энкломифен Enclomiphene citrate إينكلوميفان

Enclomiphene citrate

NDA FILED Hypogonadism, Repros Therapeutics

An estrogen receptor (ER) antagonist potentially for treatment of hypogonadotropic hypogonadism.

ICI-46476; RMI-16289

CAS No.15690-57-0(free)

7599-79-3(Enclomiphene citrate)

Molecular Weight	598.08
Formula	C26H28ClNOC6H8O7

Ethanamine, 2-[4-[(1E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)

• Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl-, (E)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)
• Triethylamine, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]-, citrate (1:1), (E)-
• (E)-Clomiphene citrate
• Androxal
• Clomiphene B citrate
• Enclomid
• Enclomiphene citrate
• trans-Clomiphene citrate

Clomifene is a mixture of two geometric isomers, enclomifene (E-clomifene) and zuclomifene (Z-clomifene). These two isomers have been found to contribute to the mixed estrogenic and anti-estrogenic properties of clomifene.

Enclomifene

Zuclomifene

 

 

PATENT

WO 2015138340

EXAMPLE 1

Preparation of trans-clomiphene citrate from

1- {4- [2-(Oiethylamino)ethoxy| phenylj-1 ,2-diphenylethanol

 Dehydration

[0023] l-{4-[2-(Diethylamino)ethoxy]phenyl}-l,2-diphenylethanol (6) dissolved in ethanol containing an excess of hydrogen chloride was refluxed 3 hours at 50 °C. The solvent and excess hydrogen chloride were removed under vacuum and the residue was dissolved in dichloromethane. 2-{4-[(Z)-l,2-diphenylvinyl]phenoxy}-N,N- diethylethanaminium hydrogen chloride (7) was obtained.

Chlorination

The hydrochloride salt (7) solution obtained above was treated with 1.05 equivalents of N-chlorosuccinimide and stirred at room temperature for about 20 hours. Completion of the reaction was confirmed by HPLC. The hydrochloride salt was converted to the free base by addition of saturated aqueous bicarbonate solution. The mixture was stirred at room temperature for 30 minutes after which the phases were separated and the organic phase was evaporated in vacuo. 2-{4-[2-chloro-l,2- diphenylvinyl]phenoxy}-N,N-diethylethanamine (clomiphene -1.8:1 E:Z mixture) (8) was obtained.

 Separation of clomiphene isomers

Clomiphene (8) obtained above is dissolved in methanol and racemic binaphthyl- phosphoric acid (BPA) is added under stirring. When the precipitate begins separating from the solution, stirring is stopped and the mixture is allowed to settle at room temperature for 2 hours. The precipitate is filtered, washed with methanol and ether and dried. Trans-clomiphene-BPA salt (3) is obtained.

 The enclomiphene-BPA salt (3) obtained above is extracted with ethyl acetate and NH₃ solution. To the organic solution washed with water and dried, citric acid dissolved in ethanol is added. The solution is allowed to settle for about one hour at room temperature; the precipitate is then filtered and dried under vacuum. The obtained precipitate, trans-clomiphene citrate (1) is dissolved in 2-butanone for storage.

EXAMPLE 2

Synthesis of Clomiphene Using a Single Solvent

 Step 1 - Dehydration of l-i4-r2-(Diethylamino)ethoxy1phenyl|-l,2- diphenylefhanol to form 2-{4-[(Z)-l,2-diphenylvinyllphenoxy}-N,N-diethylethanaminium hydrogen sulfate (7) [0030] The synthesis route described in Example 1 utilized HC1 for the dehydration step and utilized ethanol at 50 °C as the solvent. Sulfuric acid was investigated as an alternative to HC1 for the dehydration step (as described in Example 1) in part due to the more favorable corrosion profile of sulfuric acid. Dichloromethane (methylene chloride) was investigated as an alternative solvent for the dehydration step as this would render removal of the ethanol solvent prior to the chlorination step unnecessary.

 A 100 mL 3-neck round bottom flask, fitted with a temperature probe and a stir bar, was charged with l- {4-[2-(Diethylamino)ethoxy]phenyl}-l,2-diphenylethanol (6) (6.60 g, 16.9 mmol) and 66 mL (lxlO³ mmol) of methylene chloride to give a yellow solution which was cooled in an ice bath to 0 °C. Concentrated sulfuric acid (H₂S0₄, 0.96 mL, 18.1 mmol) was added at a rate such that the internal temperature did not exceed 5 °C. Upon completion of the addition, the mixture was allowed to stir one hour at ambient temperature. Completion of the reaction was confirmed by high performance liquid chromatography (HPLC). The reaction resulted in 7.96 grams of 2- (4-[(Z)- 1 ,2- diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7), a yield of 100%. Thus, sulfuric acid was demonstrated to be a suitable acid for the dehydration step.

[0042] Using these HPLC conditions, starting material has a retention time of 3.30 min and product has a retention time of 4.05 min.

It was determined that removal of water produced by the dehydration reaction was important before performing the chlorination step. When ethanol is used as the solvent for this reaction, as in Example 1, the water is removed azeotropically upon removal of the ethanol. Several methods of drying the dichloromethane solution were attempted. Drying with MgS0₄ had a deleterious effect on the subsequent chlorination step, rendering the chlorination process very messy with a number of new impurities observed following HPLC analysis which were determined to be the corresponding chlorohydrins. On the other hand, a wash with brine was sufficient to remove enough water and had no deleterious effect on the chlorination step. Accordingly, the solution was stirred vigorously with brine (66 ml) for 30 minutes and then the phases were separated prior to chlorination step.

 Step 2- Synthesis of 2-|4-r2-chloro-L2-diphenylvinyl1phenoxyl-N,N- diethylethanamine 8

The solution of 2-{4-[(Z)-l,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7.94 grams) in methylene chloride obtained in step 1 is stirred at room temperature and treated with N-chlorosuccinimide (2.37 g, 17.7 mmol, 1.05 equivalents) in a single portion and left to stir at room temperature for 12 hours. The yellow solution became orange and then went back to yellow. After 12 hours, a sample was removed, concentrated and assayed by HPLC to confirm the extent of reaction. HPLC analysis revealed that the reaction had proceeded but not to completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred at room temperature for an additional 4 hours. The reaction was again assayed by HPLC which revealed that the reaction was near completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred for an additional 12 hours at room temperature. The reaction was again assayed by HPLC and an additional 0.058 equivalents of N-chlorosuccinimide (131 mg, 0.98 mmol) was added and the solution stirred for an additional 4 hours. HPLC indicated that the reaction was complete at that point. The reaction was carefully quenched by slow addition of 66 mL (600 mmol) of saturated aqueous sodium bicarbonate solution and the quenched mixture was stirred for 30 minutes at room temperature - the reaction mixture pH should be about 8-9 after addition of saturated aqueous sodium bicarbonate solution. The reaction yielded 6.86 grams of 2-{4-[2-chloro-l,2-diphenylvinyl]phenoxy}-N,N- diethylethanamine (8). The phases were separated and the organic phase was evaporated in vacuo. The resulting light brown oil was transferred to a tared amber bottle using a small volume of dichloromethane.

[0055] Using these HPLC conditions, the retention time of product is 15 minutes.

 Chromatographic Separation of Clomiphene Isomers

Clomiphene (mixture of isomers) in free base form obtained by steps 1 and 2 is loaded onto a chromatographic column (e.g. batch high pressure chromatography or moving bed chromatography) using the same solvent as used in steps 1 and 2 (here DCM) in order to separate the cis- and trans-clomiphene isomers. Trans-clomiphene is preferably eluted using a solvent suitable for recrystallization.

 

PATENT

Indian (1978), IN 143841

http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19780211&CC=IN&NR=143841B&KC=B

 

PAPER

Separation of E- and Z-isomers of clomiphene citrate by high-performance liquid chromatography using methenamine as mobile phase modifier
Journal of Chromatography (1984), 298, (1), 172-4.

http://www.sciencedirect.com/science/article/pii/S0021967301927074

 

PATENT

http://www.google.com/patents/CN103351304A?cl=en

 

 

SYTHESIS

Patent
US2914562https://www.google.co.in/patents/US2914562
PATENT
US2914529
http://www.google.co.in/patents/US2914529
PAPER
J. Med. Chem.1967, 10, 84–86.

http://pubs.acs.org/doi/pdf/10.1021/jm00313a017

 

J. Org. Chem.1983, 48, 2782-2784.

http://pubs.acs.org/doi/pdf/10.1021/jo00164a036

 

 

PAPER

Chem Commun (London) 2015, 51(44): 9133

Chem. Commun., 2015, 51, 9133-9136
DOI: 10.1039/C5CC01968K

 

 A transition-metal-free, ambient-pressure, and general methodology for carbonylative Suzuki coupling has been developed.

  

 

 

CN103351304A *	Jul 1, 2013	Oct 16, 2013	暨明医药科技（苏州）有限公司	Synthesis method of clomiphene
US2914563 *	Aug 6, 1957	Nov 24, 1959	Wm S Merrell Co	Therapeutic composition
US3848030 *	Mar 10, 1972	Nov 12, 1974	Richardson Merrell Spa	Optical isomers of binaphthyl-phosphoric acids
US5681863 *	Dec 5, 1994	Oct 28, 1997	Merrell Pharmaceuticals Inc.	Non-metabolizable clomiphene analogs for treatment of tamoxifen-resistant tumors

 

Reference
1	*	RAO ET AL.: "Synthesis of carbon-14 labeled clomiphene.", JOUMAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 22, no. 3, 1985, pages 245 - 255, XP055180053, Retrieved from the Internet <URL:http://onlinelibrary. wiley .com/doi/10.1002/jlcr.2580220306/abstract> [retrieved on 20150504]

//////////энкломифен,  Enclomiphene citrate,  إينكلوميفان , ICI-46476,  RMI-16289, nda filed, Hypogonadism, Repros Therapeutics

Lobeglitazone Sulfate

Lobeglitazone Sulfate, CKD-501

(Duvie^®) Approved

Chong Kun Dang (Originator)

A dual PPARα and PPARγ agonist used to treat type 2 diabetes.

Trade Name：Duvie^®MOA：Dual PPARα and PPARγ agonistIndication：Type 2 diabetes

CAS No. 607723-33-1(FREE)

763108-62-9(Lobeglitazone Sulfate)

2,4-Thiazolidinedione, 5-((4-(2-((6-(4-methoxyphenoxy)-4- pyrimidinyl)methylamino)ethoxy)phenyl)methyl)-, sulfate (1:1);

Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.^[3]

Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie^® by Chong Kun Dang Corporation.

Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Duvie^® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC₅₀:  0.02 μM, PPARγ EC₅₀:  0.018 μM, rosiglitazone; PPARα EC₅₀:  >10 μM, PPARγ EC₅₀:  0.02 μM, pioglitazone PPARα EC₅₀:  >10 μM, PPARγ EC₅₀:  0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKA^y mice than rosiglitazone and pioglitazone.¹⁷ Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.

Medical uses

Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.^[4]

Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.^[4][5]

SYNTHESIS

PAPER

Org. Process Res. Dev. 2007, 11, 190-199.

Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501)

Hong Woo Lee ,*^† Joong Bok Ahn ,^‡ Sung Kwon Kang ,^† Soon Kil Ahn ,^† and Deok-Chan Ha ^‡

Process Research and Development Laboratory, Chemical Research Group, Chong Kun Dang Pharmaceutical Cooperation, Cheonan P. O. Box 74, Cheonan 330-831, South Korea, and Department of Chemistry, Korea University, 5-1-2, Anam-Dong, Seoul 136-701, Korea

Org. Process Res. Dev., 2007, 11 (2), pp 190–199

DOI: 10.1021/op060087u

http://pubs.acs.org/doi/abs/10.1021/op060087u

A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.

Silica gel TLC R_f = 0.35 (detection:  iodine char chamber, ninhydrin solution, developing solvents:  CH₂Cl₂/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH); ¹³C NMR (100 MHz, CDCl₃) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5; MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C₂₄H₂₆N₄O₉S₂:  C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found:  C, 49.85; H, 4.57; N, 9.75; S, 11.15.

PATENT

WO03080605A1.

References

1. Lee JH, Noh CK, Yim CS, Jeong YS, Ahn SH, Lee W, Kim DD, Chung SJ. (2015). "Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats.".Journal of Pharmaceutical sciences 104 (9): 3049–3059.doi:10.1002/jps.24378. PMID 25648999.
2.  Kim JW, Kim JR, Yi S, Shin KH, Shin HS, Yoon SH, Cho JY, Kim DH, Shin SG, Jang IJ, Yu KS. (2011). "Tolerability and pharmacokinetics of lobeglitazone (CKD-501), a peroxisome proliferator-activated receptor-γ agonist: a single- and multiple-dose, double-blind, randomized control study in healthy male Korean subjects.". Clinical therapeutics 33 (11): 1819–1830.doi:10.1016/j.clinthera.2011.09.023. PMID 22047812.
3.  Lee JH, Woo YA, Hwang IC, Kim CY, Kim DD, Shim CK, Chung SJ. (2009). "Quantification of CKD-501, lobeglitazone, in rat plasma using a liquid-chromatography/tandem mass spectrometry method and its applications to pharmacokinetic studies.". Journal of Pharmaceutical and Biomedical Analysis 50 (5): 872–877.doi:10.1016/j.jpba.2009.06.003. PMID 19577404.
4.  "MFDS permission information of Duvie Tablet 0.5mg"(Release of Information). Ministry of Food and Drug Safety. Retrieved2014-10-23.
5.  "국내개발 20번째 신약‘듀비에정’허가(20th new drug developed in Korea 'Duvie Tablet' was approved)". Chong Kun Dang press release. 2013-07-04. Retrieved 2014-10-23.

Lobeglitazone

Systematic (IUPAC) name
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Trade names	Duvie
Routes of administration	Oral
Legal status
Legal status	Rx-only in South Korea
Pharmacokinetic data
Protein binding	>99%[1]
Metabolism	liver (CYP2C9, 2C19, and 1A2)[1]
Biological half-life	7.8–9.8 hours[2]
Identifiers
CAS Number	607723-33-1
PubChem	CID 9826451
DrugBank	DB09198
ChemSpider	8002194
Synonyms	CKD-501
Chemical data
Formula	C24H24N4O5S
Molar mass	480.53616 g/mol
SMILES CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC

///Lobeglitazone Sulfate, CKD-501, Duvie^®,  Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes.

CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O

Istradefylline

Istradefylline, KW-6002

(Nouriast^®) Approved

A selective adenosine A2A receptor antagonist used to treat Parkinson's disease.

KW-6002

CAS No. 155270-99-8

Istradefylline; 155270-99-8; KW-6002; KW 6002; 8-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6 -dione; (E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione;

Molecular Formula:	C20H24N4O4
Molecular Weight:	384.42896 g/mol

Istradefylline (KW-6002) is a selective antagonist at the A_2A receptor. It has been found to be useful in the treatment of Parkinson's disease.^[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.

Kyowa Hakko Kirin is developing istradefylline, a selective adenosine A2A receptor antagonist, for the once-daily oral treatment of Parkinson's disease (PD). Adenosine A2A receptors are considered to be present particularly in the basal ganglia of the brain; the degeneration or abnormality observed in PD is believed to occur in the basal ganglia, which is recognized to play a significant role in motor control.

Commercially available dopamine replacement therapies effectively treat the early motor symptoms of PD; however, these agents are associated with development of motor complications, limiting usefulness in late stages of the disease. Istradefylline is proposed to possess a clearly distinct action site from existing agents which act on dopamine metabolism or dopamine receptors. Kyowa Hakko Kirin has received approval for istradefylline in the adjunctive treatment of PD in Japan. A New Drug Application was filed in the USA, but the FDA issued a non-approvable letter in February 2008.

PATENT

US5484920A

http://www.google.co.in/patents/US5484920

PAPER

http://www.sciencedirect.com/science/article/pii/S0960894X13003983

Scheme 1.

Synthesis of KW 6002 (2). Reagents and conditions: (i) acetic anhydride, 80 °C, 2 h, 83%; (ii) sodium nitrite, 50% acetic acid, 60 °C, 15 min, 86%; (iii) sodium dithionite, NH₄OH solution (12.5% (w/v)), 60 °C, 30 min, 98%; (iv) SOCl₂, toluene, 75 °C, 2 h, 97%; (v) pyridine, DCM, rt, 16 h, 66%; (vi) HMDS, cat. (NH₄)₂SO₄, CH₃CN, 160 °C, microwave, 5 h, 100% followed by (vii) MeI, K₂CO₃, DMF, rt, 2 h, 75%.

Synthesis
(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione (2)³

3. J. Hockemeyer; J. C. Burbiel; C. E. Müller, J. Org. Chem. 2004, 69, 3308.

(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-1H-purine-2,6(3H,7H)-dione (1.11 g, 3.00 mmol) was taken up in dimethylformamide (15 mL) and potassium carbonate (828 mg, 6.00 mmol). To the milky white mixture was added iodomethane (468 µL, 7.50 mmol) and it was allowed to stir at room temperature for 2 h. The mixture was then filtered and washed with water (100 mL), leaving the title compound 2 as a pale yellow solid which was dried in the oven at 110 °C (863 mg, 75%), mp: 192 °C (lit.³ 191 °C). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 15.7 Hz, 1H), 7.18 (dd, J = 8.4, 1.9 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 15.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.12 – 4.04 (m, 5H), 3.95 (s, 3H), 3.93 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.0 (C), 150.8 (C), 150.4 (C), 150.3 (C), 149.2 (C), 148.2 (C), 138.1 (CH), 128.6 (C), 121.2 (CH), 111.2 (CH), 109.5 (CH), 109.3 (CH), 108.0 (C), 55.98 (CH₃), 55.97 (CH₃), 38.4 (CH₂), 36.3 (CH₂), 31.5 (CH₃), 13.43 (CH₃), 13.39 (CH₃). LCMS: m/z (ESI 20 V) 385.2 (MH⁺, 100).

PATENT

http://www.google.com/patents/CN103254194A?cl=en

Specific synthetic route is as follows:

the above reaction is a synthetic Parkinson's disease clinical drug KW-6002 against a yield of 83%.

Example 26 (a new synthetic method for anti-Parkinson's disease in clinical drug KW-6002):

In addition to use in place of 3,4-dimethoxy-styryl boronic acid (0.4mmol, i.e., in formula IV, R5 is 3,4_-dimethoxy-styryl) benzene boronic acid in Example 23 and 1,3 - two-ethyl-8-phenylthio-9-methyl-xanthine (0.4mmol, i.e., Formula I, R1 is methyl, R2 and R3 are ethyl, R4 is a phenyl group) in place of Example 23 in 1 , 3,9-trimethyl xanthine -8- phenylthio, the remaining steps in Example 23 to give a white solid, yield 83%, mp = 101~103 ° C I1H NMR (⑶CI3, 600MHz): δ 7.71 (d, J = 15.6Hz, 1H), 7.17 (dd, J = 8.2,1.9Hz, 1H), 7.07 (d, J = L 9Hz, 1H), 6

• 88 (d, J = 8.2Hz, 1H), 6.74 (d, J = 15.8Hz, 1H), 4.19 (q, J = 7Hz, 2H), 4.07 (q, J = 7Hz, 2H), 4.03 (s , 3H), 3.93 (s, 3H), 3.90 (s, 3H), 1.36 (t, J = 7Hz, 3H), 1.23 (t, J = 7Hz, 3H); 13C NMR (150MHz, CDCl3): 155.1, 150.8,150.4,150.2,149.2,148.2,138.2,128.6,121.2, 111.2,109.5,109.3,108.0,56.0,55.9,38.4,36.3,31.5,13.4,13.4; HRMS: calcd for C20H25N4O4 (M + H) +385.187

6, Found385.1879. It indicates that the white solid was 8- (3,4-dimethoxy-styryl) structural formula shown KW-6002 (E) -1,3_ diethyl-7-methylxanthine.

 In contrast, KW-6002 is a new drug to treat Parkinson's disease developed by Kyowa Hakko in Japan, Japan and the United States is currently the second phase of clinical trials. Literature (. J.Hockemeyer, JCBurbiel andC.E.Muller, J.0rg.Chem, 2004,69,3308) through the following synthetic route:

The synthetic route requires five steps, with a total yield of 33%, and there is the use of environmentally unfriendly halogenated solvent methylene chloride, the reaction requires high pressure high temperature (170~180 ° C) and other shortcomings. By comparison, the present invention starting from 8- phenylthio xanthine coupling reaction catalyzed by palladium simple, a yield of 83% was synthesized KW6002, it is currently the most efficient synthesis route KW-6002's. In particular, the multi-step synthesis route to avoid the complex operation of the reactor, but under relatively mild conditions (60 ° C) conduct, simple operation, suitable for scale synthesis.

PATENT

http://www.google.com/patents/CN104744464A?cl=en

itraconazole theophylline (Istradefylline, KW6002), the chemical name 8 - [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl -7 - methyl-purine-2,6-dione, CAS number: 155270-99-8, structural formula shown below.

 itraconazole Theophylline is a selective adenosine A2a receptor antagonist, by changing the activity of neurons in Parkinson's disease patients to improve motor function, for the treatment of Parkinson's disease and Parkinson's disease improve early dyskinesia.

The invention and JPH0940652A European Patent 0,590,919 discloses a method for preparing itraconazole and theophylline. WO 2004/099207 published good solubility stability of a particle size of less than 50 micrometers 8 - [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3- diethyl-7-methyl-purine-2,6-dione crystallites.

Example 1 Preparation of theophylline itraconazole  Example

ships equipped with a mechanical stirrer, a thermometer, a 2L 4-neck flask was added 30g8 - [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl- -7- hydrogen - purine-2,6-dione (Intermediate A), 400mL N, N- dimethylformamide and 15g of potassium carbonate, and 25g of methyl iodide and heated to 80 ° C after the reaction was stirred 8h, added 200mL water, cooled to room temperature, and stirring was continued crystallization 2h. The resulting suspension was suction filtered, washed with water after the cake was 800mL sash, 50 ° C under blast drying 24h, 32g give a pale yellow solid, for each polymorph of itraconazole theophylline preparation example the following examples.

References

1.  Peter A. LeWitt, MD, M. Guttman, James W. Tetrud, MD, Paul J. Tuite, MD, Akihisa Mori, PhD, Philip Chaikin, PharmD, MD, Neil M. Sussman, MD (2008). "Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson's disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)". Annals of Neurology 63 (3): 295–302. doi:10.1002/ana.21315. PMID 18306243.

Reference：1. EP0590919A1.
2. US5484920A.
3. US5543415A.
4. J. Org. Chem. 2004, 69, 3308-3318.
5. Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352.
6. Bioorgan. Med. Chem. 2003, 11, 1299-1310.
7. Bioorg. Med. Chem. Lett. 2013, 23, 3427-3433.
8. Chinese Journal of Pharmaceuticals 2010, 41, 241-243.
9. JP0940652A.
10. Org. Biomo. Chem. 2010, 8, 4155-4157.

1. Chem. Commun. 2012, 48, 2864-2866.
2. CN103254194A.

CN104744464A *

Nov 15, 2013

Jul 1, 2015

南京华威医药科技开发有限公司

Istradefylline crystal forms

1. Istradefylline

   Systematic (IUPAC) name
   8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione
   Identifiers
   CAS Number	155270-99-8
   ATC code	none
   PubChem	CID 5311037
   IUPHAR/BPS	5608
   ChemSpider	4470574
   UNII	2GZ0LIK7T4
   KEGG	D04641
   ChEMBL	CHEMBL431770
   Chemical data
   Formula	C20H24N4O4
   Molar mass	384.429 g/mol

//////Istradefylline, KW-6002, Nouriast^®, Approved, A selective adenosine A2A receptor antagonist, Parkinson's disease,

O=C2N(c1nc(n(c1C(=O)N2CC)C)\C=C\c3ccc(OC)c(OC)c3)CC