>ne</strong></div>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"> CAS <a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=52-01-7" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=52-01-7" rel="nofollow">52-01-7</a></span></td></tr>
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<span class="prop_title">MF </span><span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_prop_MF">C<sub>24</sub>H<sub>32</sub>O<sub>4</sub>S, </span><span class="prop_title">MW </span>416.573 Da</div>
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<b><img alt="ChemSpider 2D Image | spironolactone | C24H32O4S" data-mce-src="http://www.chemspider.com/ImagesHandler.ashx?id=5628&w=250&h=250" src="http://www.chemspider.com/ImagesHandler.ashx?id=5628&w=250&h=250" style="height: auto; max-width: 100%;" />Spironolactone</b>, marketed under the brand name <b>Aldactone</b> among others, is a medication primarily used to treat<a data-mce-href="https://en.wikipedia.org/wiki/Edema" href="https://en.wikipedia.org/wiki/Edema" title="Edema">fluid build-up</a> due to <a data-mce-href="https://en.wikipedia.org/wiki/Heart_failure" href="https://en.wikipedia.org/wiki/Heart_failure" title="Heart failure">heart failure</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Hepatic_cirrhosis" href="https://en.wikipedia.org/wiki/Hepatic_cirrhosis" title="Hepatic cirrhosis">liver scarring</a>, or <a data-mce-href="https://en.wikipedia.org/wiki/Kidney_disease" href="https://en.wikipedia.org/wiki/Kidney_disease" title="Kidney disease">kidney disease</a>.<sup class="reference" id="cite_ref-AHFS2015_1-1"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1">[1]</a></sup> Other uses include <a data-mce-href="https://en.wikipedia.org/wiki/Hypertension" href="https://en.wikipedia.org/wiki/Hypertension" title="Hypertension">high blood pressure</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Hypokalemia" href="https://en.wikipedia.org/wiki/Hypokalemia" title="Hypokalemia">low blood potassium</a> that does not improve with supplementation, <a data-mce-href="https://en.wikipedia.org/wiki/Precocious_puberty" href="https://en.wikipedia.org/wiki/Precocious_puberty" title="Precocious puberty">early puberty</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Hirsutism" href="https://en.wikipedia.org/wiki/Hirsutism" title="Hirsutism">excessive hair growth</a> in women,<sup class="reference" id="cite_ref-AHFS2015_1-2"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1">[1]</a></sup> and as a component of <a data-mce-href="https://en.wikipedia.org/wiki/Hormone_replacement_therapy" href="https://en.wikipedia.org/wiki/Hormone_replacement_therapy" title="Hormone replacement therapy">hormone replacement therapy</a> for <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Transgender_women" href="https://en.wikipedia.org/wiki/Transgender_women" title="Transgender women">transgender women</a>.<sup class="reference" id="cite_ref-6"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-6" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-6">[6]</a></sup> It is taken by mouth.<sup class="reference" id="cite_ref-AHFS2015_1-3"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1">[1]</a></sup></div>
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Common side effects include <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Electrolyte_abnormalities" href="https://en.wikipedia.org/wiki/Electrolyte_abnormalities" title="Electrolyte abnormalities">electrolyte abnormalities</a> particularly <a data-mce-href="https://en.wikipedia.org/wiki/Hyperkalemia" href="https://en.wikipedia.org/wiki/Hyperkalemia" title="Hyperkalemia">high blood potassium</a>, nausea, vomiting, headache, a rash, and a decreased desire for sex. In those with liver or kidney problems extra care should be taken.<sup class="reference" id="cite_ref-AHFS2015_1-4"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1">[1]</a></sup>Spironolactone has not been well studied in pregnancy and should not be used to treat <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/High_blood_pressure_of_pregnancy" href="https://en.wikipedia.org/wiki/High_blood_pressure_of_pregnancy" title="High blood pressure of pregnancy">high blood pressure of pregnancy</a>.<sup class="reference" id="cite_ref-7"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-7" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-7">[7]</a></sup> It is a <a data-mce-href="https://en.wikipedia.org/wiki/Steroid" href="https://en.wikipedia.org/wiki/Steroid" title="Steroid">steroid</a> that <a data-mce-href="https://en.wikipedia.org/wiki/Antimineralocorticoid" href="https://en.wikipedia.org/wiki/Antimineralocorticoid" title="Antimineralocorticoid">blocks mineralocorticoid receptors</a>. It also <a data-mce-href="https://en.wikipedia.org/wiki/Antiandrogen" href="https://en.wikipedia.org/wiki/Antiandrogen" title="Antiandrogen">blocks androgen</a>, and <a data-mce-href="https://en.wikipedia.org/wiki/Progestogen" href="https://en.wikipedia.org/wiki/Progestogen" title="Progestogen">blocks progesterone</a>. It belongs to a class of medications known as <a data-mce-href="https://en.wikipedia.org/wiki/Potassium-sparing_diuretic" href="https://en.wikipedia.org/wiki/Potassium-sparing_diuretic" title="Potassium-sparing diuretic">potassium-sparing diuretics</a>.<sup class="reference" id="cite_ref-AHFS2015_1-5"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1">[1]</a></sup></div>
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Spironolactone was introduced in 1959.<sup class="reference" id="cite_ref-Wermuth2008_8-0"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-Wermuth2008-8" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-Wermuth2008-8">[8]</a></sup><sup class="reference" id="cite_ref-Sittig1988_9-0"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-Sittig1988-9" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-Sittig1988-9">[9]</a></sup> It is on the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/World_Health_Organization%27s_List_of_Essential_Medicines" href="https://en.wikipedia.org/wiki/World_Health_Organization%27s_List_of_Essential_Medicines" title="World Health Organization's List of Essential Medicines">World Health Organization's List of Essential Medicines</a>, the most important medications needed in a basic <a data-mce-href="https://en.wikipedia.org/wiki/Health_system" href="https://en.wikipedia.org/wiki/Health_system" title="Health system">health system</a>.<sup class="reference" id="cite_ref-10"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-10" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-10">[10]</a></sup> It is available as a <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Generic_medication" href="https://en.wikipedia.org/wiki/Generic_medication" title="Generic medication">generic medication</a>.<sup class="reference" id="cite_ref-AHFS2015_1-6"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1">[1]</a></sup> The wholesale cost in the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Developing_world" href="https://en.wikipedia.org/wiki/Developing_world" title="Developing world">developing world</a> as of 2014 is between 0.02 and 0.12 USD per day.<sup class="reference" id="cite_ref-11"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-11" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-11">[11]</a></sup> In the United States it costs about 0.50 USD per day.<sup class="reference" id="cite_ref-AHFS2015_1-7"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1">[1]</a></sup></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Title:</b> Spironolactone</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>CAS Registry Number:</b> 52-01-7</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>CAS Name:</b> (7</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">,17</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">)-7-(Acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid </span><span style="font-family: Symbol; font-size: 13px;">g</span><span style="font-family: Arial; font-size: 13px;">-lactone</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Additional Names:</b> 17-hydroxy-7</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">-mercapto-3-oxo-17</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">-pregn-4-ene-21-carboxylic acid </span><span style="font-family: Symbol; font-size: 13px;">g</span><span style="font-family: Arial; font-size: 13px;">-lactone, acetate; 3-(3-oxo-7</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">-acetylthio-17</span><span style="font-family: Symbol; font-size: 13px;">b</span><span style="font-family: Arial; font-size: 13px;">-hydroxy-4-androsten-17</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">-yl)propionic acid </span><span style="font-family: Symbol; font-size: 13px;">g</span><span style="font-family: Arial; font-size: 13px;">-lactone</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Manufacturers' Codes:</b> SC-9420</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Trademarks:</b> Aldactone (Pharmacia & Upjohn); Aquareduct (Azupharma); Practon (Pfizer); Osyrol (Aventis); Sincomen (Schering AG); Spirobeta (Betapharm); Spiroctan (Ferlux); Spirolone (APS); Spironone (Dexo); Verospiron (Richter Gedeon); Xenalon (Mepha)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Molecular Formula:</b> C</span><span style="font-family: Arial; font-size: 11px;">24</span><span style="font-family: Arial; font-size: 13px;">H</span><span style="font-family: Arial; font-size: 11px;">32</span><span style="font-family: Arial; font-size: 13px;">O</span><span style="font-family: Arial; font-size: 11px;">4</span><span style="font-family: Arial; font-size: 13px;">S</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Molecular Weight:</b> 416.57</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Percent Composition:</b> C 69.20%, H 7.74%, O 15.36%, S 7.70%</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Literature References:</b> Aldosterone antagonist. Prepn: Cella, Tweit, <i>J. Org. Chem.</i> <b>24,</b> 1109 (1959); <b>US</b> <b>3013012</b> (1961 to Searle); Tweit <i>et al.,</i> <i>J. Org. Chem.</i> <b>27,</b> 3325 (1962). Activity and metabolic studies: Gerhards, Engelhardt, <i>Arzneim.-Forsch.</i> <b>13,</b> 972 (1963). Crystal and molecular structure: Dideberg, Dupont, <i>Acta Crystallogr.</i> <b>B28,</b> 3014 (1972). Comprehensive description: J. L. Sutter, E. P. K. Lau, <i>Anal. Profiles Drug Subs.</i> <b>4,</b> 431-451 (1975). Review of carcinogenetic risk: <i>IARC Monographs</i> <b>24,</b> 259-273 (1980). Review of antiandrogen effects and clinical use in hirsutism: R. R. Tremblay, <i>Clin. Endocrinol. Metab.</i> <b>15,</b> 363-371 (1986); of clinical efficacy in hypertension: A. N. Brest, <i>Clin. Ther.</i> <b>8,</b> 568-585 (1986). Review of pharmacology: H. A. Skluth, J. G. Gums,<i>DICP Ann. Pharmacother.</i> <b>24,</b> 52-59 (1990). Clinical trial in congestive heart failure: B. Pitt <i>et al.,</i> <i>N. Engl. J. Med.</i> <b>341,</b> 709 (1999).</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Properties:</b> Crystals from methanol, mp 134-135° (resolidifies and dec 201-202°). [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D20</span><span style="font-family: Arial; font-size: 13px;"> -33.5° (chloroform). uv max: 238 nm (</span><span style="font-family: Symbol; font-size: 13px;">e</span><span style="font-family: Arial; font-size: 13px;">20200). Practically insol in water. Sol in alcohol; freely sol in benzene, chloroform. LD</span><span style="font-family: Arial; font-size: 11px;">50</span><span style="font-family: Arial; font-size: 13px;"> in rats, mice, rabbits (mg/kg): 790, 360, 870 i.p. (IARC, 1980).</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Melting point:</b> mp 134-135° (resolidifies and dec 201-202°)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Optical Rotation:</b> [</span><span style="font-family: Symbol; font-size: 13px;">a</span><span style="font-family: Arial; font-size: 13px;">]</span><span style="font-family: Arial; font-size: 11px;">D20</span><span style="font-family: Arial; font-size: 13px;"> -33.5° (chloroform)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Absorption maximum:</b> uv max: 238 nm (</span><span style="font-family: Symbol; font-size: 13px;">e</span><span style="font-family: Arial; font-size: 13px;"> 20200)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Toxicity data:</b> LD</span><span style="font-family: Arial; font-size: 11px;">50</span><span style="font-family: Arial; font-size: 13px;"> in rats, mice, rabbits (mg/kg): 790, 360, 870 i.p. (IARC, 1980)</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Therap-Cat:</b> Diuretic.</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Therap-Cat-Vet:</b> Diuretic.</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Keywords:</b> Aldosterone Antagonist; Diuretic; Steroids</span></div>
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<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Medical_uses">Medical uses</span></h2>
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Spironolactone is used primarily to treat <a data-mce-href="https://en.wikipedia.org/wiki/Heart_failure" href="https://en.wikipedia.org/wiki/Heart_failure" title="Heart failure">heart failure</a>, edematous conditions such as <a data-mce-href="https://en.wikipedia.org/wiki/Nephrotic_syndrome" href="https://en.wikipedia.org/wiki/Nephrotic_syndrome" title="Nephrotic syndrome">nephrotic syndrome</a> or <a data-mce-href="https://en.wikipedia.org/wiki/Ascites" href="https://en.wikipedia.org/wiki/Ascites" title="Ascites">ascites</a> in people with liver disease, essential <a data-mce-href="https://en.wikipedia.org/wiki/Hypertension" href="https://en.wikipedia.org/wiki/Hypertension" title="Hypertension">hypertension</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Hypokalemia" href="https://en.wikipedia.org/wiki/Hypokalemia" title="Hypokalemia">hypokalemia</a>, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Conn%27s_syndrome" href="https://en.wikipedia.org/wiki/Conn%27s_syndrome" title="Conn's syndrome">Conn's syndrome</a> (primary hyperaldosteronism). On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy.</div>
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Spironolactone is an <a data-mce-href="https://en.wikipedia.org/wiki/Receptor_antagonist" href="https://en.wikipedia.org/wiki/Receptor_antagonist" title="Receptor antagonist">antagonist</a> of the <a data-mce-href="https://en.wikipedia.org/wiki/Androgen_receptor" href="https://en.wikipedia.org/wiki/Androgen_receptor" title="Androgen receptor">androgen receptor</a> (AR) as well as an <a data-mce-href="https://en.wikipedia.org/wiki/Enzyme_inhibitor" href="https://en.wikipedia.org/wiki/Enzyme_inhibitor" title="Enzyme inhibitor">inhibitor</a> of <a data-mce-href="https://en.wikipedia.org/wiki/Androgen" href="https://en.wikipedia.org/wiki/Androgen" title="Androgen">androgen</a> <a data-mce-href="https://en.wikipedia.org/wiki/Biosynthesis" href="https://en.wikipedia.org/wiki/Biosynthesis" title="Biosynthesis">production</a>. Due to the antiandrogenic effects that result from these actions, it is frequently used off-label to treat a variety of dermatological conditions in which androgens, such as <a data-mce-href="https://en.wikipedia.org/wiki/Testosterone" href="https://en.wikipedia.org/wiki/Testosterone" title="Testosterone">testosterone</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Dihydrotestosterone" href="https://en.wikipedia.org/wiki/Dihydrotestosterone" title="Dihydrotestosterone">dihydrotestosterone</a> (DHT), play a role. Some of these uses include <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Androgenic_alopecia" href="https://en.wikipedia.org/wiki/Androgenic_alopecia" title="Androgenic alopecia">androgenic alopecia</a> in men (either at low doses or as a <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Topical" href="https://en.wikipedia.org/wiki/Topical" title="Topical">topical</a> <a data-mce-href="https://en.wikipedia.org/wiki/Pharmaceutical_formulation" href="https://en.wikipedia.org/wiki/Pharmaceutical_formulation" title="Pharmaceutical formulation">formulation</a>) and women, and <a data-mce-href="https://en.wikipedia.org/wiki/Hirsutism" href="https://en.wikipedia.org/wiki/Hirsutism" title="Hirsutism">hirsutism</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Acne" href="https://en.wikipedia.org/wiki/Acne" title="Acne">acne</a>, and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Seborrhea" href="https://en.wikipedia.org/wiki/Seborrhea" title="Seborrhea">seborrhea</a> in women.<sup class="reference" id="cite_ref-pmid2969259_12-0"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-pmid2969259-12" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-pmid2969259-12">[12]</a></sup> Spironolactone is the most commonly used drug in the treatment of hirsutism in the <a data-mce-href="https://en.wikipedia.org/wiki/United_States" href="https://en.wikipedia.org/wiki/United_States" title="United States">United States</a>.<sup class="reference" id="cite_ref-Preedy2012_13-0"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-Preedy2012-13" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-Preedy2012-13">[13]</a></sup> Higher doses of spironolactone are not recommended in males due to the high risk of <a data-mce-href="https://en.wikipedia.org/wiki/Feminization_(biology)" href="https://en.wikipedia.org/wiki/Feminization_(biology)" title="Feminization (biology)">feminization</a> and other side effects. Similarly, it is also commonly used to treat <a data-mce-href="https://en.wikipedia.org/wiki/Symptom" href="https://en.wikipedia.org/wiki/Symptom" title="Symptom">symptoms</a> of <a data-mce-href="https://en.wikipedia.org/wiki/Hyperandrogenism" href="https://en.wikipedia.org/wiki/Hyperandrogenism" title="Hyperandrogenism">hyperandrogenism</a> in <a data-mce-href="https://en.wikipedia.org/wiki/Polycystic_ovary_syndrome" href="https://en.wikipedia.org/wiki/Polycystic_ovary_syndrome" title="Polycystic ovary syndrome">polycystic ovary syndrome</a>.<sup class="reference" id="cite_ref-pmid3143568_14-0"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-pmid3143568-14" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-pmid3143568-14">[14]</a></sup></div>
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Spironolactone (SL) is known to be a potent aldosterone antagonist at mineralocorticoid steroid hormone receptors, and it is widely used in humans for the treatment of essential hypertension, congestive heat failure and refractory edema or hyperaldosteronism. However, the prolonged use of SL is associated with undesirable endocrine side effects such as gynecomastia and lose of libido in men and menstrual irregularities in women due to interaction of SL with gonadal steroid hormone biosynthesis and target cell gonadal steroid receptors.</div>
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The nature and prevalence of the undesirable side effects limit the usefulness of spironolactone as a therapeutic agent. Gynecomastia or tender breast enlargement has been found to occur in 10% of hypertensive patients using spironolactone for therapy as compared to 1% of men in the placebo group. Recent studies by Pitt, et al. with spironolactone have shown that in patients with congestive heart failure (CHF) taking digoxin and a loop diuretic—spironolactone therapy in conjunction with digitalis and ACE inhibitor—reduces mortality by 30%. See Pitt, B., et al., <i>The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure, </i>Randomized Aldactone Evaluation Study Investigors; N. Engl. J. Med., 1999, 341:709-717. These authors stated that the 30% reduction in the risk of death among patients in the group receiving spironolactone could be attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac arrhythmic causes. In addition, they found that the frequency of hospitalization for worsening heart failure is 35% lower in the spironolacotone treated group than in the placebo group. These authors concluded that patients who received spironolactone had a significant improvement in the symptoms of severe heart failure caused by systolic left ventricular dysfunction. Overall, 8% of the patients in the spironolactone group discontinued treatment because of adverse events. The purpose of the present invention is to make available the individual chiral isomers of spironolactone that would be effective in treating CHF and in reducing hypertension, and at the same time would be devoid of undesirable side effects such as gynecomastia, lose of libido in men, and menstrual irregularities in women.</div>
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Spironolactone is the name commonly used for a specific spirolactone that has the full chemical name 17-hydroxy-7-alpha-mercapto-3-oxo-17-alpha-pregn-4-ene-21-carboxylic acid gamma-lactone acetate. The term “spirolactone” denotes that a lactone 10 ring (i.e., a cyclic ester) is attached to another ring structure in a spiro configuration (i.e., the lactone ring shares a single carbon atom with the other ring). Spirolactones that are coupled to steroids are the most important class of spirolactones from a pharmaceutical perspective, so they are widely referred to in the pharmaceutical arts simply as spirolactones. As used herein, “spironolactone” refers to a molecule comprising a lactone structure coupled via a spiro configuration to a steroid structure or steroid derivative.</div>
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Spironolactone, its activities, and modes of synthesis and purification are described in a number of U.S. patents, notably U.S. Pat. Nos. 3,013,012, 4,529,811 and 4,603,128.</div>
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Intracellular receptors (IRs) form a class of structurally-related genetic regulators that act as ligand-dependent transcription factors. See Evans, R. M., “The Steroid and Thyroid Hormone Receptor Superfamily”, <i>Science, </i>May 13, 1988; 240(4854):889-95. Steroid receptors are a recognized subset of the IRs, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), which can be referred to collectively as the gonadal steroid receptors, glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand that has the ability to selectively bind to the IR in a way that affects gene transcription.</div>
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Ligands for the IRs can include low molecular weight native molecules, such as the hormones aldosterone, progesterone, estrogen and testosterone, as well as synthetic derivative compounds such as medroxyprogesterone acetate, diethylstilbesterol and 19-nortestosterone. These ligands, when present the fluid surrounding a cell, pass through the outer cell membrane by passive diffusion and bind to specific IR proteins to create a ligand/receptor complex. This complex then translocates to the cell's nucleus, where it binds to a specific gene or genes present in the cell's DNA. Once bound to DNA, the complex modulates the production of the protein encoded by that gene. In this regard, a compound that binds to an IR and mimics the effect of the native ligand is referred to as an “agonist”, while a compound that binds to an IR and inhibits the effect of the native ligand is called an “antagonist”.</div>
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The therapeutic mechanism of action of spironolactone involves binding to intracellular mineralocorticoid receptors (MRs) in kidney epithelial cells, thereby inhibiting the binding of aldosterone. Spironolactone has been found to counteract the sodium reabsorption and potassium excretion effects of aldosterone and other mineralocorticoids. Spironolactone has also been shown to interfere with testosterone biosynthesis, has anti-androgen action and inhibits adrenal aldosterone biosynthesis. Large doses of spironolactone in children appear to decrease the testosterone production rate.</div>
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Spironolactone is found to exhibit intra-individual variability of pharmacokinetic parameters and it presumably belongs to the group of drugs with high inter-subject variability. Spironolactone has poor water solubility and dissolution rate.</div>
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In order to prolong the half-life and decrease the side effects associated with spironolactone, syntheses of spironolactone derivatives have been developed (e.g. synthesis of mexrenone, prorenone, spirorenone). Slight modifications of the spironolactone steroid skeleton, e.g. such as formation of 11β-allenic and epoxy compounds, have been shown to effect important variations in the affinity and specificity for the mineralocorticoid receptor. These results suggest that it is possible to develop spironolactone analogues that do not interact with the androgen receptor or cytochrome P-450 and are therefore free of spironolactone undesirable side-effects.</div>
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METABOLISM</div>
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<img alt="Figure US20090325918A1-20091231-C00003" data-mce-src="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00003.png" src="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00003.png" style="height: auto; max-width: 100%;" /></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">SYNTHESIS</span></h1>
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METHOD 1 REF 150</div>
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REF 130, 150</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-128.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-128.jpg" rel="attachment wp-att-7912"><img alt="STR1" class="alignnone wp-image-7912" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-128.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-128.jpg" height="328" style="height: auto; max-width: 100%;" width="887" /></a></div>
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METHOD 2 REF 140</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-125.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-125.jpg" rel="attachment wp-att-7909"><img alt="STR1" class="alignnone wp-image-7909" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-125.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-125.jpg" height="684" style="height: auto; max-width: 100%;" width="904" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-126.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-126.jpg" rel="attachment wp-att-7910"><img alt="STR1" class="alignnone wp-image-7910" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-126.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-126.jpg" height="762" style="height: auto; max-width: 100%;" width="872" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-129.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-129.jpg" rel="attachment wp-att-7913"><img alt="STR1" class="alignnone wp-image-7913" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-129.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-129.jpg" height="320" style="height: auto; max-width: 100%;" width="892" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
METHOD 3 REF 150</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-127.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-127.jpg" rel="attachment wp-att-7911"><img alt="STR1" class="alignnone wp-image-7911" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-127.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-127.jpg" height="968" style="height: auto; max-width: 100%;" width="862" /></a></div>
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<br /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Synthesis</em></span></strong></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<cite class="" id="CITEREFCellaTweit1959">Cella, John A.; Tweit, Robert C. (1959). <i>Journal of Organic Chemistry</i> <b>24</b>: 1109. <a data-mce-href="http://wikidraft.referata.com/wiki/Digital_object_identifier" href="http://wikidraft.referata.com/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<span class="neverexpand"><a class="external text" data-mce-href="http://dx.doi.org/10.1021%2Fjo01090a019" href="http://dx.doi.org/10.1021%2Fjo01090a019" rel="nofollow">10.1021/jo01090a019</a></span>.</cite></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(See also part 1 and part 3)</div>
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<br /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="http://upload.wikimedia.org/wikipedia/commons/thumb/6/68/Spironolactone_synth.png/800px-Spironolactone_synth.png" src="http://upload.wikimedia.org/wikipedia/commons/thumb/6/68/Spironolactone_synth.png/800px-Spironolactone_synth.png" style="height: auto; max-width: 100%;" /></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">SPEC</span><span data-mce-style="color: #ff0000;" style="color: red;">TROSCOPY UV</span></h1>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;"><a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-130.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-130.jpg" rel="attachment wp-att-7914"><img alt="STR1" class="alignnone size-full wp-image-7914" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-130.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-130.jpg" height="566" style="height: auto; max-width: 100%;" width="419" /></a></span></h1>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">SPEC</span><span data-mce-style="color: #ff0000;" style="color: red;">TROSCOPY IR</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
KBR</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The principal absorption peaks of the spectrum shown in Figure 5 were noted at 1765,<br />
1693, 1673, 1240, 1178, 1135, 1123 and 1193 cm -1.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-131.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-131.jpg" rel="attachment wp-att-7915"><img alt="STR1" class="alignnone size-full wp-image-7915" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-131.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-131.jpg" height="422" style="height: auto; max-width: 100%;" width="425" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">SPEC</span><span data-mce-style="color: #ff0000;" style="color: red;">TROSCOPY 1H NMR</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-132.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-132.jpg" rel="attachment wp-att-7916"><img alt="STR1" class="alignnone size-full wp-image-7916" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-132.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-132.jpg" height="587" style="height: auto; max-width: 100%;" width="660" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-133.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-133.jpg" rel="attachment wp-att-7917"><img alt="STR1" class="alignnone size-full wp-image-7917" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-133.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-133.jpg" height="518" style="height: auto; max-width: 100%;" width="416" /></a></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">SPEC</span><span data-mce-style="color: #ff0000;" style="color: red;">TROSCOPY 13C NMR</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-134.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-134.jpg" rel="attachment wp-att-7918"><img alt="STR1" class="alignnone size-full wp-image-7918" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-134.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-134.jpg" height="590" style="height: auto; max-width: 100%;" width="552" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-135.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-135.jpg" rel="attachment wp-att-7919"><img alt="STR1" class="alignnone size-full wp-image-7919" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-135.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-135.jpg" height="510" style="height: auto; max-width: 100%;" width="447" /></a></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">SPEC</span><span data-mce-style="color: #ff0000;" style="color: red;">TROSCOPY MASS SPECTRUM</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-136.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-136.jpg" rel="attachment wp-att-7920"><img alt="STR1" class="alignnone size-full wp-image-7920" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-136.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-136.jpg" height="617" style="height: auto; max-width: 100%;" width="658" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-137.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-137.jpg" rel="attachment wp-att-7921"><img alt="STR1" class="alignnone size-full wp-image-7921" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-137.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-137.jpg" height="478" style="height: auto; max-width: 100%;" width="433" /></a><a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-138.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-138.jpg" rel="attachment wp-att-7922"><img alt="STR1" class="alignnone size-full wp-image-7922" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-138.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-138.jpg" height="370" style="height: auto; max-width: 100%;" width="400" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong><em><span data-mce-style="color: #000080;" style="color: navy;">130 J.A. Cola, E.A. Brown, and R.R. Burtner, 3. Org. Chem., 24, 1109(1959).</span></em></strong></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong><em><span data-mce-style="color: #000080;" style="color: navy;"> 140 Remington's: The Science and Practice of Pharmacy, 19 t~ edn.Volume II, K.G. Alfonso, ed.; Mack Publishing Co., Pennsylvania </span></em></strong><strong><em><span data-mce-style="color: #000080;" style="color: navy;">(1995) p.1048.</span></em></strong><br />
<strong><em><span data-mce-style="color: #000080;" style="color: navy;">150. G. Anner and H. Wehrli (Ciba-Geigy, A.-G.), German Often 2,625,723 (cl.C07J21/00), Dec,1976; Swiss Appl. 75/7, 696, 13</span></em></strong><strong><em><span data-mce-style="color: #000080;" style="color: navy;">Jun. 1975; pp. 37.</span></em></strong></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
ANALYTICAL</h2>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">
<li><div class="description-line" id="p-0025">
<table class="description-table mce-item-table" frame="none" style="border: 1px dashed rgb(187, 187, 187);"><thead>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">High-Performance Liquid Chromatographic Conditions</td></tr>
</thead><tbody valign="top">
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Column</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">LiChrosorb RP-8, 5 μm. 150 × 4.6 mm I.D.</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Eluent</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Acetonitrile-0.05 M phosphate buffer, pH 4 (45:55)</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Flow-rate</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1 ml/min</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Temperature</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">25° C.</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Detector</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">UV detector, wavelength 286 nm or 271 nm</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Recorder</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chart speed 0.5 cm/min</td></tr>
<tr class="description-tr"><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sample loop</td><td class="description-td" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10 μl</td></tr>
</tbody></table>
</div>
</li>
<li><div class="description-line-number">
The concentration of canrenone is determined in plasma and urine samples by high-performance liquid chromatography (HPLC) with UV-detection. An aliquot of 300 ng of spironolactone derivative is added to the samples as internal standard, which are then extracted twice with 1 ml n-hexane-toluene (1:1, v/v). The organic phase is taken to dryness and re-dissolved in 250 μl HPLC eluent (methanol-water, 60:40, v/v). (25×4.6 mm; 5 μm). Detection is performed with the UV detector set at λ=285 nm.</div>
</li>
</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Flurometric Method</div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">Five ml of water is a reagent blank and 5 ml of working standards containing 0.05 μg and 0.20 μg of SC-9376 are carried through the entire procedure. Lower sales are read vs. the 0.05 μg standard at full scale, and higher samples vs. the 0.20 μg standard. Fluorescence readings are proportional to the concentrations of the standards in this range.</ul>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">Pipette 0.2 ml of heparinized plasma into a 50-ml polyethylene-stoppered centrifuge tube, dilute to 5 ml with water and add 15 ml of methylene chloride (Du Pont refrigeration grade, redistilled). Shake for 30 seconds, centrifuge and discard the aqueous supernatant. Add 1 ml 0.1 N NaOH, shake 15 seconds, centrifuge and discard the supernatant. Transfer a 10-ml aliquot of the methylene chloride phase to another tube containing 2 ml of 65% aqueous sulfuric acid, shake 30 seconds, centrifuge and remove organic phase by aspiration. The material is allowed to stand at room temperature for about 1 hour and then about 1 ml of the sulfuric acid phase in transferred to a quartz cuvette. Fluorescence intensity is determined in an Aminco-Bowman spectrophotofluorometer (activation maximum, 465 nm).</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">Gas Liquid Chromatography</ul>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">The GLC estimation is carried out on a Fractovap Model 251 series 2150 (Carlo Erba) instrument equipped with a Nickel-63 electron capture detector. A 6-foot, 0.4 mm internal diameter, U-shaped glass column, packed with OV-17 2% or XE-60 1% on gas chrom A, 100-120 mesh (Applied Science Lab) is conditioned for 3 days before use. Argon with 10% methane which passed through a molecular sieve before entering the column is used as the carrier gas. The conditions of analysis are: column 255° C., detector 275° C., carrier gas flow 30 ml/min. Samples are injected on the column with a 10 μl Hamilton syringe. The injector in not heated.</ul>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
</h2>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
PATENT</h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/US20090325918" href="https://www.google.com/patents/US20090325918">https://www.google.com/patents/US20090325918</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
EXAMPLE 1Chiral Separation</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The separation of 7 beta isomer of SL is schematically described below.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">
<li><div class="description-line" id="p-0031">
<div class="patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00004.png" href="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00004.png"><img alt="Figure US20090325918A1-20091231-C00004" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00004.png" height="337" id="EMI-C00004" src="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00004.png" style="height: auto; max-width: 100%;" width="512" /></a></div>
<div class="patent-image">
Chromatographic Method for Isolation of SL Isomers</div>
<div class="patent-image">
The basic method is described in Chan, Ky, et al., <i>J. Chromatog, </i>Nov. 15, 1991:571 (1-2) 291-297. The separation is performed using spectra-physics HPLC instrument and UV variable wavelength detector set at 254 nm. For chiral separation, the chromatographic column is either a pre-packed 25 mm×4.6 mm ID Cyclobond 1 (5 μm particle size), or a pre-packed 150 mm×4 mm ID Resolvosil BSA-7 column (5 μm) operated using the conditions described herein.</div>
<div class="patent-image">
Analysis of the isomers present in the peaks in the chromatograms and their chiral extract purity analysis can be determined in each case by high resolution NMR spectroscopy using a chiral shift reagent. Based on this information and the determination of molecular weight by mass spectrometry and/or optical activity, structural configuration is assigned to each isomer. Eluted samples of isomers may be re-chromatographed in order to obtain adequate quantities of isomers having desired optical purity for study. For future use, reference standards that are optically pure will be compared for confirmation of purity and identity to the isolated isomers that are obtained after their chromatographic separation.</div>
</div>
</li>
</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
EXAMPLE 2Chemical Synthesis of Optical Isomers</div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">As an example, the desire spironolactone 7-beta-isomer is synthesized following the scheme that is described below:</ul>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">
<li><div class="description-line" id="p-0035">
<div class="patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00005.png" href="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00005.png"><img alt="Figure US20090325918A1-20091231-C00005" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00005.png" height="449" id="EMI-C00005" src="https://patentimages.storage.googleapis.com/US20090325918A1/US20090325918A1-20091231-C00005.png" style="height: auto; max-width: 100%;" width="470" /></a></div>
<div class="patent-image">
Diene (i) is prepared from commercially available starting materials using methods well known in the art of chemical synthesis.</div>
</div>
<div class="description-line-number">
Diene (i) is treated with acetic acid and the mixture is heated to reflux to yield 7-alpha-acetate ester (ii). The 7-alpha-ester (ii) is further subjected to nucleophilic substitution, followed by hydrolysis to obtain the 7-beta-isomer (iii). The 7-beta-isomer (iii) is then esterified with an acyl halide in the presence of a base to generate the desired spironolactone 7-beta-isomer (iv).</div>
</li>
</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
EXAMPLE 3Preparation of Radiolabeled Probe Compounds of the Invention</div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">Using known methods, the compounds of the invention may be prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from at least one of carbon (preferably</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sup>14</sup></div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">C), hydrogen (preferably</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sup>3</sup></div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">H), sulfur (preferably</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sup>35</sup></div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">S), or iodine (preferably I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in customer synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc., Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.</ul>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Tritium labeled probe compounds can also be prepared, when appropriate, by sodium borotritide reduction. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate.</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">EXAMPLE 4Isolation and Purification Procedure</ul>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">The optical isomers of spironolactones may be isolated from fluid sample such as urine or blood as follows:</ul>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">Extraction from Urine</ul>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">The urine sample is extracted with dichloromethane and the extract washed with NaOH (0.1 N) and then with water to neutrality. The residue obtained after evaporation of the dichloromethane extract is purified on TLC in three different systems: benzene-acetone-water, (150:100:0.4); chloroform-ethanol, (90:10); ethyl acetate-cyclohexane-ethanol, (45:25:10), using aldosterone as reference standard.</ul>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><ul class="description" lang="EN">The extract is then purified by high performance liquid chromatography (HPLC) on a Waters 6000 A, 480 U.V. detector instrument with radial pressure. The extract is first run through a C</ul>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sub>18</sub></div>
<ul class="description" lang="EN" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">10μ column using methanol-water (70:30) as the eluent, followed by a silica 5μ column using dichloromethane-methanol (95:5). In both cases, the rate of the eluent is 1.5 ml/min. A small part of the extract is subjected to heptafluorobutyrylation for GLC investigation.</ul>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist references-column-width" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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<li id="cite_note-SpironolactoneMedlinePlus-2"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682627.html" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682627.html" rel="nofollow">"Spironolactone: MedlinePlus Drug Information"</a><span class="reference-accessdate">. Retrieved <span class="nowrap">2016-01-20</span></span>.</cite></span></li>
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<li id="cite_note-Brittain2002-5"> <span class="reference-text"><cite class="citation book">Harry G. Brittain (26 November 2002). <a class="external text" data-mce-href="http://books.google.com/books?id=RMN5zMW64ZEC&pg=PA309" href="http://books.google.com/books?id=RMN5zMW64ZEC&pg=PA309" rel="nofollow"><i>Analytical Profiles of Drug Substances and Excipients</i></a>. Academic Press. p. 309. <a data-mce-href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a data-mce-href="https://en.wikipedia.org/wiki/Special:BookSources/978-0-12-260829-2" href="https://en.wikipedia.org/wiki/Special:BookSources/978-0-12-260829-2" title="Special:BookSources/978-0-12-260829-2">978-0-12-260829-2</a><span class="reference-accessdate">. Retrieved <span class="nowrap">27 May</span> 2012</span>.</cite></span></li>
<li id="cite_note-6"> <span class="reference-text"><cite class="citation book">Maizes, Victoria (2015). <a class="external text" data-mce-href="https://books.google.ca/books?id=uveJCgAAQBAJ&pg=PA746" href="https://books.google.ca/books?id=uveJCgAAQBAJ&pg=PA746" rel="nofollow"><i>Integrative Women's Health</i></a> (2 ed.). p. 746.<a data-mce-href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a data-mce-href="https://en.wikipedia.org/wiki/Special:BookSources/9780190214807" href="https://en.wikipedia.org/wiki/Special:BookSources/9780190214807" title="Special:BookSources/9780190214807">9780190214807</a>.</cite></span></li>
<li id="cite_note-7"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.drugs.com/pregnancy/spironolactone.html" href="http://www.drugs.com/pregnancy/spironolactone.html" rel="nofollow">"Spironolactone Pregnancy and Breastfeeding Warnings"</a><span class="reference-accessdate">. Retrieved <span class="nowrap">29 November</span>2015</span>.</cite></span></li>
<li id="cite_note-Wermuth2008-8"> <span class="reference-text"><cite class="citation book">Camille Georges Wermuth (24 July 2008). <a class="external text" data-mce-href="http://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34" href="http://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34" rel="nofollow"><i>The Practice of Medicinal Chemistry</i></a>. Academic Press. p. 34. <a data-mce-href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a data-mce-href="https://en.wikipedia.org/wiki/Special:BookSources/978-0-12-374194-3" href="https://en.wikipedia.org/wiki/Special:BookSources/978-0-12-374194-3" title="Special:BookSources/978-0-12-374194-3">978-0-12-374194-3</a><span class="reference-accessdate">. Retrieved <span class="nowrap">27 May</span> 2012</span>.</cite></span></li>
<li id="cite_note-Sittig1988-9"> <span class="reference-text"><cite class="citation book">Marshall Sittig (1988). <a class="external text" data-mce-href="http://books.google.com/books?id=XCsJgUnclbcC&pg=PA1385" href="http://books.google.com/books?id=XCsJgUnclbcC&pg=PA1385" rel="nofollow"><i>Pharmaceutical Manufacturing Encyclopedia</i></a>. William Andrew. p. 1385. <a data-mce-href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a data-mce-href="https://en.wikipedia.org/wiki/Special:BookSources/978-0-8155-1144-1" href="https://en.wikipedia.org/wiki/Special:BookSources/978-0-8155-1144-1" title="Special:BookSources/978-0-8155-1144-1">978-0-8155-1144-1</a><span class="reference-accessdate">. Retrieved <span class="nowrap">27 May</span> 2012</span>.</cite></span></li>
<li id="cite_note-10"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1" href="http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1" rel="nofollow">"WHO Model List of EssentialMedicines"</a> (PDF). <i>World Health Organization</i>. October 2013<span class="reference-accessdate">. Retrieved <span class="nowrap">22 April</span> 2014</span>.</cite></span></li>
<li id="cite_note-11"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://erc.msh.org/dmpguide/resultsdetail.cfm?language=english&code=SPI25T&s_year=2014&year=2014&str=25%20mg&desc=Spironolactone&pack=new&frm=TAB-CAP&rte=PO&class_code2=16%2E&supplement=&class_name=%2816%2E%29Diuretics%3Cbr%3E" href="http://erc.msh.org/dmpguide/resultsdetail.cfm?language=english&code=SPI25T&s_year=2014&year=2014&str=25%20mg&desc=Spironolactone&pack=new&frm=TAB-CAP&rte=PO&class_code2=16%2E&supplement=&class_name=%2816%2E%29Diuretics%3Cbr%3E" rel="nofollow">"Spironolactone"</a>. <i>International Drug Price Indicator Guide</i><span class="reference-accessdate">. Retrieved <span class="nowrap">29 November</span>2015</span>.</cite></span></li>
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</ol>
</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Spironolactone">Spironolactone</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Spironolactone.svg" href="https://en.wikipedia.org/wiki/File:Spironolactone.svg" title="Skeletal formula of spironolactone"><img alt="Skeletal formula of spironolactone" data-file-height="446" data-file-width="512" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/98/Spironolactone.svg/220px-Spironolactone.svg.png" height="192" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/98/Spironolactone.svg/220px-Spironolactone.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/9/98/Spironolactone.svg/330px-Spironolactone.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/9/98/Spironolactone.svg/440px-Spironolactone.svg.png 2x" style="height: auto; max-width: 100%;" width="220" /></a></td></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Spironolactone_3D_ball.png" href="https://en.wikipedia.org/wiki/File:Spironolactone_3D_ball.png" title="Ball-and-stick model of the spironolactone molecule"><img alt="Ball-and-stick model of the spironolactone molecule" data-file-height="1481" data-file-width="2000" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f5/Spironolactone_3D_ball.png/220px-Spironolactone_3D_ball.png" height="163" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f5/Spironolactone_3D_ball.png/220px-Spironolactone_3D_ball.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/f/f5/Spironolactone_3D_ball.png/330px-Spironolactone_3D_ball.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/f/f5/Spironolactone_3D_ball.png/440px-Spironolactone_3D_ball.png 2x" style="height: auto; max-width: 100%;" width="220" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pronunciation</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="nowrap"><span class="IPA nopopups"><a data-mce-href="https://en.wikipedia.org/wiki/Help:IPA_for_English" href="https://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English">/<span title="'s' in 'sigh'">s</span><span title="'p' in 'pie'">p</span><span title="/ɪ/ short 'i' in 'bid'">ɪ</span><span title="/ˌ/ secondary stress follows">ˌ</span><span title="'r' in 'rye'">r</span><span title="/oʊ/ long 'o' in 'code'">oʊ</span><span title="'n' in 'no'">n</span><span title="/ə/ 'a' in 'about'">ə</span><span title="/ˈ/ primary stress follows">ˈ</span><span title="'l' in 'lie'">l</span><span title="/æ/ short 'a' in 'bad'">æ</span><span title="'k' in 'kind'">k</span><span title="'t' in 'tie'">t</span><span title="/oʊ/ long 'o' in 'code'">oʊ</span><span title="'n' in 'no'">n</span>, <span title="'s' in 'sigh'">s</span><span title="'p' in 'pie'">p</span><span title="/aɪ/ long 'i' in 'tide'">aɪ</span><span title="/-/ affix">-</span>, <span title="'s' in 'sigh'">s</span><span title="'p' in 'pie'">p</span><span title="/ə/ 'a' in 'about'">ə</span><span title="/-/ affix">-</span>, <span title="/-/ affix">-</span><span title="/ˈ/ primary stress follows">ˈ</span><span title="'r' in 'rye'">r</span><span title="/ɒ/ short 'o' in 'body'">ɒ</span><span title="/-/ affix">-</span>, <span title="/-/ affix">-</span><span title="'n' in 'no'">n</span><span title="/oʊ/ long 'o' in 'code'">oʊ</span><span title="/-/ affix">-</span>/</a></span></span>or <span class="nowrap"><span class="IPA nopopups"><a data-mce-href="https://en.wikipedia.org/wiki/Help:IPA_for_English" href="https://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English">/<span title="/ˌ/ secondary stress follows">ˌ</span><span title="'s' in 'sigh'">s</span><span title="'p' in 'pie'">p</span><span title="/aɪ/ long 'i' in 'tide'">aɪ</span><span title="'r' in 'rye'">r</span><span title="/ə/ 'a' in 'about'">ə</span><span title="'n' in 'no'">n</span><span title="/oʊ/ long 'o' in 'code'">oʊ</span><span title="/ˈ/ primary stress follows">ˈ</span><span title="'l' in 'lie'">l</span><span title="/æ/ short 'a' in 'bad'">æ</span><span title="'k' in 'kind'">k</span><span title="'t' in 'tie'">t</span><span title="/oʊ/ long 'o' in 'code'">oʊ</span><span title="'n' in 'no'">n</span>/</a></span></span><sup class="reference" id="cite_ref-SpironolactoneMedlinePlus_2-0"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-SpironolactoneMedlinePlus-2" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-SpironolactoneMedlinePlus-2">[2]</a></sup><sup class="reference" id="cite_ref-3"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-3" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-3">[3]</a></sup><sup class="reference" id="cite_ref-4"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-4" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-4">[4]</a></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aldactone</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/monograph/spironolactone.html" href="https://www.drugs.com/monograph/spironolactone.html" rel="nofollow">Monograph</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/MedlinePlus" href="https://en.wikipedia.org/wiki/MedlinePlus" title="MedlinePlus">MedlinePlus</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.nlm.nih.gov"><a class="external text" data-mce-href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682627.html" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682627.html" rel="nofollow">a682627</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="Australia">AU</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#Australia" href="https://en.wikipedia.org/wiki/Pregnancy_category#Australia" title="Pregnancy category">B3</a></li>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" title="Pregnancy category">C</a> (Risk not ruled out)</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Mouth" href="https://en.wikipedia.org/wiki/Mouth" title="Mouth">Oral</a><sup class="reference" id="cite_ref-AHFS2015_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-AHFS2015-1">[1]</a></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United Kingdom">UK</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">POM</a> (Prescription only)</li>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Plasma_protein_binding" href="https://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">90%+<sup class="reference" id="cite_ref-Brittain2002_5-0"><a data-mce-href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-Brittain2002-5" href="https://en.wikipedia.org/wiki/Spironolactone#cite_note-Brittain2002-5">[5]</a></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_metabolism" href="https://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Liver" href="https://en.wikipedia.org/wiki/Liver" title="Liver">Hepatic</a> <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/CYP450" href="https://en.wikipedia.org/wiki/CYP450" title="CYP450">CYP450</a></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Biological_half-life" href="https://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1.3-2 hours</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Excretion" href="https://en.wikipedia.org/wiki/Excretion" title="Excretion">Excretion</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Urine" href="https://en.wikipedia.org/wiki/Urine" title="Urine">Urine</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Bile" href="https://en.wikipedia.org/wiki/Bile" title="Bile">bile</a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=52-01-7" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=52-01-7" rel="nofollow">52-01-7</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_C03" href="https://en.wikipedia.org/wiki/ATC_code_C03" title="ATC code C03">C03DA01</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=C03DA01" href="http://www.whocc.no/atc_ddd_index/?code=C03DA01" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5833" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5833" rel="nofollow">5833</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/IUPHAR/BPS" href="https://en.wikipedia.org/wiki/IUPHAR/BPS" title="IUPHAR/BPS">IUPHAR/BPS</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.guidetopharmacology.org"><a class="external text" data-mce-href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2875" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2875" rel="nofollow">2875</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/DrugBank" href="https://en.wikipedia.org/wiki/DrugBank" title="DrugBank">DrugBank</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugbank.ca"><a class="external text" data-mce-href="http://www.drugbank.ca/drugs/DB00421" href="http://www.drugbank.ca/drugs/DB00421" rel="nofollow">DB00421</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.5628.html" href="http://www.chemspider.com/Chemical-Structure.5628.html" rel="nofollow">5628</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=27O7W4T232" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=27O7W4T232" rel="nofollow">27O7W4T232</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/KEGG" href="https://en.wikipedia.org/wiki/KEGG" title="KEGG">KEGG</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.kegg.jp"><a class="external text" data-mce-href="http://www.kegg.jp/entry/D00443" href="http://www.kegg.jp/entry/D00443" rel="nofollow">D00443</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEBI" href="https://en.wikipedia.org/wiki/ChEBI" title="ChEBI">ChEBI</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9241" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9241" rel="nofollow">CHEBI:9241</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEMBL" href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1393" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1393" rel="nofollow">CHEMBL1393</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>24</sub><span title="Hydrogen">H</span><sub>32</sub><span title="Oxygen">O</span><sub>4</sub><span title="Sulfur">S</span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">416.574 g/mol</td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
///////Spironolactone, <strong>Supra-puren, </strong><strong>Suracton, </strong><strong>спиронолактон, </strong><strong>سبيرونولاكتون</strong> ,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>螺内酯</strong> , <span class="synonym_confirmed">Abbolactone, </span><span class="synonym_confirmed">Aldactide, </span><span class="synonym_confirmed">SNL, </span><span class="synonym_confirmed">Spiroctanie, </span><span class="synonym_confirmed">Sprioderm, </span><span class="synonym_confirmed">Verospirone, Opianin</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
O=C5O[C@@]4([C@@]3([C@H]([C@@H]2[C@H](SC(=O)C)C/C1=C/C(=O)CC[C@]1(C)[C@H]2CC3)CC4)C)CC5</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com3tag:blogger.com,1999:blog-1346483141860457136.post-18691860816103296012016-07-27T02:37:00.001-07:002016-07-27T23:59:54.052-07:00Vorinostat (Zolinza)<div dir="ltr" style="text-align: left;" trbidi="on">
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Vorinostat, MK0683</div>
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CAS 149647-78-9</div>
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Zolinza, SAHA, suberoylanilide hydroxamic acid, Suberanilohydroxamic acid, N-hydroxy-N'-phenyloctanediamide</div>
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US patent 5369108, PDT PATENT</div>
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For the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. Inhibits histone deacetylase I & 3.</div>
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<li>CCRIS 8456</li>
<li>HSDB 7930</li>
<li>M344</li>
<li>N-Hydroxy-N'-phenyloctanediamide</li>
<li>SAHA</li>
<li>SAHA cpd</li>
<li>Suberanilohydroxamic acid</li>
<li>suberoylanilide hydroxamic acid</li>
<li>UNII-58IFB293JI</li>
<li>MK0683</li>
</ul>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Average: 264.3202<br />
Monoisotopic: 264.147392516</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical Formula</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">C<sub>14</sub>H<sub>20</sub>N<sub>2</sub>O<sub>3</sub></td></tr>
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<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><i>N</i>-hydroxy-<i>N</i>'-phenyl-octanediamide</th></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Trade_name" href="http://en.wikipedia.org/wiki/Trade_name" title="Trade name">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Zolinza, 100 MG, CAPSULE, ORAL</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> <a data-mce-href="http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092" href="http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092" name="link_dailymed">ZOLINZA (VORINOSTAT) [Merck Sharp & Dohme Corp.]</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/MedlinePlus" href="http://en.wikipedia.org/wiki/MedlinePlus" title="MedlinePlus">MedlinePlus</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a607050.html" href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a607050.html" rel="nofollow">a607050</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Licence data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" href="http://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" title="U.S. Food and Drug Administration">US FDA</a>:<a data-mce-href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Vorinostat&SearchType=BasicSearch" href="http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Vorinostat&SearchType=BasicSearch" rel="nofollow">link</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> LAUNCHED 2006 MERCK<a data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021991s002lbl.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021991s002lbl.pdf">http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021991s002lbl.pdf</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Prescription_drug" href="http://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞<small>-only</small></a> <small>(<a data-mce-href="http://en.wikipedia.org/wiki/United_States" href="http://en.wikipedia.org/wiki/United_States" title="United States">US</a>)</small></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Route_of_administration" href="http://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oral</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pharmacokinetic data</th></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Plasma_protein_binding" href="http://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">71%</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Drug_metabolism" href="http://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Liver" href="http://en.wikipedia.org/wiki/Liver" title="Liver">Hepatic</a> <a data-mce-href="http://en.wikipedia.org/wiki/Glucuronidation" href="http://en.wikipedia.org/wiki/Glucuronidation" title="Glucuronidation">glucuronidation</a> and<a data-mce-href="http://en.wikipedia.org/wiki/Redox" href="http://en.wikipedia.org/wiki/Redox" title="Redox">oxidation</a><br />
<a data-mce-href="http://en.wikipedia.org/wiki/Cytochrome_P450_oxidase" href="http://en.wikipedia.org/wiki/Cytochrome_P450_oxidase" title="Cytochrome P450 oxidase">CYP</a> system not involved</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Biological_half-life" href="http://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2 hours</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Excretion" href="http://en.wikipedia.org/wiki/Excretion" title="Excretion">Excretion</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Kidney" href="http://en.wikipedia.org/wiki/Kidney" title="Kidney">Renal</a> (negligible)</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/CAS_registry_number" href="http://en.wikipedia.org/wiki/CAS_registry_number" title="CAS registry number">CAS number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=149647-78-9&rn=1" href="http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?term=149647-78-9&rn=1" rel="nofollow">149647-78-9</a><sup> </sup></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="http://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/ATC_code_L01" href="http://en.wikipedia.org/wiki/ATC_code_L01" title="ATC code L01">L01</a><a data-mce-href="http://www.whocc.no/atc_ddd_index/?code=L01XX38" href="http://www.whocc.no/atc_ddd_index/?code=L01XX38" rel="nofollow">XX38</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Chemical_formula" href="http://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Carbon" href="http://en.wikipedia.org/wiki/Carbon" title="Carbon">C</a><sub>14</sub><a data-mce-href="http://en.wikipedia.org/wiki/Hydrogen" href="http://en.wikipedia.org/wiki/Hydrogen" title="Hydrogen">H</a><sub>20</sub><a data-mce-href="http://en.wikipedia.org/wiki/Nitrogen" href="http://en.wikipedia.org/wiki/Nitrogen" title="Nitrogen">N</a><sub>2</sub><a data-mce-href="http://en.wikipedia.org/wiki/Oxygen" href="http://en.wikipedia.org/wiki/Oxygen" title="Oxygen">O</a><sub>3</sub><sup> </sup></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://en.wikipedia.org/wiki/Molecular_mass" href="http://en.wikipedia.org/wiki/Molecular_mass" title="Molecular mass">Mol. mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">264.32 g/mol</td></tr>
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CLINICAL TRIALS..<a data-mce-href="http://clinicaltrials.gov/search/intervention=Vorinostat" href="http://clinicaltrials.gov/search/intervention=Vorinostat">http://clinicaltrials.gov/search/intervention=Vorinostat</a></div>
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<b>Vorinostat</b> (<a data-mce-href="http://en.wikipedia.org/wiki/International_Nonproprietary_Name" href="http://en.wikipedia.org/wiki/International_Nonproprietary_Name" title="International Nonproprietary Name">rINN</a>) also known as <b>suberanilohydroxamic acid</b> (<a data-mce-href="http://en.wikipedia.org/wiki/Suberic_acid" href="http://en.wikipedia.org/wiki/Suberic_acid" title="Suberic acid">suberoyl</a>+<a data-mce-href="http://en.wikipedia.org/wiki/Aniline" href="http://en.wikipedia.org/wiki/Aniline" title="Aniline">anilide</a>+<a data-mce-href="http://en.wikipedia.org/wiki/Hydroxamic_acid" href="http://en.wikipedia.org/wiki/Hydroxamic_acid" title="Hydroxamic acid">hydroxamic acid</a> abbreviated as <b>SAHA</b>) is a member of a larger class of compounds that inhibit <a data-mce-href="http://en.wikipedia.org/wiki/Histone_deacetylase" href="http://en.wikipedia.org/wiki/Histone_deacetylase" title="Histone deacetylase">histone deacetylases</a> (HDAC). <a data-mce-href="http://en.wikipedia.org/wiki/Histone_deacetylase_inhibitor" href="http://en.wikipedia.org/wiki/Histone_deacetylase_inhibitor" title="Histone deacetylase inhibitor">Histone deacetylase inhibitors</a> (HDI) have a broad spectrum of <a data-mce-href="http://en.wikipedia.org/wiki/Epigenetic" href="http://en.wikipedia.org/wiki/Epigenetic" title="Epigenetic">epigenetic</a> activities.</div>
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Vorinostat is marketed under the name <b>Zolinza</b> for the treatment of <a data-mce-href="http://en.wikipedia.org/wiki/Cutaneous_T_cell_lymphoma" href="http://en.wikipedia.org/wiki/Cutaneous_T_cell_lymphoma" title="Cutaneous T cell lymphoma">cutaneous T cell lymphoma</a> (CTCL) when the disease persists, gets worse, or comes back during or after treatment with other medicines.<sup id="cite_ref-1"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-1" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-1">[1]</a></sup> The compound was developed by Columbia University chemist, Ronald Breslow.</div>
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<img alt="" data-mce-src="http://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&deposited=t&sid=46508989" src="http://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&deposited=t&sid=46508989" style="height: auto; max-width: 100%;" />VORINOSTAT</div>
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Vorinostat was the first <a data-mce-href="http://en.wikipedia.org/wiki/Histone_deacetylase_inhibitor" href="http://en.wikipedia.org/wiki/Histone_deacetylase_inhibitor" title="Histone deacetylase inhibitor">histone deacetylase inhibitor</a><sup id="cite_ref-2"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-2" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-2">[2]</a></sup> approved by the U.S. <a data-mce-href="http://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="http://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> (FDA) for the treatment of CTCL on October 6, 2006. It is manufactured by <a data-mce-href="http://en.wikipedia.org/wiki/Patheon" href="http://en.wikipedia.org/wiki/Patheon" title="Patheon">Patheon, Inc.</a>, in <a data-mce-href="http://en.wikipedia.org/wiki/Mississauga" href="http://en.wikipedia.org/wiki/Mississauga" title="Mississauga">Mississauga</a>, <a data-mce-href="http://en.wikipedia.org/wiki/Ontario" href="http://en.wikipedia.org/wiki/Ontario" title="Ontario">Ontario</a>, <a data-mce-href="http://en.wikipedia.org/wiki/Canada" href="http://en.wikipedia.org/wiki/Canada" title="Canada">Canada</a>, for <a data-mce-href="http://en.wikipedia.org/wiki/Merck_%26_Co.,_Inc." href="http://en.wikipedia.org/wiki/Merck_%26_Co.,_Inc." title="Merck & Co., Inc.">Merck & Co., Inc.</a>, <a data-mce-href="http://en.wikipedia.org/wiki/White_House_Station,_New_Jersey" href="http://en.wikipedia.org/wiki/White_House_Station,_New_Jersey" title="White House Station, New Jersey">White House Station, New Jersey</a>.<sup id="cite_ref-3"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-3" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-3">[3]</a></sup></div>
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ZOLINZA contains vorinostat, which is described chemically as N-hydroxy-N'-phenyloctanediamide. The empirical formula is C<sub>14</sub>H<sub>20</sub>N<sub>2</sub>O<sub>3</sub>. The molecular weight is 264.32 and the structural formula is:</div>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><img alt="ZOLINZA® (vorinostat) Structural Formula Illustration" data-mce-src="http://images.rxlist.com/images/rxlist/zolinza1.gif" src="http://images.rxlist.com/images/rxlist/zolinza1.gif" height="95" style="height: auto; max-width: 100%;" width="327" /></td></tr>
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Vorinostat is a white to light orange powder. It is very slightly soluble in water, slightly soluble in ethanol, isopropanol and acetone, freely soluble in dimethyl sulfoxide and insoluble in methylene chloride. It has no chiral centers and is non-hygroscopic. The differential scanning calorimetry ranged from 161.7 (endotherm) to 163.9°C. The pH of saturated water solutions of vorinostat drug substance was 6.6. The pKa of vorinostat was determined to be 9.2.</div>
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Each 100 mg ZOLINZA capsule for oral administration contains 100 mg vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium croscarmellose and magnesium stearate. The capsule shell excipients are titanium dioxide, gelatin and sodium lauryl sulfate.</div>
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Vorinostat has been shown to bind to the active site of <a data-mce-href="http://en.wikipedia.org/wiki/Histone_deacetylases" href="http://en.wikipedia.org/wiki/Histone_deacetylases" title="Histone deacetylases">histone deacetylases</a> and act as a chelator for Zinc ions also found in the active site of <a data-mce-href="http://en.wikipedia.org/wiki/Histone_deacetylases" href="http://en.wikipedia.org/wiki/Histone_deacetylases" title="Histone deacetylases">histone deacetylases</a> <sup id="cite_ref-Richon_4-0"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-Richon-4" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-Richon-4">[4]</a></sup> Vorinostat's inhibition of <a data-mce-href="http://en.wikipedia.org/wiki/Histone_deacetylases" href="http://en.wikipedia.org/wiki/Histone_deacetylases" title="Histone deacetylases">histone deacetylases</a> results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation. <sup id="cite_ref-Richon_4-1"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-Richon-4" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-Richon-4">[4]</a></sup><br />
SAHA inhibits class I and class II HDACs at nanomolar concentrations and arrests cell growth in a wide variety of transformed cells in culture at 2.5-5.0 µM. This compound efficiently suppressed MES-SA cell growth at a low dosage (3 µM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 µM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours.<br />
<img alt="" data-mce-src="http://www.uspharmacist.com/CMSImagesContent/2007/3/HSnewdrugsf3.jpg" src="http://www.uspharmacist.com/CMSImagesContent/2007/3/HSnewdrugsf3.jpg" style="height: auto; max-width: 100%;" /></div>
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Vorinostat has also been used to treat <a data-mce-href="http://en.wikipedia.org/wiki/S%C3%A9zary_syndrome" href="http://en.wikipedia.org/wiki/S%C3%A9zary_syndrome" title="Sézary syndrome">Sézary syndrome</a>, another type of lymphoma closely related to CTCL.<sup id="cite_ref-atlas_5-0"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-atlas-5" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-atlas-5">[5]</a></sup></div>
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A recent study suggested that vorinostat also possesses some activity against recurrent <a data-mce-href="http://en.wikipedia.org/wiki/Glioblastoma_multiforme" href="http://en.wikipedia.org/wiki/Glioblastoma_multiforme" title="Glioblastoma multiforme">glioblastoma multiforme</a>, resulting in a median overall survival of 5.7 months (compared to 4 - 4.4 months in earlier studies).<sup id="cite_ref-6"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-6" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-6">[6]</a></sup> Further brain tumor trials are planned in which vorinostat will be combined with other drugs.</div>
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Including vorinostat in treatment of advanced <a data-mce-href="http://en.wikipedia.org/wiki/Non-small-cell_lung_cancer" href="http://en.wikipedia.org/wiki/Non-small-cell_lung_cancer" title="Non-small-cell lung cancer">non-small-cell lung cancer</a> (NSCLC) showed improved response rates and increased median progression free survival and overall survival (although the survival improvements were not significant at the P=0.05 level).<sup id="cite_ref-7"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-7" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-7">[7]</a></sup></div>
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It has given encouraging results in a phase II trial for <a data-mce-href="http://en.wikipedia.org/wiki/Myelodysplastic_syndromes" href="http://en.wikipedia.org/wiki/Myelodysplastic_syndromes" title="Myelodysplastic syndromes">myelodysplastic syndromes</a> in combination with <a data-mce-href="http://en.wikipedia.org/wiki/Idarubicin" href="http://en.wikipedia.org/wiki/Idarubicin" title="Idarubicin">Idarubicin</a> and <a data-mce-href="http://en.wikipedia.org/wiki/Cytarabine" href="http://en.wikipedia.org/wiki/Cytarabine" title="Cytarabine">Cytarabine</a>.<sup id="cite_ref-8"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-8" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-8">[8]</a></sup></div>
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</h2>
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Vorinostat is an interesting target for scientists interested in eradicating <a data-mce-href="http://en.wikipedia.org/wiki/HIV" href="http://en.wikipedia.org/wiki/HIV" title="HIV">HIV</a> from infected persons.<sup id="cite_ref-9"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-9" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-9">[9]</a></sup> Vorinostat was recently shown to have both <i>in vitro</i> and <i>in vivo</i> effects against latently HIV infected T-cells.<sup id="cite_ref-pmid19239360_10-0"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-pmid19239360-10" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-pmid19239360-10">[10]</a></sup><sup id="cite_ref-pmid19136668_11-0"><a data-mce-href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-pmid19136668-11" href="http://en.wikipedia.org/wiki/Vorinostat#cite_note-pmid19136668-11">[11]</a></sup></div>
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Vorinostat, represented by structural formula (I) and chemically named as N-hydroxy-N'- phenyl-octanediamide or suberoylanilide hydroxamic acid (SAElA), is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities and vorinostat is marketed, under the brand name Zolinza<sup>®</sup>, for the treatment of a type of skin cancer called cutaneous T-cell lymphoma (CTCL). Vorinostat is approved to be used when the disease persists, gets worse, or comes back during or after treatment with other medicines. Vorinostat has also been used to treat Sέzary's disease and, in addition, possesses some activity against recurrent glioblastoma multiforme.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000002_0001.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000002_0001.png"><img alt="Figure imgf000002_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000002_0001.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000002_0001.png" height="112" id="imgf000002_0001" style="height: auto; max-width: 100%;" width="360" /></a></div>
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Vorinostat was first described in US patent 5369108, wherein four different synthetic routes for the preparation of vorinostat are disclosed (Schemes 1 to 4).</div>
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The single step process illustrated in Scheme 1 involves coupling of the diacid chloride of suberic acid with aniline and hydiOxylamine hydrochloride. However, the yield of this reaction is only 15-30%.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0001.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0001.png"><img alt="Figure imgf000003_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0001.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0001.png" height="192" id="imgf000003_0001" style="height: auto; max-width: 100%;" width="468" /></a></div>
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Scheme 1</div>
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The multistep process illustrated in Scheme 2 begins with the monomethyl ester of suberic acid, which undergoes conversion to the corresponding acid chloride. Further coupling with aniline gives the methyl ester of suberanilic acid. Hydrolysis of the ester and further coupling with benzyl protected hydroxylamine gives benzyl protected vorinostat which on deprotection gives vorinostat.</div>
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HO. (CH<sub>2</sub>J<sub>6</sub> OMe . ,OOMM e</div>
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O O</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0002.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0002.png"><img alt="Figure imgf000003_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0002.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0002.png" height="68" id="imgf000003_0002" style="height: auto; max-width: 100%;" width="320" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0003.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0003.png"><img alt="Figure imgf000003_0003" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0003.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0003.png" height="84" id="imgf000003_0003" style="height: auto; max-width: 100%;" width="428" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0004.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0004.png"><img alt="Figure imgf000003_0004" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0004.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000003_0004.png" height="88" id="imgf000003_0004" style="height: auto; max-width: 100%;" width="608" /></a></div>
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Scheme 2</div>
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In addition to the disadvantage of being a five-step process with overall yields reported as 35-65%, this process suffers from further disadvantages such as the use of the expensive monomethyl ester of suberic acid.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000004_0001.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000004_0001.png"><img alt="Figure imgf000004_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000004_0001.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000004_0001.png" height="196" id="imgf000004_0001" style="height: auto; max-width: 100%;" width="436" /></a></div>
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Scheme 3</div>
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The two step process illustrated in Scheme 3 involves coupling of the diacid chloride of suberic acid with aniline and O-benzyl hydroxylamine and then deprotection. However, the overall yield of this reaction is only 20-35%.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000004_0002.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000004_0002.png"><img alt="Figure imgf000004_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000004_0002.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000004_0002.png" height="188" id="imgf000004_0002" style="height: auto; max-width: 100%;" width="448" /></a></div>
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Scheme 4</div>
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The process illustrated in Scheme 4 is similar to that illustrated in Scheme 3, with the exception that O-trimethylsilyl hydroxylamine was used instead of O-benzyl hydroxylamine. The overall yield of this reaction is reported as 20-33%.</div>
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Another process for the preparation of vorinostat has been reported in J. Med. Chem.,</div>
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1995, vol. 38(8), pages 1411-1413. The reported process, illustrated in Scheme 5, begins with the conversion of suberic acid to suberanilic acid by a high temperature melt reaction.</div>
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Suberanilic acid is further converted to the corresponding methyl ester using Dowex resin and the methyl ester of suberanilic acid thus formed is converted to vorinostat by treatment with hydroxylamine hydrochloride. However, this process employs high temperatures (190<sup>0</sup>C) in the preparation of vorinostat which adds to the inefficiency and high processing costs on commercial scale. The high temperatures also increase the likelihood of impurities being formed during manufacture and safety concerns. The overall yield reported was a poor 35%.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0001.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0001.png"><img alt="Figure imgf000005_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0001.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0001.png" height="76" id="imgf000005_0001" style="height: auto; max-width: 100%;" width="604" /></a></div>
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MeOH, Dowex, 22 hours</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0002.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0002.png"><img alt="Figure imgf000005_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0002.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0002.png" height="76" id="imgf000005_0002" style="height: auto; max-width: 100%;" width="224" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0003.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0003.png"><img alt="Figure imgf000005_0003" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0003.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000005_0003.png" height="76" id="imgf000005_0003" style="height: auto; max-width: 100%;" width="424" /></a></div>
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Scheme 5</div>
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Another process for the preparation of vorinostat has been reported in OPPI Briefs, 2001, vol. 33(4), pages 391-394. The reported process, illustrated in Scheme 6, involves conversion of suberic acid to suberic anhydride, which on treatment with aniline gives suberanilic acid. Coupling of this suberanilic acid with ethyl chloroformate gives a mixed anhydride which upon treatment with hydroxylamine gives vorinostat in an overall yield of 58%. In the first step, there is competition between the formation of suberic anhydride and the linear anhydride and consequently isolation of pure suberic anhydride from the reaction mixture is very difficult. This process step is also hindered by the formation of process impurities and competitive reactions. In the second step, there is formation of dianilide by reaction of two moles of aniline with the linear anhydride. In the third step, suberanilic acid is an inconvenient by-product as the suberanilic acid is converted to a mixed anhydride with ethyl chloroformate, which is highly unstable and is converted back into suberanilic acid. Consequently, it is very difficult to obtain pure vorinostat from the reaction mixture. Although the reported yield was claimed to be 58%, when repeated a yield of only 38% was obtained.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0001.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0001.png"><img alt="Figure imgf000006_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0001.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0001.png" height="308" id="imgf000006_0001" style="height: auto; max-width: 100%;" width="608" /></a></div>
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Scheme 6</div>
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A further process for the preparation of vorinostat has been reported in J. Med. Chem., 2005, vol. 48(15), pages 5047-5051. The reported process, illustrated in Scheme 7, involves conversion of monomethyl suberate to monomethyl suberanilic acid, followed by coupling with hydroxylamine hydrochloride to afford vorinostat in an overall yield of 79%. However, the process uses the expensive monomethyl ester of suberic acid as starting material.</div>
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HOBt, DCC, DMF, RT, 4 hours</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0002.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0002.png"><img alt="Figure imgf000006_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0002.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0002.png" height="64" id="imgf000006_0002" style="height: auto; max-width: 100%;" width="276" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0003.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0003.png"><img alt="Figure imgf000006_0003" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0003.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0003.png" height="68" id="imgf000006_0003" style="height: auto; max-width: 100%;" width="208" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0004.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0004.png"><img alt="Figure imgf000006_0004" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0004.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000006_0004.png" height="68" id="imgf000006_0004" style="height: auto; max-width: 100%;" width="380" /></a></div>
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</div>
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Processes for the preparation of vorinostat, and its form 1 crystalline polymorph, have been disclosed in patent applications US 2004/0122101 and WO 2006/127319. However, the disclosed processes, comprising the preparation of vorinostat from suberic acid, are a cumbersome three step process comprising the sequential steps of amidation of suberic acid with aniline, esterification of the mono-amide product with methanol, and finally reaction with hydroxylamine hydrochloride and sodium methoxide to afford vorinostat. This process is not very convenient as it involves elevated temperatures, lengthy reaction times and has a low overall yield of around 23%. In addition, the intermediate products and final product are not very pure and require exhaustive purification steps.</div>
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</div>
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CLIP</div>
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Vorinostat (ZolinzaTM) Vorinostat, a histone deacetylase (HDAC) inhibitor from Merck, was approved for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin’s lymphoma.</div>
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Vorinostat was shown to inhibit HDAC1, HDAC2, HDAC3 and HDAC6 at nanomolar concentrations. HDAC inhibitors are potent differentiating agents toward a variety of neoplasms, including leukemia and breast and prostate cancers [58].</div>
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Commercially available monomethyl ester 125 wasVorinostat (ZolinzaTM) Vorinostat, a histone deacetylase (HDAC) inhibitor from Merck, was approved for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin’s lymphoma.</div>
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Vorinostat was shown to inhibit HDAC1, HDAC2, HDAC3 and HDAC6 at nanomolar concentrations. HDAC inhibitors are potent differentiating agents toward a variety of neoplasms, including leukemia and breast and prostate cancers [58].</div>
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Commercially available monomethyl ester 125 was reacted with aniline in the presence of DCC and HOBt in DMF to give amide 127 in 89%yield [59] (Scheme 16).</div>
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Methyl ester amide 127 was then reacted with hydroxylamine HCl salt and potassium hydroxide in methanol to give vorinostat(XVI) in 90% yield.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-106.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-106.jpg" rel="attachment wp-att-7873"><img alt="STR1" class="alignnone size-full wp-image-7873" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-106.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-106.jpg?w=680" data-wpmedia-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-106.jpg" height="271" style="height: auto; max-width: 100%;" width="776" /></a></div>
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[58] Breslow, R.; Marks, P.A.; Rifkind, R. A.; Jursic, B. WO9307148,2003.<br />
[59] Gediya, L. K.; Chopra, P.; Purushottamachar, P.; Maheshwari, N.;Njar, V. C. O. J. Med. Chem., 2005, 48, 5047.</div>
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PATENT</div>
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<img alt="" data-mce-src="http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0149647789" src="http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0149647789" style="height: auto; max-width: 100%;" />VORINOSTAT</div>
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<a data-mce-href="http://www.google.com/patents/EP2349985A2?cl=en" href="http://www.google.com/patents/EP2349985A2?cl=en">http://www.google.com/patents/EP2349985A2</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A preferred embodiment of the first aspect of the present invention is illustrated in Scheme</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000016_0001.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000016_0001.png"><img alt="Figure imgf000016_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000016_0001.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000016_0001.png" height="92" id="imgf000016_0001" style="height: auto; max-width: 100%;" width="576" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
suberic acid subefanilic acid NH<sub>2</sub>OHHCl, CDI</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000016_0002.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000016_0002.png"><img alt="Figure imgf000016_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000016_0002.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000016_0002.png" height="80" id="imgf000016_0002" style="height: auto; max-width: 100%;" width="264" /></a></div>
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suberoylanilide hydroxamic acid (T)</div>
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Scheme 8</div>
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Optionally, an activating agent can be used in step (a) and/ or step (b) to afford products with high yields and purity. Preferably, the activating agent is selected from cyanuric chloride, cyanuric fluoride, catecholborane, or a mixture thereof. The activating agent is preferably used in combination with the coupling agent. A preferred embodiment of the process according to the first aspect of the present invention comprises the following steps:</div>
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(i) taking a mixture of THF, CDI and DCC;</div>
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(ii) adding suberic acid; (iii) adding aniline in THF to the solution from step (ii);</div>
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(iv) stirring at 25-30°C;</div>
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(v) filtering off the solid dicyclohexyl urea formed in the reaction;</div>
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(vi) concentrating the filtrate in vacuo;</div>
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(vii) adding a solution of KOH in water; (vϋi) filtering off the solid by-product;</div>
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(ix) heating the filtrate;</div>
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(x) adding aq. HCl;</div>
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(xi) isolating suberanilic acid;</div>
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(xii) mixing the suberanilic acid and CDI in DMF; (xiii) adding hydroxylamine hydrochloride as solid to the mixture from step (xii);</div>
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(xiv) isolating vorinostat from the mixture obtained in step (xiii);</div>
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(xv) adding acetonitrile and aq. ammonia to the vorinostat from step (xiv);</div>
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(xvi) heating the mixture;</div>
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(xvii) cooling the mixture to 20-27°C; and (xvϋi) isolating pure vorinostat from the mixture obtained in step (xvii).</div>
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Preferably, by utilising the same organic solvent in steps (a) and (b), pure vorinostat can be obtained without isolation of any synthetic intermediate^).</div>
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A preferred embodiment of the second aspect of the present invention is illustrated in Scheme 9.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000018_0001.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000018_0001.png"><img alt="Figure imgf000018_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000018_0001.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000018_0001.png" height="64" id="imgf000018_0001" style="height: auto; max-width: 100%;" width="560" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
suberic acid N-hydtoxy-7-carboxy-heptanamide</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000018_0002.png" href="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000018_0002.png"><img alt="Figure imgf000018_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000018_0002.png" src="http://patentimages.storage.googleapis.com/WO2010043904A2/imgf000018_0002.png" height="112" id="imgf000018_0002" style="height: auto; max-width: 100%;" width="408" /></a></div>
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Example 1</div>
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Stage 1 : Conversion of suberic acid to suberanilic acid</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A mixture of CDI (0.5eq) and DCC (0.8eq) in THF (15 vol) was stirred for 1 hour at 25- 3O<sup>0</sup>C. Suberic acid (leq) and aniline (leq) in THF (1 vol) was added and the mixture stirred for a further 16-20 hours. The solid by-product was removed by filtration and the filtrate was concentrated in vacuo at 5O<sup>0</sup>C. The solid residue obtained was treated with a solution of KOH (2eq) in water (10 vol) and stirred for 30 minutes at 25-30<sup>0</sup>C and any solid byproduct formed was removed by filtration. The filtrate obtained was heated at 6O<sup>0</sup>C for 3-4 hours and cooled to 20<sup>0</sup>C before addition of an aqueous solution of HCl (17.5%, 3 vol). The mixture was stirred for 30 minutes and the solid filtered, washed with water (2x5 vol) and dried under vacuum at 60-65<sup>0</sup>C. Molar Yield = 60-65% Purity by HPLC = 99.5%</div>
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Stage 2: Conversion of suberanilic acid to crude vorinostat The suberanilic acid (leq) obtained in stage 1 was dissolved in DMF (5 vol) and CDI (2eq) was added at 25-3O<sup>0</sup>C and maintained for 30 minutes under stirring. Hydroxylamine hydrochloride (4eq) was added and stirring continued for 30 minutes. Water (25 vol) was then added and the mixture stirred for 2 hours. The precipitated solid was filtered, washed with water (2x5 vol) and dried under vacuum at 50<sup>0</sup>C. Molar Yield = 70-75% Purity by HPLC = 99% Stage 3: Purification of crude vorinostat</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Aqueous ammonia (2.5 vol) was added to the crude vorinostat (leq) in acetonitrile (15 vol) at 25-30°C. The mixture was then maintained at 55-60°C for 1 hour before being cooled to 20-25°C and being stirred for a further hour. The resulting solid was filtered, washed with acetonitrile (2x0.5 vol) and dried under vacuum at 45-5O<sup>0</sup>C for 5 hours. Molar Yield = 55-60% Purity by HPLC > 99.8%</div>
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Example 2</div>
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Stage 1 : Conversion of suberic acid to crude vorinostat</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A mixture of CDI (0.5eq) and DCC (0.8eq) in THF (15 vol) was stirred for 1 hour at 25- 30°C. Suberic acid (leq) and hydroxylamine (leq) in THF (1 vol) was added and the mixture stirred for a further 1 hour. Then CDI (0.5eq), DCC (0.8eq) and aniline (leq) were added to the mixture and the mixture was stirred for a further 16-20 hours. The solid byproduct was removed by filtration and the filtrate was concentrated in vacuo at 50°C to obtain crude vorinostat. Molar Yield = 55-60% Purity by HPLC > 95.8%</div>
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Stage 2: Purification of crude vorinostat</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Aqueous ammonia (2.5 vol) was added to the crude vorinostat (leq) in acetonitrile (15 vol) at 25-3O<sup>0</sup>C. The mixture was then maintained at 55-60<sup>0</sup>C for 1 hour before being cooled to 20-25<sup>0</sup>C and being stirred for a further hour. The resulting solid was filtered, washed with acetonitrile (2x0.5 vol) and dried under vacuum at 45-50<sup>0</sup>C for 5 hours. Molar Yield = 35-40% Purity by HPLC > 99.8%</div>
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PATENT</div>
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SYNTHESIS</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.com/patents/WO2009098515A1?cl=en" href="http://www.google.com/patents/WO2009098515A1?cl=en">WO2009098515A1</a></div>
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Scheme V. - -</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009098515A1/imgf000012_0001.png" href="http://patentimages.storage.googleapis.com/WO2009098515A1/imgf000012_0001.png"><img alt="Figure imgf000012_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2009098515A1/imgf000012_0001.png" src="http://patentimages.storage.googleapis.com/WO2009098515A1/imgf000012_0001.png" height="292" id="imgf000012_0001" style="height: auto; max-width: 100%;" width="600" /></a></div>
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</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Vorinostat<br />
Suberic acid (l.Oeq) was dissolved in tetrahydrofuran (15vol) and the clear solution was chilled to 0-5°C. Methyl chloro formate (l.leq) and triethylamine (1.1 eq) were added to the solution at the same temperature and the mixture was stirred for 15 minutes. The triethylamine.HCl salt formed was filtered off, then aniline (leq) was added to the reaction mixture at 0-5<sup>0</sup>C and stirring was continued for 15 minutes. Methyl chloroformate (l.leq) and triethylamine (l.leq) were added to the clear solution and stirring was continued for a further 15 minutes at 0-5°C. This chilled reaction mixture was added to a freshly prepared hydroxylamine solution in methanol (*see below) chilled to 0-5°C and stirred for 15 minutes at 0-5°C. The solvent was removed under vacuum at 40°C and the residue obtained was taken in methylene dichloride and the organic solution was washed with water and dried over anhydrous sodium sulfate. Methylene dichloride was removed under vacuum at 40°C and acetonitrile was added to the residue. This mixture was stirred for 15 minutes before the solid was filtered under vacuum and dried under vacuum at 60°C to afford the product as a white solid. Molar yield = 35-41%; HPLC purity = 99.90%.<br />
VORINOSTAT<img alt="" data-mce-src="http://www.exchemistry.com/hdacs-images/SAHA.gif" src="http://www.exchemistry.com/hdacs-images/SAHA.gif" style="height: auto; max-width: 100%;" /><br />
<sup>1</sup>H-NMR (DMSO-d<sub>6</sub>): 1.27 (m, 4H, 2 x -CH<sub>2</sub>-), 1.53 (m, 4H, 2 x -CH<sub>2</sub>-), 1.94 (t, J = 7.3 Hz, 2H, -CH<sub>2</sub>-), 2.29 (t, J = 7.4 Hz, 2H, -CH<sub>2</sub>-), 7.03 (t, J = 7.35 Hz, IH, aromatic para position), 7.27 (t, J = 7.90 Hz, 2H, aromatic meta position), 7.58 (t, J = 7.65 Hz, 2H, aromatic ortho position), 8.66 (s, IH, -OH, D<sub>2</sub>O exchangeable), 9.85 (s, IH, amide -NH-, D<sub>2</sub>O exchangeable), 10.33 (s, IH, -NH-OH, D<sub>2</sub>O exchangeable).<br />
<sup>13</sup>C-NMR (DMSO-d<sub>6</sub>): 25.04 (2C, 2 x -CH<sub>2</sub>-), 28.43 (2C, 2 x -CH<sub>2</sub>-), 32.24 (1C, -CH<sub>2</sub>-), 36.34 (1C, -CH<sub>2</sub>-), 119.01 (2C, Ar-C), 122.96 (1C, Ar-C), 128.68 (2C, Ar-C), 139.24 (1C, Ar- C, =CNH-), 169.23 (1C, -CO-), 171.50 (1C, -CO-).<br />
*Preparation of hydroxylamine solution:<br />
Potassium hydroxide (l.leq) was added to methanol (8vol) and the solution was chilled to 0-5°C. Similarly hydroxylamine hydrochloride (l.leq) was added to methanol (8vol) and chilled to 0-5°C. The chilled amine solution was added to the chilled alkali solution and stirred for 15 minutes at 0-5<sup>0</sup>C. The white potassium chloride salt was filtered off and the filtrate was used as such.</div>
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PATENT</div>
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POLYMORPHS</div>
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</div>
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<a data-mce-href="http://www.google.com/patents/US20040122101" href="http://www.google.com/patents/US20040122101">US20040122101</a></div>
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</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The present invention is directed to a Form I polymorph of SAHA characterized by an X-ray diffraction pattern substantially similar to that set forth in FIG. 13A. SAHA Form I is also characterized by an X-ray diffraction pattern including characteristic peaks at about at about 9.0, 9.4, 17.5, 19.4, 20.0, 24.0, 24.4, 24.8, 25.0, 28.0, and 43.3 degrees 2θ. SAHA Form I is further characterized by an X-ray diffraction pattern including characteristic peaks at about 9.0, 9.4, 17.5, 19.4, 20.0, 24.0, 24.4, 24.8, 25.0, 28.0, 43.3 degrees 20, and lacking at least one peak at about <8.7, 10.0-10.2, 13.4-14.0, 15.0-15.2, 17.5-19.0, 20.1-20.3, 21.1-21.3, 22.0-22.22, 22.7-23.0, 25.0-25.5, 26.0-26.2, and 27.4-27.6 degrees 2θ.</div>
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PAPER</div>
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SPECTRAL DATA AND SYNTHESIS<br />
Journal of Medicinal Chemistry, <b>2011 </b>, vol. 54, 13 pg. 4694 - 4720<br />
<a data-mce-href="http://pubs.acs.org/doi/full/10.1021/jm2003552" href="http://pubs.acs.org/doi/full/10.1021/jm2003552">http://pubs.acs.org/doi/full/10.1021/jm2003552</a><br />
<a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf" href="http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf"> http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf</a><br />
for structures see above link<br />
Suberoylanilide hydroxamic acid (26, SAHA, vorinostat).<br />
Suberic acid monomethyl ester (23) (15.09 g, 80.2 mmol) and DMF (0.10 mL) in anhydrous<br />
DCM (300 mL) was added SOCl2 (34.6 mL, 0.481 mol), and the reaction mixture was refluxed for 3<br />
h. The mixture was then concentrated. Toluene (300 mL) was added to the residue and evaporated<br />
to afford crude acid chloride 24. Crude 24 was dissolved in DCM (240 mL), and followed by<br />
addition of aniline (7.3 mL, 80.2 mmol) and Et3N (16.9 mL, 0.120 mol). The reaction mixture was<br />
stirred for 90 min at room temp. The course of reaction was monitored by TLC (30% EtOAc in<br />
hexanes) and LC–MS. DCM was removed, and ethyl acetate (500 mL) was added to dissolve the<br />
residue. The organic layer was washed with aqueous NaHCO3 (500 mL × 2), 1 N HCl (400 mL × 2),<br />
water, dried (Na2SO4), and evaporated to dryness under reduced pressure. The residue was purified<br />
by vacuum liquid chromatography (silica, 20% EtOAc in hexanes) to afford compound 25as white crystalline solids (20.15 g, 96 %). NaOMe in MeOH solution (5.4 M, 106 mL, 0.573 mol) was added to a solution of compound 25 (10.05 g, 38.2 mmol) and NH2OH·HCl (26.54 g, 0.382 mol) in<br />
dry MeOH (375 mL). The reaction mixture was stirred for 40 min at room temp. The reaction was<br />
quenched by adding of 1 N HCl to pH 7–8. MeOH was removed under reduced pressure and water<br />
(1 L) was added to the residue. The precipitated solid was filtered and washed with water (300 mL)<br />
and EtOAc (150 mL) to afford crude 26 which was further purified by recrystallization. MeOH (200<br />
mL) was added to crude 26 (5 g) and warmed to dissolve all solids. The MeOH solution was filtered,<br />
and deionized water (400 mL) was added to the filtrate, the resulting solution was placed at 4 oC<br />
overnight. Crystals obtained were filtered and washed with deionized water (100 mL) to afford pure<br />
26 (vorinostat, SAHA) as off-white crystals. Overall yield: 80–85% from compound 23. Compound<br />
26,<br />
LC–MS m/z 265.1 ([M + H]+).<br />
<img alt="" data-mce-src="http://www.exchemistry.com/hdacs-images/SAHA.gif" src="http://www.exchemistry.com/hdacs-images/SAHA.gif" style="height: auto; max-width: 100%;" /><br />
1H NMR (DMSO-d6) 10.35 (1H, s), 9.86 (1H, s), 8.68 (1H, s),<br />
7.58 (2H, d, J = 7.6 Hz), 7.28 (2H, t, J = 7.5 Hz), 7.02 (1H, t, J = 7.4 Hz), 2.29 (2H, t, J = 7.4 Hz),<br />
1.94 (2H, t, J = 7.4 Hz), 1.57 (2H, m), 1.49 (2H, m), 1.33 - 1.20 (2H, m); 13C NMR (DMSO-d6) <br />
171.2, 169.1, 139.3, 128.6, 122.9, 119.0, 36.3, 32.2, 28.4, 28.3, 25.0. Anal. (C10H20N2O3) C, H, N.<br />
CLIP<br />
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Suberic acid monomethyl ester (23) (15.09 g, 80.2 mmol) and DMF (0.10 mL) in anhydrous DCM (300 mL) was added SOCl2 (34.6 mL, 0.481 mol), and the reaction mixture was refluxed for 3 h. The mixture was then concentrated. Toluene (300 mL) was added to the residue and evaporated to afford crude acid chloride 24. Crude 24 was dissolved in DCM (240 mL), and followed by addition of aniline (7.3 mL, 80.2 mmol) and Et3N (16.9 mL, 0.120 mol). The reaction mixture was stirred for 90 min at room temp. The course of reaction was monitored by TLC (30% EtOAc in hexanes) and LC–MS. DCM was removed, and ethyl acetate (500 mL) was added to dissolve the residue. The organic layer was washed with aqueous NaHCO3 (500 mL × 2), 1 N HCl (400 mL ×2), water, dried (Na2SO4), and evaporated to dryness under reduced pressure. The residue was purified by vacuum liquid chromatography (silica, 20% EtOAc in hexanes) to afford compound 25 as white crystalline solids (20.15 g, 96 %). NaOMe in MeOH solution (5.4 M, 106 mL, 0.573 mol) was added to a solution of compound 25 (10.05 g, 38.2 mmol) and NH2OH·HCl (26.54 g, 0.382 mol) in dry MeOH (375 mL). The reaction mixture was stirred for 40 min at room temp. The reaction was quenched by adding of 1 N HCl to pH 7–8. MeOH was removed under reduced pressure and water (1 L) was added to the residue. The precipitated solid was filtered and washed with water (300 mL) and EtOAc (150 mL) to afford crude 26 which was further purified by recrystallization. MeOH (200 mL) was added to crude 26 (5 g) and warmed to dissolve all solids. The MeOH solution was filtered, S37 and deionized water (400 mL) was added to the filtrate, the resulting solution was placed at 4 oC overnight. Crystals obtained were filtered and washed with deionized water (100 mL) to afford pure 26 (vorinostat, SAHA) as off-white crystals. Overall yield: 80–85% from compound 23.<br />
. Compound 26,<br />
LC–MS m/z 265.1 ([M + H] + ).<br />
1H NMR (DMSO-d6) 10.35 (1H, s), 9.86 (1H, s), 8.68 (1H, s), 7.58 (2H, d, J = 7.6 Hz), 7.28 (2H, t, J = 7.5 Hz), 7.02 (1H, t, J = 7.4 Hz), 2.29 (2H, t, J = 7.4 Hz), 1.94 (2H, t, J = 7.4 Hz), 1.57 (2H, m), 1.49 (2H, m), 1.33 - 1.20 (2H, m);<br />
13C NMR (DMSO-d6) 171.2, 169.1, 139.3, 128.6, 122.9, 119.0, 36.3, 32.2, 28.4, 28.3, 25.0.<br />
Anal. (C10H20N2O3) C, H, N.</div>
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NMR</div>
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<em> 1H NMR spectrum of C14H20N2O3 in CDCL3 at 400 MHz.</em></div>
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SEE <a data-mce-href="http://www.abmole.com/download/vorinostat-hnmr.pdf" href="http://www.abmole.com/download/vorinostat-hnmr.pdf">http://www.abmole.com/download/vorinostat-hnmr.pdf</a></div>
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<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
References</h2>
<ol style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li id="cite_note-1"> <a data-mce-href="http://www.merck.com/newsroom/press_releases/research_and_development/2006_0607.html" href="http://www.merck.com/newsroom/press_releases/research_and_development/2006_0607.html" rel="nofollow">"ZOLINZA, Merck's Investigational Medicine for Advanced Cutaneous T-Cell Lymphoma (CTCL), To Receive Priority Review from U.S. Food and Drug Administration"</a> (Press release). Merck & Co. June 7, 2006. Retrieved 2006-10-06.</li>
<li id="cite_note-2"> <a data-mce-href="http://www.hdacis.com/zolinza.html" href="http://www.hdacis.com/zolinza.html" rel="nofollow">HDAC Inhibitors Base (vorinostat)</a></li>
<li id="cite_note-3"> <a data-mce-href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108758.htm" href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108758.htm" rel="nofollow">"FDA Approves New Drug for Skin Cancer, Zolinza"</a> (Press release). Food and Drug Administration. October 6, 2006. Retrieved 2006-10-06.</li>
<li id="cite_note-Richon-4"> Richon, Victoria. <a data-mce-href="http://www.nature.com/bjc/journal/v95/n1s/full/6603463a.html" href="http://www.nature.com/bjc/journal/v95/n1s/full/6603463a.html" rel="nofollow">"Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor"</a>. British Journal of Cancer. Retrieved 3 May 2012.</li>
<li id="cite_note-atlas-5"> Cuneo A, Castoldi. <a data-mce-href="http://atlasgeneticsoncology.org/Anomalies/MycosFungID2039.html" href="http://atlasgeneticsoncology.org/Anomalies/MycosFungID2039.html" rel="nofollow">"Mycosis fungoides/Sezary's syndrome"</a>. Retrieved 2008-02-15.</li>
<li id="cite_note-6"> <a data-mce-href="http://www.eurekalert.org/pub_releases/2007-06/mc-vsa053007.php" href="http://www.eurekalert.org/pub_releases/2007-06/mc-vsa053007.php" rel="nofollow">"Vorinostat shows anti-cancer activity in recurrent gliomas"</a> (Press release). Mayo Clinic. June 3, 2007. Retrieved 2007-06-03.</li>
<li id="cite_note-7"> <a data-mce-href="http://www.rtmagazine.com/reuters_article.asp?id=20091209clin013.html" href="http://www.rtmagazine.com/reuters_article.asp?id=20091209clin013.html" rel="nofollow">http://www.rtmagazine.com/reuters_article.asp?id=20091209clin013.html</a> Dec 2009. URL dead Jan 2012</li>
<li id="cite_note-8"> <a data-mce-href="http://www.mdsbeacon.com/news/2012/01/11/zolinza-vorinostat-idarubicin-cytarabine-combination-yields-high-response-rates-for-mds-patients-ash-2011/" href="http://www.mdsbeacon.com/news/2012/01/11/zolinza-vorinostat-idarubicin-cytarabine-combination-yields-high-response-rates-for-mds-patients-ash-2011/" rel="nofollow">"Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)"</a>.</li>
<li id="cite_note-9"> <a data-mce-href="http://www.clinicaltrials.gov/ct2/show/NCT01319383" href="http://www.clinicaltrials.gov/ct2/show/NCT01319383" rel="nofollow">"Study of the Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART"</a>. <i>ClinicalTrials.gov</i>. 2011-03-21.</li>
<li id="cite_note-pmid19239360-10"> Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM (2009). <a data-mce-href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853863" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853863" rel="nofollow">"Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid."</a>. <i>AIDS Res Hum Retroviruses</i> <b>25</b> (2): 207–12. <a data-mce-href="http://en.wikipedia.org/wiki/Digital_object_identifier" href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a data-mce-href="http://dx.doi.org/10.1089%2Faid.2008.0191" href="http://dx.doi.org/10.1089%2Faid.2008.0191" rel="nofollow">10.1089/aid.2008.0191</a>. <a data-mce-href="http://en.wikipedia.org/wiki/PubMed_Central" href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a data-mce-href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853863" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853863" rel="nofollow">2853863</a>. <a data-mce-href="http://en.wikipedia.org/wiki/PubMed_Identifier" href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/19239360" href="http://www.ncbi.nlm.nih.gov/pubmed/19239360" rel="nofollow">19239360</a>.</li>
<li id="cite_note-pmid19136668-11"> Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J et al. (2009). <a data-mce-href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652322" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652322" rel="nofollow">"Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells."</a>. <i>J Biol Chem</i> <b>284</b> (11): 6782–9.<a data-mce-href="http://en.wikipedia.org/wiki/Digital_object_identifier" href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a data-mce-href="http://dx.doi.org/10.1074%2Fjbc.M807898200" href="http://dx.doi.org/10.1074%2Fjbc.M807898200" rel="nofollow">10.1074/jbc.M807898200</a>. <a data-mce-href="http://en.wikipedia.org/wiki/PubMed_Central" href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a data-mce-href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652322" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652322" rel="nofollow">2652322</a>. <a data-mce-href="http://en.wikipedia.org/wiki/PubMed_Identifier" href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/19136668" href="http://www.ncbi.nlm.nih.gov/pubmed/19136668" rel="nofollow">19136668</a>.</li>
<li><a data-mce-href="http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=SHH" href="http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=SHH" rel="nofollow">Vorinostat bound to proteins</a> in the <a data-mce-href="http://en.wikipedia.org/wiki/Protein_Data_Bank" href="http://en.wikipedia.org/wiki/Protein_Data_Bank" title="Protein Data Bank">PDB</a></li>
<li>J. Med. Chem.,1995, vol. 38(8), pages 1411-1413.</li>
<li>A new simple and high-yield synthesis of suberoylanilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells<br />J Med Chem 2005, 48(15): 5047</li>
<li>A new facile and expeditious synthesis of N-hydroxy-N'-phenyloctanediamide, a potent inducer of terminal cytodifferentiation<br />Org Prep Proced Int 2001, 33(4): 391</li>
<li>US patent 5369108, PDT PATENT</li>
<li>WO2007/22408.........</li>
<li>WO 1993007148</li>
<li>CN 102344392</li>
</ol>
<table class="mce-item-table" id="patents" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">United States</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7456219</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> APPROVAL 2006-11-14</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">EXPIRY 2026-11-14</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">United States</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6087367</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> 1994-10-04</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> 2011-10-04</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Canada</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2120619</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> 2006-11-21</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> 2012-10-05</td></tr>
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<tr><th scope="col" style="font-family: inherit; font-size: inherit;">Patent</th><th scope="col" style="font-family: inherit; font-size: inherit;">Patent Expiry</th><th scope="col" style="font-family: inherit; font-size: inherit;">pat use code</th></tr>
<tr><td style="font-family: inherit; font-size: inherit;">7399787</td><td style="font-family: inherit; font-size: inherit;">Feb 9, 2025</td><td style="font-family: inherit; font-size: inherit;">U-892</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">7456219</td><td style="font-family: inherit; font-size: inherit;">Mar 11, 2027</td><td style="font-family: inherit; font-size: inherit;"></td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">7652069</td><td style="font-family: inherit; font-size: inherit;">Mar 4, 2023</td><td style="font-family: inherit; font-size: inherit;"></td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">7732490</td><td style="font-family: inherit; font-size: inherit;">Mar 4, 2023</td><td style="font-family: inherit; font-size: inherit;">U-892</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">7851509</td><td style="font-family: inherit; font-size: inherit;">Feb 21, 2024</td><td style="font-family: inherit; font-size: inherit;">U-892</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">8067472</td><td style="font-family: inherit; font-size: inherit;">Mar 4, 2023</td><td style="font-family: inherit; font-size: inherit;">U-892</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">8093295</td><td style="font-family: inherit; font-size: inherit;">May 16, 2026</td><td style="font-family: inherit; font-size: inherit;"></td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">8101663</td><td style="font-family: inherit; font-size: inherit;">Mar 4, 2023</td><td style="font-family: inherit; font-size: inherit;">U-892</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">RE38506</td><td style="font-family: inherit; font-size: inherit;">Nov 29, 2013</td><td style="font-family: inherit; font-size: inherit;"></td></tr>
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U 892 =TREATMENT OF CUTANEOUS MANIFESTATIONS IN PATIENTS WTIH CUTANEOUS T-CELL LYMPHOMA (CTCL)</div>
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<tr><th scope="col" style="font-family: inherit; font-size: inherit;">Exclusivity Code</th><th scope="col" style="font-family: inherit; font-size: inherit;">Exclusivity_Date</th></tr>
<tr><td style="font-family: inherit; font-size: inherit;">ODE</td><td style="font-family: inherit; font-size: inherit;">Oct 6, 2013</td></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2009098515A1?cl=en" href="http://www.google.com/patents/WO2009098515A1?cl=en">WO2009098515A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feb 6, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 13, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Generics Uk Ltd</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Novel process for the preparation of vorinostat</td></tr>
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Marks, P.A., Breslow, R. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotech 25(1) 84-90 (2007). DOI: 10.1038/nbt1272<br />
Takashi Kumagai, et al. Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells. International Journal of Cancer. 2007 Aug 1;121(3):656-65. DOI: 10.1002/ijc.22558<br />
Hrzenjak A, et al. Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo. Mol Cancer. 2010 Mar 4;9:49. DOI: 10.1186/1476-4598-9-49</div>
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<tr><td><img alt="Vorinostat" src="http://www.druglead.com/cds/structure/Vorinostat.gif" /></td></tr>
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<span style="font-family: Arial; font-size: 13px;"><b>Title:</b> Vorinostat</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>CAS Registry Number:</b> 149647-78-9</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>CAS Name:</b> <i>N</i>-Hydroxy-<i>N</i></span><span style="font-family: Symbol; font-size: 13px;">¢</span><span style="font-family: Arial; font-size: 13px;">-phenyloctanediamide</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Additional Names:</b> suberoylanilide hydroxamic acid; SAHA</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Molecular Formula:</b> C</span><span style="font-family: Arial; font-size: 11px;">14</span><span style="font-family: Arial; font-size: 13px;">H</span><span style="font-family: Arial; font-size: 11px;">20</span><span style="font-family: Arial; font-size: 13px;">N</span><span style="font-family: Arial; font-size: 11px;">2</span><span style="font-family: Arial; font-size: 13px;">O</span><span style="font-family: Arial; font-size: 11px;">3</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Molecular Weight:</b> 264.32</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Percent Composition:</b> C 63.62%, H 7.63%, N 10.60%, O 18.16%</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Literature References:</b> Second generation hybrid polar compound; histone deacetylase (HDAC) inhibitor that induces cell cycle arrest, differentiation and apoptosis in tumor cells. Prepn: R. Breslow <i>et al.,</i> <b>WO</b> <b>9307148</b>; <i>eidem,</i> <b>US</b> <b>5369108</b> (1993, 1994 both to Sloan-Kettering Inst.; Columbia Univ.); J. C. Stowell <i>et al.,</i> <i>J. Med. Chem.</i> <b>38</b>, 1411 (1995). Synthesis: A. Mai <i>et al.,</i> <i>Org. Prep. Proceed. Int.</i> <b>33</b>, 391 (2001). HTLC determn in serum: L. Du <i>et al.,</i> <i>Rapid Commun. Mass Spectrom.</i> <b>19</b>, 1779 (2005). <i>In vitro</i>antiproliferative activity: P. N. Munster <i>et al.,</i> <i>Cancer Res.</i> <b>61</b>, 8492 (2001). <i>In vivo</i> antineoplastic activity: L. A. Cohen <i>et al.,</i><i>Anticancer Res.</i> <b>22</b>, 1497 (2002). Clinical pharmacokinetics and activity in cancer patients: W. K. Kelly <i>et al.,</i> <i>J. Clin. Oncol.</i> <b>23</b>, 3923 (2005). Review of mechanism of action: V. M. Richon <i>et al.,</i> <i>Blood Cells Mol. Dis. </i><b>27</b>, 260-264 (2001); of development and therapeutic potential: R. W. Johnstone, <i>IDrugs </i><b>7</b>, 674-682 (2004).</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Properties:</b> White solid, mp 159-160.5°.</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Melting point:</b> mp 159-160.5°</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Therap-Cat:</b> Antineoplastic.</span></div>
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<span style="font-family: Arial; font-size: 13px;"><b>Keywords:</b> Antineoplastic.</span></div>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/US20110313044" href="http://www.google.com/patents/US20110313044">US20110313044</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 16, 2011</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 22, 2011</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Urquima S.A.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Polymorphs of Suberoylanilide Hydroxamic Acid</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/EP2079304A1?cl=en" href="http://www.google.com/patents/EP2079304A1?cl=en">EP2079304A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 24, 2007</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 22, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Merck &amp; Co., Inc.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Amine base salts of saha and polymorphs thereof</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/EP2229941A1?cl=en" href="http://www.google.com/patents/EP2229941A1?cl=en">EP2229941A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 16, 2006</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 22, 2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Merck Sharp & Dohme Corp.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Formulations of suberoylanilide hydroxamic acid and methods for producing same</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/EP2292221A2?cl=en" href="http://www.google.com/patents/EP2292221A2?cl=en">EP2292221A2</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 16, 2006</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 9, 2011</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Merck Sharp & Dohme Corp.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Formulations of suberoylanilide hydroxamic acid and methods for producing same</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2006127319A2?cl=en" href="http://www.google.com/patents/WO2006127319A2?cl=en">WO2006127319A2</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 16, 2006</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 30, 2006</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Merck & Co Inc</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Formulations of suberoylanilide hydroxamic acid and methods for producing same</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2006127321A2?cl=en" href="http://www.google.com/patents/WO2006127321A2?cl=en">WO2006127321A2</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 16, 2006</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 30, 2006</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Merck & Co Inc</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Formulations of suberoylanilide hydroxamic acid and methods for producing same</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2008039421A2?cl=en" href="http://www.google.com/patents/WO2008039421A2?cl=en">WO2008039421A2</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 24, 2007</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 3, 2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Arlene E Mckeown</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pharmaceutical compositions of hdac inhibitors and chelatable metal compounds, and metal-hdac inhibitor chelate complexes</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2008042146A1?cl=en" href="http://www.google.com/patents/WO2008042146A1?cl=en">WO2008042146A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 24, 2007</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 10, 2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Arlene E Mckeown</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Amine base salts of saha and polymorphs thereof</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2008097654A1?cl=en" href="http://www.google.com/patents/WO2008097654A1?cl=en">WO2008097654A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feb 8, 2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 14, 2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nancie M Archin</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methods of using saha for treating hiv infection</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2009020565A1?cl=en" href="http://www.google.com/patents/WO2009020565A1?cl=en">WO2009020565A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 1, 2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feb 12, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Lixte Biotechnology Inc</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Use of phosphatases to treat neuroblastomas and medulloblastomas</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2010061220A2?cl=en" href="http://www.google.com/patents/WO2010061220A2?cl=en">WO2010061220A2</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 25, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 3, 2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Generics [Uk] Limited</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Novel processes and pure polymorphs</td></tr>
</tbody></table>
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EXTRAS</div>
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<a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/MS-275.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/MS-275.html">MS-275 (Entinostat)</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/CI-994.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/CI-994.html">CI-994 (Tacedinaline)</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/BML-210.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/BML-210.html">BML-210</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/M344.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/M344.html">M344</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/MGCD0103.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/MGCD0103.html">MGCD0103 (Mocetinostat)</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/PXD101.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/PXD101.html">PXD101 (Belinostat)</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/LBH-589.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/LBH-589.html">LBH-589 (Panobinostat)</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Tubastatin-A.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Tubastatin-A.html">Tubastatin A</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Scriptaid.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Scriptaid.html">Scriptaid</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/NSC-3852.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/NSC-3852.html">NSC 3852</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/NCH-51.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/NCH-51.html">NCH 51</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/HNHA.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/HNHA.html">HNHA</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/BML-281.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/BML-281.html">BML-281</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/CBHA.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/CBHA.html">CBHA</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Salermide.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Salermide.html">Salermide</a><a href="https://www.blogger.com/null">; </a><a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Pimelic-Diphenylamide.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Pimelic-Diphenylamide.html">Pimelic Diphenylamide</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/ITF2357.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/ITF2357.html">ITF2357 (Givinostat)</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/PCI-24781.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/PCI-24781.html">PCI-24781</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/APHA-Compound-8.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/APHA-Compound-8.html">APHA Compound 8</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Droxinostat.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/Droxinostat.html">Droxinostat</a>; <a data-mce-href="http://www.exchemistry.com/histone-deacetylase-inhibitors/SB939.html" href="http://www.exchemistry.com/histone-deacetylase-inhibitors/SB939.html">SB939</a>.</div>
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SEE COMPILATION ON SIMILAR COMPOUNDS AT ..............<a data-mce-href="http://drugsynthesisint.blogspot.in/p/nostat-series.html" href="http://drugsynthesisint.blogspot.in/p/nostat-series.html">http://drugsynthesisint.blogspot.in/p/nostat-series.html</a></div>
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//////////////149647-78-9, MK0683, VORINOSTAT, Zolinza</div>
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ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1</div>
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///////</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-1346483141860457136.post-88017614406121223472016-07-27T00:31:00.001-07:002016-07-27T00:31:36.734-07:00Prucalopride succinate (Resolor )<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="Prucalopride.svg" class="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/76/Prucalopride.svg/260px-Prucalopride.svg.png" height="256" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/76/Prucalopride.svg/260px-Prucalopride.svg.png" style="height: auto; max-width: 100%;" width="634" /></div>
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Prucalopride (Resolor )</div>
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<strong>CAS 179474-81-8</strong> , R-093877; R-108512</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>4-Amino-5-chlor-N-[<wbr></wbr>1-(3-methoxypropyl)<wbr></wbr>-4-piperidinyl]-2,3<wbr></wbr>-dihydro-1-benzofur<wbr></wbr>an-7-carboxamid</strong></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">R-093877|R-108512|R<wbr></wbr>esolor®</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">Resolor;Resotran</span></div>
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<span class="">Resotran</span></div>
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<span class="">UNII:0A09IUW5TP</span></div>
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SHIRE 2010 LAUNCHED</div>
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JANNSEN PHASE 3 IRRITABLE BOWL SYNDROME</div>
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<a data-mce-href="http://www.google.co.in/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Janssen+Pharmaceutica+N.V.%22" href="http://www.google.co.in/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22Janssen+Pharmaceutica+N.V.%22">Janssen Pharmaceutica N.V.</a>, INNOVATOR</div>
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</div>
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<img alt="Prucalopride succinate.png" class="" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=9870009&t=l" height="647" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=9870009&t=l" style="height: auto; max-width: 100%;" width="647" /></div>
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<table class="top-summary-items mce-item-table" data-mce-style="height: 80px;" style="border: 1px dashed rgb(187, 187, 187); height: 80px; width: 637px;"><tbody>
<tr><td class="breakword" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride succinate; 179474-85-2; Resolor; Prucalopride (succinate); UNII-4V2G75E1CK; R-108512;</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Formula:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C22H32ClN3O7&sort=mw&sort_dir=asc" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C22H32ClN3O7&sort=mw&sort_dir=asc" title="Find all compounds with formula C22H32ClN3O7">C<sub>22</sub>H<sub>32</sub>ClN<sub>3</sub>O<sub>7</sub></a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Weight:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">485.95838 g/mol</td></tr>
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Drug Name:Prucalopride Succinate</div>
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Trade Name:Resolor<sup>®, </sup>MOA:Serotonin (5-HT4) receptor agonist, Indication:Chronic constipation</div>
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Company:Shire (Originator) , Johnson & Johnson</div>
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APPROVED EU 2009-10-15</div>
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CHINA 2014-01-21</div>
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<a class="ml20" data-mce-href="http://www.selleckchem.com/coa/prucalopride-succinat-COA-S424701.html" href="http://www.selleckchem.com/coa/prucalopride-succinat-COA-S424701.html" target="_blank"><b class="ico_co"></b>COA</a> <a class="ml20" data-mce-href="http://file.selleckchem.com/downloads/nmr/S424701-Prucalopride-succinat-HNMR-Selleck.pdf" href="http://file.selleckchem.com/downloads/nmr/S424701-Prucalopride-succinat-HNMR-Selleck.pdf" rel="nofollow" target="_blank"><b class="t_ico"></b>NMR</a> <a class="ml20" data-mce-href="http://file.selleckchem.com/downloads/hplc/S424701-Prucalopride-succinat-HPLC-Selleck.pdf" href="http://file.selleckchem.com/downloads/hplc/S424701-Prucalopride-succinat-HPLC-Selleck.pdf" rel="nofollow" target="_blank"><b class="t_ico"></b>HPLC</a> CLICK<b class="ico_co"></b></div>
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<b>Prucalopride</b> (brand name <b>Resolor</b>, developed by <a data-mce-href="https://en.wikipedia.org/wiki/Johnson_%26_Johnson" href="https://en.wikipedia.org/wiki/Johnson_%26_Johnson" title="Johnson & Johnson">Johnson & Johnson</a> and licensed to <a data-mce-href="https://en.wikipedia.org/wiki/Movetis" href="https://en.wikipedia.org/wiki/Movetis" title="Movetis">Movetis</a>) is a <a data-mce-href="https://en.wikipedia.org/wiki/Pharmaceutical_drug" href="https://en.wikipedia.org/wiki/Pharmaceutical_drug" title="Pharmaceutical drug">drug</a> acting as a selective, high affinity <a data-mce-href="https://en.wikipedia.org/wiki/5-HT4_receptor" href="https://en.wikipedia.org/wiki/5-HT4_receptor" title="5-HT4 receptor">5-HT<sub>4</sub> receptor</a> <a data-mce-href="https://en.wikipedia.org/wiki/Agonist" href="https://en.wikipedia.org/wiki/Agonist" title="Agonist">agonist</a><sup class="reference" id="cite_ref-Briejer_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Briejer-1" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Briejer-1">[1]</a></sup> which targets the impaired motility associated with chronic <a data-mce-href="https://en.wikipedia.org/wiki/Constipation" href="https://en.wikipedia.org/wiki/Constipation" title="Constipation">constipation</a>, thus normalizing bowel movements.<sup class="reference" id="cite_ref-2"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-2" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-2">[2]</a></sup><sup class="reference" id="cite_ref-3"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-3" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-3">[3]</a></sup><sup class="reference" id="cite_ref-4"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-4" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-4">[4]</a></sup><sup class="reference" id="cite_ref-5"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-5" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-5">[5]</a></sup><sup class="reference" id="cite_ref-6"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-6" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-6">[6]</a></sup><sup class="reference" id="cite_ref-Tack_7-0"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Tack-7" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Tack-7">[7]</a></sup> Prucalopride was approved for use in Europe in 2009,<sup class="reference" id="cite_ref-8"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-8" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-8">[8]</a></sup> in Canada (named <b>Resotran</b>) on December 7, 2011<sup class="reference" id="cite_ref-9"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-9" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-9">[9]</a></sup> and in Israel in 2014<sup class="reference" id="cite_ref-10"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-10" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-10">[10]</a></sup> but it has not been approved by the <a data-mce-href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> for use in the United States. The drug has also been tested for the treatment of <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Chronic_intestinal_pseudo-obstruction" href="https://en.wikipedia.org/wiki/Chronic_intestinal_pseudo-obstruction" title="Chronic intestinal pseudo-obstruction">chronic intestinal pseudo-obstruction</a>.<sup class="reference" id="cite_ref-11"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-11" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-11">[11]</a></sup><sup class="reference" id="cite_ref-12"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-12" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-12">[12]</a></sup></div>
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<span class="mw-headline" id="Mechanism_of_action">Mechanism of action</span></h2>
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Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity <a data-mce-href="https://en.wikipedia.org/wiki/Serotonin" href="https://en.wikipedia.org/wiki/Serotonin" title="Serotonin">serotonin</a> (<a data-mce-href="https://en.wikipedia.org/wiki/5-HT4_receptor" href="https://en.wikipedia.org/wiki/5-HT4_receptor" title="5-HT4 receptor">5-HT<sub>4</sub></a>) receptor agonist with enterokinetic activities.<sup class="reference" id="cite_ref-SmPC_13-0"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13">[13]</a></sup> Prucalopride alters colonic motility patterns via serotonin 5-HT<sub>4</sub> receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for <a data-mce-href="https://en.wikipedia.org/wiki/Defecation" href="https://en.wikipedia.org/wiki/Defecation" title="Defecation">defecation</a>.</div>
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<img alt="" data-mce-src="http://www.mims.com/resources/drugs/Philippines/packshot/Resolor6001PPS0.JPG" src="http://www.mims.com/resources/drugs/Philippines/packshot/Resolor6001PPS0.JPG" style="height: auto; max-width: 100%;" /></div>
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The observed effects are exerted via highly selective action on 5-HT<sub>4</sub> receptors:<sup class="reference" id="cite_ref-SmPC_13-1"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13">[13]</a></sup> prucalopride has >150-fold higher affinity for 5-HT<sub>4</sub> receptors than for other receptors.<sup class="reference" id="cite_ref-Briejer_1-1"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Briejer-1" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Briejer-1">[1]</a></sup><sup class="reference" id="cite_ref-DeMaeyer_14-0"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-DeMaeyer-14" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-DeMaeyer-14">[14]</a></sup> Prucalopride differs from other 5-HT<sub>4</sub> agonists such as <a data-mce-href="https://en.wikipedia.org/wiki/Tegaserod" href="https://en.wikipedia.org/wiki/Tegaserod" title="Tegaserod">tegaserod</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Cisapride" href="https://en.wikipedia.org/wiki/Cisapride" title="Cisapride">cisapride</a>, which at therapeutic concentrations also interact with other receptors (5-HT<sub>1B/D</sub> and the cardiac <a data-mce-href="https://en.wikipedia.org/wiki/HERG" href="https://en.wikipedia.org/wiki/HERG" title="HERG">human ether-a-go-go K<sup>+</sup> or hERG channel</a>respectively) and this may account for the adverse <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Cardiovascular" href="https://en.wikipedia.org/wiki/Cardiovascular" title="Cardiovascular">cardiovascular</a> events that have resulted in the restricted availability of these drugs.<sup class="reference" id="cite_ref-DeMaeyer_14-1"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-DeMaeyer-14" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-DeMaeyer-14">[14]</a></sup> <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Clinical_trials" href="https://en.wikipedia.org/wiki/Clinical_trials" title="Clinical trials">Clinical trials</a> evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.<sup class="reference" id="cite_ref-SmPC_13-2"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13">[13]</a></sup></div>
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<img alt="ChemSpider 2D Image | prucalopride | C18H26ClN3O3" class="" data-mce-src="http://www.chemspider.com/ImagesHandler.ashx?id=2314539&w=250&h=250" height="412" src="http://www.chemspider.com/ImagesHandler.ashx?id=2314539&w=250&h=250" style="height: auto; max-width: 100%;" width="412" /></div>
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<span class="mw-headline" id="Pharmacokinetics">Pharmacokinetics</span></h2>
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Prucalopride is rapidly absorbed (<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/CMax" href="https://en.wikipedia.org/wiki/CMax" title="CMax">C<sub>max</sub></a> attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. <a data-mce-href="https://en.wikipedia.org/wiki/Metabolism" href="https://en.wikipedia.org/wiki/Metabolism" title="Metabolism">Metabolism</a> is not the major route of elimination. <i>In vitro</i>, human liver metabolism is very slow and only minor amounts of <a data-mce-href="https://en.wikipedia.org/wiki/Metabolite" href="https://en.wikipedia.org/wiki/Metabolite" title="Metabolite">metabolites</a> are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in <a data-mce-href="https://en.wikipedia.org/wiki/Urine" href="https://en.wikipedia.org/wiki/Urine" title="Urine">urine</a> and at least 6% in <a data-mce-href="https://en.wikipedia.org/wiki/Feces" href="https://en.wikipedia.org/wiki/Feces" title="Feces">feces</a>).<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Renal_excretion" href="https://en.wikipedia.org/wiki/Renal_excretion" title="Renal excretion">Renal excretion</a> of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours,<sup class="reference" id="cite_ref-15"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-15" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-15">[15]</a></sup> and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.<sup class="reference" id="cite_ref-SmPC_13-3"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13">[13]</a></sup></div>
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<i>In vitro</i> data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.<sup class="reference" id="cite_ref-SmPC_13-4"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13">[13]</a></sup></div>
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<img alt="" class="" data-mce-src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcRmQ_n1_g6wLtVOmdG24EKQbdnC6OBcSsyQn_4n9MZVCJdPtXYa" height="386" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcRmQ_n1_g6wLtVOmdG24EKQbdnC6OBcSsyQn_4n9MZVCJdPtXYa" style="height: auto; max-width: 100%;" width="515" /></div>
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<span class="mw-headline" id="Efficacy">Efficacy</span></h2>
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The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week.<sup class="reference" id="cite_ref-Tack_7-1"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Tack-7" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Tack-7">[7]</a></sup><sup class="reference" id="cite_ref-Camilleri_16-0"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Camilleri-16" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Camilleri-16">[16]</a></sup><sup class="reference" id="cite_ref-Quigley_17-0"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Quigley-17" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Quigley-17">[17]</a></sup> Further measures are improvements in PAC-QOL<sup class="reference" id="cite_ref-18"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-18" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-18">[18]</a></sup> (a quality of life measure) and PAC-SYM<sup class="reference" id="cite_ref-19"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-19" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-19">[19]</a></sup> (a range of <a data-mce-href="https://en.wikipedia.org/wiki/Human_feces" href="https://en.wikipedia.org/wiki/Human_feces" title="Human feces">stool</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Abdominal" href="https://en.wikipedia.org/wiki/Abdominal" title="Abdominal">abdominal</a>, and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Rectal" href="https://en.wikipedia.org/wiki/Rectal" title="Rectal">rectal</a> symptoms associated with chronic constipation). Infrequent bowel movements, <a data-mce-href="https://en.wikipedia.org/wiki/Bloating" href="https://en.wikipedia.org/wiki/Bloating" title="Bloating">bloating</a>, straining, <a data-mce-href="https://en.wikipedia.org/wiki/Abdominal_pain" href="https://en.wikipedia.org/wiki/Abdominal_pain" title="Abdominal pain">abdominal pain</a>, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.<sup class="reference" id="cite_ref-20"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-20" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-20">[20]</a></sup><sup class="reference" id="cite_ref-21"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-21" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-21">[21]</a></sup><sup class="reference" id="cite_ref-22"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-22" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-22">[22]</a></sup><sup class="reference" id="cite_ref-23"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-23" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-23">[23]</a></sup><sup class="reference" id="cite_ref-24"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-24" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-24">[24]</a></sup></div>
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In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with <a data-mce-href="https://en.wikipedia.org/wiki/Placebo" href="https://en.wikipedia.org/wiki/Placebo" title="Placebo">placebo</a>.<sup class="reference" id="cite_ref-Tack_7-2"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Tack-7" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Tack-7">[7]</a></sup><sup class="reference" id="cite_ref-Camilleri_16-1"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Camilleri-16" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Camilleri-16">[16]</a></sup><sup class="reference" id="cite_ref-Quigley_17-1"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Quigley-17" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Quigley-17">[17]</a></sup> There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants).<sup class="reference" id="cite_ref-Tack_7-3"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Tack-7" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Tack-7">[7]</a></sup><sup class="reference" id="cite_ref-Camilleri_16-2"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Camilleri-16" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Camilleri-16">[16]</a></sup><sup class="reference" id="cite_ref-Quigley_17-2"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Quigley-17" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-Quigley-17">[17]</a></sup> The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.<sup class="reference" id="cite_ref-25"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-25" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-25">[25]</a></sup><sup class="reference" id="cite_ref-26"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-26" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-26">[26]</a></sup></div>
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<span class="mw-headline" id="Side_effects">Side effects</span></h2>
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Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are <a data-mce-href="https://en.wikipedia.org/wiki/Headache" href="https://en.wikipedia.org/wiki/Headache" title="Headache">headache</a> and<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Gastrointestinal_symptom" href="https://en.wikipedia.org/wiki/Gastrointestinal_symptom" title="Gastrointestinal symptom">gastrointestinal symptoms</a> (abdominal pain, <a data-mce-href="https://en.wikipedia.org/wiki/Nausea" href="https://en.wikipedia.org/wiki/Nausea" title="Nausea">nausea</a> or <a data-mce-href="https://en.wikipedia.org/wiki/Diarrhea" href="https://en.wikipedia.org/wiki/Diarrhea" title="Diarrhea">diarrhea</a>). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.<sup class="reference" id="cite_ref-SmPC_13-5"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13">[13]</a></sup></div>
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<span class="mw-headline" id="Approval">Approval</span></h2>
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In the <a data-mce-href="https://en.wikipedia.org/wiki/European_Economic_Area" href="https://en.wikipedia.org/wiki/European_Economic_Area" title="European Economic Area">European Economic Area</a>, prucalopride was originally approved for the <a data-mce-href="https://en.wikipedia.org/wiki/Symptomatic_treatment" href="https://en.wikipedia.org/wiki/Symptomatic_treatment" title="Symptomatic treatment">symptomatic treatment</a> of chronic constipation in women in whom <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Laxatives" href="https://en.wikipedia.org/wiki/Laxatives" title="Laxatives">laxatives</a> fail to provide adequate relief.<sup class="reference" id="cite_ref-SmPC_13-6"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13">[13]</a></sup> Subsequently, it has been approved by the European Commission for use in adults – that is, including male patients – for the same indication.<sup class="reference" id="cite_ref-27"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-27" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-27">[27]</a></sup></div>
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<span class="mw-headline" id="Contraindications">Contraindications</span></h2>
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Prucalopride is contraindicated where there is <a data-mce-href="https://en.wikipedia.org/wiki/Hypersensitivity" href="https://en.wikipedia.org/wiki/Hypersensitivity" title="Hypersensitivity">hypersensitivity</a> to the active substance or to any of the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Excipients" href="https://en.wikipedia.org/wiki/Excipients" title="Excipients">excipients</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Renal_impairment" href="https://en.wikipedia.org/wiki/Renal_impairment" title="Renal impairment">renal impairment</a> requiring dialysis, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Intestinal" href="https://en.wikipedia.org/wiki/Intestinal" title="Intestinal">intestinal</a> <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Intestinal_perforation" href="https://en.wikipedia.org/wiki/Intestinal_perforation" title="Intestinal perforation">perforation</a> or<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Intestinal_obstruction" href="https://en.wikipedia.org/wiki/Intestinal_obstruction" title="Intestinal obstruction">obstruction</a> due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Intestinal_tract" href="https://en.wikipedia.org/wiki/Intestinal_tract" title="Intestinal tract">intestinal tract</a>, such as <a data-mce-href="https://en.wikipedia.org/wiki/Crohn%27s_disease" href="https://en.wikipedia.org/wiki/Crohn%27s_disease" title="Crohn's disease">Crohn's disease</a>, and <a data-mce-href="https://en.wikipedia.org/wiki/Ulcerative_colitis" href="https://en.wikipedia.org/wiki/Ulcerative_colitis" title="Ulcerative colitis">ulcerative colitis</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Toxic_megacolon" href="https://en.wikipedia.org/wiki/Toxic_megacolon" title="Toxic megacolon">toxic megacolon</a>/megarectum.<sup class="reference" id="cite_ref-SmPC_13-7"><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13" href="https://en.wikipedia.org/wiki/Prucalopride#cite_note-SmPC-13">[13]</a></sup></div>
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CLIP</div>
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Prucalopride succinate, a first-in-class dihydrobenzofurancarboxamide, is a selective serotonin (5-HT4) receptor agonist.86–94 The drug, marketed under the brand name Resolor , possesses enterokinetic activity and was developed by the Belgian-based pharmaceutical firm Movetis. Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation, triggering the central propulsive force for defecation.95–97 The preparation of prucalopride succinate begins with the commercially available salicylic aniline 124 (Scheme 18). Acidic esterification, acetylation of the aniline nitrogen atom, and ambient-temperature chlorination via sulfuryl chloride (SO2Cl2) converted aminophenol 124 to acetamidoester 125 in 83% yield over the course of three steps.98–102 An unique set of conditions involving sodium tosylchloramide (chloramine T) trihydrate and sodium iodide were then employed to convert 125 to o-phenolic iodide 126, which then underwent sequential Sonogashira/cyclization reaction utilizing TMS-acetylene with tetramethylguanidine (TMG) in the presence of silica gel to furnish the benzofuran progenitor of 127.103 Hydrogenation of this intermediate benzofuranyl Sonagashira product saturated the 2,3-benzofuranyl bond while leaving the chlorine atom intact, ultimately delivering dihydrobenzofuran 127 in excellent yield for the two step sequence. Base-induced saponification and acetamide removal gave rise to acid 128. This acid was activated as the corresponding mixed anhydride and treated with commercial piperidine 129 to construct prucalopride which was stirred at room temperature for 24 h in ethanolic succinic acid to provide prucalopride succinate (XI). The yield for the formation of the salt was not provided.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-122.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-122.jpg" rel="attachment wp-att-7897"><img alt="STR1" class="alignnone size-full wp-image-7897" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-122.jpg" height="394" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-122.jpg" style="height: auto; max-width: 100%;" width="552" /></a></div>
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86. Briejer, M. R.; Bosmans, J. P.; Van Daele, P.; Jurzak, M.; Heylen, L.; Leysen, J. E.;Prins, N. H.; Schuurkes, J. A. J. Eur. J. Pharmacol. 2001, 423, 71.<br />87. Briejer, M. R.; Prins, N. H.; Schuurkes, J. A. J. Neurogastroenterol. Motil. 2001, 13,465.<br />88. Coggrave, M.; Wiesel, P. H.; Norton, C. Cochrane Database Syst. Rev. 2006.CD002115.<br />89. Coremans, G.; Kerstens, R.; De Pauw, M.; Stevens, M. Digestion 2003, 67, 82.<br />90. De Winter, B. Y.; Boeckxstaens, G. E.; De Man, J. G.; Moreels, T. G.; Schuurkes, J.A. J.; Peeters, T. L.; Herman, A. G.; Pelckmans, P. A. Gut 1999, 45, 713.<br />91. Emmanuel, A. V.; Roy, A. J.; Nicholls, T. J.; Kamm, M. A. Aliment. Pharmacol.Ther. 2002, 16, 1347.<br />92. Frampton, J. E. Drugs 2009, 69, 2463.<br />93. Krogh, K.; Bach Jensen, M.; Gandrup, P.; Laurberg, S.; Nilsson, J.; Kerstens, R.;De Pauw, M. Scand. J. Gastroenterol. 2002, 37, 431.<br />94. Pau, D.; Workman, A. J.; Kane, K. A.; Rankin, A. C. J. Pharmacol. Exp. Ther. 2005,313, 146.<br />95. De Maeyer, J. H.; Schuurkes, J. A. J.; Lefebvre, R. A. Br. J. Pharmacol. 2009, 156,362.<br />96. Irving, H. R.; Tochon-Danguy, N.; Chinkwo, K. A.; Li, J. G.; Grabbe, C.; Shapiro,M.; Pouton, C. W.; Coupar, I. M. Pharmacology 2010, 85, 224.<br />97. Ray, A. M.; Kelsell, R. E.; Houp, J. A.; Kelly, F. M.; Medhurst, A. D.; Cox, H. M.;Calver, A. R. Eur. J. Pharmacol. 2009, 604, 1.<br />98. Baba, Y.; Usui, T.; Iwata, N. EP 640602 A1, 1995.<br />99. Fancelli, D.; Caccia, C.; Severino, D.; Vaghi, F.; Varasi, M. WO 9633186 A1,1996.<br />100. Hirokawa, Y.; Fujiwara, I.; Suzuki, K.; Harada, H.; Yoshikawa, T.; Yoshida, N.;Kato, S. J. Med. Chem. 2003, 46, 702.<br />101. Kakigami, T.; Usui, T.; Tsukamoto, K.; Kataoka, T. Chem. Pharm. Bull. 1998, 46,42.<br />102. Van Daele, G. H. P.; Bosmans, J.-P. R. M. A.; Schuurkes, J. A. J. WO 9616060 A1,1996.<br />103. Candiani, I.; DeBernadinis, S.; Cabri, W.; Marchi, M.; Bedeschi, A.; Penco, S.Synlett 1993, 269.</div>
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PAPER</div>
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Synlett 1993, 269</div>
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<a data-mce-href="https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-1993-22663" href="https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-1993-22663">https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-1993-22663</a></div>
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PAPER</div>
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Chem. Pharm. Bull. 1998, 46,42.</div>
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<a data-mce-href="https://www.jstage.jst.go.jp/article/cpb1958/46/1/46_1_42/_article" href="https://www.jstage.jst.go.jp/article/cpb1958/46/1/46_1_42/_article">https://www.jstage.jst.go.jp/article/cpb1958/46/1/46_1_42/_article</a></div>
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<a data-mce-href="https://www.jstage.jst.go.jp/article/cpb1958/46/1/46_1_42/_pdf" href="https://www.jstage.jst.go.jp/article/cpb1958/46/1/46_1_42/_pdf">https://www.jstage.jst.go.jp/article/cpb1958/46/1/46_1_42/_pdf</a></div>
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PATENT</div>
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US5948794</div>
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<a data-mce-href="http://www.google.co.in/patents/US5948794" href="http://www.google.co.in/patents/US5948794">http://www.google.co.in/patents/US5948794</a></div>
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EXAMPLE 1</div>
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In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ±5° C. N,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10° C. The resulting mixture was added dropwise over a 20-min period to a solution of 1-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCl<sub>3</sub>. The filtrate was separated in it's layers. The separated organic layer was washed with water (50 ml)+a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50° C.), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-N- 1-(3-methoxypropyl)-4-piperidinyl!-7-benzofurancarboxamide monohydrochloride (comp. 1).</div>
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US5854260</div>
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<a data-mce-href="http://www.google.co.in/patents/US5854260" href="http://www.google.co.in/patents/US5854260">http://www.google.co.in/patents/US5854260</a></div>
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EXPERIMENTAL PART EXAMPLE 1</div>
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In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ±5° C. N,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10° C. The resulting mixture was added dropwise over a 20-min period to a solution of 1-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCl<sub>3</sub>. The filtrate was separated in it's layers. The separated organic layer was washed with water (50 ml)+ a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50° C.), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-N- 1-(3-methoxypropyl)-4-piperidinyl!-7-benzofurancarboxamide monohydrochloride (comp. 1).</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-32.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-32.jpg" rel="attachment wp-att-7851"><img alt="str1" class="alignnone wp-image-7851" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-32.jpg" height="441" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-32.jpg" style="height: auto; max-width: 100%;" width="917" /></a></div>
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PATENT</div>
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WO199616060A1</div>
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<a data-mce-href="http://www.google.co.in/patents/WO1996016060A1?cl=en" href="http://www.google.co.in/patents/WO1996016060A1?cl=en">http://www.google.co.in/patents/WO1996016060A1?cl=en</a></div>
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EP-0,389,037-A, published on September 26, 1990, N-(3-hydroxy-4-piperidin- yl) (dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives are disclosed as having gastrointestinal motility stimulating properties. In our EP-0,445,862-A, published on September 11, 1991, N-(4-piperidinyl) (dihydrobenzo¬ furan or dihydro-2H-benzopyran)carboxamide derivatives are disclosed also having gastrointestinal motility stimulating properties.</div>
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The compound subject to the present application differs therefrom by showing superior enterokinetic properties.</div>
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The present invention concerns a compound of formula</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO1996016060A1/imgf000003_0001.png" href="http://patentimages.storage.googleapis.com/WO1996016060A1/imgf000003_0001.png"><img alt="Figure imgf000003_0001" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/WO1996016060A1/imgf000003_0001.png" height="96" id="imgf000003_0001" src="http://patentimages.storage.googleapis.com/WO1996016060A1/imgf000003_0001.png" style="height: auto; max-width: 100%;" width="376" /></a></div>
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and the pharmaceutically acceptable acid addition salts thereof.</div>
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The chemical name of the compound of formula (I) is 4-amino-5-chloro-2,3-dihydro-N- [l-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-33.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-33.jpg" rel="attachment wp-att-7852"><img alt="str1" class="alignnone wp-image-7852" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-33.jpg" height="414" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-33.jpg" style="height: auto; max-width: 100%;" width="885" /></a></div>
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Example 1</div>
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In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ± 5 °C. H,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10 °C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10°C. The resulting mixture was added dropwise over a 20-min period to a solution of l-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCI3. The filtrate was separated in it's layers. The separated organic layer was washed with water (50 ml) + a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50 °C), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-M-[ 1 -(3-methoxypropyl)-4-piperidinyl]-7- benzofurancarboxamide monohydrochloride (comp. 1).</div>
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Example 2</div>
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A mixture of 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzofuran- carboxamide(O.Olmol), l-chloro-3-methoxypropane (0.012mol), M,M-diethyl- ethanamine (2Jml) and KI (catalytic amount) in N,M-dimethylformamide (75ml) was stirred overnight at 50°C. The reaction mixture was cooled. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3/(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried (vacuum; 80°C), yielding 1.40g (35%) of 4-amino-5-chloro-2,3-dihydro-N-[l-(3-methoxypropyl)- 4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (comp. 1).</div>
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PAPER</div>
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<em>Chinese Journal of Pharmaceuticals</em> <strong>2012</strong>,<em> 43</em>, 5-8.</div>
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CLIP</div>
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Chinese Patent CN 103012337 A report is as follows:</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00053.png" href="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00053.png"><img alt="Figure CN104529960AD00053" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00053.png" id="idf0005" src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00053.png" style="height: auto; max-width: 100%;" /></a></div>
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PAPER</div>
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<em>Pharmaceutical & Clinical Research</em> <strong>2011</strong>, <em>19</em>, 306-307.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-36.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-36.jpg" rel="attachment wp-att-7855"><img alt="str1" class="alignnone wp-image-7855" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-36.jpg" height="394" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-36.jpg" style="height: auto; max-width: 100%;" width="901" /></a></div>
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CLIP</div>
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US5374637 (CN1045781, EP389037) and J. Het Chem, 1980,17 (6): 1333-5 reported synthetic route, as follows:</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00051.png" href="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00051.png"><img alt="Figure CN104529960AD00051" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00051.png" id="idf0003" src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00051.png" style="height: auto; max-width: 100%;" /></a></div>
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CLIP</div>
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Chinese Patent CN 104016949 A synthetic route reported as follows:</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00052.png" href="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00052.png"><img alt="Figure CN104529960AD00052" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00052.png" id="idf0004" src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00052.png" style="height: auto; max-width: 100%;" /></a></div>
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PATENT</div>
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CN104529960A</div>
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<a data-mce-href="https://www.google.com/patents/CN104529960A?cl=zh" href="https://www.google.com/patents/CN104529960A?cl=zh">https://www.google.com/patents/CN104529960A?cl=zh</a></div>
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<img alt="Figure CN104529960AD00061" data-mce-src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00061.png" src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00061.png" style="height: auto; max-width: 100%;" /></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-37.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-37.jpg" rel="attachment wp-att-7856"><img alt="str1" class="alignnone wp-image-7856" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-37.jpg" height="478" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-37.jpg" style="height: auto; max-width: 100%;" width="908" /></a>.</div>
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</h2>
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<img alt="Figure CN104529960AD00081" data-mce-src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00081.png" src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00081.png" style="height: auto; max-width: 100%;" /></div>
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Example 1</div>
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1. Preparation of Compound II</div>
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Compound I (167. lg, Imol), triethylamine (111. lg, I. Imol) and methylene chloride (KMOg) added to the reaction flask, nitrogen cooled to 5 ° C, was slowly added dropwise trifluoroacetic anhydride (220. 5g, 1.05mol) / methylene chloride (150g) solution, maintaining the temperature throughout 5~15 ° C, dropping was completed, the reaction after 3 hours at room temperature, TLC (DCM = MeOH = 25: 1) The reaction was monitored to complete the reaction; the reaction mixture was slowly poured into ice water (560g) and stirred for 20 minutes, standing layer, the aqueous phase was separated, the organic phase was washed with saturated aqueous sodium bicarbonate (IOOg) wash sash; IM hydrochloric acid (IlOg) wash sash, then with saturated brine (200g) washed sash, magnesium sulfate (40g) dried, filtered and concentrated to give compound II (250. Ig), yield: 952%.</div>
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[0066] 2. Preparation of Compound III</div>
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[0067] Chloroacetyl chloride (101. 7g, 0. 9mol), nitrobenzene (20g) and dichloroethane (580 g) added to the reaction flask, nitrogen cooled to 5 ° C, was slowly added anhydrous trichloro aluminum powder (359. 2g, 2. 7mol), to keep the whole temperature 5~20 ° C, plus complete, insulation 15~25 ° C for 30 minutes to obtain a mixture A.</div>
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[0068] Compound II (. 236. 7g, 0 9mol) and dichloroethane (500g) added to the reaction flask, nitrogen cooled to 15 ° C; the mixture was added Compound II A quick solution, plus complete, rapid heating 65~75 ° C, 1 hours later once every 15 minutes in the control, monitoring TLC (DCM = MeOH = 50: 1) to complete the reaction; the reaction mixture was immediately poured into ice water (800g) and stirred for 30 minutes, controlling the temperature between 15~25 ° C, the organic phase was separated, the organic phase washed with water (180g) was washed with saturated brine (240g), dried over magnesium sulfate (45g) was dried, filtered and concentrated to give crude compound III (303 . 2g).</div>
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[0069] Take the crude compound III (291. 3g) / ethanol 1 dichloromethane: 1 solution (1500ml) was dissolved, and then adding activated carbon (14. 5g) was refluxed for one hour, cooled to room temperature filtered and the filtrate concentrated at room temperature to 600~ 650g, stop and concentrated down to 5~10 ° C, filtered to give a yellow solid (204. 7g); the resulting yellow solid (207. 6g) in tetrahydrofuran (510g) was purified, reduced to 10~15 ° C, filtered, The filter cake was washed with tetrahydrofuran (90g) dip, dried under vacuum to give compound III (181. 3g), yield: 61.7% billion</div>
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[0070] 3. Preparation of Compound IV</div>
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[0071] Compound 111 (! 169.68,0.5 11〇1), methanol (5,801,111) and sodium acetate (123.38,1.5111〇1) was added to the reaction flask. After 6 hours of reaction, began TLC (DCM: MeOH = 30: 1 ) the reaction was monitored to completion of the reaction; the reaction mixture was cooled to room temperature, concentrated, and the residue with ethyl acetate (500g) and water (200g) was dissolved, the organic phase was separated, the organic phase was washed with 2M sodium hydrogen carbonate (120g) was washed, then with saturated brine (IOOg), dried over magnesium sulfate (50g) was dried, filtered and concentrated to 250~280g, cooled to room temperature with stirring was added cyclohexane (200 g of), after stirring for 1 hour and then filtered and dried to obtain compound IV (126. 7g), yield: 83.4% billion</div>
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[0072] 4. Preparation of Compound V</div>
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[0073] Compound IV (12L 2g, 0. 4mol), methanol (380g) and Raney-Ni (12. 5g) added to the autoclave, purged with nitrogen, hydrogen is introduced (3. Ompa), the reaction was heated to 45 ° C after 8 hours, TLC (DCM = MeOH = 30: 1) to monitor the reaction, to complete the reaction, cooled to room temperature and pressure, and then purged with nitrogen, the reaction solution was filtered and concentrated to give crude compound V (103. 7g), taking compound V crude product (103g) was refluxed with ethyl acetate (420g) (1 hour) was purified, cooled to room temperature and stirred for 30 minutes and filtered to give a yellow solid was dried in vacuo to give compound V (76 8g.), yield: 663 %.</div>
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[0074] 5. Preparation of Compound VI</div>
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[0075] Compound ¥ (57.88,0.2111〇1), 1 ^ dimethylformamide (4.58) and acetonitrile (30 (^) was added to the reaction flask and heated 74~76 ° C; solution of N- chlorosuccinimide imide (. 26. 7g, 0 2mol) and acetonitrile (45g) was added dropwise over 30 minutes and maintaining the temperature finished 76~82 ° C, dropping was completed, the reaction was kept, after one hour the reaction started TLC (DCM: MeOH = 30: 1) to monitor the reaction, the reaction is complete the reaction solution cooled to 5~8 ° C, the filter cake was washed with water (210g) washed stirred, filtered, and dried in vacuo to give compound VI (57. 6g), yield. rate of 89.1%.</div>
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6. Preparation of Compound VII</div>
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Compound VI (48. 5g, 0. 15mol) and methanol (80g) added to the reaction flask, stirring at room temperature was added dropwise 4M aqueous sodium hydroxide (HOg), dropwise complete, for the reaction, 25 ° C~35 after 4 hours of reaction ° C, samples of about 7:00 adjust PH TLC (DCM = MeOH = 30: 1) to monitor the reaction, until the reaction was complete, down to 5~10 ° C, with 6M hydrochloric acid solution PH ~ 7. 5, half the solution was concentrated, then 2M hydrochloric acid solution PH ~ 7, reduced to 15~20 ° C was stirred for 30 minutes, filtered, the filter cake with methyl tert-butyl ether (70g) beating, filtration, and dried in vacuo to give compound VII (28. 7g), yield: 903%.</div>
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PAPER</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Chem Pharm Bull 46 (1), 42-52 (1998) and Pharmaceutical and clinical study based on 2011 (4) 306-307 reported synthetic route is as follows:</div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00041.png" href="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00041.png"><img alt="Figure CN104529960AD00041" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00041.png" id="idf0002" src="https://patentimages.storage.googleapis.com/CN104529960A/CN104529960AD00041.png" style="height: auto; max-width: 100%;" /></a></div>
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<h3 id="biologicalActivity" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Biological Activity</h3>
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<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="16%">Description</th><td colspan="6" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride is a selective, high affinity <b>5-HT4 receptor</b> agonist, inhibiting human 5-HT(4a) and 5-HT(4b) receptor with <b>K<sub>i</sub></b> value of 2.5 nM and 8 nM, respectively.</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Targets</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5-HT4A <sup><a class="sref" data-mce-href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref" href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref">[1]</a></sup></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5-HT4B <sup><a class="sref" data-mce-href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref" href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref">[1]</a></sup></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">IC50</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2.5 nM(Ki)</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8 nM(Ki)</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><i>In vitro</i></th><td colspan="6" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride induces contractions in a concentration-dependent manner with pEC50 of 7.5. Prucalopride (1 mM) significantly amplifies the rebound contraction of the guinea-pig proximal colon after electrical field stimulation. Prucalopride induces relaxation of the rat oesophagus preparation of rat oesophagus tunica muscularis mucosae with pEC50 of 7.8, yielding a monophasic concentration–response curve. <sup><a class="sref" data-mce-href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref" href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref">[1]</a></sup> Prucalopride (0.1 μM) concentration-dependently increases the amplitude of submaximal cholinergic contractions and of acetylcholine release induced by electrical field stimulation in pig gastric circular muscle, and the effect is induced and enhanced IBMX (10 μM). <sup><a class="sref" data-mce-href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref" href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref">[2]</a></sup> Prucalopride (1 μM) significantly enhances the electrically induced cholinergic contractions in pig descending colon, and the facilitating effect is significantly enhanced by Rolipram. <sup><a class="sref" data-mce-href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref" href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref">[3]</a></sup></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><i>In vivo</i></th><td colspan="6" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride alters colonic contractile motility patterns in a dose-dependent fashion by stimulating high-amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon of fasted dogs. Prucalopride also causes a dose-dependent decrease in the time to the first giant migrating contraction (GMC); at higher doses of prucalopride, the first GMC generally occurres within the first half-hour after treatment. <sup><a class="sref" data-mce-href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref" href="http://www.selleckchem.com/products/prucalopride-succinat.html#s_ref">[4]</a></sup></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Features</th><td colspan="6" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td></tr>
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<h4 class="margin_t" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)</h4>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Species</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mouse</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Rat</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Rabbit</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Guinea pig</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Hamster</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dog</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Weight (kg)</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.02</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.15</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1.8</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.4</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.08</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">10</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Body Surface Area (m<sup>2</sup>)</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.007</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.025</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.15</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.05</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.02</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.5</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">K<sub>m</sub> factor</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">12</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20</td></tr>
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<tr><td nowrap="nowrap" rowspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Animal A (mg/kg) = Animal B (mg/kg) multiplied by </b></td><td nowrap="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Animal B K<sub>m</sub></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Animal A K<sub>m</sub></td></tr>
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<div>
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K<sub>m</sub> factor for a mouse and then divide by the K<sub>m</sub> factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.<br />
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<tr><td nowrap="nowrap" rowspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×</td><td nowrap="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">mouse K<sub>m</sub>(3)</td><td nowrap="nowrap" rowspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> = 11.2 mg/kg</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">rat K<sub>m</sub>(6)</td></tr>
</tbody></table>
</div>
</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<a class="mce-item-anchor" href="https://www.blogger.com/null" id="s_ref" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url("img/anchor.gif") center center no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;"></a>1</h2>
<h4 class="reference margin_t" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
References</h4>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/11438309" href="http://www.ncbi.nlm.nih.gov/pubmed/11438309" rel="nofollow" target="_blank">[1] Briejer MR, et al. Eur J Pharmacol, 2001, 423(1), 71-83.</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/22266217" href="http://www.ncbi.nlm.nih.gov/pubmed/22266217" rel="nofollow" target="_blank">[2] Priem E, et al. Neuropharmacology, 2012, 62(5-6), 2126-2135.</a></div>
<h4 class="reference margin_t" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</h4>
<h3 id="clinical" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
Clinical Trial Information<span class="inpo">( data from http://clinicaltrials.gov, updated on 2016-07-23)</span></h3>
<table border="0" cellpadding="0" cellspacing="0" class="inpo_table mce-item-table" data-mce-style="height: 366px;" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: 366px; line-height: 24px; width: 784px;"><tbody>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="15%">NCT Number</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="12%">Recruitment</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="35%">Conditions</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="19%">Sponsor<br />/Collaborators</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="10%">Start Date</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="9%">Phases</th></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://clinicaltrials.gov/show/NCT02806206" href="https://clinicaltrials.gov/show/NCT02806206" target="_blank">NCT02806206</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Not yet recruiting</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Gastrointestinal Hemorrhage|Crohn Disease|Celiac Disease|Intestinal Diseases|Inflammatory Bowel Diseases</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">University of British Columbia</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">July 2016</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Phase 4</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://clinicaltrials.gov/show/NCT02781493" href="https://clinicaltrials.gov/show/NCT02781493" target="_blank">NCT02781493</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Not yet recruiting</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride Plus Polyethylene Glycol in Bowel Preparation for Colonoscopyp</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="fold">Shandong University|Binzhou Peoples Hospital|Taian People ...more</span></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">June 2016</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Phase 4</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://clinicaltrials.gov/show/NCT02538367" href="https://clinicaltrials.gov/show/NCT02538367" target="_blank">NCT02538367</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Recruiting</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Functional Constipation</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Yuhan Corporation</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">August 2015</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Phase 1|Phase 2</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://clinicaltrials.gov/show/NCT02228616" href="https://clinicaltrials.gov/show/NCT02228616" target="_blank">NCT02228616</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Recruiting</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Constipation</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Xian-Janssen Pharmaceutical Ltd.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">October 2014</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Phase 4</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://clinicaltrials.gov/show/NCT02425774" href="https://clinicaltrials.gov/show/NCT02425774" target="_blank">NCT02425774</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Recruiting</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Postoperative Ileus</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="fold">Katholieke Universiteit Leuven|Universitaire Ziekenhuizen ...more</span></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">July 2014</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Phase 4</td></tr>
</tbody></table>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist columns references-column-count references-column-count-2" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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<li id="cite_note-2"> <span class="reference-text">Clinical trial number <i><a class="external autonumber" data-mce-href="http://www.clinicaltrials.gov/show/" href="http://www.clinicaltrials.gov/show/" rel="nofollow">[1]</a></i> for "NCT00793247" at <a data-mce-href="https://en.wikipedia.org/wiki/ClinicalTrials.gov" href="https://en.wikipedia.org/wiki/ClinicalTrials.gov" title="ClinicalTrials.gov">ClinicalTrials.gov</a></span></li>
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<li id="cite_note-5"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-5" href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-5"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Bouras, E. P.; Camilleri, M.; Burton, D. D.; McKinzie, S. (1999). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727485" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727485" rel="nofollow">"Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans"</a>. <i>Gut</i><b>44</b> (5): 682–686. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1136%2Fgut.44.5.682" href="https://dx.doi.org/10.1136%2Fgut.44.5.682" rel="nofollow">10.1136/gut.44.5.682</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727485" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727485" rel="nofollow">1727485</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/10205205" href="https://www.ncbi.nlm.nih.gov/pubmed/10205205" rel="nofollow">10205205</a>.</cite></span></li>
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<li id="cite_note-Tack-7"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Tack_7-0" href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Tack_7-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Tack_7-1" href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Tack_7-1"><sup><i><b>b</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Tack_7-2" href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Tack_7-2"><sup><i><b>c</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Tack_7-3" href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Tack_7-3"><sup><i><b>d</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Tack, J.; Van Outryve, M.; Beyens, G.; Kerstens, R.; Vandeplassche, L. (2008). "Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives". <i>Gut</i> <b>58</b> (3): 357–365. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1136%2Fgut.2008.162404" href="https://dx.doi.org/10.1136%2Fgut.2008.162404" rel="nofollow">10.1136/gut.2008.162404</a>.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/18987031" href="https://www.ncbi.nlm.nih.gov/pubmed/18987031" rel="nofollow">18987031</a>.</cite></span></li>
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<li id="cite_note-Quigley-17"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Quigley_17-0" href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Quigley_17-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Quigley_17-1" href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Quigley_17-1"><sup><i><b>b</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Quigley_17-2" href="https://en.wikipedia.org/wiki/Prucalopride#cite_ref-Quigley_17-2"><sup><i><b>c</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Quigley, E. M. M.; Vandeplassche, L.; Kerstens, R.; Ausma, J. (2009). "Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation – a 12-week, randomized, double-blind, placebo-controlled study".<i>Alimentary Pharmacology & Therapeutics</i> <b>29</b> (3): 315–328. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1111%2Fj.1365-2036.2008.03884.x" href="https://dx.doi.org/10.1111%2Fj.1365-2036.2008.03884.x" rel="nofollow">10.1111/j.1365-2036.2008.03884.x</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/19035970" href="https://www.ncbi.nlm.nih.gov/pubmed/19035970" rel="nofollow">19035970</a>.</cite></span></li>
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<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="External_links">External links</span></h2>
<ul style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li><a class="external text" data-mce-href="http://www.movetis.com/products/resolor-prucalopride" href="http://www.movetis.com/products/resolor-prucalopride" rel="nofollow">Resolor (prucalopride)- Movetis</a></li>
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<div class="patent-section patent-tabular-section" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/EP0389037A1?cl=en" href="http://www.google.co.in/patents/EP0389037A1?cl=en">EP0389037A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13 Mar 1990</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26 Sep 1990</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Janssen Pharmaceutica N.V.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/EP0445862A2?cl=en" href="http://www.google.co.in/patents/EP0445862A2?cl=en">EP0445862A2</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">22 Feb 1991</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">11 Sep 1991</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Janssen Pharmaceutica N.V.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives</td></tr>
</tbody></table>
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<div class="patent-section patent-tabular-section" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><thead class="patent-data-table-thead">
<tr class="patent-data-table"><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Citing Patent</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Filing date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Publication date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title</th></tr>
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO1999058527A2?cl=en" href="http://www.google.co.in/patents/WO1999058527A2?cl=en">WO1999058527A2</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13 May 1999</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Nov 1999</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">EGIS Gyógyszergyár Rt.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO1999058527A3?cl=en" href="http://www.google.co.in/patents/WO1999058527A3?cl=en">WO1999058527A3</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13 May 1999</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">27 Jan 2000</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Bela Agai</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO2000030640A1?cl=en" href="http://www.google.co.in/patents/WO2000030640A1?cl=en">WO2000030640A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">16 Nov 1999</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2 Jun 2000</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Janssen Pharmaceutica N.V.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Use of prucalopride for the manufacture of a medicament for the treatment of dyspepsia</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO2000066170A1?cl=en" href="http://www.google.co.in/patents/WO2000066170A1?cl=en">WO2000066170A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20 Apr 2000</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">9 Nov 2000</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Janssen Pharmaceutica N.V.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride oral solution</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO2003059906A1?cl=en" href="http://www.google.co.in/patents/WO2003059906A1?cl=en">WO2003059906A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13 Jan 2003</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">24 Jul 2003</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Janssen Pharmaceutica N.V.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride-n-oxide</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO2012116976A1?cl=en" href="http://www.google.co.in/patents/WO2012116976A1?cl=en">WO2012116976A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">28 Feb 2012</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7 Sep 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Shire - Movetis Nv</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride oral solution</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/WO2013024164A1?cl=en" href="http://www.google.co.in/patents/WO2013024164A1?cl=en">WO2013024164A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">17 Aug 2012</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Feb 2013</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Shire Ag</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Combinations of a 5-ht4 receptor agonist and a pde4 inhibitor for use in therapy</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/US6413988" href="http://www.google.co.in/patents/US6413988">US6413988</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">20 Apr 2000</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2 Jul 2002</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Janssen Pharmaceutica N.V.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride oral solution</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.co.in/patents/US8063069" href="http://www.google.co.in/patents/US8063069">US8063069</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">30 Oct 2007</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">22 Nov 2011</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Janssen Pharmaceutica N.V.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride-N-oxide</td></tr>
</tbody></table>
</div>
<table class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><thead>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent ID</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Date</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent Title</th></tr>
</thead><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20160082123.PGNR.&OS=DN/20160082123&RS=DN/20160082123" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20160082123.PGNR.&OS=DN/20160082123&RS=DN/20160082123">US2016082123</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2016-03-24</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Hydrogel-Linked Prodrugs Releasing Tagged Drugs</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150202317.PGNR.&OS=DN/20150202317&RS=DN/20150202317" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20150202317.PGNR.&OS=DN/20150202317&RS=DN/20150202317">US2015202317</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2015-07-23</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DIPEPTIDE-BASED PRODRUG LINKERS FOR ALIPHATIC AMINE-CONTAINING DRUGS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140323402.PGNR.&OS=DN/20140323402&RS=DN/20140323402" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140323402.PGNR.&OS=DN/20140323402&RS=DN/20140323402">US2014323402</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-10-30</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Protein Carrier-Linked Prodrugs</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140296257.PGNR.&OS=DN/20140296257&RS=DN/20140296257" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140296257.PGNR.&OS=DN/20140296257&RS=DN/20140296257">US2014296257</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-10-02</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">High-Loading Water-Soluable Carrier-Linked Prodrugs</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140243254.PGNR.&OS=DN/20140243254&RS=DN/20140243254" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20140243254.PGNR.&OS=DN/20140243254&RS=DN/20140243254">US2014243254</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2014-08-28</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Polymeric Hyperbranched Carrier-Linked Prodrugs</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20130053301.PGNR.&OS=DN/20130053301&RS=DN/20130053301" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20130053301.PGNR.&OS=DN/20130053301&RS=DN/20130053301">US2013053301</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2013-02-28</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DIPEPTIDE-BASED PRODRUG LINKERS FOR ALIPHATIC AMINE-CONTAINING DRUGS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20120220630.PGNR.&OS=DN/20120220630&RS=DN/20120220630" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20120220630.PGNR.&OS=DN/20120220630&RS=DN/20120220630">US2012220630</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2012-08-30</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">PRUCALOPRIDE ORAL SOLUTION</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20120156259.PGNR.&OS=DN/20120156259&RS=DN/20120156259" href="http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20120156259.PGNR.&OS=DN/20120156259&RS=DN/20120156259">US2012156259</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2012-06-21</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Biodegradable Polyethylene Glycol Based Water-Insoluble Hydrogels</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6413988.PN.&OS=PN/6413988&RS=PN/6413988" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6413988.PN.&OS=PN/6413988&RS=PN/6413988">US6413988</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2002-07-02</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prucalopride oral solution</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6310077.PN.&OS=PN/6310077&RS=PN/6310077" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6310077.PN.&OS=PN/6310077&RS=PN/6310077">US6310077</a></td><td class="nowrap" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2001-10-30</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Enterokinetic benzamide</td></tr>
</tbody></table>
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Prucalopride">Prucalopride</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Prucalopride.svg" href="https://en.wikipedia.org/wiki/File:Prucalopride.svg"><img alt="Prucalopride.svg" data-file-height="206" data-file-width="512" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/76/Prucalopride.svg/260px-Prucalopride.svg.png" height="105" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/76/Prucalopride.svg/260px-Prucalopride.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/7/76/Prucalopride.svg/390px-Prucalopride.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/7/76/Prucalopride.svg/520px-Prucalopride.svg.png 2x" style="height: auto; max-width: 100%;" width="260" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">4-Amino-5-chloro-<i>N</i>-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Resolor, Resotran</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/international/prucalopride.html" href="https://www.drugs.com/international/prucalopride.html" rel="nofollow">International Drug Names</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">License data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small>EU</small> <a data-mce-href="https://en.wikipedia.org/wiki/European_Medicines_Agency" href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency">EMA</a>: <span title="www.ema.europa.eu"><a class="external text" data-mce-href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Resolor" href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Resolor" rel="nofollow">Resolor</a></span></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="Australia">AU</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#Australia" href="https://en.wikipedia.org/wiki/Pregnancy_category#Australia" title="Pregnancy category">B1</a></li>
</ul>
<ul>
<li>Not recommended</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oral</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="Australia">AU</abbr>:</small> <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" href="https://en.wikipedia.org/wiki/Standard_for_the_Uniform_Scheduling_of_Drugs_and_Poisons#Schedule_4_Prescription_Only_Medicine" title="Standard for the Uniform Scheduling of Drugs and Poisons">S4</a> (Prescription only)</li>
<li>℞ (Prescription only)</li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=179474-81-8" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=179474-81-8" rel="nofollow">179474-81-8</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_A06" href="https://en.wikipedia.org/wiki/ATC_code_A06" title="ATC code A06">A06AX05</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=A06AX05" href="http://www.whocc.no/atc_ddd_index/?code=A06AX05" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3052762" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3052762" rel="nofollow">3052762</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/IUPHAR/BPS" href="https://en.wikipedia.org/wiki/IUPHAR/BPS" title="IUPHAR/BPS">IUPHAR/BPS</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.guidetopharmacology.org"><a class="external text" data-mce-href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=243" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=243" rel="nofollow">243</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.2314539.html" href="http://www.chemspider.com/Chemical-Structure.2314539.html" rel="nofollow">2314539</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=0A09IUW5TP" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=0A09IUW5TP" rel="nofollow">0A09IUW5TP</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>18</sub><span title="Hydrogen">H</span><sub>26</sub><span title="Chlorine">Cl</span><span title="Nitrogen">N</span><sub>3</sub><span title="Oxygen">O</span><sub>3</sub></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">367.870 g/mol</td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
//////////Prucalopride succinate, Resolor , <span class="">R-093877, R-108512, R<wbr></wbr>esolor®, </span><span class="">Resolor, Resotran, </span><span class="">UNII:0A09IUW5TP, <strong>179474-81-8</strong> , R-093877, R-108512, Shire , Johnson & Johnson, 179474-85-2, UNII-4V2G75E1CK, </span>SHIRE, 2010, LAUNCHED, JANNSEN , PHASE 3, IRRITABLE BOWL SYNDROME</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
COCCCN1CCC(CC1)NC(=O)C2=CC(=C(C3=C2OCC3)N)Cl</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
COCCCN1CCC(CC1)NC(=O)C2=CC(=C(C3=C2OCC3)N)Cl.C(CC(=O)O)C(=O)O</div>
</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com3tag:blogger.com,1999:blog-1346483141860457136.post-10857801894003800602016-07-26T21:33:00.001-07:002016-07-26T21:33:14.502-07:00Mifamurtide (Mepact ) мифамуртид , ميفامورتيد , 米法莫肽 ,<div dir="ltr" style="text-align: left;" trbidi="on">
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="Mifamurtide.svg" class="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/fe/Mifamurtide.svg/300px-Mifamurtide.svg.png" height="276" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/fe/Mifamurtide.svg/300px-Mifamurtide.svg.png" style="height: auto; max-width: 100%;" width="587" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-105.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-105.jpg" rel="attachment wp-att-7867"><img alt="STR1" class="alignnone size-full wp-image-7867" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-105.jpg" height="609" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/STR1-105.jpg" style="height: auto; max-width: 100%;" width="2000" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Mifamurtide (Mepact )</div>
<ul class="struct-props" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li><span class="prop_title">MF </span><span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_prop_MF">C<sub>59</sub>H<sub>109</sub>N<sub>6</sub>O<sub>19</sub>P</span></li>
<li><span class="prop_title">MW </span>1237.499</li>
</ul>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">CGP-19835, </span><span class="">MFCD09954133, </span><span class="">MTP-cephalin, </span><span class="">Mtp-PE</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">Muramyl tripeptide <wbr></wbr>phosphatidylethanol<wbr></wbr>amine</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">N-(N-Acetylmuramoyl<wbr></wbr>)-L-alanyl-D-α-glu<wbr></wbr>taminyl-N-[(7R)-4-h<wbr></wbr>ydroxy-4-oxido-10-o<wbr></wbr>xo-7-[(1-oxohexadec<wbr></wbr>yl)oxy]-3,5,9-triox<wbr></wbr>a-4-phosphapentacos<wbr></wbr>-1-yl]-L-alaninamide</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">N-Acetylmuramyl-L-a<wbr></wbr>lanyl-D-isoglutamin<wbr></wbr>e-L-alanine 2-(1',2<wbr></wbr>'-dipalmitoyl-sn-gl<wbr></wbr>ycero-3'-hydroxypho<wbr></wbr>sphoryloxy)ethylami<wbr></wbr>de</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>(2R,5S,8R,13S,22R)-<wbr></wbr>2-{[(3R,4R,5S,6R)-3<wbr></wbr>-Acetamido-2,5-dihy<wbr></wbr>droxy-6-(hydroxymet<wbr></wbr>hyl)tetrahydro-2H-p<wbr></wbr>yran-4-yl]oxy}-8-ca<wbr></wbr>rbamoyl-19-hydroxy-<wbr></wbr>5,13-dimethyl-19-ox<wbr></wbr>ido-3,6,11,14,25-pe<wbr></wbr>ntaoxo-18,20,24-tri<wbr></wbr>oxa-4,7,12 <wbr></wbr>;,15-tetraaza-19λ<sup>5</sup><wbr></wbr>-phosphatetracontan<wbr></wbr>-22-yl hexadecanoate</strong></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=83461-56-7" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=83461-56-7" rel="nofollow">83461-56-7</a></span><sup> CAS</sup><br /><a class="external text" data-mce-href="https://tools.wmflabs.org/magnustools/cas.php?language=en&cas=838853-48-8&title=" href="https://tools.wmflabs.org/magnustools/cas.php?language=en&cas=838853-48-8&title=">838853-48-8</a> (mifamurtide sodium · xH<sub>2</sub>O)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b>Mifamurtide</b> (trade name Mepact, marketed by <a data-mce-href="https://en.wikipedia.org/wiki/Takeda_Pharmaceutical_Company" href="https://en.wikipedia.org/wiki/Takeda_Pharmaceutical_Company" title="Takeda Pharmaceutical Company">Takeda</a>) is a drug against <a data-mce-href="https://en.wikipedia.org/wiki/Osteosarcoma" href="https://en.wikipedia.org/wiki/Osteosarcoma" title="Osteosarcoma">osteosarcoma</a>, a kind of bone <a data-mce-href="https://en.wikipedia.org/wiki/Cancer" href="https://en.wikipedia.org/wiki/Cancer" title="Cancer">cancer</a> mainly affecting children and young adults, which is lethal in about a third of cases. The drug was approved in Europe in March 2009.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="ChemSpider 2D Image | Mifamurtide | C59H109N6O19P" class="" data-mce-src="http://www.chemspider.com/ImagesHandler.ashx?id=9847332&w=250&h=250" height="567" src="http://www.chemspider.com/ImagesHandler.ashx?id=9847332&w=250&h=250" style="height: auto; max-width: 100%;" width="567" /></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="History">History</span></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The drug was invented by <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Ciba-Geigy" href="https://en.wikipedia.org/wiki/Ciba-Geigy" title="Ciba-Geigy">Ciba-Geigy</a> (now <a data-mce-href="https://en.wikipedia.org/wiki/Novartis" href="https://en.wikipedia.org/wiki/Novartis" title="Novartis">Novartis</a>) in the early 1980s and sold to <a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=Jenner_Biotherapies&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=Jenner_Biotherapies&action=edit&redlink=1" title="Jenner Biotherapies (page does not exist)">Jenner Biotherapies</a> in the 1990s. In 2003,<a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=IDM_Pharma&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=IDM_Pharma&action=edit&redlink=1" title="IDM Pharma (page does not exist)">IDM Pharma</a> bought the rights and developed it further.<sup class="reference" id="cite_ref-DrugsRD_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-DrugsRD-1" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-DrugsRD-1">[1]</a></sup> IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.<sup class="reference" id="cite_ref-2"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-2" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-2">[2]</a></sup></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Mifamurtide had already been granted <a data-mce-href="https://en.wikipedia.org/wiki/Orphan_drug" href="https://en.wikipedia.org/wiki/Orphan_drug" title="Orphan drug">orphan drug</a> status by the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration" title="U.S. Food and Drug Administration">U.S. Food and Drug Administration</a> (FDA) in 2001, and the<a data-mce-href="https://en.wikipedia.org/wiki/European_Medicines_Agency" href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency">European Medicines Agency</a> (EMA) followed in 2004. It was approved in the 27 <a data-mce-href="https://en.wikipedia.org/wiki/European_Union" href="https://en.wikipedia.org/wiki/European_Union" title="European Union">European Union</a> member states plus Iceland, Liechtenstein, and Norway by a centralized marketing authorization in March 2009. The drug was denied approval by the FDA in 2007.<sup class="reference" id="cite_ref-3"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-3" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-3">[3]</a></sup><sup class="reference" id="cite_ref-4"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-4" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-4">[4]</a></sup> Mifamurtide has been licensed by the EMA since March, 2009.<sup class="reference" id="cite_ref-5"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-5" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-5">[5]</a></sup></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Indications">Indications</span></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Mifamurtide is indicated for the treatment of high-grade, non<a data-mce-href="https://en.wikipedia.org/wiki/Metastasis" href="https://en.wikipedia.org/wiki/Metastasis" title="Metastasis">metastasizing</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Segmental_resection" href="https://en.wikipedia.org/wiki/Segmental_resection" title="Segmental resection">resectable</a> osteosarcoma following complete surgical removal in children, adolescents, and young adults, aged two to 30 years.<sup class="reference" id="cite_ref-DrugsRD_1-1"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-DrugsRD-1" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-DrugsRD-1">[1]</a></sup><sup class="reference" id="cite_ref-SPC_6-0"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-SPC-6" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-SPC-6">[6]</a></sup><sup class="reference" id="cite_ref-7"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-7" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-7">[7]</a></sup> Osteosarcoma is diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30.<sup class="reference" id="cite_ref-8"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-8" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-8">[8]</a></sup> The drug is used in combination with postoperative, multiagent <a data-mce-href="https://en.wikipedia.org/wiki/Chemotherapy" href="https://en.wikipedia.org/wiki/Chemotherapy" title="Chemotherapy">chemotherapy</a> to kill remaining cancer cells and improve a patient's chance of overall survival.<sup class="reference" id="cite_ref-SPC_6-1"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-SPC-6" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-SPC-6">[6]</a></sup></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
In a phase-III <a data-mce-href="https://en.wikipedia.org/wiki/Clinical_trial" href="https://en.wikipedia.org/wiki/Clinical_trial" title="Clinical trial">clinical trial</a> in about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents <a data-mce-href="https://en.wikipedia.org/wiki/Doxorubicin" href="https://en.wikipedia.org/wiki/Doxorubicin" title="Doxorubicin">doxorubicin</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Methotrexate" href="https://en.wikipedia.org/wiki/Methotrexate" title="Methotrexate">methotrexate</a>, with or without <a data-mce-href="https://en.wikipedia.org/wiki/Cisplatin" href="https://en.wikipedia.org/wiki/Cisplatin" title="Cisplatin">cisplatin</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Ifosfamide" href="https://en.wikipedia.org/wiki/Ifosfamide" title="Ifosfamide">ifosfamide</a>. The <a data-mce-href="https://en.wikipedia.org/wiki/Mortality_rate" href="https://en.wikipedia.org/wiki/Mortality_rate" title="Mortality rate">mortality</a> could be lowered by 30% versus chemotherapy plus <a data-mce-href="https://en.wikipedia.org/wiki/Placebo" href="https://en.wikipedia.org/wiki/Placebo" title="Placebo">placebo</a>. Six years after the treatment, 78% of patients were still alive. This equals an absolute risk reduction of 8% .<sup class="reference" id="cite_ref-DrugsRD_1-2"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-DrugsRD-1" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-DrugsRD-1">[1]</a></sup></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Adverse_effects">Adverse effects</span></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
In a clinical study, mifamurtide was given to 332 subjects (half of whom were under age of 16) and most side effects were found to be mild to moderate in nature. Most patients experience fewer adverse events with subsequent administration.<sup class="reference" id="cite_ref-PMID18235123_9-0"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-PMID18235123-9" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-PMID18235123-9">[9]</a></sup><sup class="reference" id="cite_ref-PMID15774791_10-0"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-PMID15774791-10" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-PMID15774791-10">[10]</a></sup>Common side effects include <a data-mce-href="https://en.wikipedia.org/wiki/Fever" href="https://en.wikipedia.org/wiki/Fever" title="Fever">fever</a> (about 90%), vomiting, <a data-mce-href="https://en.wikipedia.org/wiki/Fatigue_(medical)" href="https://en.wikipedia.org/wiki/Fatigue_(medical)" title="Fatigue (medical)">fatigue</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Tachycardia" href="https://en.wikipedia.org/wiki/Tachycardia" title="Tachycardia">tachycardia</a> (about 50%), <a data-mce-href="https://en.wikipedia.org/wiki/Infection" href="https://en.wikipedia.org/wiki/Infection" title="Infection">infections</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Anaemia" href="https://en.wikipedia.org/wiki/Anaemia" title="Anaemia">anaemia</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Anorexia_(symptom)" href="https://en.wikipedia.org/wiki/Anorexia_(symptom)" title="Anorexia (symptom)">anorexia</a>, headache, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Diarrhoea" href="https://en.wikipedia.org/wiki/Diarrhoea" title="Diarrhoea">diarrhoea</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Constipation" href="https://en.wikipedia.org/wiki/Constipation" title="Constipation">constipation</a>(>10%).<sup class="reference" id="cite_ref-DrugsRD_1-3"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-DrugsRD-1" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-DrugsRD-1">[1]</a></sup><sup class="reference" id="cite_ref-11"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-11" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-11">[11]</a></sup></div>
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<span class="mw-headline" id="Pharmacokinetics">Pharmacokinetics</span></h2>
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After application of the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Liposomal" href="https://en.wikipedia.org/wiki/Liposomal" title="Liposomal">liposomal</a> infusion, the drug is cleared from the plasma within minutes and is concentrated in lung, liver, <a data-mce-href="https://en.wikipedia.org/wiki/Spleen" href="https://en.wikipedia.org/wiki/Spleen" title="Spleen">spleen</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Nasopharynx" href="https://en.wikipedia.org/wiki/Nasopharynx" title="Nasopharynx">nasopharynx</a>, and <a data-mce-href="https://en.wikipedia.org/wiki/Thyroid" href="https://en.wikipedia.org/wiki/Thyroid" title="Thyroid">thyroid</a>. The terminal half-life is 18 hours. In patients receiving a second treatment after 11–12 weeks, no accumulation effects were observed.<sup class="reference" id="cite_ref-12"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-12" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-12">[12]</a></sup></div>
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<span class="mw-headline" id="Pharmacodynamics">Pharmacodynamics</span></h2>
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Mifamurtide is a fully synthetic derivative of <a data-mce-href="https://en.wikipedia.org/wiki/Muramyl_dipeptide" href="https://en.wikipedia.org/wiki/Muramyl_dipeptide" title="Muramyl dipeptide">muramyl dipeptide</a> (MDP), the smallest naturally occurring immune stimulatory component of cell walls from <i><a data-mce-href="https://en.wikipedia.org/wiki/Mycobacterium" href="https://en.wikipedia.org/wiki/Mycobacterium" title="Mycobacterium">Mycobacterium</a></i> species. It has similar immunostimulatory effects as natural MDP with the advantage of a longer half-life in plasma.</div>
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<a data-mce-href="https://en.wikipedia.org/wiki/NOD2" href="https://en.wikipedia.org/wiki/NOD2" title="NOD2">NOD2</a> is a <a data-mce-href="https://en.wikipedia.org/wiki/Pattern_recognition_receptor" href="https://en.wikipedia.org/wiki/Pattern_recognition_receptor" title="Pattern recognition receptor">pattern recognition receptor</a> which is found in several kinds of <a data-mce-href="https://en.wikipedia.org/wiki/White_blood_cell" href="https://en.wikipedia.org/wiki/White_blood_cell" title="White blood cell">white blood cells</a>, mainly <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Monocytes" href="https://en.wikipedia.org/wiki/Monocytes" title="Monocytes">monocytes</a> and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Macrophages" href="https://en.wikipedia.org/wiki/Macrophages" title="Macrophages">macrophages</a>. It recognises muramyl dipeptide, a component of the cell wall of <a data-mce-href="https://en.wikipedia.org/wiki/Bacteria" href="https://en.wikipedia.org/wiki/Bacteria" title="Bacteria">bacteria</a>. Mifamurtide simulates a bacterial infection by binding to NOD2, activating white cells. This results in an increased production of <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/TNF-%CE%B1" href="https://en.wikipedia.org/wiki/TNF-%CE%B1" title="TNF-α">TNF-α</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Interleukin_1" href="https://en.wikipedia.org/wiki/Interleukin_1" title="Interleukin 1">interleukin 1</a>,<a data-mce-href="https://en.wikipedia.org/wiki/Interleukin_6" href="https://en.wikipedia.org/wiki/Interleukin_6" title="Interleukin 6">interleukin 6</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Interleukin_8" href="https://en.wikipedia.org/wiki/Interleukin_8" title="Interleukin 8">interleukin 8</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Interleukin_12" href="https://en.wikipedia.org/wiki/Interleukin_12" title="Interleukin 12">interleukin 12</a>, and other <a data-mce-href="https://en.wikipedia.org/wiki/Cytokine" href="https://en.wikipedia.org/wiki/Cytokine" title="Cytokine">cytokines</a>, as well as <a data-mce-href="https://en.wikipedia.org/wiki/ICAM-1" href="https://en.wikipedia.org/wiki/ICAM-1" title="ICAM-1">ICAM-1</a>. The activated white cells attack cancer cells, but not, at least <i><a data-mce-href="https://en.wikipedia.org/wiki/In_vitro" href="https://en.wikipedia.org/wiki/In_vitro" title="In vitro">in vitro</a></i>, other cells.<sup class="reference" id="cite_ref-13"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-13" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-13">[13]</a></sup></div>
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<span class="mw-headline" id="Interactions">Interactions</span></h2>
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<li>Theoretical considerations suggest <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Calcineurin_inhibitor" href="https://en.wikipedia.org/wiki/Calcineurin_inhibitor" title="Calcineurin inhibitor">calcineurin inhibitors</a> like <a data-mce-href="https://en.wikipedia.org/wiki/Ciclosporin" href="https://en.wikipedia.org/wiki/Ciclosporin" title="Ciclosporin">ciclosporin</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Tacrolimus" href="https://en.wikipedia.org/wiki/Tacrolimus" title="Tacrolimus">tacrolimus</a> might interact with mifamurtide because of their effect on macrophages.</li>
<li>High-dose <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/NSAID" href="https://en.wikipedia.org/wiki/NSAID" title="NSAID">NSAIDs</a> block the mechanism of mifamurtide <i>in vitro</i>.</li>
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Consequently, the combination of mifamurtide with these types of drugs is contraindicated. However, mifamurtide can be coadministered with low doses of NSAIDs. No evidence suggests mifamurtide interacts with the studied chemotherapeutics, or with the <a data-mce-href="https://en.wikipedia.org/wiki/Cytochrome_P450" href="https://en.wikipedia.org/wiki/Cytochrome_P450" title="Cytochrome P450">cytochrome P450</a> system.<sup class="reference" id="cite_ref-14"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-14" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-14">[14]</a></sup></div>
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<span class="mw-headline" id="Chemistry">Chemistry</span></h2>
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<a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Liposome_scheme-en.svg" href="https://en.wikipedia.org/wiki/File:Liposome_scheme-en.svg"><img alt="" class="thumbimage" data-file-height="781" data-file-width="1103" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/0/01/Liposome_scheme-en.svg/220px-Liposome_scheme-en.svg.png" height="156" src="https://upload.wikimedia.org/wikipedia/commons/thumb/0/01/Liposome_scheme-en.svg/220px-Liposome_scheme-en.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/0/01/Liposome_scheme-en.svg/330px-Liposome_scheme-en.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/0/01/Liposome_scheme-en.svg/440px-Liposome_scheme-en.svg.png 2x" style="height: auto; max-width: 100%;" width="220" /></a><br />
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Scheme of a liposome formed by phospholipids in an aqueous solution</div>
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Mifamurtide is muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic analogue of muramyl dipeptide. The side chains of the molecule give it a longer <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Elimination_half-life" href="https://en.wikipedia.org/wiki/Elimination_half-life" title="Elimination half-life">elimination half-life</a> than the natural substance. The substance is applied encapsulated into <a data-mce-href="https://en.wikipedia.org/wiki/Liposome" href="https://en.wikipedia.org/wiki/Liposome" title="Liposome">liposomes</a> (L-MTP-PE). Being a <a data-mce-href="https://en.wikipedia.org/wiki/Phospholipid" href="https://en.wikipedia.org/wiki/Phospholipid" title="Phospholipid">phospholipid</a>, it accumulates in the <a data-mce-href="https://en.wikipedia.org/wiki/Lipid_bilayer" href="https://en.wikipedia.org/wiki/Lipid_bilayer" title="Lipid bilayer">lipid bilayer</a> of the liposomes in the infusion.<sup class="reference" id="cite_ref-15"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-15" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-15">[15]</a></sup></div>
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<span class="mw-headline" id="Synthesis">Synthesis</span></h3>
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One method of synthesis (shown first) is based on <a data-mce-href="https://en.wikipedia.org/wiki/N,N%27-Dicyclohexylcarbodiimide" href="https://en.wikipedia.org/wiki/N,N%27-Dicyclohexylcarbodiimide" title="N,N'-Dicyclohexylcarbodiimide"><i>N,N'</i>-dicyclohexylcarbodiimide</a> (DCC) assisted <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Esterification" href="https://en.wikipedia.org/wiki/Esterification" title="Esterification">esterification</a> of <i>N</i>-acetylmuramyl-<small>L</small>-alanyl-<small>D</small>-<a data-mce-href="https://en.wikipedia.org/wiki/Isoglutamine" href="https://en.wikipedia.org/wiki/Isoglutamine" title="Isoglutamine">isoglutaminyl</a>-<small>L</small>-alanine with <a data-mce-href="https://en.wikipedia.org/wiki/N-Hydroxysuccinimide" href="https://en.wikipedia.org/wiki/N-Hydroxysuccinimide" title="N-Hydroxysuccinimide"><i>N</i>-hydroxysuccinimide</a>, followed by a condensation with 2-aminoethyl-2,3-di<a data-mce-href="https://en.wikipedia.org/wiki/Palmitic_acid" href="https://en.wikipedia.org/wiki/Palmitic_acid" title="Palmitic acid">palmitoyl</a>glycerylphosphoric acid in <a data-mce-href="https://en.wikipedia.org/wiki/Triethylamine" href="https://en.wikipedia.org/wiki/Triethylamine" title="Triethylamine">triethylamine</a> (Et<sub>3</sub>N).<sup class="reference" id="cite_ref-16"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-16" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-16">[16]</a></sup> A different approach (shown second) uses <i>N</i>-acetylmuramyl-<small>L</small>-alanyl-<small>D</small>-isoglutamine, hydroxysuccinimide and alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid;<sup class="reference" id="cite_ref-17"><a data-mce-href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-17" href="https://en.wikipedia.org/wiki/Mifamurtide#cite_note-17">[17]</a></sup> that is, the alanine is introduced in the second step instead of the first.</div>
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<tr><td style="font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Mifamurtide_synthesis.png" href="https://en.wikipedia.org/wiki/File:Mifamurtide_synthesis.png"><img alt="Mifamurtide synthesis.png" data-file-height="1884" data-file-width="1375" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9d/Mifamurtide_synthesis.png/400px-Mifamurtide_synthesis.png" height="548" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/9d/Mifamurtide_synthesis.png/400px-Mifamurtide_synthesis.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/9/9d/Mifamurtide_synthesis.png/600px-Mifamurtide_synthesis.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/9/9d/Mifamurtide_synthesis.png/800px-Mifamurtide_synthesis.png 2x" style="height: auto; max-width: 100%;" width="400" /></a></td><td style="font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Mifamurtide_synthesis2.png" href="https://en.wikipedia.org/wiki/File:Mifamurtide_synthesis2.png"><img alt="Mifamurtide synthesis2.png" data-file-height="1891" data-file-width="1552" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c0/Mifamurtide_synthesis2.png/450px-Mifamurtide_synthesis2.png" height="548" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c0/Mifamurtide_synthesis2.png/450px-Mifamurtide_synthesis2.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/c/c0/Mifamurtide_synthesis2.png/675px-Mifamurtide_synthesis2.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/c/c0/Mifamurtide_synthesis2.png/900px-Mifamurtide_synthesis2.png 2x" style="height: auto; max-width: 100%;" width="450" /></a></td></tr>
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Synthesis</h2>
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Mifamurtide is an anticancer agent for the treatment of osteosarcoma, the most common primary malignancy of bone tissue mainly affecting children and adolescents.10</div>
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The drug was invented by Ciba-Geigy (now Novartis) in the early 1980s and the agent was subsequently licensed to Jenner Biotherapies in the 1990s.</div>
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IDM Pharma bought the rights to the drug from Jenner in April 2003.78 In March 2009, mifamurtide was approved in the 27 European Union member states plus Iceland, Liechtenstein and Norway via a centralized marketing authorization.</div>
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After the approval, IDM Pharma was acquired by Takeda, which began launching mifamurtide, as Mepact , in February 2010.</div>
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Mifamurtide, a fully synthetic lipophilic derivative of muramyl dipeptide (MDP), is muramyl tripeptide phosphatidylethanolamine (MTP-PE), which is formulated as a liposomal infusion.79 Being a phospholipid, mifamurtide accumulates in the lipid bilayer of the liposomes upon infusion.</div>
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After application of the liposomal infusion, the drug is cleared from the plasma within minutes. However, it is concentrated in lung, liver, spleen, nasopharynx and thyroid, and the terminal half-life is 18 h, which is longer than the natural substance.</div>
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Two synthetic routes have been reported,80,81 and Scheme 16 describes the more processamenable route.</div>
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Commercially available 1,2-dipalmitoyl-sn-glycero- 3-phosphoethanolamine (110) was coupled with N-Boc-L-alanine (111) by means of N-hydroxysuccinimide (112), DCC in DMF to give amide 113, which was followed by hydrogenolysis of the CBZ group to give the corresponding L-alanyl-phosphoric acid 114.</div>
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Next, commercially available N-acetylmuramoyl-L-alanyl-Disoglutamine (115) was subjected to hydroxybenzotriazole (HOBT) and DIC in DMF to provide the corresponding succinimide ester 116 which was condensed with compound 114 to provide mifamurtide (IX).</div>
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No yields were provided for these transformations.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-38.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-38.jpg" rel="attachment wp-att-7863"><img alt="str1" class="alignnone wp-image-7863" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-38.jpg" height="632" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-38.jpg" style="height: auto; max-width: 100%;" width="787" /></a></div>
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79. Prous, J. R.; Castaner, J. Drugs Future 1989, 14, 220.<br />80. Baschang, G.; Tarcsay, L.; Hartmann, A.; Stanek, J. EP 0027258 A1, 1980.<br />81. Brundish, D. E.; Wade, R. J. Labelled Compd. Radiopharm. 1985, 22, 29.</div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/CN103408635A?cl=en" href="https://www.google.com/patents/CN103408635A?cl=en">https://www.google.com/patents/CN103408635A?cl=en</a></div>
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<span class="notranslate">mifamurtide, the English called mifamurtide, formula C59Hltl9N6O19P, primarily for the treatment of non-metastatic</span></div>
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<span class="notranslate">Resectable osteosarcoma (a rare but the main cause of death for children and young people osteoma), having the formula as follows:</span></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AD00051.png" href="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AD00051.png"><img alt="Figure CN103408635AD00051" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AD00051.png" id="idf0001" src="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AD00051.png" style="height: auto; max-width: 100%;" /></a></div>
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<span class="notranslate">mifamurtide by certain stimuli such as macrophages and other white blood cells to kill tumor cells.</span> <span class="notranslate">Currently, mifamurtide listed injections into spherical liposome vesicles are muramyl tripeptide (MTP).</span> <span class="notranslate">This lipid trigger macrophages to consume mifamurtide.</span> <span class="notranslate">Once consumed mifamurtide, MTP-stimulated macrophages, in particular we will look for tumors in the liver, spleen and lung macrophages and kill it.</span></div>
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<span class="notranslate"> mifamurtide injection approved for marketing based on the results of phase III clinical study.</span> <span class="notranslate">Taiwan's National Cancer Institute Cooperative Group (NCI) established by the Children's Oncology Group (COG) study, complete treatment of this product in patients with osteosarcoma largest research project in the book of about 800 cases.</span> <span class="notranslate">Evaluation of mifamurtide and 3-4 adjuvant chemotherapy (cis molybdenum, doxorubicin, methotrexate, cyclophosphamide with or the same as) the results of combination therapy.</span> <span class="notranslate">Studies have shown that mifamurtide used in combination with chemotherapy can reduce the mortality rate of about 30%, 78% of treated patients survived more than six years.</span></div>
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<span class="notranslate">Shortcomings disclosed the full liquid phase synthesis technology route mifamurtide, but all-liquid phase synthesis: [0006] Currently, mifamurtide universal rely wholly liquid phase synthesis, relevant literature (220 Drugs Futl989, 14, (3)) that the synthesis requires intermediate purification steps cumbersome, time-consuming, and the total yield of the whole liquid phase synthesis is less than 30%, which has been the main factors affecting the productivity of mifamurtide</span></div>
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<span class="notranslate">A method for logging meter synthetic peptide, characterized in that it comprises the following steps: Step 1, under the effect of coupling agent, an amino group, and Fmoc-D-Glu on the amino resin (OPG) -OH main chain carboxyl acylation, a compound of formula I; Step 2, Fmoc removal of the protecting group the compound of formula I, under the effect of coupling with Fmoc-L-Ala-OH acylation, a compound of formula 2; step 3, Fmoc removal of the protecting group the compound of formula 2, in the role of a coupling agent, with a compound of formula 3 for acylation, a compound of formula 4; step 4, PG protecting group removing compound of formula 4, the coupling the role of agent, and HL-Ala-OPG acylation, a compound of formula 5; Step 5, PG protecting group removal compound of formula 5, under the effect of coupling agent, and an amino acid performed on brain phospholipids reaction of a compound of formula 6, and then the resin was added Lysates deaminated compound of formula 7; Step 6, the compound of formula 7 to obtain the removal of benzyl mifamurtide;</span></div>
<div class="patent-image small-patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AC00021.png" href="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AC00021.png"><img alt="Figure CN103408635AC00021" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AC00021.png" id="icf0001" src="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AC00021.png" style="height: auto; max-width: 100%;" /></a></div>
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<a data-mce-href="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AC00031.png" href="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AC00031.png"><img alt="Figure CN103408635AC00031" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AC00031.png" id="icf0002" src="https://patentimages.storage.googleapis.com/CN103408635A/CN103408635AC00031.png" style="height: auto; max-width: 100%;" /></a></div>
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<span class="notranslate">Wherein Fmoc is the amino protecting group; wherein PG is a carboxy-protecting group for Allyl or Dmab; Resin as the amino resin.</span></div>
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<span class="notranslate">Example: Synthesis of mifamurtide crude peptide</span></div>
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<span class="notranslate"> Example 11 to give the formula hydrogenolysis at atmospheric pressure to 16 hours Example 7 was added to 7.42 g compound 250ml single neck flask, dried 150ml of methanol was added to dissolve 0.4 g of 10% palladium on carbon.</span><span class="notranslate">Completion of the reaction, palladium-carbon was filtered off, the filtrate was concentrated by rotary evaporation to 65ml, is mifamurtide crude peptide solution.</span> <span class="notranslate">Mifamurtide synthetic crude peptide: 15 [0173] Example</span></div>
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<span class="notranslate"> Example 12 to give the formula hydrogenolysis at atmospheric pressure to 16 hours Example 7 was added to 4.21 g compound 150ml single neck flask, dried 85ml of methanol was added to dissolve 0.2 g of 10% palladium on carbon.</span><span class="notranslate">Completion of the reaction, palladium-carbon was filtered off, the filtrate was concentrated by rotary evaporation to 37ml, is mifamurtide crude peptide solution.</span></div>
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<span class="notranslate">16 [0175] Example 2: Preparation of mifamurtide</span></div>
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<span class="notranslate"> The embodiment 14 of crude peptide solution obtained in Example 65ml, IOOOml round bottom flask was added, under magnetic stirring, 650ml of anhydrous diethyl ether was added dropwise.</span> <span class="notranslate">Upon completion, at room temperature for crystallization.</span> <span class="notranslate">After filtration and drying the filter cake, the filter cake was again dissolved in 65ml of methanol.</span> <span class="notranslate">This methanol solution was added IOOOml round bottom flask, under magnetic stirring, 650ml of anhydrous diethyl ether was added dropwise.</span> <span class="notranslate">Upon completion, at room temperature for crystallization.</span> <span class="notranslate">Filtered cake was dried in vacuo to give mifamurtide 5.62g, yield 86.5%, purity 99.4%, total yield 74.5%</span></div>
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<span class="notranslate">Preparation of mifamurtide of: 17 Example</span></div>
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<span class="notranslate"> The embodiment of the crude peptide solution obtained in Example 15, 37ml, 500ml round bottom flask was added, under magnetic stirring, 370ml of anhydrous diethyl ether was added dropwise.</span> <span class="notranslate">Upon completion, at room temperature for crystallization.</span> <span class="notranslate">After filtration and drying the filter cake, the filter cake was again dissolved in 37ml of methanol.</span> <span class="notranslate">This solution was added to methanol 500ml round bottom flask, under magnetic stirring, 370ml of anhydrous diethyl ether was added dropwise.</span> <span class="notranslate">Upon completion, at room temperature for crystallization.</span> <span class="notranslate">Filtered, the filter cake was dried under vacuum to give · mifamurtide 3.16g, yield 85.8%, purity 99.5%, 72.2% overall yield.</span></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="References">References</span></h2>
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<tr class="patent-data-table"><th class="patent-data-table-th" colspan="3" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Reference</th></tr>
</thead><tbody>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">PROUS, J. ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22ENV+2-3%2FMTP-PE%22" href="http://scholar.google.com/scholar?q=%22ENV+2-3%2FMTP-PE%22">ENV 2-3/MTP-PE</a>", 《DRUGS FUT》, vol. 14, no. 3, 31 March 1989 (1989-03-31), pages 220</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">黄胜炎: "<a data-mce-href="http://scholar.google.com/scholar?q=%22%E6%8A%97%E8%82%BF%E7%98%A4%E8%8D%AF%E6%96%B0%E5%93%81%E4%B8%8E%E7%A0%94%E5%8F%91%E8%BF%9B%E5%B1%95%22" href="http://scholar.google.com/scholar?q=%22%E6%8A%97%E8%82%BF%E7%98%A4%E8%8D%AF%E6%96%B0%E5%93%81%E4%B8%8E%E7%A0%94%E5%8F%91%E8%BF%9B%E5%B1%95%22">抗肿瘤药新品与研发进展</a>", 《上海医药》, vol. 30, no. 9, 30 September 2009 (2009-09-30), pages 412 - 414</td></tr>
</tbody></table>
</div>
</div>
<table class="infobox mce-item-table" data-mce-style="height: 959px;" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: 959px; line-height: 24px; width: 766px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Mifamurtide">Mifamurtide</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Mifamurtide.svg" href="https://en.wikipedia.org/wiki/File:Mifamurtide.svg"><img alt="Mifamurtide.svg" data-file-height="630" data-file-width="1340" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/fe/Mifamurtide.svg/300px-Mifamurtide.svg.png" height="141" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/fe/Mifamurtide.svg/300px-Mifamurtide.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/f/fe/Mifamurtide.svg/450px-Mifamurtide.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/f/fe/Mifamurtide.svg/600px-Mifamurtide.svg.png 2x" style="height: auto; max-width: 100%;" width="300" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2-[(<i>N</i>-{(2<i>R</i>)-[(2-acetamido-2,3-dideoxy-D-glucopyranos-3-yl)oxy]-propanoyl}-<small>L</small>-alanyl-<small>D</small>-isoglutaminyl-<small>L</small>-alanyl)amino]ethyl (2<i>R</i>)-2,3-bis(hexadecanoyloxy)propyl hydrogen phosphate</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">License data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small>EU</small> <a data-mce-href="https://en.wikipedia.org/wiki/European_Medicines_Agency" href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency">EMA</a>: <span title="www.ema.europa.eu"><a class="external text" data-mce-href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Mepact" href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Mepact" rel="nofollow">Mepact</a></span></li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li>not investigated</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Intravenous" href="https://en.wikipedia.org/wiki/Intravenous" title="Intravenous">intravenous</a> <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Liposomal" href="https://en.wikipedia.org/wiki/Liposomal" title="Liposomal">liposomal</a> infusion over one hour</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li>℞ (Prescription only)</li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Bioavailability" href="https://en.wikipedia.org/wiki/Bioavailability" title="Bioavailability">Bioavailability</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">N/A</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Biological_half-life" href="https://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">minutes (in plasma)<br />18 hrs (terminal)</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=83461-56-7" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=83461-56-7" rel="nofollow">83461-56-7</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup><br /><a class="external text" data-mce-href="https://tools.wmflabs.org/magnustools/cas.php?language=en&cas=838853-48-8&title=" href="https://tools.wmflabs.org/magnustools/cas.php?language=en&cas=838853-48-8&title=">838853-48-8</a> (mifamurtide sodium · xH<sub>2</sub>O)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_L03" href="https://en.wikipedia.org/wiki/ATC_code_L03" title="ATC code L03">L03AX15</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=L03AX15" href="http://www.whocc.no/atc_ddd_index/?code=L03AX15" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11672602" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11672602" rel="nofollow">11672602</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.9847332.html" href="http://www.chemspider.com/Chemical-Structure.9847332.html" rel="nofollow">9847332</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=EQD2NNX741" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=EQD2NNX741" rel="nofollow">EQD2NNX741</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/KEGG" href="https://en.wikipedia.org/wiki/KEGG" title="KEGG">KEGG</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.kegg.jp"><a class="external text" data-mce-href="http://www.kegg.jp/entry/D06619" href="http://www.kegg.jp/entry/D06619" rel="nofollow">D06619</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>59</sub><span title="Hydrogen">H</span><sub>109</sub><span title="Nitrogen">N</span><sub>6</sub><span title="Oxygen">O</span><sub>19</sub><span title="Phosphorus">P</span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1237.499 g/mol</td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
//////////83461-56-7, 838853-48-8, CGP-19835, Mepact, MFCD09954133, Mifamurtide, mifamurtide sodium, MTP-cephalin, Mtp-PE, Muramyl tripeptide phosphatidylethanolamine, PEPTIDE, мифамуртид, ميفامورتيد, 米法莫肽</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCNC(=O)[C@H](C)NC(=O)CC[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1C(O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O)C(N)=O)OC(=O)CCCCCCCCCCCCCCC</div>
</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-1346483141860457136.post-74985328574724363322016-07-25T00:49:00.001-07:002016-07-25T00:49:37.904-07:00Pidotimod, 匹多莫德 , пидотимод , بيدوتيمود ,<div dir="ltr" style="text-align: left;" trbidi="on">
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="http://media.scbt.com/image.php?image=/i/09/23/92327.jpg" src="http://media.scbt.com/image.php?image=/i/09/23/92327.jpg" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="http://www.chemspider.com/ImagesHandler.ashx?id=59348&w=250&h=250" src="http://www.chemspider.com/ImagesHandler.ashx?id=59348&w=250&h=250" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="http://www.drugfuture.com/synth/img/14/144458.gif" src="http://www.drugfuture.com/synth/img/14/144458.gif" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Pidotimod</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
H-Pyr-Thz-OH</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(4R)-3-[(2S)-5-oxopyrrolidine-2-carbonyl]-1,3-thiazolidine-4-carboxylic acid</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong>CAS 121808-62-6</strong></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Thymodolic acid, Pidotimod, Timodolic acid, PGT/1A, Axil, Onaka, Pigitil, Polimod</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(4R)-3-(5-oxo-L-prolyl)-l ,3-thiazolidine-4-carboxylic acid, ITI 231723.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylic acid</div>
<ul style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li>4-Thiazolidinecarboxylic acid, 3-[(5-oxo-2-pyrrolidinyl)carbonyl]-, [R-(R*,S*)]-</li>
<li class="alt">(4R)-3-[[(2S)-5-Oxo-2-pyrrolidinyl]carbonyl]-4-thiazolidinecarboxylic acid</li>
<li>Adimod</li>
<li class="alt">Axil (pharmaceutical)</li>
<li>Pigitil</li>
</ul>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">QA-7522</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">SMR000466390</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">Thymodolic acid</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">Timodolic acid</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">UNII:785363R681</span></div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
</div>
<table class="top-summary-items mce-item-table" data-mce-style="height: 81px;" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: 81px; line-height: 24px; width: 440px;"><tbody>
<tr><td class="breakword" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pidotimod; 121808-62-6; (R)-3-((S)-5-Oxopyrrolidine-2-carbonyl)thiazolidine-4-carboxylic acid; Pidotomod; PGT/1A; Pidotimod [INN];</td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Formula:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C9H12N2O4S&sort=mw&sort_dir=asc" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C9H12N2O4S&sort=mw&sort_dir=asc" title="Find all compounds with formula C9H12N2O4S">C<sub>9</sub>H<sub>12</sub>N<sub>2</sub>O<sub>4</sub>S</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Weight:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">244.26758 g/mol</td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="patent-bibdata-value"><a data-mce-href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Stefano+Poli%22" href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Stefano+Poli%22">Stefano Poli</a>, </span><span class="patent-bibdata-value"><a data-mce-href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Corona+Lucio+Del%22" href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Corona+Lucio+Del%22">Corona Lucio Del</a></span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b><a data-mce-href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22POLI+INDUSTRIA+CHIMICA+S.p.A.%22" href="http://www.google.com/search?tbo=p&tbm=pts&hl=en&q=inassignee:%22POLI+INDUSTRIA+CHIMICA+S.p.A.%22">POLI INDUSTRIA CHIMICA S.p.A.</a></b></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b>Pidotimod</b> is an <a data-mce-href="https://en.wikipedia.org/wiki/Immunostimulant" href="https://en.wikipedia.org/wiki/Immunostimulant" title="Immunostimulant">immunostimulant</a>.<sup class="reference" id="cite_ref-pmid18806958_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Pidotimod#cite_note-pmid18806958-1" href="https://en.wikipedia.org/wiki/Pidotimod#cite_note-pmid18806958-1">[1]</a></sup></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<img alt="Pidotimod.png" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=65944&t=l" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=65944&t=l" style="height: auto; max-width: 100%;" /> <img data-mce-src="http://image.ecplaza.com/offer/j/jkcoscl/8841911.jpg" src="http://image.ecplaza.com/offer/j/jkcoscl/8841911.jpg" style="height: auto; max-width: 100%;" /></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Pidotimod, whose chemical name is (4R)-3-(5-oxo-L-prolyl)-l ,3-thiazolidine-4-carboxylic acid, was first disclosed in ITI 231723. It is a synthetic peptide-like molecule provided with an in vitro and in vivo immunomodulating action (Giagulli et al., International Immunopharmacology, 9, 2009, 1366-1373). The immune system assists in maintaining a homeostatic balance between the human body and all foreign substances. An abnormality in this balance may cause a defective or aberrant response towards non-self substances, as well as loss of tolerance toward self-antigens, in such cases, the immune system imbalance exhibits clinically as signs of disease.</div>
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Pidotimod has been shown to induce dendritic cell maturation and up-regulate the expression of HLA-DR and co-stimulatory molecules CD83 and CD86, which are integral to communication with adaptive immunity cells. Pidotimod has also been shown to stimulate dendritic cells to release pro-inflammatory molecules such as MCP-1 and TNF-a cytokines, and to inhibit thymocyte apoptosis caused by a variety of apoptosis-inducing molecules. Pidotimod exerts a protective action against infectious processes, although not through direct antimicrobial or antiviral action. Rather, pidotimod stimulates both innate and acquired immunity by enhancing humoral and cell-mediated immunity mechanisms.</div>
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Pidotimod, which may be administered as solid or liquid forms, for example, via an oral route, has been shown to increase natural resistance to viral or bacterial infections in animal models. Efficacy demonstrated in patients includes respiratory, urinary and genital infections, in particular recurrent respiratory infections in pediatric patients, respiratory infections in asthmatic patients and chronic obstructive pulmonary disease in adults and elderly patients.</div>
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Besides exhibiting activity to illnesses characterized by immune defects, pidotimod has been reported to be of benefit in to patients with other kinds of diseases, not directly related to immune defects, including gastroenterology diseases such as ulcerative colitis and irritable bowel syndrome, and dermatological diseases such as psoriasis and atopic dermatitis where symptoms relating to these diseases have been attenuated. In gastroenterology diseases pidotimod may be administered either by oral or by rectal route. Oral route or topical application, for example in creams or gels containing pidotimod, may be used to treat dermal conditions.</div>
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Further use of pidotimod includes treatment of inflammatory diseases, in particular those characterized by an aberrant activation of the non-canonical NF-kB pathway. Diseases implicated by such activation include allergic diseases, autoimmune diseases, and numerous other inflammatory diseases. Allergic diseases include allergic rhinitis, allergic conjunctivitis, contact dermatitis, eczema and allergic vasculitis.</div>
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Autoimmune diseases include alopecia areata, ankylosing spondylitis, autoimmune cardiomyopathy, autoimmune connective tissue diseases, autoimmune enteropathy, autoimmune hepatitis, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, celiac disease, chronic fatigue syndrome, cystic fibrosis, hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IGA nephropathy, juvenile idiopathic arthritis for juvenile rheumatoid arthritis, or Still's disease) Kawasaki's disease, lichen planus, lupus erythematosus, rheumatoid arthritis, rheumatic fever, Sj5gren's syndrome, spondyloarthropathy, temporal arteritis (or giant cell arteritis), urticarial vasculitis, and vitiligo.</div>
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Other inflammatory diseases include Alzheimer's disease, atherosclerosis, chronic liver diseases, chronic nephropathy, gastritis, glomerulonephritis, hydradenitis suppurativa, hypogammaglobulinemia, interstitial cystitis, lichen sclerosus, liver steatosis, metabolic syndrome, obesity, Parkinson's disease, pemphigus vulgaris, post-ischemic inflammation, raynaud phenomenon, restless leg syndrome, retroperitoneal fibrosis, and thrombocytopenia.</div>
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<br /></div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2016/07/str13.png" href="https://newdrugapprovals.files.wordpress.com/2016/07/str13.png"><img alt="STR1" class="alignnone size-medium wp-image-19230" data-mce-src="https://newdrugapprovals.files.wordpress.com/2016/07/str13.png?w=300" height="158" src="https://newdrugapprovals.files.wordpress.com/2016/07/str13.png?w=300" style="height: auto; max-width: 100%;" width="300" /></a></div>
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PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/CN104926922A?cl=en" href="https://www.google.com/patents/CN104926922A?cl=en">CN 104926922</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Synthesis pidotimod</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A method for producing pidotimod, characterized in that: comprising the steps of: a) L- thiazolidine-4-carboxylic acid: L- cysteine formaldehyde solution was added dropwise, stirred at room temperature, filtered to give L- thiazolidine-4-carboxylic acid; (2) metal ion load type cation exchange resin preparation: strongly acidic with hydrochloric acid cation exchange resin is converted to the hydrogen form, the hydrogen form strong acid cation exchange resin was added a solution of a metal ion compound In, 40 ~ 80 ° C for 1 to 6 hours, cooled to room temperature, and dried to obtain a supported metal ion cation exchange resin; (3) Synthesis of pidotimod: the step (1) of L- thiazolidine - 4- carboxylic acid, in step (2) of the load as a catalyst metal ion type cation exchange resin, L- pyroglutamic acid and N, N- dimethylformamide mixed, 40 ~ 80 ° C for 1 to 4 hours, filtered to give a white solid, the white solid was acidified with hydrochloric acid, to give the finished pidotimod.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<div class="patent-image small-patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN104926922A/CN104926922AD00042.png" href="https://patentimages.storage.googleapis.com/CN104926922A/CN104926922AD00042.png"><img alt="Figure CN104926922AD00042" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104926922A/CN104926922AD00042.png" id="idf0002" src="https://patentimages.storage.googleapis.com/CN104926922A/CN104926922AD00042.png" style="height: auto; max-width: 100%;" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">In four flask IOg L- thiazolidine-4-carboxylic acid, 11. 3g g L- pyroglutamic acid, 320mL N, N- dimethylformamide, 12g modified resin, 70 ° C the reaction 2 hours.</span> <span class="notranslate">Filtration, the reaction mixture by rotary evaporation, after removal of part of the solvent, placed in an ice bath to cool, the precipitated solid was suction filtered to give a white solid, this white solid was acidified with 37% hydrochloric acid, was allowed to stand at KTC, crystallization, filtration, a white product 14. 4g, a yield of 78.3%.</span> <span class="notranslate">Measured melting point 192 ~ 194 ° C, [a] 25D = - 150 ° (literature values mp: 192 ~ 194 ° C, [a] 25D = - 150 °).</span><span class="notranslate">The whole preparation reaction pidotimod total yield of 64%.</span> <span class="notranslate">By HPLC, pidotimod content of 98.5%.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PAPER</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a class="refDetailQuickLink" href="https://www.blogger.com/null">Zhang, Yi; Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(24), PG 2566-2570</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://europepmc.org/abstract/med/19604731" href="http://europepmc.org/abstract/med/19604731">http://europepmc.org/abstract/med/19604731</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
10.1016/j.jchromb.2009.06.038</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
PATENT</h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016113242&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016113242&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription">WO2016113242</a>,</div>
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Example 14 - Preparation of Pidotimod</div>
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Pidotimod was prepared following Example 1 of EP0422566 Al .</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
WO2015036009,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/WO2015036009A1?cl=en" href="https://www.google.com/patents/WO2015036009A1?cl=en">https://www.google.com/patents/WO2015036009A1?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
EP276752,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://google.com/patents/EP0422566B1?cl=en" href="http://google.com/patents/EP0422566B1?cl=en">http://google.com/patents/EP0422566B1?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<u><b>EXAMPLE 1</b></u></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A solution of 16.78 g (0.084 mole) of ethyl L-thiazolidine-4-carboxylate hydrochloride in 33 ml of water is treated with 16.78 g of potassium carbonate and extracted with 40 ml of ethyl acetate. The organic phase is dried over sodium sulfate, filtered and diluted to 85 ml with ethyl acetate. The solution is stirred and cooled to 0-5°C, then 19.2 g (0.093 mole) of dicyclohexylcarbodiimide dissolved in 20 ml of ethyl acetate and 12 g (0.093 mole) of L-pyroglutamic acid are added thereto. The reaction mixture is stirred for 1 hour at 0-5°C, then 12 hours at room temperature, dicyclohexylurea is filtered, the filtrate is evaporated under vacuum and the oily residue, consisting in ethyl 3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylate is taken up into 25 ml of water. 3.73 g of sodium hydroxide dissolved in 13.3 ml of water are dropped into the resulting solution. After 30 minutes, the reaction mixture is acidified with concentrated hydrochloric acid at 0-5°C, kept for 2 hours at 5°C, then filtered washing with little cool water and dried to obtain 17.8 g (87.6%) of 3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylic acid, m.p. 193-194°C.</div>
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<u><b>EXAMPLE 2</b></u></div>
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23 g (0.1 mol) of L-N-t-butoxycarbonylpyroglutamic acid (E. Schröder and E. Klinger, Ann. Chem., 673, 1964, 202) and 16.1 g (0.1 mol) of ethyl L-thiazolidine-4-carboxylate are dissolved in 150 ml of THF, to the solution stirred at 0-5°C, 21 g (0.105 mol) of dicyclohexylcarbodiimide are added and the slurry is stirred for 15 hours at room temperature. The dicyclohexylurea is filtered, the wear filtrate is evaporated u.v. and the oily residue is kept in 40 ml of water. In the solution 6.6 g of potassium hydroxyde in a little water are dropped in 30′ at 15-20°C, the pH is adjusted to 2 with hydrochloric acid at 0-5°C and after 2 hours the precipitated L-pyroglutamyl-L-thiazolidine-4-carboxylic acid is filtered and dried, giving 88%, mp. 193-4°.</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
CLIP</h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Drugs Fut 1991,16(12),1096</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Liebigs Ann Chem 1964,673</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<img data-mce-src="http://www.drugfuture.com/synth/img/sch/14/14445801a.gif" src="http://www.drugfuture.com/synth/img/sch/14/14445801a.gif" style="height: auto; max-width: 100%;" /></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The synthesis of pidotimod has been carried out using N-tert-butoxycarbonyl-L-pyroglutamic acid as starting material, in order to avoid the formation of diketopiperazine derivatives. L-Glutamic acid (I) was condensed with di-tert-butyl dicarbonate by means of triethylamine in DMF to give N-(tert-butoxycarbonyl)-L-glutamic acid (II), which is dissolved in THF and treated with dicyclohexylcarbodiimide (DCC) to obtain N-(tert-butoxycarbonyl)-L-glutamic anhydride (III). The treatment of anhydride (III) with dicyclohexylamine in THF-ethyl ether affords the dicyclohexylamine salt of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (IV), which by acidification with aqueous citric acid yields the corresponding free acid (V). The condensation of equimolecular amounts of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (V) with L-thiazolidine-4-carboxylic acid ethyl ester (VIII) by means of DCC in methylene chloride gives the coupled ester (IX), which is hydrolyzed with aqueous NaOH, and the corresponding sodium salt acidified to yield the N-tert-butoxycarbonyl derivative (X). Finally, this compound is deprotected with trifluoroacetic acid to obtain crystalline pidotimod (XI). The intermediate thiazolidine (VIII) has been obtained as follows: Esterification of L-thiazolidine-4-carboxylic acid (VI) with ethanol by means of SOCl2 gives the corresponding ethyl ester hydrochloride (VII), which by treatment with K2CO3 in water yields the free ester (VIII).</div>
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<br /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcS9kb0VQJPl4bwa8YWnFnTEgebpH2TD4UL8ieHOj24rptmWEDC1" src="https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcS9kb0VQJPl4bwa8YWnFnTEgebpH2TD4UL8ieHOj24rptmWEDC1" style="height: auto; max-width: 100%;" /></div>
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CLIP</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Arzneim-Forsch Drug Res 1994,44(12a),1402</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="http://www.drugfuture.com/synth/img/sch/14/14445802a.gif" src="http://www.drugfuture.com/synth/img/sch/14/14445802a.gif" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Two new related routes for the synthesis of pidotimod have been reported: 1) The condensation of L-pyroglutamic acid (I) with L-thiazolidine-4-carboxylic acid ethyl ester (II) by means of dicyclohexylcarbodiimide (DCC) in methylene chloride gives the corresponding dipeptide ethyl ester (III), which is saponified with aqueous 1N NaOH. 2) By condensation of the activated ester L-pyroglutamic acid pentachlorophenyl ester (IV) with L-thiazolidine-4-carboxylic acid (V) by means of triethylamine in DMF.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016112977&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription" href="https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016112977&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription">WO-2016112977</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Novel crystalline, amorphous and solid forms of di-pidotimod benzathine (designated as Forms M and H), their hydrates, processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating viral or bacterial infections, respiratory, urinary and/or genital infections, ulcerative colitis, irritable bowel syndrome, psoriasis and atopic dermatitis</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Example 14 - Preparation of Pidotimod</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Pidotimod was prepared following Example 1 of EP0422566 Al .</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
NMR</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Figure 17 is a Ή solution-state NMR spectrum of Form H</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="https://patentscope.wipo.int/search/docservice_image_drawings/WO@@@id00000034207355@@@11014607@@@200@@@0@@@000063.tif" src="https://patentscope.wipo.int/search/docservice_image_drawings/WO@@@id00000034207355@@@11014607@@@200@@@0@@@000063.tif" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
SEE</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
CN 104447947</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Indian Pat. Appl. (2014), IN 2013MU00181 A</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
WO 2014111957</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
CN 103897025</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<div class="patent-section patent-tabular-section" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/CN1557303A?cl=en" href="https://www.google.com/patents/CN1557303A?cl=en">CN1557303A</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jan 16, 2004</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 29, 2004</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">太阳石(唐山)药业有限公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Use of Pidotimod in preparation of hepatitis B treating medicine</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/EP0382180A2?cl=en" href="https://www.google.com/patents/EP0382180A2?cl=en">EP0382180A2</a><span class="patent-tooltip-anchor"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feb 7, 1990</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 16, 1990</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">POLI INDUSTRIA CHIMICA S.p.A.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Derivatives of thiazolidine-4-carboxylic acid, its preparation and pharmaceutical compositions containing it</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/url?id=iVVECQABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DIT%26NR%3D1231723B%26KC%3DB%26FT%3DD&usg=AFQjCNGSEiMRKn4zYd_o0stsc-wwwNcsjQ" href="https://www.google.com/url?id=iVVECQABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DIT%26NR%3D1231723B%26KC%3DB%26FT%3DD&usg=AFQjCNGSEiMRKn4zYd_o0stsc-wwwNcsjQ">IT1231723B</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td citation-no-title" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title not available</td></tr>
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<div class="patent-section-footer">
</div>
</div>
<div class="patent-section patent-tabular-section" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table class="patent-data-table mce-item-table" data-mce-style="height: 570px;" style="border: 1px dashed rgb(187, 187, 187); height: 570px; width: 758px;"><thead class="patent-data-table-thead">
<tr class="patent-data-table"><th class="patent-data-table-th" colspan="3" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Reference</th></tr>
</thead><tbody>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; DUAN, RUOZHU ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Application+and+prospects+of+immunostimulants%22" href="http://scholar.google.com/scholar?q=%22Application+and+prospects+of+immunostimulants%22">Application and prospects of immunostimulants</a>", XP002722997, retrieved from STN Database accession no. 2006:478774</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; LI, YIPING ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Effects+of++++pidotimod+on+immune+function+of+patients+with+chronic+hepatitis+C%22" href="http://scholar.google.com/scholar?q=%22Effects+of++++pidotimod+on+immune+function+of+patients+with+chronic+hepatitis+C%22">Effects of pidotimod on immune function of patients with chronic hepatitis C</a>", XP002722996, retrieved from STN Database accession no. 2007:598452</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; WU, RONGRONG ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Application+of+immunomodulatory+drugs+in+treatment+of+chronic+hepatitis+B%22" href="http://scholar.google.com/scholar?q=%22Application+of+immunomodulatory+drugs+in+treatment+of+chronic+hepatitis+B%22">Application of immunomodulatory drugs in treatment of chronic hepatitis B</a>", XP002722995, retrieved from STN Database accession no. 2010:125278</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">4</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; March 2002 (2002-03), VARGAS CORREA JORGE B ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22%5BPidotimod+in+recurring+respiratory+infection+in+children+with+allergic+rhinitis%2C+asthma%2C+or+both+conditions%5D.%22" href="http://scholar.google.com/scholar?q=%22%5BPidotimod+in+recurring+respiratory+infection+in+children+with+allergic+rhinitis%2C+asthma%2C+or+both+conditions%5D.%22">[Pidotimod in recurring respiratory infection in children with allergic rhinitis, asthma, or both conditions].</a>", XP002722994, Database accession no. NLM12092522 & VARGAS CORREA JORGE B ET AL: REVISTA ALERGIA MEXICO (TECAMACHALCO, PUEBLA, MEXICO : 1993) 2002 MAR-APR, vol. 49, no. 2, March 2002 (2002-03), pages 27-32, XP8168769, ISSN: 0002-5151</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">GOURGIOTIS DIMITRIOS ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Immune+modulator+pidotimod+decreases+the+in+vitro+expression+of+CD30+in+peripheral+blood+mononuclear+cells+of+atopic+asthmatic+and+normal+children%22" href="http://scholar.google.com/scholar?q=%22Immune+modulator+pidotimod+decreases+the+in+vitro+expression+of+CD30+in+peripheral+blood+mononuclear+cells+of+atopic+asthmatic+and+normal+children%22">Immune modulator pidotimod decreases the in vitro expression of CD30 in peripheral blood mononuclear cells of atopic asthmatic and normal children</a>", JOURNAL OF ASTHMA, ASTHMA PUBLICATIONS SOCIETY, OSSINING, NY, US, vol. 41, no. 3, 1 January 2004 (2004-01-01), pages 285-287, XP008164025, ISSN: 0277-0903, DOI: 10.1081/JAS-120026085</td></tr>
<tr><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="patent-tooltip-anchor">*</span></td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XIN JIN ET AL: "<a data-mce-href="http://scholar.google.com/scholar?q=%22Sublingual+Surprise%3A+A+New+Variant+of+Oral+Lichen+Planus%22" href="http://scholar.google.com/scholar?q=%22Sublingual+Surprise%3A+A+New+Variant+of+Oral+Lichen+Planus%22">Sublingual Surprise: A New Variant of Oral Lichen Planus</a>", THE AMERICAN JOURNAL OF MEDICINE, vol. 127, no. 1, 1 January 2014 (2014-01-01), pages 28-30, XP055112640, ISSN: 0002-9343, DOI: 10.1016/j.amjmed.2013.10.002</td></tr>
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<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<ol class="references">
<li id="cite_note-pmid18806958-1"> <span class="reference-text"><cite class="citation journal">Du XF, Jiang CZ, Wu CF, Won EK, Choung SY (September 2008). "Synergistic immunostimulating activity of pidotimod and red ginseng acidic polysaccharide against cyclophosphamide-induced immunosuppression". <i>Archives of pharmacal research</i> <b>31</b> (9): 1153–9.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1007%2Fs12272-001-1282-6" href="https://dx.doi.org/10.1007%2Fs12272-001-1282-6" rel="nofollow">10.1007/s12272-001-1282-6</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/18806958" href="https://www.ncbi.nlm.nih.gov/pubmed/18806958" rel="nofollow">18806958</a>.</cite></span></li>
</ol>
</div>
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Pidotimod">Pidotimod</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Pidotimod.png" href="https://en.wikipedia.org/wiki/File:Pidotimod.png"><img alt="Pidotimod.png" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/e1/Pidotimod.png/220px-Pidotimod.png" height="113" src="https://upload.wikimedia.org/wikipedia/commons/thumb/e/e1/Pidotimod.png/220px-Pidotimod.png" style="height: auto; max-width: 100%;" width="220" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">(4<i>R</i>)-3-(5-oxo-<small>L</small>-prolyl)-1,3-thiazolidine-4-carboxylic acid</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/international/pidotimod.html" href="https://www.drugs.com/international/pidotimod.html" rel="nofollow">International Drug Names</a></span></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_L03" href="https://en.wikipedia.org/wiki/ATC_code_L03" title="ATC code L03">L03AX05</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=L03AX05" href="http://www.whocc.no/atc_ddd_index/?code=L03AX05" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=65944" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=65944" rel="nofollow">65944</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.59348.html" href="http://www.chemspider.com/Chemical-Structure.59348.html" rel="nofollow">59348</a></span><sup> <img alt="Yes" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=785363R681" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=785363R681" rel="nofollow">785363R681</a></span><sup> <img alt="Yes" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/KEGG" href="https://en.wikipedia.org/wiki/KEGG" title="KEGG">KEGG</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.kegg.jp"><a class="external text" data-mce-href="http://www.kegg.jp/entry/D07261" href="http://www.kegg.jp/entry/D07261" rel="nofollow">D07261</a></span><sup> <img alt="Yes" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEMBL" href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1488165" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1488165" rel="nofollow">CHEMBL1488165</a></span><sup> <img alt="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Synonym" href="https://en.wikipedia.org/wiki/Synonym" title="Synonym">Synonyms</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><small>(4<i>R</i>)-3-[(2<i>S</i>)-5-oxopyrrolidine-2-carbonyl]-1,3-thiazolidine-4-carboxylic acid</small></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>9</sub><span title="Hydrogen">H</span><sub>12</sub><span title="Nitrogen">N</span><sub>2</sub><span title="Oxygen">O</span><sub>4</sub><span title="Sulfur">S</span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">244.26758 g/mol</td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
//////////////Pidotimod, Thymodolic acid, Pidotimod, Timodolic acid, PGT/1A, Axil, Onaka, Pigitil, Polimod, H-Pyr-Thz-OH, <strong> 121808-62-6, ITI 231723, peptide, </strong><span class="">QA-7522, </span><span class="">SMR000466390, </span><span class="">Thymodolic acid, </span><span class="">Timodolic acid, </span><span class="">UNII:785363R681, <strong>匹多莫德 , пидотимод , </strong></span><strong>بيدوتيمود</strong> ,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
O=C(O)[C@H]2N(C(=O)[C@H]1NC(=O)CC1)CSC2</div>
</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-1346483141860457136.post-71103831175342359302016-07-24T21:36:00.000-07:002016-07-24T21:36:32.352-07:00Belinostat (PXD101), a novel HDAC inhibitor<div dir="ltr" style="text-align: left;" trbidi="on">
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="File:Belinostat.svg" data-mce-src="http://upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Belinostat.svg/512px-Belinostat.svg.png" src="http://upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Belinostat.svg/512px-Belinostat.svg.png" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b>Belinostat</b> (<b>PXD101</b>)</div>
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<a data-mce-href="http://www.lgmpharma.com/blog/belinostat-granted-priority-review-status-lymphoma-treatment/" href="http://www.lgmpharma.com/blog/belinostat-granted-priority-review-status-lymphoma-treatment/"> FAST TRACK FDA</a> , ORPHAN STATUS</div>
<div class="syn" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="">PXD101;PX105684;PXD<wbr></wbr>-101;PXD 101;PX-105<wbr></wbr>684</span></div>
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<span class="">UNII:F4H96P17NZ</span></div>
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<span class="">N-Hydroxy-3-(3-phen<wbr></wbr>ylsulphamoylphenyl)<wbr></wbr>acrylamide</span></div>
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<span class="">N-HYDROXY-3-[3-[(PH<wbr></wbr>ENYLAMINO)SULFONYL]<wbr></wbr>PHENYL]-2-PROPENAMI<wbr></wbr>DE</span></div>
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<span class="">NSC726630</span></div>
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<span class="">(E)-N-hydroxy-3-[3-<wbr></wbr>(phenylsulfamoyl)ph<wbr></wbr>enyl]prop-2-enamide</span></div>
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<span class="">414864-00-9</span> <a class="synonym_ref" data-mce-href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=pccompound&amp;term=%22414864-00-9%22[CompleteSynonym]" href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=pccompound&amp;term=%22414864-00-9%22[CompleteSynonym]" target="reference" title="RN">[RN]</a></div>
<div class="syn">
<span class="">866323-14-0</span> <a class="synonym_ref" data-mce-href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=pccompound&amp;term=%22866323-14-0%22[CompleteSynonym]" href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=pccompound&amp;term=%22866323-14-0%22[CompleteSynonym]" target="reference" title="RN">[RN]</a></div>
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<span class="">Beleodaq®</span></div>
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<img alt="" class="irc_mut" data-mce-src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcRtwLRJQfinLxTHcJ_RrZh23qig7b6PBn2vHC7nh0UNpDFU33EnmA" data-mce-style="margin-top: 119px;" height="155" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcRtwLRJQfinLxTHcJ_RrZh23qig7b6PBn2vHC7nh0UNpDFU33EnmA" style="height: auto; margin-top: 119px; max-width: 100%;" width="162" /><img alt="" class="" data-mce-src="http://www.lgmpharma.com/blog/wp-content/uploads/2014/07/Belinostat-Early-Approval-for-Lymphoma-Treatment.png" height="306" src="http://www.lgmpharma.com/blog/wp-content/uploads/2014/07/Belinostat-Early-Approval-for-Lymphoma-Treatment.png" style="height: auto; max-width: 100%;" width="204" /></div>
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Approved by FDA......<a data-mce-href="http://www.drugs.com/newdrugs/fda-approves-beleodaq-belinostat-peripheral-t-cell-lymphoma-4052.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+July+3%2C+2014" href="http://www.drugs.com/newdrugs/fda-approves-beleodaq-belinostat-peripheral-t-cell-lymphoma-4052.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+July+3%2C+2014">http://www.drugs.com/newdrugs/fda-approves-beleodaq-belinostat-peripheral-t-cell-lymphoma-4052.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+July+3%2C+2014</a></div>
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July 3, 2014 -- The U.S. Food and Drug Administration today approved Beleodaq (belinostat) for the treatment of patients with peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The action was taken under the agency’s accelerated approval program.</div>
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Belinostat (PXD101) is a novel HDAC inhibitor with IC50 of 27 nM, with activity demonstrated in cisplatin-resistant tumors.</div>
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CLINICAL TRIALS...<a data-mce-href="http://clinicaltrials.gov/search/intervention=Belinostat+OR+PXD101" href="http://clinicaltrials.gov/search/intervention=Belinostat+OR+PXD101">http://clinicaltrials.gov/search/intervention=Belinostat+OR+PXD101</a></div>
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<strong><em>MP 172–174 °C, (lit.<a class="ref" href="https://www.blogger.com/null">(@)</a> 172 °C). <sup>1</sup>H NMR (400 MHz, DMSO-d<sub>6</sub>) δ = 10.75–10.42 (m, 2H), 9.15 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),7.47 (d, J = 15.8 Hz, 1H), 7.24 (m, 2H), 7.10–7.01 (m, 3H), 6.51 (d, J = 15.8 Hz, 1H). MS (ESI): m/z = 318.6 [M+H] <sup>+</sup>.</em></strong></div>
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<strong><em>@ <span class="hlFld-ContribAuthor ">Finn<span class="NLM_x">, </span>P. W.</span>; <span class="hlFld-ContribAuthor ">Bandara<span class="NLM_x">, </span>M.</span>; <span class="hlFld-ContribAuthor ">Butcher<span class="NLM_x">, </span>C.</span>; <span class="hlFld-ContribAuthor ">Finn<span class="NLM_x">, </span>A.</span>; <span class="hlFld-ContribAuthor ">Hollinshead<span class="NLM_x">, </span>R.</span>; <span class="hlFld-ContribAuthor ">Khan<span class="NLM_x">, </span>N.</span>; <span class="hlFld-ContribAuthor ">Law<span class="NLM_x">, </span>N.</span>; <span class="hlFld-ContribAuthor ">Murthy<span class="NLM_x">, </span>S.</span>; <span class="hlFld-ContribAuthor ">Romero<span class="NLM_x">,</span>R.</span>; <span class="hlFld-ContribAuthor ">Watkins<span class="NLM_x">, </span>C.</span>; <span class="hlFld-ContribAuthor ">Andrianov<span class="NLM_x">, </span>V.</span>; <span class="hlFld-ContribAuthor ">Bokaldere<span class="NLM_x">, </span>R. M.</span>; <span class="hlFld-ContribAuthor ">Dikovska<span class="NLM_x">, </span>K.</span>; <span class="hlFld-ContribAuthor ">Gailite<span class="NLM_x">, </span>V.</span>; <span class="hlFld-ContribAuthor ">Loza<span class="NLM_x">, </span>E.</span>; <span class="hlFld-ContribAuthor ">Piskunova<span class="NLM_x">, </span>I.</span>;<span class="hlFld-ContribAuthor ">Starchenkov<span class="NLM_x">, </span>I.</span>; <span class="hlFld-ContribAuthor ">Vorona<span class="NLM_x">, </span>M.</span>; <span class="hlFld-ContribAuthor ">Kalvinsh<span class="NLM_x">, </span>I.</span> <span class="citation_source-journal">Helv. Chim. Acta</span> <span class="NLM_year">2005</span>, <span class="NLM_volume">88</span>, <span class="NLM_fpage">1630</span>, <span class="refDoi">DOI: 10.1002/hlca.200590129</span></em></strong></div>
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Beleodaq and Folotyn are marketed by Spectrum Pharmaceuticals, Inc., based in Henderson, Nevada. Istodax is marketed by Celgene Corporation based in Summit, New Jersey.</div>
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Belinostat was granted orphan drug status for the treatment of Peripheral T-cell lymphoma (PTCL) in the US in September 2009 and the EU in October 2012. In July 2015, an orphan drug designation has also been granted for malignant thymoma in the EU.</div>
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Belinostat received its first global approval in the US-FDA on 3 July 2014 for the intravenous (IV) treatment of relapsed or refractory PTCL in adults.</div>
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Belinostat was approved by the U.S. Food and Drug Administration (FDA) on July 3, 2014. It was originally developed by CuraGen Pharma,then developed by Spectrum Pharmaceuticals cooperating with Onxeo, then marketed as Beleodaq<sup>®</sup> by Spectrum.<br />
Beleodaq is a pan-histone deacetylase (HDAC) inhibitor selectively causing the accumulation of acetylated histones and other proteinsin tumor cells. It is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).<br />
Beleodaq<sup>®</sup> is available as lyophilized powder for intravenous infusion, containing 500 mg of free Belinostat. The recommended dose is 1,000 mg/m<sup>2</sup> once daily on days 1-5 of a 21-day cycle.<br />
<img alt="" data-mce-src="https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcSimHswgnTes-W3f-3t7VPDR-5L1F6pSsrI-cqqvxS1YDMF_0Nx" src="https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcSimHswgnTes-W3f-3t7VPDR-5L1F6pSsrI-cqqvxS1YDMF_0Nx" style="height: auto; max-width: 100%;" /><br />
<img alt="" data-mce-src="http://actlifesciences.com/wp-content/uploads/2015/07/beleodaq-300x183.jpg" src="http://actlifesciences.com/wp-content/uploads/2015/07/beleodaq-300x183.jpg" style="height: auto; max-width: 100%;" /></div>
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Index:</h4>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">MW 318.07</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" title="SM:22-SM_Molecular_Formula:String representation of the compound with addends; type and number of the different atoms in the compound; without structural details"><b>MF</b></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">C15H14N2O4S</td></tr>
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414864-00-9 cas no</div>
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866323-14-0</div>
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(2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]acrylamide</div>
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A novel HDAC inhibitor</div>
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<img alt="Chemical structure for belinostat" border="0" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&cid=6918638" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&cid=6918638" style="height: auto; max-width: 100%;" title="Chemical structure for belinostat, click to zoom." /><br />PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous. In 2014, the National Cancer Institute estimates that 70,800 Americans will be diagnosed with NHL and 18,990 will die. PTCL represents about 10 to 15 percent of NHLs in North America.Belinostat inhibits the growth of tumor cells (A2780, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852) with IC50 from 0.2-0.66 μM. PD101 shows low activity in A2780/cp70 and 2780AD cells. Belinostat inhibits bladder cancer cell growth, especially in 5637 cells, which shows accumulation of G0-G1 phase, decrease in S phase, and increase in G2-M phase. Belinostat also shows enhanced tubulin acetylation in ovarian cancer cell lines. A recent study shows that Belinostat activates protein kinase A in a TGF-β signaling-dependent mechanism and decreases survivin mRNA.</div>
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<img alt="" data-mce-src="http://media.chemotherapyadvisor.com/images/2014/04/15/cancer_cell_2_682x392_580146.jpg?format=jpg&zoom=1&quality=70&anchor=middlecenter&width=320&mode=pad" src="http://media.chemotherapyadvisor.com/images/2014/04/15/cancer_cell_2_682x392_580146.jpg?format=jpg&zoom=1&quality=70&anchor=middlecenter&width=320&mode=pad" style="height: auto; max-width: 100%;" /></div>
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Beleodaq works by stopping enzymes that contribute to T-cells, a type of immune cell, becoming cancerous. It is intended for patients whose disease returned after treatment (relapsed) or did not respond to previous treatment (refractory).</div>
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“This is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval expands the number of treatment options available to patients with serious and life-threatening diseases.”</div>
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The FDA granted accelerated approval to Folotyn (pralatrexate) in 2009 for use in patients with relapsed or refractory PTCL and Istodax (romidepsin) in 2011 for the treatment of PTCL in patients who received at least one prior therapy.</div>
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The safety and effectiveness of Beleodaq was evaluated in a clinical study involving 129 participants with relapsed or refractory PTCL. All participants were treated with Beleodaq until their disease progressed or side effects became unacceptable. Results showed 25.8 percent of participants had their cancer disappear (complete response) or shrink (partial response) after treatment.</div>
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The most common side effects seen in Beleodaq-treated participants were nausea, fatigue, fever (pyrexia), low red blood cells (anemia), and vomiting.</div>
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The FDA’s accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs. Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit. Beleodaq also received orphan product designation by the FDA because it is intended to treat a rare disease or condition.</div>
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<img alt="" data-mce-src="https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcRheCi9y48yWvlAeqfggqbQiyAw0kzEG2L40qvf7QY0NBtlXuhe" src="https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcRheCi9y48yWvlAeqfggqbQiyAw0kzEG2L40qvf7QY0NBtlXuhe" style="height: auto; max-width: 100%;" /></div>
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<img alt="" data-mce-src="http://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&cid=6918638" src="http://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&cid=6918638" style="height: auto; max-width: 100%;" />BELINOSTAT</div>
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<b>Belinostat</b> (trade name <b>Beleodaq</b>, previously known as <b>PXD101</b>) is a <a data-mce-href="https://en.wikipedia.org/wiki/Histone_deacetylase_inhibitor" href="https://en.wikipedia.org/wiki/Histone_deacetylase_inhibitor" title="Histone deacetylase inhibitor">histone deacetylase inhibitor</a> drug developed by <a data-mce-href="https://en.wikipedia.org/wiki/TopoTarget" href="https://en.wikipedia.org/wiki/TopoTarget" title="TopoTarget">TopoTarget</a>for the treatment of hematological malignancies and solid tumors.<sup class="reference" id="cite_ref-2"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-2" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-2">[2]</a></sup></div>
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It was approved in July 2014 by the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/US_FDA" href="https://en.wikipedia.org/wiki/US_FDA" title="US FDA">US FDA</a> to treat <a data-mce-href="https://en.wikipedia.org/wiki/Peripheral_T-cell_lymphoma" href="https://en.wikipedia.org/wiki/Peripheral_T-cell_lymphoma" title="Peripheral T-cell lymphoma">peripheral T-cell lymphoma</a>.<sup class="reference" id="cite_ref-FDA-2014_3-0"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-FDA-2014-3" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-FDA-2014-3">[3]</a></sup></div>
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In 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with <a data-mce-href="https://en.wikipedia.org/wiki/Carboplatin" href="https://en.wikipedia.org/wiki/Carboplatin" title="Carboplatin">carboplatin</a> and<a data-mce-href="https://en.wikipedia.org/wiki/Paclitaxel" href="https://en.wikipedia.org/wiki/Paclitaxel" title="Paclitaxel">paclitaxel</a> for relapsed <a data-mce-href="https://en.wikipedia.org/wiki/Ovarian_cancer" href="https://en.wikipedia.org/wiki/Ovarian_cancer" title="Ovarian cancer">ovarian cancer</a>.<sup class="reference" id="cite_ref-4"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-4" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-4">[4]</a></sup> Final results in late 2009 of a phase II trial for <a data-mce-href="https://en.wikipedia.org/wiki/T-cell_lymphoma" href="https://en.wikipedia.org/wiki/T-cell_lymphoma" title="T-cell lymphoma">T-cell lymphoma</a> were encouraging.<sup class="reference" id="cite_ref-5"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-5" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-5">[5]</a></sup>Belinostat has been granted <a data-mce-href="https://en.wikipedia.org/wiki/Orphan_drug" href="https://en.wikipedia.org/wiki/Orphan_drug" title="Orphan drug">orphan drug</a> and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/FDA_Fast_Track_Development_Program" href="https://en.wikipedia.org/wiki/FDA_Fast_Track_Development_Program" title="FDA Fast Track Development Program">fast track</a> designation by the FDA,<sup class="reference" id="cite_ref-6"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-6" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-6">[6]</a></sup> and was approved in the US for the use against<a data-mce-href="https://en.wikipedia.org/wiki/Peripheral_T-cell_lymphoma" href="https://en.wikipedia.org/wiki/Peripheral_T-cell_lymphoma" title="Peripheral T-cell lymphoma">peripheral T-cell lymphoma</a> on 3 July 2014.<sup class="reference" id="cite_ref-FDA-2014_3-1"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-FDA-2014-3" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-FDA-2014-3">[3]</a></sup> It is not approved in Europe as of August 2014.<sup class="reference" id="cite_ref-Spreitzer_7-0"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-Spreitzer-7" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-Spreitzer-7">[7]</a></sup></div>
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The approved <a data-mce-href="https://en.wikipedia.org/wiki/Pharmaceutical_formulation" href="https://en.wikipedia.org/wiki/Pharmaceutical_formulation" title="Pharmaceutical formulation">pharmaceutical formulation</a> is given <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Intravenous" href="https://en.wikipedia.org/wiki/Intravenous" title="Intravenous">intravenously</a>.<sup class="reference" id="cite_ref-DIHO_2016_14_8-0"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-DIHO_2016_14-8" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-DIHO_2016_14-8">[8]</a></sup><sup class="reference">:180</sup> Belinostat is primarily metabolized by <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/UGT1A1" href="https://en.wikipedia.org/wiki/UGT1A1" title="UGT1A1">UGT1A1</a>; the initial dose should be reduced if the recipient is known to be <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Homozygous" href="https://en.wikipedia.org/wiki/Homozygous" title="Homozygous">homozygous</a> for the UGT1A1*28 <a data-mce-href="https://en.wikipedia.org/wiki/Allele" href="https://en.wikipedia.org/wiki/Allele" title="Allele">allele</a>.<sup class="reference" id="cite_ref-DIHO_2016_14_8-1"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-DIHO_2016_14-8" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-DIHO_2016_14-8">[8]</a></sup><sup class="reference">:179 and 181</sup></div>
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NCI: A novel hydroxamic acid-type histone deacetylase (HDAC) inhibitor with antineoplastic activity. Belinostat targets HDAC enzymes, thereby inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis. This agent may sensitize drug-resistant tumor cells to other antineoplastic agents, possibly through a mechanism involving the down-regulation of thymidylate synthase</div>
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<img alt="" data-mce-src="http://www.mdpi.com/molecules/molecules-20-03898/article_deploy/html/images/molecules-20-03898-g003-1024.png" src="http://www.mdpi.com/molecules/molecules-20-03898/article_deploy/html/images/molecules-20-03898-g003-1024.png" style="height: auto; max-width: 100%;" /></div>
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<img alt="" data-mce-src="http://www.sppirx.com/images/spectrum-pharmaceuticals-belinostat.jpg" src="http://www.sppirx.com/images/spectrum-pharmaceuticals-belinostat.jpg" style="height: auto; max-width: 100%;" /></h2>
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The study of inhibitors of histone deacetylases indicates that these enzymes play an important role in cell proliferation and differentiation. The inhibitor Trichostatin A (TSA) (Yoshida et al., 1990a) causes cell cycle arrest at both G1 and G2 phases (Yoshida and Beppu, 1988), reverts the transformed phenotype of different cell lines, and induces differentiation of Friend leukaemia cells and others (Yoshida et al., 1990b). TSA (and SAHA) have been reported to inhibit cell growth, induce terminal differentiation, and prevent the formation of tumours in mice (Finnin et al., 1999).</div>
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Trichostatin A (TSA)</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000005_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000005_0001.png"><img alt="Figure imgf000005_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000005_0001.png" height="84" id="imgf000005_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000005_0001.png" style="height: auto; max-width: 100%;" width="280" /></a></div>
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Suberoylanilide Hydroxamic Acid (SAHA)</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000005_0002.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000005_0002.png"><img alt="Figure imgf000005_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000005_0002.png" height="80" id="imgf000005_0002" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000005_0002.png" style="height: auto; max-width: 100%;" width="276" /></a></div>
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Cell cycle arrest by TSA correlates with an increased expression of gelsolin (Hoshikawa et al., 1994), an actin regulatory protein that is down regulated in malignant breast cancer (Mielnicki et al., 1999). Similar effects on cell cycle and differentiation have been observed with a number of deacetylase inhibitors (Kim et al., 1999). Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g., liver fibrosis and liver cirrhosis. See, e.g., Geerts et al., 1998.</div>
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Recently, certain compounds that induce differentiation have been reported to inhibit histone deacetylases. Several experimental antitumour compounds, such as trichostatin A (TSA), trapoxin, suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have been reported to act, at least in part, by inhibiting histone deacetylase (see, e.g., Yoshida et al., 1990; Richon et al., 1998; Kijima et al., 1993). Additionally, diallyl sulfide and related molecules (see, e.g., Lea et al., 1999), oxamflatin (see, e.g., Kim et al., 1999), MS-27-275, a synthetic benzamide derivative (see, e.g., Saito et al., 1999; Suzuki et al., 1999; note that MS-27-275 was later re-named as MS-275), butyrate derivatives (see, e.g., Lea and Tulsyan, 1995), FR901228 (see, e.g., Nokajima et al., 1998), depudecin (see, e.g., Kwon et al., 1998), and m-carboxycinnamic acid bishydroxamide (see, e.g., Richon et al., 1998) have been reported to inhibit histone deacetylases. In vitro, some of these compounds are reported to inhibit the growth of fibroblast cells by causing cell cycle arrest in the G1 and G2 phases, and can lead to the terminal differentiation and loss of transforming potential of a variety of transformed cell lines (see, e.g., Richon et al, 1996; Kim et al., 1999; Yoshida et al., 1995; Yoshida & Beppu, 1988). In vivo, phenybutyrate is reported to be effective in the treatment of acute promyelocytic leukemia in conjunction with retinoic acid (see, e.g., Warrell et al., 1998). SAHA is reported to be effective in preventing the formation of mammary tumours in rats, and lung tumours in mice (see, e.g., Desai et al., 1999).</div>
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The clear involvement of HDACs in the control of cell proliferation and differentiation suggest that aberrant HDAC activity may play a role in cancer. The most direct demonstration that deacetylases contribute to cancer development comes from the analysis of different acute promyelocytic leukaemias (APL). In most APL patients, a translocation of chromosomes 15 and 17 (t(15;17)) results in the expression of a fusion protein containing the N-terminal portion of PML gene product linked to most of RARσ (retinoic acid receptor). In some cases, a different translocation (t(11 ;17)) causes the fusion between the zinc finger protein PLZF and RARα. In the absence of ligand, the wild type RARα represses target genes by tethering HDAC repressor complexes to the promoter DNA. During normal hematopoiesis, retinoic acid (RA) binds RARα and displaces the repressor complex, allowing expression of genes implicated in myeloid differentiation. The RARα fusion proteins occurring in APL patients are no longer responsive to physiological levels of RA and they interfere with the expression of the RA- inducible genes that promote myeloid differentiation. This results in a clonal expansion of promyelocytic cells and development of leukaemia. In vitro experiments have shown that TSA is capable of restoring RA-responsiveness to the fusion RARα proteins and of allowing myeloid differentiation. These results establish a link between HDACs and oncogenesis and suggest that HDACs are potential targets for pharmaceutical intervention in APL patients. (See, for example, Kitamura et al., 2000; David et al., 1998; Lin et al., 1998).</div>
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<img alt="" data-mce-src="http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0414864009" src="http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0414864009" style="height: auto; max-width: 100%;" />BELINOSTAT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Furthermore, different lines of evidence suggest that HDACs may be important therapeutic targets in other types of cancer. Cell lines derived from many different cancers (prostate, coloreetal, breast, neuronal, hepatic) are induced to differentiate by HDAC inhibitors (Yoshida and Horinouchi, 1999). A number of HDAC inhibitors have been studied in animal models of cancer. They reduce tumour growth and prolong the lifespan of mice bearing different types of transplanted tumours, including melanoma, leukaemia, colon, lung and gastric carcinomas, etc. (Ueda et al., 1994; Kim et al., 1999).</div>
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Psoriasis is a common chronic disfiguring skin disease which is characterised by well-demarcated, red, hardened scaly plaques: these may be limited or widespread. The prevalence rate of psoriasis is approximately 2%, i.e., 12.5 million sufferers in the triad countries (US/Europe/Japan). While the disease is rarely fatal, it clearly has serious detrimental effects upon the quality of life of the patient: this is further compounded by the lack of effective therapies. Present treatments are either ineffective, cosmetically unacceptable, or possess undesired side effects. There is therefore a large unmet clinical need for effective and safe drugs for this condition. Psoriasis is a disease of complex etiology. Whilst there is clearly a genetic component, with a number of gene loci being involved, there are also undefined environmental triggers. Whatever the ultimate cause of psoriasis, at the cellular level, it is characterised by local T-cell mediated inflammation, by keratinocyte hyperproliferation, and by localised angiogenesis. These are all processes in which histone deacetylases have been implicated (see, e.g., Saunders et al., 1999; Bernhard et al, 1999; Takahashi et al, 1996; Kim et al , 2001 ). Therefore HDAC inhibitors may be of use in therapy for psoriasis. Candidate drugs may be screened, for example, using proliferation assays with T-cells and/or keratinocytes.</div>
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<h1>
<span data-mce-style="color: #ff0000;" style="color: red;"> CLIP</span></h1>
PXD101/Belinostat®<br />
(E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as PXD101 and Belinostat®, shown below, is a well known histone deacetylate (HDAC) inhibitor. It is being developed for treatment of a range of disorders mediated by HDAC, including proliferative conditions (such as cancer and psoriasis), malaria, etc.<br />
<div>
<a data-mce-href="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00001.png" href="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00001.png"><img alt="Figure US20100286279A1-20101111-C00001" data-mce-src="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00001.png" height="72" id="EMI-C00001" src="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00001.png" style="height: auto; max-width: 100%;" width="245" /></a></div>
PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.<br />
<div>
<a data-mce-href="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00002.png" href="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00002.png"><img alt="Figure US20100286279A1-20101111-C00002" data-mce-src="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00002.png" height="990" id="EMI-C00002" src="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00002.png" style="height: auto; max-width: 100%;" width="302" /></a></div>
<div>
<a data-mce-href="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00003.png" href="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00003.png"><img alt="Figure US20100286279A1-20101111-C00003" data-mce-src="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00003.png" height="250" id="EMI-C00003" src="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00003.png" style="height: auto; max-width: 100%;" width="302" /></a></div>
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
GENERAL SYNTHESIS<br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-26.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-26.jpg" rel="attachment wp-att-7815"><img alt="str1" class="alignnone size-full wp-image-7815" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-26.jpg" height="400" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-26.jpg" style="height: auto; max-width: 100%;" width="783" /></a><br />
<a data-mce-href="http://www.google.com/patents/WO2002030879A2?cl=en" href="http://www.google.com/patents/WO2002030879A2?cl=en">WO2002030879A2</a><br />
IGNORE 10<br />
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000060_0002.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000060_0002.png"><img alt="Figure imgf000060_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000060_0002.png" height="176" id="imgf000060_0002" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000060_0002.png" style="height: auto; max-width: 100%;" width="616" /></a><br />
ENTRY 45 IS BELINOSTAT<br />
Scheme 1<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000101_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000101_0001.png"><img alt="Figure imgf000101_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000101_0001.png" height="584" id="imgf000101_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000101_0001.png" style="height: auto; max-width: 100%;" width="440" /></a></div>
By using amines instead of aniline, the corresponding products may be obtained. The use of aniline, 4-methoxyaniline, 4-methylaniline, 4-bromoaniline, 4-chloroaniline, 4-benzylamine, and 4-phenethyamine, among others, is described in the Examples below.<br />
In another method, a suitable amino acid (e.g., ω-amino acid) having a protected carboxylic acid (e.g., as an ester) and an unprotected amino group is reacted with a sulfonyl chloride compound (e.g., RSO<sub>2</sub>CI) to give the corresponding sulfonamide having a protected carboxylic acid. The protected carboxylic acid is then deprotected using base to give the free carboxylic acid, which is then reacted with, for example, hydroxylamine 2-chlorotrityl resin followed by acid (e.g., trifluoroacetic acid), to give the desired carbamic acid.<br />
One example of this approach is illustrated below, in Scheme 2, wherein the reaction conditions are as follows: (i) RSO<sub>2</sub>CI, pyridine, DCM, room temperature, 12 hours; (ii) 1 M LiOH or 1 M NaOH, dioxane, room temperature, 3-48 hours; (iii) hydroxylamine 2-chlorotrityl resin, HOAt, HATU, DIPEA, DCM, room temperature, 16 hours; and (iv) TFA/DCM (5:95, v/v), room temperature, 1.5 hours.<br />
Scheme 2<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000102_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000102_0001.png"><img alt="Figure imgf000102_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000102_0001.png" height="228" id="imgf000102_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000102_0001.png" style="height: auto; max-width: 100%;" width="476" /></a></div>
Additional methods for the synthesis of compounds of the present invention are illustrated below and are exemplified in the examples below.<br />
Scheme 3A<br />
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000102_0002.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000102_0002.png"><img alt="Figure imgf000102_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000102_0002.png" height="156" id="imgf000102_0002" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000102_0002.png" style="height: auto; max-width: 100%;" width="476" /></a></div>
Scheme 3B<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000103_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000103_0001.png"><img alt="Figure imgf000103_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000103_0001.png" height="328" id="imgf000103_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000103_0001.png" style="height: auto; max-width: 100%;" width="552" /></a></div>
Scheme 4<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000104_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000104_0001.png"><img alt="Figure imgf000104_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000104_0001.png" height="684" id="imgf000104_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000104_0001.png" style="height: auto; max-width: 100%;" width="424" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000105_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000105_0001.png"><img alt="Figure imgf000105_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000105_0001.png" height="388" id="imgf000105_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000105_0001.png" style="height: auto; max-width: 100%;" width="500" /></a></div>
Scheme 8<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000108_0002.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000108_0002.png"><img alt="Figure imgf000108_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000108_0002.png" height="340" id="imgf000108_0002" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000108_0002.png" style="height: auto; max-width: 100%;" width="508" /></a></div>
Scheme 9<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000109_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000109_0001.png"><img alt="Figure imgf000109_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000109_0001.png" height="336" id="imgf000109_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000109_0001.png" style="height: auto; max-width: 100%;" width="528" /></a></div>
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
SYNTHESIS<br />
<a data-mce-href="http://www.google.com/patents/WO2002030879A2?cl=en" href="http://www.google.com/patents/WO2002030879A2?cl=en">WO2002030879A2</a><br />
Example 1<br />
3-Formylbenzenesulfonic acid, sodium salt (1)<br />
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000123_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000123_0001.png"><img alt="Figure imgf000123_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000123_0001.png" height="76" id="imgf000123_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000123_0001.png" style="height: auto; max-width: 100%;" width="152" /></a></div>
Oleum (5 ml) was placed in a reaction vessel and benzaldehyde (2.00 g, 18.84 mmol) was slowly added not exceeding the temperature of the reaction mixture more than 30°C. The obtained solution was stirred at 40°C for ten hours and at ambient temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The aqueous phase was treated with CaC0<sub>3</sub> until the evolution of C0<sub>2</sub> ceased (pH~6-7), then the precipitated CaSO<sub>4</sub>was filtered off and washed with water. The filtrate was treated with Na<sub>2</sub>CO<sub>3</sub> until the pH of the reaction medium increased to pH 8, obtained CaCO3 was filtered off and water solution was evaporated in vacuum. The residue was washed with methanol, the washings were evaporated and the residue was dried in desiccator over P<sub>2</sub>Oβ affording the title compound (2.00 g, 51%). <sup>1</sup>H NMR (D<sub>2</sub>0), δ: 7.56-8.40 (4H, m); 10.04 ppm (1 H, s).<br />
Example 2 3-(3-Sulfophenyl)acrylic acid methyl ester, sodium salt (2)<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000124_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000124_0001.png"><img alt="Figure imgf000124_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000124_0001.png" height="76" id="imgf000124_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000124_0001.png" style="height: auto; max-width: 100%;" width="212" /></a></div>
Sodium salt of 3-formylbenzenesulfonic acid (1) (1.00 g, 4.80 mmol), potassium carbonate (1.32 g, 9.56 mmol), trimethyl phosphonoacetate (1.05 g, 5.77 mmol) and water (2 ml) were stirred at ambient temperature for 30 min., precipitated solid was filtered and washed with methanol. The filtrate was evaporated and the title compound (2) was obtained as a white solid (0.70 g, 55%). <sup>1</sup>H NMR (DMSO- d<sub>βl</sub> HMDSO), δ: 3.68 (3H, s); 6.51 (1 H, d, J=16.0 Hz); 7.30-7.88 (5H, m).<br />
Example 3 3-(3-Chlorosulfonylphenyl)acrylic acid methyl ester (3)<br />
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000124_0002.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000124_0002.png"><img alt="Figure imgf000124_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000124_0002.png" height="76" id="imgf000124_0002" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000124_0002.png" style="height: auto; max-width: 100%;" width="200" /></a></div>
To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2) (0.670 g, 2.53 mmol) benzene (2 ml), thionyl chloride (1.508 g, 0.9 ml, 12.67 mmol) and 3 drops of dimethylformamide were added and the resultant suspension was stirred at reflux for one hour. The reaction mixture was evaporated, the residue was dissolved in benzene (3 ml), filtered and the filtrate was evaporated to give the title compound (0.6'40 g, 97%).<br />
Example 4 3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a)<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000125_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000125_0001.png"><img alt="Figure imgf000125_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000125_0001.png" height="76" id="imgf000125_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000125_0001.png" style="height: auto; max-width: 100%;" width="252" /></a></div>
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture of aniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultant solution was stirred at 50°C for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCI. The organic layer was washed successively with water, saturated NaCl, and dried (Na<sub>2</sub>S0 ). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (7:1 , v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.226 g, 29%). <sup>1</sup>H NMR (CDCI<sub>3</sub>, HMDSO), δ: 3.72 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1 H, br s); 6.92-7.89 (10H, m).<br />
Example 5 3-(3-Phenylsulfamoylphenyl)acrylic acid (5a)<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000125_0002.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000125_0002.png"><img alt="Figure imgf000125_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000125_0002.png" height="76" id="imgf000125_0002" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000125_0002.png" style="height: auto; max-width: 100%;" width="236" /></a></div>
3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a) (0.220 g, 0.69 mmol) was dissolved in methanol (3 ml), 1N NaOH (2.08 ml, 2.08 mmol) was added and the resultant solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 10% HCI and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P<sub>2</sub>Os to give the title compound as a white solid (0.173 g, 82%). Example 6 3-(3-Phenylsulfamoylphenyl)acryloyl chloride (6a)<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000126_0001.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000126_0001.png"><img alt="Figure imgf000126_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000126_0001.png" height="76" id="imgf000126_0001" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000126_0001.png" style="height: auto; max-width: 100%;" width="228" /></a></div>
To a suspension of 3-(3-phenylsulfamoylphenyl)acrylic acid (5a) (0.173 g, 0.57 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17 ml, 1.95 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40°C for one hour and concentrated under reduced pressure to give crude title compound (0.185 g).<br />
Example 7<br />
N-Hydroxy-3-(3-phenylsulfamoylphenyl)acrylamide (7a) (PX105684) BELINOSTAT<br />
<div>
<a data-mce-href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000126_0002.png" href="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000126_0002.png"><img alt="Figure imgf000126_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000126_0002.png" height="76" id="imgf000126_0002" src="http://patentimages.storage.googleapis.com/WO2002030879A2/imgf000126_0002.png" style="height: auto; max-width: 100%;" width="252" /></a></div>
To a suspension of hydroxylamine hydrochloride (0.200 g, 2.87 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCOβ solution (2.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a 3-(3-phenylsulfamoylphenyl)acryloyl chloride (6a) (0.185 g) solution in tetrahydrofuran (2.3 ml) was added and stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCI. The organic layer was washed successively with water and saturated NaCl, the solvent was removed and the residue was washed with acetonitrile and diethyl ether.<br />
The title compound was obtained as a white solid (0.066 g, 36%), m.p. 172°C. BELINOSTAT<br />
<img alt="" data-mce-src="http://www.exchemistry.com/hdacs-images/Belinostat.gif" src="http://www.exchemistry.com/hdacs-images/Belinostat.gif" style="height: auto; max-width: 100%;" /><br />
<sup>1</sup>H NMR (DMSO-d6, HMDSO), δ: 6.49 (1 H, d, J=16.0 Hz); 7.18-8.05 (10H, m); 9.16 (1 H, br s); 10.34 (1 H, s); 10.85 ppm (1 H, br s).<br />
HPLC analysis on Symmetry C<sub>18</sub>column: impurities 4% (column size 3.9x150 mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 40:60; sample concentration 1 mg/ml; flow rate 0.8 ml/ min; detector UV 220 nm).<br />
Anal. Calcd for C<sub>15</sub>Hι<sub>4</sub>N<sub>2</sub>0<sub>4</sub>S, %: C 56.59, H 4.43, N 8.80. Found, %: C 56.28, H 4.44, N 8.56.<br />
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<a data-mce-href="https://www.google.com/patents/CN102786448A?cl=en" href="https://www.google.com/patents/CN102786448A?cl=en">https://www.google.com/patents/CN102786448A?cl=en</a><br />
<span class="notranslate">Example: belinostat (compound of formula I) Preparation of</span><br />
<br />
<div class="patent-image small-patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00092.png" href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00092.png"><img alt="Figure CN102786448AD00092" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00092.png" id="idf0016" src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00092.png" style="height: auto; max-width: 100%;" /></a></div>
<span class="notranslate">Methods of operation:</span><br />
<span class="notranslate">The compound of formula II (4. Og) added to the reactor, was added methanol 30ml, and stirred to dissolve, was added IM aqueous sodium hydroxide solution (38mL), stirred at room temperature overnight, the reaction was completed, ethyl acetate was added (IOmL) ^ K (20mL), stirred for 5 minutes, phase separation, the ethyl acetate phase was discarded, the aqueous phase was acidified with 10% hydrochloric acid to pH2, stirred at room temperature for 30 minutes, filtered, washed with water, and dried to give hydrolyzate 3. lg, yield rate of 81.6%.</span><br />
<span class="notranslate"> The hydrolyzate (3. Og) added to the reactor, was added methylene chloride (53. 2g), dissolved with stirring, was added oxalyl chloride (2.8mL, 0.0032mol) at room temperature was added I drop DMF, reflux I hours, concentrated and the residue was dissolved in THF (30mL) alternate, the other to take a reaction flask was added hydroxylamine hydrochloride (3. 5g, 0.05mol), THF (50mL), saturated aqueous sodium bicarbonate (40mL), the mixture at room temperature under stirring for 10 minutes, then was added to spare, stirred at room temperature for I hour, the reaction was complete, at - at room temperature was added ethyl acetate (50mL), 2M hydrochloric acid (50mL), stirred for 5 minutes the phases were separated, the aqueous phase was discarded, the organic layer was washed with water, saturated brine, dried, filtered and concentrated to give crude product belinostat, recrystallized from ethyl acetate, 50 ° C and dried for 8 hours to give white crystals 2. 6g, yield 83.8%.</span> <span class="notranslate">.<span data-mce-style="color: #ff0000;" style="color: red;"> 1H-NMR (DMS0-d6, 400MHz) δ: 6 50 (1H, d, J = 16. OHz); 7 07 (d, J = 7. 8Hz, 2H); 7 16 (t.. , J = 7. 3Hz, 1H);. 7 25 (m, 2H);. 7 45 (t, J = 7. 8Hz, 1H);. 7 60 (d, J = 15. 9Hz, 1H); 7 . 62 (d, J = 7. 7Hz, 1H);. 7 75 (d, J = 7. 8Hz, 1H);. 7 88 (br s. '1H);. 9 17 (br s' 1H); 10. 35 (s, 1H);. 10 82ppm (br s, 1H).</span></span><span class="notranslate" data-mce-style="color: #ff0000;" style="color: red;"> ·</span><br />
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-28.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-28.jpg" rel="attachment wp-att-7817"><img alt="str1" class="alignnone size-full wp-image-7817" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-28.jpg" height="504" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-28.jpg" style="height: auto; max-width: 100%;" width="749" /></a><br />
<br />
<span class="notranslate">Step a): Preparation of Compound III</span><br />
<br />
<div class="patent-image small-patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00071.png" href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00071.png"><img alt="Figure CN102786448AD00071" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00071.png" id="idf0010" src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00071.png" style="height: auto; max-width: 100%;" /></a></div>
<span class="notranslate"> The carboxy benzene sulfonate (224g, Imol), anhydrous methanol (2300g), concentrated hydrochloric acid (188. 6g) refluxing</span><br />
<span class="notranslate">3-5 hours, filtered and the filtrate was added anhydrous sodium bicarbonate powder (200g), stirred for I hour, filtered, the filter residue was discarded, the filtrate was concentrated. The concentrate was added methanol (2000g), stirred at room temperature for 30 minutes, filtered and the filtrate was concentrated to dryness, 80 ° C and dried for 4 hours to give a white solid compound III147g, yield 61.8%.</span><br />
<span class="notranslate">Step b): Preparation of Compound IV</span><br />
<br />
<div class="patent-image small-patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00072.png" href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00072.png"><img alt="Figure CN102786448AD00072" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00072.png" id="idf0011" src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00072.png" style="height: auto; max-width: 100%;" /></a></div>
<span class="notranslate"> Compound III (50g, 0. 21mol), phosphorus oxychloride (250mL) was refluxed for 2_6 hours, completion of the reaction, cooled to</span><br />
<span class="notranslate">0-5 ° C, was slowly added to ice water, stirred for 2 hours and filtered to give a brown solid compound IV40 g, due to the instability of Compound IV, directly into the next reaction without drying.</span><br />
<span class="notranslate">Preparation of Compound V: [0040] Step c)</span><br />
<br />
<div class="patent-image small-patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00073.png" href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00073.png"><img alt="Figure CN102786448AD00073" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00073.png" id="idf0012" src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00073.png" style="height: auto; max-width: 100%;" /></a></div>
<span class="notranslate">The aniline (5. 58g, 0. 06mol) and 30mL of toluene added to the reactor, stirred to dissolve, in step b) the resulting compound IV (7. 05g, O. 03mol) was dissolved in 60 ml of toluene, at room temperature dropwise added to the reactor, the addition was completed, stirring at room temperature for 1-2 hours, the reaction was completed, the filtered solid washed with water, and then recrystallized from toluene, 50 ° C and dried for 4 hours to obtain a white crystalline compound V6. Og, yield 73%.</span> <span class="notranslate">mp:.. 144 4-145 2.</span> <span class="notranslate">.</span> <span class="notranslate">.</span><br />
<span class="notranslate"> 1H- bandit R (CDCl3, 400MHz) δ:.... 3 92 (s, 3H); 6 80 (. Br s, 1H); 7 06-7 09 (m, 2H); 7 11. . -7 15 (m, 1H);.. 7 22-7 26 (m, 2H);. 7 51 (t, J = 7. 8Hz, 1H);.. 7 90-7 93 (dt, J = . 1.2,7 8Hz, 1H); 8 18-8 21 (dt, J = I. 4, 7. 8Hz, 1H);... 8 48 (t, J = L 6Hz, 1H).</span><br />
<span class="notranslate"> IR v ™ r: 3243,3198,3081,2953,1705,1438,1345,766,702,681cm-1.</span><br />
<span class="notranslate"> Step d): Preparation of Compound VI</span><br />
<br />
<div class="patent-image small-patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00081.png" href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00081.png"><img alt="Figure CN102786448AD00081" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00081.png" id="idf0013" src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00081.png" style="height: auto; max-width: 100%;" /></a></div>
<span class="notranslate"> The anhydrous lithium chloride 2. 32g, potassium borohydride 2. 96g, THF50mL added to the reactor, stirring evenly, Compound V (8g, 0. 027mol) was dissolved in 7mL of tetrahydrofuran, was slowly dropped into the reactor was heated under reflux for 5 hours, the reaction was completed, the force mouth 40mL water and ethyl acetate 40mL, stirred for half an hour, allowed to stand for separation, the organic layer was washed with 40mL water, concentrated under reduced pressure to give the crude product, the crude product was recrystallized from toluene, solid 50 V dried for 4 hours to give a white crystalline compound VI6. 82g, yield 90. O%.</span> <span class="notranslate">mp:.. 98 2-98 6.</span> <span class="notranslate">.</span> <span class="notranslate">.</span><br />
<span class="notranslate">1H-NMR (DMS0-d6, 400ΜΗζ) δ:..... 4 53 (s, 2H); 5 39 (s, 1H); 6 99-7 03 (m, 1H); 7 08- 7. ll (m, 2H);.. 7 19-7 24 (m, 2H);.. 7 45-7 52 (m, 2H);.. 7 61-7 63 (dt, J = I. 8 , 7 4Hz, 1H);.. 7 79 (br s, 1H);. 10. 26 (s, 1H).</span><br />
<span class="notranslate">IRv =: 3453,3130,2964,1488,1151,1031, 757,688cm_10</span><br />
<span class="notranslate">Step e): Preparation of Compound VII</span><br />
<div class="patent-image small-patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00082.png" href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00082.png"><img alt="Figure CN102786448AD00082" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00082.png" id="idf0014" src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00082.png" style="height: auto; max-width: 100%;" /></a></div>
<span class="notranslate">After Compound VI (7.5g, 0.028mol) dissolved in acetone was added 7ml, dichloromethane was added 60mL, supported on silica gel was added PCC at room temperature 20g, stirred at room temperature for 12-24 hours, the reaction was complete, filtered and the filtrate was purified The layers were separated and the aqueous layer was discarded after the organic phase is washed 30mL5% aqueous sodium bicarbonate, evaporated to dryness under reduced pressure to give the crude product, the crude product was recrystallized from toluene, 50 ° C and dried for 8 hours to give white crystalline compound VII4. 7g, yield 62.7%.</span> <span class="notranslate">mp:.. 128 1-128 5 ° C.</span><br />
<span class="notranslate"> 1H- bandit R (CDCl3,400MHz) δ:.... 7 08-7 15 (m, 4Η); 7 · 23-7 27 (m, 2H); 7 · 60-7 64 (t, J = 7 7Hz, 1Η);.. 8 00 (d, J = 7. 6Hz, 1Η);. 8 04 (d, J = 7. 6Hz, 1Η);. 8 30 (br s' 1Η).; 10. 00 (S, 1Η).</span><br />
<span class="notranslate"> IR ν ™ Γ: 3213,3059,2964,2829,1687,1480,1348,1159,1082,758,679cm_10</span><br />
<span class="notranslate">Preparation of compounds of formula II: [0055] Step f)</span><br />
<br />
<div class="patent-image small-patent-image">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00091.png" href="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00091.png"><img alt="Figure CN102786448AD00091" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00091.png" id="idf0015" src="https://patentimages.storage.googleapis.com/CN102786448A/CN102786448AD00091.png" style="height: auto; max-width: 100%;" /></a></div>
<span class="notranslate"> phosphoryl trimethylorthoacetate (2. 93g, 0. 0161mol) added to the reaction vessel, THF30mL, stirring to dissolve, cooled to -5-0 ° C, was added sodium hydride (O. 8g, content 80%) , the addition was completed, stirring for 10-20 minutes, was added dropwise the compound VII (4g, O. 0156mol) and THF (20mL) solution, stirred for 1_4 hours at room temperature, the reaction was complete, 10% aqueous ammonium chloride solution was added dropwise 50mL, and then After addition of 50mL of ethyl acetate, stirred 30min rested stratification, the aqueous layer was discarded, the organic phase was concentrated under reduced pressure to give the crude product, the crude product was recrystallized from methanol 60mL, 50 ° C and dried for 8 hours to give white crystalline compound 113. 6g, yield 75%.</span> <span class="notranslate">mp:.. 152 0-152 5 ° C.</span><br />
<span class="notranslate"> 1H-Nmr (Cdci3JOOmHz) δ:.... 3 81 (s, 3H); 6 40 (d, J = 16. 0Hz, 1H); 6 79 (. Br s, 1H); 7 08 ( d, J = 7. 8Hz, 2H);. 7 14 (t, J = 7. 3Hz, 1H);. 7 24 (m, 2H);. 7 46 (t, J = 7. 8Hz, 1H); 7. 61 (d, J = 16. ΟΗζ, ΙΗ);. 7 64 (d, J = 7. 6Hz, 1H);. 7 75 (d, J = 7. 8Hz, 1H);. 7 89 (br . s, 1H).</span><br />
<span class="notranslate">IR v ^ :: 3172,3081,2954,2849,1698,1475,1345,1157,773,714,677cm-1.</span><br />
<br />
<h1>
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
SYNTHESIS<br />
US20100286279<br />
<img alt="Figure US20100286279A1-20101111-C00034" data-mce-src="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00034.png" height="634" src="https://patentimages.storage.googleapis.com/US20100286279A1/US20100286279A1-20101111-C00034.png" style="height: auto; max-width: 100%;" width="323" /></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">CLIP</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
SYNTHESIS AND SPECTRAL DATA</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Journal of Medicinal Chemistry, <b>2011 </b>, vol. 54, 13 pg. 4694 - 4720</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(E)-N-Hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (28, belinostat, PXD101).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://pubs.acs.org/doi/full/10.1021/jm2003552" href="http://pubs.acs.org/doi/full/10.1021/jm2003552">http://pubs.acs.org/doi/full/10.1021/jm2003552</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf" href="http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf"> http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The methyl ester (27) (8.0 g) was prepared according to reported synthetic route,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
(Watkins, C. J.; Romero-Martin, M.-R.; Moore, K. G.; Ritchie, J.; Finn, P. W.; Kalvinsh, I.;<br />Loza, E.; Dikvoska, K.; Gailite, V.; Vorona, M.; Piskunova, I.; Starchenkov, I.; Harris, C. J.;<br />Duffy, J. E. S. Carbamic acid compounds comprising a sulfonamide linkage as HDAC<br />inhibitors. PCT Int. Appl. WO200230879A2, April 18, 2002.)<br />but using procedure D (Experimental Section) or method described for 26 to convert the methyl ester to crude<br />hydroxamic acid which was further purified by chromatography (silica, MeOH/DCM = 1:10) to<br />afford 28 (PXD101) as off-white or pale yellow powder (2.5 g, 31%).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="http://www.exchemistry.com/hdacs-images/Belinostat.gif" src="http://www.exchemistry.com/hdacs-images/Belinostat.gif" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
LC–MS m/z 319.0 ([M +H]+).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
1H NMR (DMSO-d6) 12–9 (very broad, 2H), 7.90 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.70 (d, J</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
= 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 15.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.08 (d,J = 7.8 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H);</div>
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13C NMR (DMSO-d6) 162.1, 140.6, 138.0, 136.5, 135.9, 131.8, 130.0, 129.2, 127.1, 124.8, 124.1, 121.3, 120.4.</div>
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Anal.<br />(C15H14N2O4S) C, H, N</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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SYNTHESIS</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-29.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-29.jpg" rel="attachment wp-att-7818"><img alt="str1" class="alignnone size-full wp-image-7818" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-29.jpg" height="313" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-29.jpg" style="height: auto; max-width: 100%;" width="706" /></a></div>
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<a data-mce-href="http://www.google.com/patents/WO2009040517A2?cl=en" href="http://www.google.com/patents/WO2009040517A2?cl=en">WO2009040517A2</a></div>
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PXDIOI / Belinostat®</div>
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(E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as PXD101 and Belinostat®, shown below, is a well known histone deacetylate (HDAC) inhibitor. It is being developed for treatment of a range of disorders mediated by HDAC, including proliferative conditions (such as cancer and psoriasis), malaria, etc.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0001.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0001.png"><img alt="Figure imgf000003_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0001.png" height="80" id="imgf000003_0001" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0001.png" style="height: auto; max-width: 100%;" width="252" /></a></div>
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PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.</div>
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Scheme 1</div>
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Not isolated</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0002.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0002.png"><img alt="Figure imgf000003_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0002.png" height="92" id="imgf000003_0002" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0002.png" style="height: auto; max-width: 100%;" width="436" /></a></div>
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ed on (A)</div>
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on (D)</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0003.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0003.png"><img alt="Figure imgf000003_0003" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0003.png" height="304" id="imgf000003_0003" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000003_0003.png" style="height: auto; max-width: 100%;" width="544" /></a></div>
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d on (H)</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000004_0001.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000004_0001.png"><img alt="Figure imgf000004_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000004_0001.png" height="344" id="imgf000004_0001" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000004_0001.png" style="height: auto; max-width: 100%;" width="568" /></a></div>
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There is a need for alternative methods for the synthesis of PXD101 and related compounds for example, methods which are simpler and/or employ fewer steps and/or permit higher yields and/or higher purity product.</div>
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Scheme 5</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0001.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0001.png"><img alt="Figure imgf000052_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0001.png" height="60" id="imgf000052_0001" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0001.png" style="height: auto; max-width: 100%;" width="84" /></a></div>
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DMAP, toluene</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0003.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0003.png"><img alt="Figure imgf000052_0003" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0003.png" height="76" id="imgf000052_0003" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0003.png" style="height: auto; max-width: 100%;" width="124" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0002.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0002.png"><img alt="Figure imgf000052_0002" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0002.png" height="80" id="imgf000052_0002" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0002.png" style="height: auto; max-width: 100%;" width="172" /></a></div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0004.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0004.png"><img alt="Figure imgf000052_0004" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0004.png" height="300" id="imgf000052_0004" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0004.png" style="height: auto; max-width: 100%;" width="440" /></a></div>
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Synthesis 1 3-Bromo-N-phenyl-benzenesulfonamide (3)</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0005.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0005.png"><img alt="Figure imgf000052_0005" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0005.png" height="80" id="imgf000052_0005" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000052_0005.png" style="height: auto; max-width: 100%;" width="168" /></a></div>
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To a 30 gallon (-136 L) reactor was charged aniline (2) (4.01 kg; 93.13 g/mol; 43 mol), toluene (25 L), and 4-(dimethylamino)pyridine (DMAP) (12 g), and the mixture was heated to 50-60<sup>0</sup>C. 3-Bromobenzenesulfonyl chloride (1) (5 kg; 255.52 g/mol; 19.6 mol) was charged into the reactor over 30 minutes at 50-60<sup>0</sup>C and progress of the reaction was monitored by HPLC. After 19 hours, toluene (5 L) was added due to losses overnight through the vent line and the reaction was deemed to be complete with no compound (1) being detected by HPLC. The reaction mixture was diluted with toluene (10 L) and then quenched with 2 M aqueous hydrochloric acid (20 L). The organic and aqueous layers were separated, the aqueous layer was discarded, and the organic layer was washed with water (20 L), and then 5% (w/w) sodium bicarbonate solution (20 L), while maintaining the batch temperature at 45-55°C. The batch was then used in the next synthesis.</div>
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Synthesis 2 (E)-3-(3-Phenylsulfamoyl-phenyl)-acrylic acid ethyl ester (5)</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000053_0001.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000053_0001.png"><img alt="Figure imgf000053_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000053_0001.png" height="80" id="imgf000053_0001" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000053_0001.png" style="height: auto; max-width: 100%;" width="260" /></a></div>
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To the batch containing 3-bromo-N-phenyl-benzenesulfonamide (3) (the treated organic layer obtained in the previous synthesis) was added triethylamine (2.97 kg; 101.19 g/mol; 29.4 mol), tri(o-tolyl)phosphine (119 g; 304.37 g/mol; 0.4 mol), and palladium (II) acetate (44 g; 224.51 g/mol; 0.2 mol), and the resulting mixture was degassed four times with a vacuum/nitrogen purge at 45-55°C. Catalytic palladium (0) was formed in situ. The batch was then heated to 80-90<sup>0</sup>C and ethyl acrylate (4) (2.16 kg; 100.12 g/mol; 21.6 mol) was slowly added over 2.75 hours. The batch was sampled after a further 2 hours and was deemed to be complete with no compound (3) being detected by HPLC. The batch was cooled to 45-55°C and for convenience was left at this temperature overnight.</div>
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The batch was then reduced in volume under vacuum to 20-25 L, at a batch temperature of 45-55°C, and ethyl acetate (20 L) was added. The batch was filtered and the residue washed with ethyl acetate (3.5 L). The residue was discarded and the filtrates were sent to a 100 gallon (-454 L) reactor, which had been pre-heated to 60<sup>0</sup>C. The 30 gallon (-136 L) reactor was then cleaned to remove any residual Pd, while the batch in the 100 gallon (-454 L) reactor was washed with 2 M aqueous hydrochloric acid and water at 45-55°C. Once the washes were complete and the 30 gallon (-136 L) reactor was clean, the batch was transferred from the 100 gallon (-454 L) reactor back to the 30 gallon (-136 L) reactor and the solvent was swapped under vacuum from ethyl acetate/toluene to toluene while maintaining a batch temperature of 45-55°C (the volume was reduced to 20-25 L). At this point, the batch had precipitated and heptanes (10 L) were added to re-dissolve it. The batch was then cooled to 0-10<sup>0</sup>C and held at this temperature over the weekend in order to precipitate the product. The batch was filtered and the residue was washed with heptanes (5 L). A sample of the wet-cake was taken for Pd analysis. The Pd content of the crude product (5) was determined to be 12.9 ppm.</div>
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The wet-cake was then charged back into the 30 gallon (-136 L) reactor along with ethyl acetate (50 L) and heated to 40-50<sup>0</sup>C in order to obtain a solution. A sparkler filter loaded with 12 impregnated Darco G60® carbon pads was then connected to the reactor and the solution was pumped around in a loop through the sparkler filter. After 1 hour, a sample was taken and evaporated to dryness and analysed for Pd content. The amount of Pd was found to be 1.4 ppm. A second sample was taken after 2 hours and evaporated to dryness and analysed for Pd content. The amount of Pd had been reduced to 0.6 ppm. The batch was blown back into the reactor and held at 40-50<sup>0</sup>C overnight before the solvent was swapped under vacuum from ethyl acetate to toluene while maintaining a batch temperature of 45-55°C (the volume was reduced to 20-25 L). At this point, the batch had precipitated and heptanes (10 L) were added to re-dissolve it and the batch was cooled to 0-10<sup>0</sup>C and held at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with heptanes (5 L). The filtrate was discarded and the residue was dried at 45-55°C under vacuum for 25 hours. A first lot of the title compound (5) was obtained as an off-white solid (4.48 kg, 69% overall yield from 3-bromobenzenesulfonyl chloride (1)) with a Pd content of 0.4 ppm and a purity of 99.22% (AUC) by HPLC.</div>
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Synthesis 3 (E)-3-(3-Phenylsulfamoyl-phenyl)-acrvlic acid (6)</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000054_0001.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000054_0001.png"><img alt="Figure imgf000054_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000054_0001.png" height="80" id="imgf000054_0001" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000054_0001.png" style="height: auto; max-width: 100%;" width="232" /></a></div>
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To the 30 gallon (-136 L) reactor was charged the (E)-3-(3-phenylsulfamoyl-phenyl)- acrylic acid ethyl ester (5) (4.48 kg; 331.39 g/mol; 13.5 mol) along with 2 M aqueous sodium hydroxide (17.76 L; -35 mol). The mixture was heated to 40-50°C and held at this temperature for 2 hours before sampling, at which point the reaction was deemed to be complete with no compound (5) being detected by HPLC. The batch was adjusted to pH 2.2 using 1 M aqueous hydrochloric acid while maintaining the batch temperature between 40-50<sup>0</sup>C. The product had precipitated and the batch was cooled to 20-30<sup>0</sup>C and held at this temperature for 1 hour before filtering and washing the cake with water (8.9 L). The filtrate was discarded. The batch was allowed to condition on the filter overnight before being charged back into the reactor and slurried in water (44.4 L) at 40-50<sup>0</sup>C for 2 hours. The batch was cooled to 15-20°C, held for 1 hour, and then filtered and the residue washed with water (8.9 L). The filtrate was discarded. The crude title compound (6) was transferred to an oven for drying at 45-55°C under vacuum with a slight nitrogen bleed for 5 days (this was done for convenience) to give a white solid (3.93 kg, 97% yield). The moisture content of the crude material was measured using Karl Fischer (KF) titration and found to be <0.1% (w/w). To the 30 gallon (-136 L) reactor was charged the crude compound (6) along with acetonitrile (47.2 L). The batch was heated to reflux (about 80°C) and held at reflux for 2 hours before cooling to 0-10°C and holding at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with cold acetonitrile (7.9 L). The filtrate was discarded and the residue was dried under vacuum at 45-55°C for 21.5 hours. The title compound (6) was obtained as a fluffy white solid (3.37 kg, 84% yield with respect to compound (5)) with a purity of 99.89% (AUC) by HPLC.</div>
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Synthesis 4 (E)-N-Hvdroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (PXD101) BELINOSTAT</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000055_0001.png" href="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000055_0001.png"><img alt="Figure imgf000055_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000055_0001.png" height="80" id="imgf000055_0001" src="http://patentimages.storage.googleapis.com/WO2009040517A2/imgf000055_0001.png" style="height: auto; max-width: 100%;" width="252" /></a></div>
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To the 30 gallon (-136 L) reactor was charged (E)-3-(3-phenylsulfamoyl-phenyl)-acrylic acid (6) (3.37 kg; 303.34 g/mol; 11.1 mol) and a pre-mixed solution of 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in isopropyl acetate (IPAc) (27 g in 30 L; 152.24 g/mol; 0.18 mol). The slurry was stirred and thionyl chloride (SOCI<sub>2</sub>) (960 mL; density ~1.631 g/mL; 118.97 g/mol; -13 mol) was added to the reaction mixture and the batch was stirred at 20-30<sup>0</sup>C overnight. After 18.5 hours, the batch was sampled and deemed to be complete with no compound (6) being detected by HPLC. The resulting solution was transferred to a 100 L Schott reactor for temporary storage while the</div>
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30 gallon (-136 L) reactor was rinsed with isopropyl acetate (IPAc) and water. Deionized water (28.9 L) was then added to the 30 gallon (-136 L) reactor followed by 50% (w/w) hydroxylamine (6.57 L; -1.078 g/mL; 33.03 g/mol; -214 mol) and another charge of deionized water (1.66 L) to rinse the lines free of hydroxylamine to make a 10% (w/w) hydroxylamine solution. Tetrahydrofuran (THF) (6.64 L) was then charged to the</div>
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30 gallon (-136 L) reactor and the mixture was stirred and cooled to 0-10<sup>0</sup>C. The acid chloride solution (from the 100 L Schott reactor) was then slowly charged into the hydroxylamine solution over 1 hour maintaining a batch temperature of 0-10°C during the addition. The batch was then allowed to warm to 20-30<sup>0</sup>C. The aqueous layer was separated and discarded. The organic layer was then reduced in volume under vacuum while maintaining a batch temperature of less than 30<sup>0</sup>C. The intention was to distill out 10-13 L of solvent, but this level was overshot. A larger volume of isopropyl acetate (IPAc) (16.6 L) was added and about 6 L of solvent was distilled out. The batch had precipitated and heptanes (24.9 L) were added and the batch was held at 20-30°C overnight. The batch was filtered and the residue was washed with heptanes (6.64 L). The filtrate was discarded and the residue was dried at 45-55°C under vacuum with a slight nitrogen bleed over the weekend. The title compound (PXD101) was obtained as a light orange solid (3.11 kg, 89% yield with respect to compound (6)) with a purity of 99.25% (AUC) by HPLC.</div>
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The title compound (PXD101) (1.2 kg, 3.77 mol) was dissolved in 8 volumes of 1:1 (EtOH/water) at 60<sup>0</sup>C. Sodium bicarbonate (15.8 g, 5 mol%) was added to the solution. Water (HPLC grade) was then added at a rate of 65 mL/min while keeping the internal temperature >57°C. After water (6.6 L) had been added, crystals started to form and the water addition was stopped. The reaction mixture was then cooled at a rate of 10°C/90 min to a temperature of 0-10<sup>c</sup>C and then stirred at ambient temperature overnight. The crystals were then filtered and collected. The filter cake was washed by slurrying in water (2 x 1.2 L) and then dried in an oven at 45°C for 60 hours with a slight nitrogen bleed. 1.048 kg (87% recovery) of a light orange solid was recovered. Microscopy and XRPD data showed a conglomerate of irregularly shaped birefringant crystalline particles. The compound was found to contain 0.02% water.</div>
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As discussed above: the yield of compound (5) with respect to compound (1) was 69%. the yield of compound (6) with respect to compound (5) was 84%. the yield of PXD101 with respect to compound (6) was 89%.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PAPER</span></h1>
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<a data-mce-href="http://ocean.sci-hub.bz/2f00077ab5de46eac344e54f29638606/yang2010.pdf?download=true" href="http://ocean.sci-hub.bz/2f00077ab5de46eac344e54f29638606/yang2010.pdf?download=true" target="_blank"><em>Synthetic Commun.</em> <strong>2010</strong>, <em>40</em>, 2520-2524</a>.</div>
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<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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FORMULATION</div>
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<a data-mce-href="http://www.google.com/patents/WO2006120456A1?cl=en" href="http://www.google.com/patents/WO2006120456A1?cl=en">WO2006120456A1</a></div>
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Formulation Studies</div>
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These studies demonstrate a substantial enhancement of HDACi solubility (on the order of a 500-fold increase for PXD-101) using one or more of: cyclodextrin, arginine, and meglumine. The resulting compositions are stable and can be diluted to the desired target concentration without the risk of precipitation. Furthermore, the compositions have a pH that, while higher than ideal, is acceptable for use.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2006120456A1/imgf000047_0001.png" href="http://patentimages.storage.googleapis.com/WO2006120456A1/imgf000047_0001.png"><img alt="Figure imgf000047_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2006120456A1/imgf000047_0001.png" height="76" id="imgf000047_0001" src="http://patentimages.storage.googleapis.com/WO2006120456A1/imgf000047_0001.png" style="height: auto; max-width: 100%;" width="376" /></a></div>
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UV Absorbance</div>
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The ultraviolet (UV absorbance E\ value for PXD-101 was determined by plotting a calibration curve of PXD-101 concentration in 50:50 methanol/water at the λ<sub>max</sub> for the material, 269 nm. Using this method, the E<sup>1</sup>i value was determined as 715.7.</div>
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Methanol/water was selected as the subsequent diluting medium for solubility studies rather than neat methanol (or other organic solvent) to reduce the risk of precipitation of the cyclodextrin.</div>
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Solubility in Demineralised Water</div>
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The solubility of PXD-101 was determined to be 0.14 mg/mL for demineralised water. Solubility Enhancement with Cvclodextrins</div>
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Saturated samples of PXD-101 were prepared in aqueous solutions of two natural cyclodextrins (α-CD and γ-CD) and hydroxypropyl derivatives of the α, β and Y cyclodextrins (HP-α-CD, HP-β-CD and HP-γ-CD). All experiments were completed with cyclodextrin concentrations of 250 mg/mL, except for α-CD, where the solubility of the cyclodextrin was not sufficient to achieve this concentration. The data are summarised in the following table. HP-β-CD offers the best solubility enhancement for PXD-101.</div>
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<a data-mce-href="http://patentimages.storage.googleapis.com/WO2006120456A1/imgf000048_0001.png" href="http://patentimages.storage.googleapis.com/WO2006120456A1/imgf000048_0001.png"><img alt="Figure imgf000048_0001" data-mce-src="http://patentimages.storage.googleapis.com/WO2006120456A1/imgf000048_0001.png" height="224" id="imgf000048_0001" src="http://patentimages.storage.googleapis.com/WO2006120456A1/imgf000048_0001.png" style="height: auto; max-width: 100%;" width="536" /></a></div>
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Phase Solubility Determination of HP-β-CD</div>
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The phase solubility diagram for HP-β-CD was prepared for concentrations of cyclodextrin between 50 and 500 mg/mL (5-50% w/v). The calculated saturated solubilities of the complexed HDACi were plotted against the concentration of cyclodextrin. See Figure 1.</div>
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SPECTRUM</div>
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<a data-mce-href="http://www.google.com/url?sa=X&q=http://www.forbes.com/sites/genemarcial/2013/07/14/tiny-biotech-with-three-cancer-drugs-is-more-alluring-takeover-bet-now/&ct=ga&cad=CAcQARgBIAAoATAAOABAiPeLjwVIAVAAWABiBWVuLVVT&cd=5G_FrGFTtOk&usg=AFQjCNFNPzMzQbt1KK-sFSWEjmAiOvOj7w" href="http://www.google.com/url?sa=X&q=http://www.forbes.com/sites/genemarcial/2013/07/14/tiny-biotech-with-three-cancer-drugs-is-more-alluring-takeover-bet-now/&ct=ga&cad=CAcQARgBIAAoATAAOABAiPeLjwVIAVAAWABiBWVuLVVT&cd=5G_FrGFTtOk&usg=AFQjCNFNPzMzQbt1KK-sFSWEjmAiOvOj7w">Tiny Biotech With <b>Three</b> Cancer <b>Drugs</b> Is More Alluring Takeover Bet Now</a><br />Forbes<br />The <b>drug</b> is one of Spectrum’s two <b>drugs</b> undergoing <b>phase 3</b> clinical trials. Allergan paid Spectrum $41.5 million and will make additional payments of up to $304 million based on achieving certain milestones. So far, Raj Shrotriya, Spectrum’s chairman, <b>…</b></div>
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<a data-mce-href="http://www.forbes.com/sites/genemarcial/2013/07/14/tiny-biotech-with-three-cancer-drugs-is-more-alluring-takeover-bet-now/" href="http://www.forbes.com/sites/genemarcial/2013/07/14/tiny-biotech-with-three-cancer-drugs-is-more-alluring-takeover-bet-now/">http://www.forbes.com/sites/genemarcial/2013/07/14/tiny-biotech-with-three-cancer-drugs-is-more-alluring-takeover-bet-now/</a></div>
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Copenhagen, December 10, 2013</div>
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Topotarget announces the submission of a New Drug Application (NDA) for belinostat for the treatment of relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) to the US Food and Drug Administration (FDA). The NDA has been filed for Accelerated Approval with a request for Priority Review. Response from the FDA regarding acceptance to file is expected within 60 days from the FDA receipt date.</div>
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read all this <a data-mce-href="http://www.drugs.com/nda/belinostat_131210.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+December+10%2C+2013" href="http://www.drugs.com/nda/belinostat_131210.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+December+10%2C+2013">here</a></div>
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<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00170" href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00170">http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00170</a></div>
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<span class="hlFld-Title">The Development of an Effective Synthetic Route of Belinostat</span></h1>
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<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Bao%2C+Xuefei" href="http://pubs.acs.org/author/Bao%2C+Xuefei" id="authors">Xuefei Bao</a></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Song%2C+Dake" href="http://pubs.acs.org/author/Song%2C+Dake" id="authors">Dake Song</a></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Qiao%2C+Xuejun" href="http://pubs.acs.org/author/Qiao%2C+Xuejun" id="authors">Xuejun Qiao</a></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Zhao%2C+Xuan" href="http://pubs.acs.org/author/Zhao%2C+Xuan" id="authors">Xuan Zhao</a></span><span class="NLM_x">, and </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Chen%2C+Guoliang" href="http://pubs.acs.org/author/Chen%2C+Guoliang" id="authors">Guoliang Chen</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00170#cor1" href="http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00170#cor1"><sup>*</sup></a></span></div>
<div class="affiliations">
<div id="aff1">
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, <span class="institution">Shenyang Pharmaceutical University</span>, Shenyang 110016, <span class="country">China</span></div>
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<div id="citation">
<cite>Org. Process Res. Dev.</cite>, Article ASAP</div>
<div id="doi">
<strong>DOI: </strong>10.1021/acs.oprd.6b00170</div>
<div id="pubDate">
Publication Date (Web): July 12, 2016</div>
<div id="artCopyright">
Copyright © 2016 American Chemical Society</div>
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*E-mail: <a data-mce-href="mailto:guoliang222@gmail.com" href="mailto:guoliang222@gmail.com">guoliang222@gmail.com</a>.</div>
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A practical synthetic route of belinostat is reported. Belinostat was obtained via a five-step process starting from benzaldehyde and including addition reaction with sodium bisulfite, sulfochlorination with chlorosulfonic acid, sulfonamidation with aniline, Knoevenagel condensation, and the final amidation with hydroxylamine. Key to the strategy is the preparation of 3-formylbenzenesulfonyl chloride using an economical and practical protocol. The main advantages of the route include inexpensive starting materials and acceptable overall yield. The scale-up experiment was carried out to provide 169 g of belinostat with 99.6% purity in 33% total yield.</div>
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(<i>E</i>)-<i>N</i>-Hydroxy-3-((phenylamino)sulfonyl)phenyl)acrylamide (Belinostat, <b>1</b>)</div>
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1</div>
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mp 172–174 °C, (lit.<a class="ref" href="https://www.blogger.com/null">(@)</a> 172 °C). <sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><sub>6</sub>) δ = 10.75–10.42 (m, 2H), 9.15 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),7.47 (d, J = 15.8 Hz, 1H), 7.24 (m, 2H), 7.10–7.01 (m, 3H), 6.51 (d, J = 15.8 Hz, 1H). MS (ESI): <i>m</i>/<i>z</i> = 318.6 [M+H] <sup>+</sup>.</div>
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@ <span class="hlFld-ContribAuthor ">Finn<span class="NLM_x">, </span>P. W.</span>; <span class="hlFld-ContribAuthor ">Bandara<span class="NLM_x">, </span>M.</span>; <span class="hlFld-ContribAuthor ">Butcher<span class="NLM_x">, </span>C.</span>; <span class="hlFld-ContribAuthor ">Finn<span class="NLM_x">, </span>A.</span>; <span class="hlFld-ContribAuthor ">Hollinshead<span class="NLM_x">, </span>R.</span>; <span class="hlFld-ContribAuthor ">Khan<span class="NLM_x">, </span>N.</span>; <span class="hlFld-ContribAuthor ">Law<span class="NLM_x">, </span>N.</span>; <span class="hlFld-ContribAuthor ">Murthy<span class="NLM_x">, </span>S.</span>; <span class="hlFld-ContribAuthor ">Romero<span class="NLM_x">,</span>R.</span>; <span class="hlFld-ContribAuthor ">Watkins<span class="NLM_x">, </span>C.</span>; <span class="hlFld-ContribAuthor ">Andrianov<span class="NLM_x">, </span>V.</span>; <span class="hlFld-ContribAuthor ">Bokaldere<span class="NLM_x">, </span>R. M.</span>; <span class="hlFld-ContribAuthor ">Dikovska<span class="NLM_x">, </span>K.</span>; <span class="hlFld-ContribAuthor ">Gailite<span class="NLM_x">, </span>V.</span>; <span class="hlFld-ContribAuthor ">Loza<span class="NLM_x">, </span>E.</span>; <span class="hlFld-ContribAuthor ">Piskunova<span class="NLM_x">, </span>I.</span>;<span class="hlFld-ContribAuthor ">Starchenkov<span class="NLM_x">, </span>I.</span>; <span class="hlFld-ContribAuthor ">Vorona<span class="NLM_x">, </span>M.</span>; <span class="hlFld-ContribAuthor ">Kalvinsh<span class="NLM_x">, </span>I.</span> <span class="citation_source-journal">Helv. Chim. Acta</span> <span class="NLM_year">2005</span>, <span class="NLM_volume">88</span>, <span class="NLM_fpage">1630</span>, <span class="refDoi">DOI: 10.1002/hlca.200590129</span></div>
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Belinostat (Beleodaq ),</div>
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Belinostat is a drug which was developed by Spectrum Pharmaceuticals and is currently marketed by Onxeo as Beleodaq . The<br />drug, which received fast track designation by the United States Food and Drug Administration (US FDA) and was approved for<br />the treatment of hematological malignancies and solid tumors associated with peripheral T-cell lymphoma (PTCL) in 2014,58 is a histone deacetylase (HDAC) inhibitor and is the third such treatment to receive accelerated approval for PTCL, the others being<br />vorinostat (Zolinza ) and pralatrexate (Folotyn ).58 Although belinostat was not yet approved in Europe as of August 2014,58 the<br />compound exhibits a safety profile considered to be acceptable for HDAC inhibitors–less than 25% of patients reported adverse<br />effects and these most frequently were nausea, fatigue, pyrexia,anemia, and emesis.58 While several different synthetic approaches<br />have been reported for the preparation of belinostat and related HDAC inhibitors,59–62 the most likely process-scale approach has<br />been described in a patent application filed by Reisch and co-workers at Topotarget UK, which exemplifies the synthesis described in<br />Scheme 8 on kilogram scale.63</div>
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Commercially available 3-bromobenzenesulfonyl chloride (41) was reacted with aniline in the presence of aqueous sodium carbonate<br />to deliver sulfonamide 42 in 94% yield. Next, this aryl bromide was subjected to a Heck reaction involving ethyl acrylate to<br />give rise to cinnamate ester 43, which was immediately saponified under basic conditions and acidic workup to furnish the corresponding acid 44. This acid was activated as the corresponding acid chloride prior to subjection to hydroxylamine under basic conditions to form the hydroxamic acid, which was then recrystallized from an 8:1 ethanol/water mixture in the presence of a catalytic<br />amount of sodium bicarbonate to furnish crystalline belinostat (VI) in 87% overall yield from acid 44.61</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-31.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-31.jpg" rel="attachment wp-att-7825"><img alt="str1" class="alignnone size-full wp-image-7825" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-31.jpg" height="324" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-31.jpg" style="height: auto; max-width: 100%;" width="539" /></a></div>
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Lee, H. Z.; Kwitkowski, V. E.; Del Valle, P. L.; Ricci, M. S.; Saber, H.;Habtemariam, B. A.; Bullock, J.; Bloomquist, E.; Li Shen, Y.; Chen, X. H.;Brown, J.; Mehrotra, N.; Dorff, S.; Charlab, R.; Kane, R. C.; Kaminskas, E.;Justice, R.; Farrell, A. T.; Pazdur, R. Clin. Cancer Res. 2015, 21, 2666.<br />59. Qian, J.; Zhang, G.; Qin, H.; Zhu, Y.; Xiao, Y. CN Patent 102786448A, 2012.<br />60. Wang, H.; Yu, N.; Chen, D.; Lee, K. C.; Lye, P. L.; Chang, J. W.; Deng, W.; Ng, M.C.; Lu, T.; Khoo, M. L.; Poulsen, A.; ngthongpitag, K.; Wu, X.; Hu, C.; Goh, K.C.; Wang, X.; Fang, L.; Goh, K. L.; Khng, H. H.; Goh, S. K.; Yeo, P.; Liu, X.; Bonday, Z.; Wood, J. M.; Dymock, B. W.; Kantharaj, E.; Sun, E. T. J. Med. Chem.2011, 54, 4694.<br />61. Yang, L.; Xue, X.; Zhang, Y. Synth. Comm. 2010, 40, 2520.</div>
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Let's Research !!!!!</div>
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<a data-mce-href="https://ayurajan.blogspot.in/2016/06/belinostat-hdac-inhibitor.html" href="https://ayurajan.blogspot.in/2016/06/belinostat-hdac-inhibitor.html">https://ayurajan.blogspot.in/2016/06/belinostat-hdac-inhibitor.html</a></div>
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<b>Helv Chim Acta 2005, 88(7), 1630-1657</b>: It is first reported synthesis for Belinostat and many other derivatives. The procedure uses oleum, thionyl chloride (SOCl<sub>2</sub>) as well as oxalyl chloride (COCl)<sub>2</sub>, no wonder better procedures were derived from it. ABOVE<br /><strong>Synth Comm 2010, <em>40(17)</em>, 2520–2524</strong>: The synthesis avoids the use of the extremely corrosive oleum and thionyl chloride (SOCl<sub>2</sub>) and therefore is possibly better for scaled-up production. Second, synthetic steps do not involve tedious separations and give a better overall yield. BELOW<img alt="" data-mce-src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhwjk_PlVQEKSb1JNxmdOXsrfVkry3i80KSfGFYLIzROhn2wKkWGVB_uGJEyo5MJPHozV7fHO_-wGw6y73Jl-MAcTdKoSDbdx2MQy6eiCtNkrPO0e9vllezBgFvrB8tH03cwy68KppDJvnG/s640/Belinostat-syn2.png" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhwjk_PlVQEKSb1JNxmdOXsrfVkry3i80KSfGFYLIzROhn2wKkWGVB_uGJEyo5MJPHozV7fHO_-wGw6y73Jl-MAcTdKoSDbdx2MQy6eiCtNkrPO0e9vllezBgFvrB8tH03cwy68KppDJvnG/s640/Belinostat-syn2.png" style="height: auto; max-width: 100%;" /><strong><u>Identifications:</u></strong></div>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><strong>1H NMR (Estimated) for Belinostat</strong></td></tr>
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<img alt="" data-mce-src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimMbgXHLSP3peqzv9gzhqjG36GPhVC8Q9DauW3hxOOu4ZY4cr-z40nOrfn-PFpRJF6LNxqe5N5BWCmOh-D2atL-GCWM-o2GcWrhyphenhyphen0dkx2iYvWr94PJ0eFqyU_q3fYaEZutgsMbynWMyMnc/s640/NMR-Belinostat.png" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimMbgXHLSP3peqzv9gzhqjG36GPhVC8Q9DauW3hxOOu4ZY4cr-z40nOrfn-PFpRJF6LNxqe5N5BWCmOh-D2atL-GCWM-o2GcWrhyphenhyphen0dkx2iYvWr94PJ0eFqyU_q3fYaEZutgsMbynWMyMnc/s640/NMR-Belinostat.png" style="height: auto; max-width: 100%;" /></div>
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<strong>Experimental:</strong> <sup>1</sup>H NMR (300 MHz, DMSO-d<sub>6</sub>): δ 6.52 (d, J=15.9 Hz, 1H), 6.81–7.12 (m, 6H), 7.33 (d, J=15.9 Hz, 1H), 7.47–7.67 (m, 3 H), 7.87 (s, 1H), 9.00–11.20 (br, 3H).</div>
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SEE COMPILATION ON SIMILAR COMPOUNDS AT ..............<a data-mce-href="http://drugsynthesisint.blogspot.in/p/nostat-series.html" href="http://drugsynthesisint.blogspot.in/p/nostat-series.html">http://drugsynthesisint.blogspot.in/p/nostat-series.html</a></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">HPLC</span></h1>
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ANALYTICAL HPLC TEST METHOD</div>
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HPLC spectrum of Belinostat.</div>
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<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
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<a data-mce-href="http://www.google.si/patents/CN102531972A?cl=en" href="http://www.google.si/patents/CN102531972A?cl=en">http://www.google.si/patents/CN102531972A?cl=en</a></div>
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Belinostat synthesis process related to the first report of the literature of W002 / 30879 A2, including preparation for Belinostat described as follows:</div>
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<img alt="" data-mce-src="http://patentimages.storage.googleapis.com/CN102531972A/CN102531972AD00041.png" src="http://patentimages.storage.googleapis.com/CN102531972A/CN102531972AD00041.png" style="height: auto; max-width: 100%;" /></div>
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<img alt="Figure CN102531972AD00031" data-mce-src="http://patentimages.storage.googleapis.com/CN102531972A/CN102531972AD00031.png" src="http://patentimages.storage.googleapis.com/CN102531972A/CN102531972AD00031.png" style="height: auto; max-width: 100%;" /></div>
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<span class="notranslate">Example 3:</span></div>
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<span class="notranslate">3- (3-sulfonate-yl) phenyl - acrylate preparation:</span></div>
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<span class="notranslate">First, 3-bromophenyl sulfonate 37. Ig (257. 90g / mol, 0. 1439mol) was dissolved with stirring in 260mL toluene IL reactor was then added triethylamine 36. 5g (101. 19g / mol, 0. 3604mol), tri (o-methylphenyl) phosphine 0. 875g (304. 37g / mol, 0. 002874mol), palladium acetate 0. 324g (224. 51g, 0. 001441mol), the reaction mixture was heated to 45- 55 ° C with nitrogen pumping ventilation four, this time in the reaction system to generate the catalytically active 1 ^ (0).</span> <span class="notranslate">The temperature of the reaction system was raised to 80-90 ° C, within 2. 75h dropwise methacrylate 13. 6g (86. 04g / mol, 0. 1586mol), the reaction was continued after the cell by HPLC 3- bromophenyl sulfonyl chloride was completion of the reaction.</span> <span class="notranslate">The temperature of the reaction system was reduced to 45-55 ° C.</span></div>
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<span class="notranslate">[0021] In at 45-55 ° C, the reaction mixture was concentrated under reduced pressure, ethyl acetate and n-heptane and recrystallized to give the product 29. 4g, 83% yield.</span></div>
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<span class="notranslate">[0022] The spectral data:</span></div>
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<span class="notranslate">1HNMR (DMS0-d6, HMDS0), δ (ppm): 3. 65 (3H, S, H-1); 6. 47 (1H, d, J = 16 0 Hz, H-2.); 7. 30 -8 00 (5H, m, H-3, H_4, H_5, H_6, H_7) m / e:. 264. 23</span></div>
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<img alt="Figure CN102531972AD00061" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN102531972A/CN102531972AD00061.png" height="344" id="idf0005" src="http://patentimages.storage.googleapis.com/CN102531972A/CN102531972AD00061.png" style="height: auto; max-width: 100%;" width="733" /></div>
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<img alt="Links" data-mce-src="http://lem.ch.unito.it/didattica/infochimica/Liquidi%20Ionici/LiquidiIonici_File/links1.gif" src="http://lem.ch.unito.it/didattica/infochimica/Liquidi%20Ionici/LiquidiIonici_File/links1.gif" style="height: auto; max-width: 100%;" /><br />
<span class="mw-headline" id="References">References</span><br />
<ol>
<li id="cite_note-1"><div class="reflist columns references-column-count references-column-count-2">
<ol class="references">
<li id="cite_note-1"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.beleodaq.com/downloads/Final_Beleodaq_PI.pdf" href="http://www.beleodaq.com/downloads/Final_Beleodaq_PI.pdf" rel="nofollow">"Beleodaq (belinostat) For Injection, For Intravenous Administration. Full Prescribing Information"</a> (PDF). Spectrum Pharmaceuticals, Inc. Irvine, CA 92618<span class="reference-accessdate">. Retrieved <span class="nowrap">21 November</span>2015</span>.</cite></span></li>
<li id="cite_note-2"><span class="reference-text"><cite class="citation journal">Plumb JA; Finn PW; Williams RJ; et al. (2003). "Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101". <i>Molecular Cancer Therapeutics</i> <b>2</b> (8): 721–728.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/12939461" href="https://www.ncbi.nlm.nih.gov/pubmed/12939461" rel="nofollow">12939461</a>.</cite></span></li>
<li id="cite_note-FDA-2014-3"> <span class="reference-text"><cite class="citation news"><a class="external text" data-mce-href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403929.htm" href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403929.htm" rel="nofollow">"FDA approves Beleodaq to treat rare, aggressive form of non-Hodgkin lymphoma"</a>. FDA. 3 July 2014.</cite></span></li>
<li id="cite_note-4"> <span class="reference-text"><cite class="citation news"><a class="external text" data-mce-href="http://www.biospace.com/news_story.aspx?NewsEntityId=75000" href="http://www.biospace.com/news_story.aspx?NewsEntityId=75000" rel="nofollow">"CuraGen Corporation (CRGN) and TopoTarget A/S Announce Presentation of Belinostat Clinical Trial Results at AACR-NCI-EORTC International Conference"</a>. October 2007.</cite></span></li>
<li id="cite_note-5"> <span class="reference-text"><cite class="citation"><a class="external text" data-mce-href="http://ash.confex.com/ash/2009/webprogram/Paper20945.html" href="http://ash.confex.com/ash/2009/webprogram/Paper20945.html" rel="nofollow"><i>Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma</i></a>, December 2009</cite></span></li>
<li id="cite_note-6"> <span class="reference-text"><cite class="citation news"><a class="external text" data-mce-href="http://www.fiercebiotech.com/story/spectrum-adds-cancer-pipeline-350m-deal/2010-02-02#ixzz0fBunZz8B" href="http://www.fiercebiotech.com/story/spectrum-adds-cancer-pipeline-350m-deal/2010-02-02#ixzz0fBunZz8B" rel="nofollow">"Spectrum adds to cancer pipeline with $350M deal."</a>. February 2010.</cite></span></li>
<li id="cite_note-Spreitzer-7"> <span class="reference-text"><cite class="citation journal">H. Spreitzer (4 August 2014). "Neue Wirkstoffe – Belinostat".<i>Österreichische Apothekerzeitung</i> (in German) (16/2014): 27.</cite></span></li>
<li id="cite_note-DIHO_2016_14-8"> <span class="reference-text"><cite class="citation book">Lexicomp, (corporate author) (2016). Bragalone, DL, ed.<i>Drug Information Handbook for Oncology</i> (14th ed.). Wolters Kluwer. <a data-mce-href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a data-mce-href="https://en.wikipedia.org/wiki/Special:BookSources/9781591953517" href="https://en.wikipedia.org/wiki/Special:BookSources/9781591953517" title="Special:BookSources/9781591953517">9781591953517</a>.</cite></span></li>
</ol>
</div>
</li>
<li>Helvetica Chimica Acta, <b>2005 </b>, vol. 88, 7 PG. 1630 - 1657, MP 172</li>
<li>WO2009/40517 A2, ....</li>
<li>WO2006/120456 A1, .....</li>
<li>Synthetic Communications, <b>2010 </b>, vol. 40, 17 PG. 2520 - 2524, MP 172</li>
<li>Journal of Medicinal Chemistry, <b>2011 </b>, vol. 54, 13 PG. 4694 - 4720, NMR IN SUP INFO</li>
</ol>
<a data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206256Orig1s000PharmR.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206256Orig1s000PharmR.pdf" target="_blank">Drug@FDA, NDA206256 Pharmacology Review(s).</a><br />
<em> <a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Determination%20of%20the%20class%20and%20isoform%20selectivity%20of%20small-molecule%20histone%20deacetylase%20inhibitors" href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Determination%20of%20the%20class%20and%20isoform%20selectivity%20of%20small-molecule%20histone%20deacetylase%20inhibitors" target="_blank">Biochem. J.</a></em><a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Determination%20of%20the%20class%20and%20isoform%20selectivity%20of%20small-molecule%20histone%20deacetylase%20inhibitors" href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Determination%20of%20the%20class%20and%20isoform%20selectivity%20of%20small-molecule%20histone%20deacetylase%20inhibitors" target="_blank"> <strong>2008</strong>, <em>409</em>, 581-589.</a><br />
<a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/?term=The+histone+deacetylase+inhibitor+belinostat+(PXD101)+suppresses+bladder+cancer+cell+growth+in+vitro+and+in+vivo" href="http://www.ncbi.nlm.nih.gov/pubmed/?term=The+histone+deacetylase+inhibitor+belinostat+(PXD101)+suppresses+bladder+cancer+cell+growth+in+vitro+and+in+vivo" target="_blank"><em>J. Transl. Med.</em> <strong>2007</strong>, <em>5</em>, 1-12.</a><br />
<a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Qian%2C+X.%3B+LaRochelle%2C+W.+J.%3B+Ara%2C+G.%2C+et+al.+Mol.+Cancer+Ther.+2006%2C+5%2C+2086-2095." href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Qian%2C+X.%3B+LaRochelle%2C+W.+J.%3B+Ara%2C+G.%2C+et+al.+Mol.+Cancer+Ther.+2006%2C+5%2C+2086-2095." target="_blank"><em>Mol. Cancer Ther.</em> <strong>2006</strong>,<em> 5</em>, 2086-2095.</a><br />
<a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Qian%2C+X.%3B+Ara%2C+G.%3B+Mills%2C+E.%2C+et+al.+Int.+J.+Cancer+2008%2C+122%2C+1400-1410." href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Qian%2C+X.%3B+Ara%2C+G.%3B+Mills%2C+E.%2C+et+al.+Int.+J.+Cancer+2008%2C+122%2C+1400-1410." target="_blank"><em>Int. J. Cancer</em> <strong>2008</strong>, <em>122</em>, 1400-1410.</a><br />
. <a data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Glucuronidation+by+UGT1A1+Is+the+Dominant+Pathway+of+the+Metabolic+Disposition+of+Belinostat+in+Liver+Cancer+Patients" href="http://www.ncbi.nlm.nih.gov/pubmed/?term=Glucuronidation+by+UGT1A1+Is+the+Dominant+Pathway+of+the+Metabolic+Disposition+of+Belinostat+in+Liver+Cancer+Patients" target="_blank"><em>PLoS One</em> <strong>2013</strong>, <em>8</em>, e54522.</a><br />
<a data-mce-href="http://ocean.sci-hub.bz/2f00077ab5de46eac344e54f29638606/yang2010.pdf?download=true" href="http://ocean.sci-hub.bz/2f00077ab5de46eac344e54f29638606/yang2010.pdf?download=true" target="_blank"><em>Synthetic Commun.</em> <strong>2010</strong>, <em>40</em>, 2520-2524</a>.<br />
<div class="patent-section patent-tabular-section">
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<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/CN101868446A?cl=en" href="https://www.google.com/patents/CN101868446A?cl=en">CN101868446A</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 23, 2008</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oct 20, 2010</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">托波塔吉特英国有限公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methods of synthesis of certain hydroxamic acid compounds</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/CN102531972A?cl=en" href="https://www.google.com/patents/CN102531972A?cl=en">CN102531972A</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 31, 2010</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 4, 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">北京万全阳光医药科技有限公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Preparation method of intermediate of antitumor medicament Belinostat</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/EP2093292A2?cl=en" href="https://www.google.com/patents/EP2093292A2?cl=en">EP2093292A2</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 26, 2001</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Aug 26, 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methylgene, Inc.</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Inhibition of specific histone deacetylase isoforms</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/url?id=5XKvBwABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DGB%26NR%3D2378179A%26KC%3DA%26FT%3DD&usg=AFQjCNEbtATC2mujuw3i1A1_y9KK771_ig" href="https://www.google.com/url?id=5XKvBwABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DGB%26NR%3D2378179A%26KC%3DA%26FT%3DD&usg=AFQjCNEbtATC2mujuw3i1A1_y9KK771_ig">GB2378179A</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </td><td class="patent-data-table-td citation-no-title" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title not available</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2002030879A2?cl=en" href="https://www.google.com/patents/WO2002030879A2?cl=en">WO2002030879A2</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 27, 2001</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 18, 2002</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prolifix Limited</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2008068170A1?cl=en" href="https://www.google.com/patents/WO2008068170A1?cl=en">WO2008068170A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 27, 2007</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 12, 2008</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">William Paul Jackson</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Hdac inhibitors</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://www.google.com/patents/WO2009146871A1?cl=en" href="https://www.google.com/patents/WO2009146871A1?cl=en">WO2009146871A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 1, 2009</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 10, 2009</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">William Paul Jackson</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5-lipoxygenase inhibitors</td></tr>
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<tr class="patent-data-table"><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Citing Patent</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Filing date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Publication date</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Applicant</th><th class="patent-data-table-th" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title</th></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20080274120.PN.&OS=PN/20080274120&RS=PN/20080274120" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20080274120.PN.&OS=PN/20080274120&RS=PN/20080274120">US2008274120</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">11-7-2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Histone Deacetylase (Hdac) Inhibitors (Pxd101) for the Treatment of Cancer Alone or in Combination With Chemotherapeutic Agent</td></tr>
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<tr id="ext-gen1652"><td id="ext-gen1653" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20080194690.PN.&OS=PN/20080194690&RS=PN/20080194690" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20080194690.PN.&OS=PN/20080194690&RS=PN/20080194690">US2008194690</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8-15-2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pharmaceutical Formulations Of Hdac Inhibitors</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7407988.PN.&OS=PN/7407988&RS=PN/7407988" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7407988.PN.&OS=PN/7407988&RS=PN/7407988">US7407988</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8-6-2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7402603.PN.&OS=PN/7402603&RS=PN/7402603" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7402603.PN.&OS=PN/7402603&RS=PN/7402603">US7402603</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7-23-2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7183298.PN.&OS=PN/7183298&RS=PN/7183298" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7183298.PN.&OS=PN/7183298&RS=PN/7183298">US7183298</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2-28-2007</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20050107445.PN.&OS=PN/20050107445&RS=PN/20050107445" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20050107445.PN.&OS=PN/20050107445&RS=PN/20050107445">US2005107445</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5-20-2005</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors</td></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20110077305.PN.&OS=PN/20110077305&RS=PN/20110077305" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20110077305.PN.&OS=PN/20110077305&RS=PN/20110077305">US2011077305</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3-32-2011</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5-LIPOXYGENASE INHIBITORS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20110003777.PN.&OS=PN/20110003777&RS=PN/20110003777" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20110003777.PN.&OS=PN/20110003777&RS=PN/20110003777">US2011003777</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1-7-2011</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methods of Treatment Employing Prolonged Continuous Infusion of Belinostat</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20100286279.PN.&OS=PN/20100286279&RS=PN/20100286279" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20100286279.PN.&OS=PN/20100286279&RS=PN/20100286279">US2010286279</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">11-12-2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methods of Synthesis of Certain Hydroxamic Acid Compounds</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20100190694.PN.&OS=PN/20100190694&RS=PN/20100190694" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20100190694.PN.&OS=PN/20100190694&RS=PN/20100190694">US2010190694</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7-30-2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methods for identifying patients who will respond well to cancer treatment</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20100010010.PN.&OS=PN/20100010010&RS=PN/20100010010" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20100010010.PN.&OS=PN/20100010010&RS=PN/20100010010">US2010010010</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1-15-2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">HDAC INHIBITORS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090312311.PN.&OS=PN/20090312311&RS=PN/20090312311" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090312311.PN.&OS=PN/20090312311&RS=PN/20090312311">US2009312311</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">12-18-2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">COMBINATION OF ORGANIC COMPOUNDS</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090192211.PN.&OS=PN/20090192211&RS=PN/20090192211" href="http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090192211.PN.&OS=PN/20090192211&RS=PN/20090192211">US2009192211</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7-31-2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CYCLOOXYGENASE-2 INHIBITOR/HISTONE DEACETYLASE INHIBITOR COMBINATION</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7557140.PN.&OS=PN/7557140&RS=PN/7557140" href="http://patft.uspto.gov/netacgi/nph-Parser?d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7557140.PN.&OS=PN/7557140&RS=PN/7557140">US7557140</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7-8-2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CARBAMIC ACID COMPOUNDS COMPRISING A SULFONAMIDE LINKAGE AS HDAC INHIBITORS</td></tr>
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<div>
<table class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO1998038859A1?cl=en" href="http://www.google.com/patents/WO1998038859A1?cl=en">WO1998038859A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 4, 1998</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 11, 1998</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Thomas E Barta</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sulfonyl divalent aryl or heteroaryl hydroxamic acid compounds</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO1999024399A1?cl=en" href="http://www.google.com/patents/WO1999024399A1?cl=en">WO1999024399A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 12, 1998</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 20, 1999</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Darwin Discovery Ltd</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Hydroxamic and carboxylic acid derivatives having mmp and tnf inhibitory activity</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2000056704A1?cl=en" href="http://www.google.com/patents/WO2000056704A1?cl=en">WO2000056704A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 22, 2000</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 28, 2000</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Duncan Batty</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Hydroxamic and carboxylic acid derivatives</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2000069819A1?cl=en" href="http://www.google.com/patents/WO2000069819A1?cl=en">WO2000069819A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 12, 2000</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 23, 2000</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Thomas E Barta</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Hydroxamic acid derivatives as matrix metalloprotease inhibitors</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2001038322A1?cl=en" href="http://www.google.com/patents/WO2001038322A1?cl=en">WO2001038322A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 22, 2000</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 31, 2001</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methylgene Inc</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Inhibitors of histone deacetylase</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/EP0570594A1?cl=en" href="http://www.google.com/patents/EP0570594A1?cl=en">EP0570594A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 7, 1992</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 24, 1993</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">SHIONOGI &amp; CO., LTD.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Hydroxamic acid derivative based on aromatic sulfonamide</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/EP0931788A2?cl=en" href="http://www.google.com/patents/EP0931788A2?cl=en">EP0931788A2</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 16, 1998</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 28, 1999</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pfizer Inc.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Metalloprotease inhibitors</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/url?id=_4yhBAABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DGB%26NR%3D2312674A%26KC%3DA%26FT%3DD&usg=AFQjCNEjm1P3vVzL3ynjg3y3tFoo1rlfmg" href="http://www.google.com/url?id=_4yhBAABERAJ&q=http://worldwide.espacenet.com/publicationDetails/biblio%3FCC%3DGB%26NR%3D2312674A%26KC%3DA%26FT%3DD&usg=AFQjCNEjm1P3vVzL3ynjg3y3tFoo1rlfmg">GB2312674A</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Title not available</td></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2002030879A2?cl=en" href="http://www.google.com/patents/WO2002030879A2?cl=en">WO2002030879A2</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 27, 2001</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 18, 2002</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Prolifix Ltd</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2005063806A1?cl=en" href="http://www.google.com/patents/WO2005063806A1?cl=en">WO2005063806A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dec 30, 2003</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 14, 2005</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Council Scient Ind Res</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Arginine hydrochloride enhances chaperone-like activity of alpha crystallin</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/US4642316" href="http://www.google.com/patents/US4642316">US4642316</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">May 20, 1985</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Feb 10, 1987</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Warner-Lambert Company</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Parenteral phenytoin preparations</td></tr>
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<table class="mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2008090585A2?cl=en" href="http://www.google.com/patents/WO2008090585A2?cl=en">WO2008090585A2</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jan 25, 2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jul 31, 2008</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Univ Roma</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Soluble forms of inclusion complexes of histone deacetylase inhibitors and cyclodextrins, their preparation processes and uses in the pharmaceutical field</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2009109861A1?cl=en" href="http://www.google.com/patents/WO2009109861A1?cl=en">WO2009109861A1</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 6, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sep 11, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Topotarget A/S</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methods of treatment employing prolonged continuous infusion of belinostat</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2010048332A2?cl=en" href="http://www.google.com/patents/WO2010048332A2?cl=en">WO2010048332A2</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Oct 21, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Apr 29, 2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Acucela, Inc.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Compounds for treating ophthalmic diseases and disorders</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/WO2011064663A1?cl=en" href="http://www.google.com/patents/WO2011064663A1?cl=en">WO2011064663A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Nov 24, 2010</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jun 3, 2011</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Festuccia, Claudio</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Combination treatment employing belinostat and bicalutamide</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com/patents/US20110003777" href="http://www.google.com/patents/US20110003777">US20110003777</a> *</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Mar 6, 2009</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Jan 6, 2011</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Topotarget A/S</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Methods of Treatment Employing Prolonged Continuous Infusion of Belinostat</td></tr>
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<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.si/patents/CN102786448A?cl=en" href="http://www.google.si/patents/CN102786448A?cl=en">CN102786448A</a><span class="patent-tooltip-anchor" data-tooltip-text="Navedel patentni preizkuševalec" data-tooltip="Navedel patentni preizkuševalec"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">9 avg 2012</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 nov 2012</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">深圳万乐药业有限公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Method of synthesizing belinostat</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.si/patents/CN102786448B?cl=en" href="http://www.google.si/patents/CN102786448B?cl=en">CN102786448B</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">9 avg 2012</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">12 mar 2014</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">深圳万乐药业有限公司</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Method of synthesizing belinostat</td></tr>
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CLIP</div>
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<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Belinostat">Belinostat</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Belinostat.svg" href="https://en.wikipedia.org/wiki/File:Belinostat.svg"><img alt="Belinostat.svg" data-file-height="163" data-file-width="512" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Belinostat.svg/220px-Belinostat.svg.png" height="70" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Belinostat.svg/220px-Belinostat.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Belinostat.svg/330px-Belinostat.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Belinostat.svg/440px-Belinostat.svg.png 2x" style="height: auto; max-width: 100%;" width="220" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">(2<i>E</i>)-<i>N</i>-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Beleodaq</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/beleodaq.html" href="https://www.drugs.com/beleodaq.html" rel="nofollow">beleodaq</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" title="Pregnancy category">D</a> (Evidence of risk)</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Intravenous" href="https://en.wikipedia.org/wiki/Intravenous" title="Intravenous">Intravenous</a> (IV)</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Bioavailability" href="https://en.wikipedia.org/wiki/Bioavailability" title="Bioavailability">Bioavailability</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">100% (IV)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Plasma_protein_binding" href="https://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">92.9–95.8%<sup class="reference" id="cite_ref-1"><a data-mce-href="https://en.wikipedia.org/wiki/Belinostat#cite_note-1" href="https://en.wikipedia.org/wiki/Belinostat#cite_note-1">[1]</a></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_metabolism" href="https://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/UDP_glucuronosyltransferase_1_family,_polypeptide_A1" href="https://en.wikipedia.org/wiki/UDP_glucuronosyltransferase_1_family,_polypeptide_A1" title="UDP glucuronosyltransferase 1 family, polypeptide A1">UGT1A1</a></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Excretion" href="https://en.wikipedia.org/wiki/Excretion" title="Excretion">Excretion</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Urine</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=866323-14-0" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=866323-14-0" rel="nofollow">866323-14-0</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_L01" href="https://en.wikipedia.org/wiki/ATC_code_L01" title="ATC code L01">L01XX49</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=L01XX49" href="http://www.whocc.no/atc_ddd_index/?code=L01XX49" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6918638" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6918638" rel="nofollow">6918638</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.5293831.html" href="http://www.chemspider.com/Chemical-Structure.5293831.html" rel="nofollow">5293831</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=F4H96P17NZ" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=F4H96P17NZ" rel="nofollow">F4H96P17NZ</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEBI" href="https://en.wikipedia.org/wiki/ChEBI" title="ChEBI">ChEBI</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:61076" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:61076" rel="nofollow">CHEBI:61076</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEMBL" href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL408513" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL408513" rel="nofollow">CHEMBL408513</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Synonym" href="https://en.wikipedia.org/wiki/Synonym" title="Synonym">Synonyms</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">PXD101</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>15</sub><span title="Hydrogen">H</span><sub>14</sub><span title="Nitrogen">N</span><sub>2</sub><span title="Oxygen">O</span><sub>4</sub><span title="Sulfur">S</span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">318.348 g/mol</td></tr>
</tbody></table>
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<a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf" href="http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf">//////</a>//////Belinostat, PXD101, novel HDAC inhibitor, Beleodaq, Folotyn, Spectrum Pharmaceuticals, Inc., Henderson, Nevada, Istodax, Celgene Corporation, Summit, New Jersey, CuraGen Pharma, FDA 2014</div>
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<ul class="publicationFormatrightList">
<li><a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00170" href="http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00170">Supporting Info</a></li>
</ul>
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O=S(=O)(Nc1ccccc1)c2cc(\C=C\C(=O)NO)ccc2</div>
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SEE COMPILATION ON SIMILAR COMPOUNDS AT ..............<a data-mce-href="http://drugsynthesisint.blogspot.in/p/nostat-series.html" href="http://drugsynthesisint.blogspot.in/p/nostat-series.html">http://drugsynthesisint.blogspot.in/p/nostat-series.html</a></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1