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Monday, 11 January 2016

SCHEMBL12065086.png
SKLB 1028
IND Filed
A multi-targeted inhibitor potentially for the treatment of leukemia and non small cell lung cancer.
SKLB-1028
CAS 1350544-93-2
9-isopropyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-(pyridin-3-yl)-9H-purine- 2,8-diamine
2-N-[4-(4-methylpiperazin-1-yl)phenyl]-9-propan-2-yl-8-N-pyridin-3-ylpurine-2,8-diamine
9-Isopropyl-N2-[4-(4-methylpiperazin-1-yl)phenyl]-N8-(3-pyridyl)-9H-purine-2,8-diamine, 443.5474, C24H29N9, Preclinical
9-isopropyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-(pyridin-3-yl)-9H-purine- 2,8-diamine. Yield 65.6 %. HPLC>98.6%. 1H NMR(400 MHz, DMSO-d6): δ 9.22(s, 1H), 9.05(s, 1H), 8.94(d, J=2.8Hz, 1H), 8.39(s, 1H), 8.34(d,J=8.4Hz, 1H), 8.20(m, 1H), 7.63(d, J=8.8Hz, 2H), 7.37(m, 1H), 6.88 (d, J=8.8Hz, 2H), 4.88(m, 1H), 3.05(m, 4H), 2.45(m, 4H), 2.22(s, 3H), 1.69(s, 3H), 1.68(s, 3H)ppm。HRMS (ESI) m/z [M-H]- calcd for C24H29N9: 443.2546, found: 442.2538………..Leukemia (2012), 26(8)

PATENT

Synthetic route is as follows:

Example reaction is as follows:
8

str1
Preparation of chloro-4-amino-5-nitro pyrimidine of Example 12-
Was added dropwise 2,4-dichloro-5-nitro-pyrimidine (lO Aqueous ammonia (8.0ml) and Ν, Ν- diisopropylethylamine (13.2ml) was dissolved in 150ml dichloromethane, 0 ° C when .Og) in dichloromethane (30ml) solution, after dropwise, maintaining the temperature of the reaction one hour, the precipitate was filtered off, the filter cake was recrystallized to give a yellow solid 8.1g, yield 90.1%
Product 1HNMR (400MHz, DMSO-i¾): δ 9.20 (s, 1H), 9.02 (s, 1H), 8.60 (s, lH) ppm
Preparation of pyrimidine
Isopropylamine (4.5ml) and Ν, Ν- diisopropylethylamine (13.2ml) was dissolved in 150ml of dichloromethane, was added dropwise 2,4-dichloro-5-nitro-pyrimidine at 0 ° C ( lO.Og) in dichloromethane (30ml) solution, after dropwise, maintaining the reaction temperature for half an hour, and purified by column chromatography to give a light yellow solid was 10.1g, 90.4% yield of product 1H NMR (400 MHz, CDCl 3 ): [delta] 9.03 (s, 1H), 8.24 (s, 1H), 4.53 (m, 1H), 1.34 (d, J = 6.8 Hz, 6H) ppm 0

Example 16, 4-amino-2- (4- (4-methyl-piperazin-1-yl) anilino) -5-nitro-pyrimidin embodiment
4- (4-methylpiperazine) aniline (3.8g) was added to the compound 2-l (3.5g) in n-butanol (150ml) solution, the reaction for 4.5 hours at 90 ° C, cooled to room temperature, filtered , washed, and dried to give a red solid (5.2g), a yield of 79.5%. Product ‘H NMR (400 MHz, CDCl 3 ): [delta] 9.07 (s, 1H), 8.52 (s, 2H), 8.40 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.10 (m, 2H), 3.3 l (t, J = 4.8Hz, 4H), 2.81 (t, J = 4.8Hz, 4H), 2.30 (s, 3H) ppm.
Example 90,
9-isopropyl-2- (4- (4-methyl-piperazin-1-yl) anilino) -8- (pyridin-3-yl) -9H- purine
The compound 5- 7 (2.05g) was dissolved in dichloromethane (90ml), were added sequentially EDCI (2.3g), Ν, Ν- diisopropylethylamine (4.9ml), 3- pyridyl isothiocyanate ester (1.0g), stirred at room temperature for half an hour, then refluxed for 10 hours, TLC monitoring completion of the reaction the raw material 5-7 was cooled and purified by column chromatography to give a light red solid, yield 65.7%.
Product ESI-MS (m / z,%) 442.26 (MH) -. Ή NMR (400 MHz, DMSO-d 6 ): [delta] 9.38 (s, IH), 9.13 (s, IH), 8.99 (s, IH), 8.40 (s, IH), 8.36 (d, J = 8.4 Hz, IH), 8.20 (d, J = 4.4Hz, IH), 7.70 (d, J = 8.8Hz, 2H), 7.37 (m, IH), 6.96 (d, J = 8.8Hz, 2H), 4.97-4.92 ( m, IH), 3.35 (s, 6H), 2.80 (s, 3H): 2.53 (s, 2H), 1.69 (s, 6H) ppm.
/////////SKLB 1028, IND Filed, Preclinical
CN1CCN(CC1)c5ccc(Nc3nc4n(C(C)C)c(Nc2cccnc2)nc4cn3)cc5

Saturday, 9 January 2016

Vibegron, MK-4618 for for the treatment of overactive bladder



Chemical structure for Vibegron (USAN)
 
Vibegron, MK-4618, KRP114V
UNII-M5TSE03W5U; M5TSE03W5U; D10433
Molecular Formula: C26H28N4O3   Molecular Weight: 444.52552
phase 2 for the treatment of overactive bladder
 (6S)-N-[4-([(2S,5R)-5-[(R)-Hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide
(6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide
Target-based Actions Beta 3 adrenoceptor agonist
Indications Overactive bladder; Urinary incontinence
Kyorin Pharmaceutical, under license from Merck, is developing vibegron (phase II, September 2014) for the treating of overactive bladder. In July 2014, Merck has granted to Kyorin an exclusive license to develop, manufacture and commercialize vibegron in Japan.
MK-4618 is being developed in phase II clinical trials at Merck & Co. for the treatment of overactive bladder. The company had been developing the compound for the treatment of endocrine disorders and hypertension; however, recent progress reports are not available at present.
In 2014, Merck licensed the product to Kyorin for development and commercialization in Japan.
The function of the lower urinary tract is to store and periodically release urine. This requires the orchestration of storage and micturition reflexes which involve a variety of afferent and efferent neural pathways, leading to modulation of central and peripheral neuroeffector mechanisms, and resultant coordinated regulation of sympathetic and parasympathetic components of the autonomic nervous system as well as somatic motor pathways. These proximally regulate the contractile state of bladder (detrusor) and urethral smooth muscle, and urethral sphincter striated muscle.
β Adrenergic receptors (βAR) are present in detrusor smooth muscle of various species, including human, rat, guinea pig, rabbit, ferret, dog, cat, pig and non-human primate. However, pharmacological studies indicate there are marked species differences in the receptor subtypes mediating relaxation of the isolated detrusor; β1AR predominate in cats and guinea pig, β2AR predominate in rabbit, and β3AR contribute or predominate in dog, rat, ferret, pig, cynomolgus and human detrusor. Expression of βAR subtypes in the human and rat detrusor has been examined by a variety of techniques, and the presence of β3AR was confirmed using in situ hybridization and/or reverse transcription-polymerase chain reaction (RT-PCR). Real time quantitative PCR analyses of β1AR, β2AR and β3AR mRNAs in bladder tissue from patients undergoing radical cystectomy revealed a preponderance of β3AR mRNA (97%, cf 1.5% for β1AR mRNA and 1.4% for β2AR mRNA). Moreover, β3AR mRNA expression was equivalent in control and obstructed human bladders. These data suggest that bladder outlet obstruction does not result in downregulation of β3AR, or in alteration of β3AR-mediated detrusor relaxation. β3AR responsiveness also has been compared in bladder strips obtained during cystectomy or enterocystoplasty from patients judged to have normal bladder function, and from patients with detrusor hyporeflexia or hyperreflexia. No differences in the extent or potency of β3AR agonist mediated relaxation were observed, consistent with the concept that the β3AR activation is an effective way of relaxing the detrusor in normal and pathogenic states.
Functional evidence in support of an important role for the β3AR in urine storage emanates from studies in vivo. Following intravenous administration to rats, the rodent selective β3AR agonist CL316243 reduces bladder pressure and in cystomeric studies increases bladder capacity leading to prolongation of micturition interval without increasing residual urine volume.
Overactive bladder is characterized by the symptoms of urinary urgency, with or without urgency urinary incontinence, usually associated with frequency and nocturia. The prevalence of OAB in the United States and Europe has been estimated at 16 to 17% in both women and men over the age of 18 years. Overactive bladder is most often classified as idiopathic, but can also be secondary to neurological condition, bladder outlet obstruction, and other causes. From a pathophysiologic perspective, the overactive bladder symptom complex, especially when associated with urge incontinence, is suggestive of detrusor overactivity. Urgency with or without incontinence has been shown to negatively impact both social and medical well-being, and represents a significant burden in terms of annual direct and indirect healthcare expenditures. Importantly, current medical therapy for urgency (with or without incontinence) is suboptimal, as many patients either do not demonstrate an adequate response to current treatments, and/or are unable to tolerate current treatments (for example, dry mouth associated with anticholinergic therapy). Therefore, there is need for new, well-tolerated therapies that effectively treat urinary frequency, urgency and incontinence, either as monotherapy or in combination with available therapies. Agents that relax bladder smooth muscle, such as β3AR agonists, are expected to be effective for treating such urinary disorders.

PATENT

http://www.google.com/patents/WO2013062881A1?cl=en
Figure imgf000013_0001
EXAMPLE 3
To a three neck flask equipped with a N2 inlet, a thermo couple probe was charged pyrrolidine i-11 (10.0 g), sodium salt i-12 (7.87 g), followed by IPA (40 mL) and water (24 mL). 5 N HC1 (14.9 mL) was then slowly added over a period of 20 min to adjust pH = 3.3- 3.5, maintaining the batch temperature below 35 °C. Solid EDC hydrochloride (7.47 g) was charged in portions over 30 min. The reaction mixture was aged at RT for additional 0.5 – 1 h, aqueous ammonia (14%) was added dropwise to pH ~8.6. The batch was seeded and aged for additional 1 h to form a slurry bed. The rest aqueous ammonia (14%, 53.2 ml total) was added dropwise over 6 h. The resulting thick slurry was aged 2-3 h before filtration. The wet-cake was displacement washed with 30% IPA (30 mL), followed by 15% IPA (2 x 20mL) and water (2 X 20mL). The cake was suction dried under N2 overnight to afford 14.3 g of compound of Formula (I)-
1H NMR (DMSO) δ 10.40 (s, NH), 7.92 (d, J = 6.8, 1H), 7.50 (m, 2H), 7.32 (m, 2H), 7.29 (m, 2H), 7.21 (m, 1H), 7.16 (m, 2H), 6.24 (d, J = 6.8, 1H), 5.13 (dd, J = 9.6, 3.1, 1H), 5.08 (br s, OH), 4.22 (d, J = 7.2, 1H), 3.19 (p, J = 7.0, 1H), 3.16-3.01 (m, 3H), 2.65 (m, 1H), 2.59-2.49 (m, 2H), 2.45 (br s, NH), 2.16 (ddt, J = 13.0, 9.6, 3.1, 1H), 1.58 (m, 1H), 1.39 (m, 1H), 1.31-1.24 (m, 2H).
13C NMR (DMSO) δ 167.52, 165.85, 159.83, 154.56, 144.19, 136.48, 135.66, 129.16, 127.71, 126.78, 126.62, 119.07, 112.00, 76.71, 64.34, 61.05, 59.60, 42.22, 31.26, 30.12, 27.09, 23.82.
HPLC method – For monitoring conversion
Column: XBridge C18 cm 15 cm x 4.6 mm, 3.5 μιη particle size;
Column Temp. : 35 °C; Flow rate: 1.5 mL/min; Detection: 220 nm;
Mobile phase: A. 5 mM Na2B407.10 H20 B: Acetonitrile
Gradient:
HPLC method – For level of amide epimer detection
Column: Chiralpak AD-H 5 μηι, 250 mm x 4.6 mm.
Column Temp: 35 °C; Flow rate: 1.0 mL/min; Detection: 250 nm;
Mobile phase: Isocratic 30% Ethanol in hexanes + 0.1% isobutylamine

PATENT

WO 2009124167
http://www.google.com/patents/WO2009124167A1?cl=en

EXAMPLE 103
(6y)-N-r4-({(25′. 5R)-5-r(R)-hvdroxy(phenvnmethyl1pyrrolidin-2-yl}methvnphenyl1-4-oxo- 4,6J,8-tetrahydropyiτolori,2-α1pyrimidine-6-carboxamide
ter?-butyl(2R. 55f)-2-rCR)-hvdroxy(phenvnmethyl1-5-r4-({r(65f)-4-oxo-4.6.7.8-
tetrahydropyrrolof 1.2-alpyrimidin-6- yl]carbonyl} amino)benzyl]pyrrolidine- 1 – carboxylate
To a solution of i-13a (21.4 g, 55.9 mmol) in N,N-dimethylformamide (100 ml) at O0C was added [(65)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-α]pyrimidine-6-carboxylic acid (11.1 g, 61.5 mmol), followed by 1 -hydroxybenzotriazole (i-44, 7.55 g, 55.9 mmol), N-(3- dimethylaminopropyl)-Nl-ethylcarbodiimide hydrochloride (16.1 g, 84.0 mmol) and N,N- diisopropylethylamine (29.2 ml, 168 mmol). The reaction mixture was stirred from O0C to ambient temperature for 2 h. Water (600 ml) was added and it was extracted with dichloromethane (600 ml x 2). The combined organic layers were dried over Na2SO4. After removal of the volatiles, the residue was purified by using a Biotage Horizon® system (0-5% then 5% methanol with 10% ammonia/dichloromethane mixture) to afford the title compound which contained 8% of the minor diastereomer. It was further purified by supercritical fluid chromatography (chiral AS column, 40% methanol) to afford the title compound as a pale yellow solid (22.0 g, 72%). 1H NMR (CDCl3): δ 9.61 (s, IH), 7.93 (d, J = 6.6 Hz, IH), 7.49 (d, J = 8.4 Hz, 2H), 7.35-7.28 (m, 5H), 7.13 (d, J = 8.5 Hz, 2H), 6.40 (d, J = 6.7 Hz, IH), 5.36 (d, J = 8.6 Hz, IH), 4.38 (m, IH), 4.12-4.04 (m, 2H), 3.46 (m,lH), 3.15-3.06 (m, 2H), 2.91 (dd, J = 13.1, 9.0 Hz, IH), 2.55 (m, IH), 2.38 (m, IH), 1.71-1.49 (m, 13H). LC-MS 567.4 (M+23).
(6S)-N-\4-( U2S. 5R)-5-r(R)-hvdroxy(phenyl)methyl1pyrrolidin-2-
yl}methyl)phenyl1-4-oxo-4,6J,8-tetrahvdropyrrolori,2-α1pyrimidine-6- carboxamide
To a solution of the intermediate from Step A (2.50 g, 4.59 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 1.5 h. After removal of the volatiles, saturated NaHCCh was added to make the PH value to 8-9. The mixture was then extracted with dichloromethane. The combined organic layers were dried over Na2SO4. After concentration, crystallization from methanol/acetonitrile afforded the title compound as a white solid (1.23g, 60%). 1H NMR (DMSO-Cl6): δ 10.40 (s, IH), 7.91 (d, J = 6.7 Hz, IH), 7.49 (d, J = 8.3 Hz, 2H), 7.32-7.26 (m, 4H), 7.21 (m, IH), 7.15 (d, J = 8.4 Hz, 2H), 6.23 (d, J = 6.7 Hz, IH), 5.11 (dd, J = 9.6, 2.9 Hz, IH), 5.10 (br, IH), 4.21 (d, J = 7.1 Hz, IH), 3.20-3.00 (m, 4H), 2.66-2.51 (m, 3H), 2.16 (m, IH), 1.57 (m, IH), 1.38 (m, IH), 1.29-1.23 (m, 2H). LC-MS 445.3 (M+l).
Using the Biological Assays described above, the human β3 functional activity of Example 103 was determined to be between 11 to 100 nM.

PATENT

CHECK STRUCTURE…………….CAUTION

http://www.google.com/patents/US8247415
Figure US08247415-20120821-C00547

Figure US08247415-20120821-C00015

CAUTION…………….

Example 103(6S)-N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxamide
Step A: tert-butyl(2R,5S)-2-[(R)-hydroxy(phenyl)methyl]-5-[4-({[(6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidin-6-yl]carbonyl}amino)benzyl]pyrrolidine-1-carboxylate
To a solution of i-13a (21.4 g, 55.9 mmol) in N,N-dimethylformamide (100 ml) at 0° C. was added [(6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxylic acid (11.1 g, 61.5 mmol), followed by 1-hydroxybenzotriazole (i-44, 7.55 g, 55.9 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (16.1 g, 84.0 mmol) and N,N-diisopropylethylamine (29.2 ml, 168 mmol). The reaction mixture was stirred from 0° C. to ambient temperature for 2 h. Water (600 ml) was added and it was extracted with dichloromethane (600 ml×2). The combined organic layers were dried over Na2SO4. After removal of the volatiles, the residue was purified by using a Biotage Horizon® system (0-5% then 5% methanol with 10% ammonia/dichloromethane mixture) to afford the title compound which contained 8% of the minor diastereomer. It was further purified by supercritical fluid chromatography (chiral AS column, 40% methanol) to afford the title compound as a pale yellow solid (22.0 g, 72%). 1H NMR (CDCl3): δ 9.61 (s, 1H), 7.93 (d, J=6.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.35-7.28 (m, 5H), 7.13 (d, J=8.5 Hz, 2H), 6.40 (d, J=6.7 Hz, 1H), 5.36 (d, J=8.6 Hz, 1H), 4.38 (m, 1H), 4.12-4.04 (m, 2H), 3.46 (m, 1H), 3.15-3.06 (m, 2H), 2.91 (dd, J=13.1, 9.0 Hz, 1H), 2.55 (m, 1H), 2.38 (m, 1H), 1.71-1.49 (m, 13H). LC-MS 567.4 (M+23).
Step B: (6S)-N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxamide
To a solution of the intermediate from Step A (2.50 g, 4.59 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 1.5 h. After removal of the volatiles, saturated NaHCO3 was added to make the PH value to 8-9. The mixture was then extracted with dichloromethane. The combined organic layers were dried over Na2SO4. After concentration, crystallization from methanol/acetonitrile afforded the title compound as a white solid (1.23 g, 60%). 1H NMR (DMSO-d6): δ 10.40 (s, 1H), 7.91 (d, J=6.7 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.32-7.26 (m, 4H), 7.21 (m, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.23 (d, J=6.7 Hz, 1H), 5.11 (dd, J=9.6, 2.9 Hz, 1H), 5.10 (br, 1H), 4.21 (d, J=7.1 Hz, 1H), 3.20-3.00 (m, 4H), 2.66-2.51 (m, 3H), 2.16 (m, 1H), 1.57 (m, 1H), 1.38 (m, 1H), 1.29-1.23 (m, 2H). LC-MS 445.3 (M+1).
Using the Biological Assays described above, the human β3 functional activity of Example 103 was determined to be between 11 to 100 nM.

PATENT

WO2014150639
http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014150639&recNum=4&docAn=US2014023858&queryString=EN_ALL:nmr%20AND%20PA:merck&maxRec=11148
Step 6. Preparation of Compound 1-7 from Compound 1-6 and Compound A-2

To a three neck flask equipped with a N2 inlet, a thermo couple probe was charged pyrrolidine hemihydrate 1-6 (10.3 g), sodium salt A-2 (7.87 g), followed by IPA (40 mL) and water (24 mL). 5 N HC1 (14.9 mL) was then slowly added over a period of 20 minutes to adjust pH = 3.3-3.5, maintaining the batch temperature below 35°C. Solid EDC hydrochloride (7.47 g) was charged in portions over 30 minutes. The reaction mixture was aged at RT for additional 0.5 – 1 hour, aqueous ammonia (14%) was added dropwise to pH -8.6. The batch was seeded and aged for additional 1 hour to form a slurry bed. The rest aqueous ammonia (14%, 53.2 ml total) was added dropwise over 6 hours. The resulting thick slurry was aged 2-3 hours before filtration. The wet-cake was displacement washed with 30% IPA (30 mL), followed by 15% IPA (2 x 20mL) and water (2 X 20mL). The cake was suction dried under N2 overnight to afford 14.3 g of compound 1-7.
1H NMR (DMSO) δ 10.40 (s, NH), 7.92 (d, J = 6.8, 1H), 7.50 (m, 2H), 7.32 (m, 2H), 7.29 (m, 2H), 7.21 (m, 1H), 7.16 (m, 2H), 6.24 (d, J = 6.8, 1H), 5.13 (dd, J = 9.6, 3.1, 1H), 5.08 (br s, OH), 4.22 (d, J = 7.2, 1H), 3.19 (p, J = 7.0, 1H), 3.16-3.01 (m, 3H), 2.65 (m, 1H), 2.59-2.49 (m, 2H), 2.45 (br s, NH), 2.16 (ddt, J = 13.0, 9.6, 3.1, 1H), 1.58 (m, 1H), 1.39 (m, 1H), 1.31-1.24 (m, 2H).
13C NMR (DMSO) δ 167.52, 165.85, 159.83, 154.56, 144.19, 136.48, 135.66, 129.16, 127.71, 126.78, 126.62, 119.07, 112.00, 76.71, 64.34, 61.05, 59.60, 42.22, 31.26, 30.12, 27.09, 23.82.
The crystalline freebase anhydrous form I of Compound 1-7 can be characterized by XRPD by



PATENT

WO-2014150633
Merck Sharp & Dohme Corp
Process for preparing stable immobilized ketoreductase comprises bonding of recombinant ketoreductase to the resin in a solvent. Useful for synthesis of vibegron intermediates. For a concurrent filling see WO2014150639, claiming the method for immobilization of ketoreductase. Picks up from WO2013062881, claiming the non enzymatic synthesis of vibegron and intermediates.

PAPER

Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder

Merck Research Laboratories, 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.5b01372
Publication Date (Web): December 27, 2015
Copyright © 2015 American Chemical Society
*Telephone: (908) 740-0287. E-mail scott.edmondson@merck.com.
http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01372
http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01372/suppl_file/jm5b01372_si_001.pdf

Abstract Image
The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure–activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.


SYNTHESIS








Reference
1
H.P. Kaiser, et al., “Catalytic Hydrogenation of Pyrroles at Atmospheric Pressure“, J. Org. Chem., vol. 49, No. 22, p. 4203-4209 (1984).
A study of the efficacy and safety of MK-4618 in patients with overactive bladder (OAB) (MK-4618-008 EXT1) (NCT01314872)
ClinicalTrials.gov Web Site 2011, April 28

WO2011043942A1 * Sep 27, 2010 Apr 14, 2011 Merck Sharp & Dohme Corp. Combination therapy using a beta 3 adrenergic receptor agonist and an antimuscarinic agent
US20090253705 * Apr 2, 2009 Oct 8, 2009 Richard Berger Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
US20110028481 * Apr 2, 2009 Feb 3, 2011 Richard Berger Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
Citing Patent Filing date Publication date Applicant Title
US8642661 Aug 2, 2011 Feb 4, 2014 Altherx, Inc. Pharmaceutical combinations of beta-3 adrenergic receptor agonists and muscarinic receptor antagonists
US8653260 Jun 20, 2012 Feb 18, 2014 Merck Sharp & Dohme Corp. Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
US20120202819 * Sep 27, 2010 Aug 9, 2012 Merck Sharp & Dohme Corporation Combination therapy using a beta 3 adrenergic receptor agonists and an antimuscarinic agent
US20020028835 Jul 12, 2001 Mar 7, 2002 Baihua Hu Cyclic amine phenyl beta-3 adrenergic receptor agonists
US20070185136 Feb 2, 2007 Aug 9, 2007 Sanofi-Aventis Sulphonamide derivatives, their preparation and their therapeutic application
US20110028481 Apr 2, 2009 Feb 3, 2011 Richard Berger Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
WO2003072572A1 Feb 17, 2003 Sep 4, 2003 Jennifer Anne Lafontaine Beta3-adrenergic receptor agonists



8-22-2012
Hydroxymethyl pyrrolidines as [beta]3 adrenergic receptor agonists


////////////C1CC(NC1CC2=CC=C(C=C2)NC(=O)C3CCC4=NC=CC(=O)N34)C(C5=CC=CC=C5)O

Thursday, 7 January 2016

MS-209, Dofequidar fumarate,

Dofequidar fumarate
Dofequidar fumarate
Phase III
A P-glycoprotein inhibitor potentially for the treatment of breast cancer and non-small lung cancer (NSCLC).
MS-209; Dofequidar fumarate
CAS No. 129716-58-1 (Dofequidar FREE )
CAS No 153653-30-6 (Dofequidar fumarate 1;1)…..C34H35N3O7, 597.66
5-[3-[4-(2,2-Diphenylacetyl)piperazin-1-yl]-2-hydroxypropoxy]quinoline sesquifumarate
1-[4-(2,2-Diphenylacetyl)piperazin-1-yl]-3-(quinoliln-5-yloxy)-2-propanol sesquifumarate
1-(Diphenylacetyl)-4-[(2RS)-2-hydroxy-3-(5-quinolyloxy)propyl]piperazine sesquifumarate
CAS Number 158681-49-3,  C30H31N3O3 · 1.5 C4H4O4, Molecular Weight 655.69
4-(Diphenylacetyl)-a-[(5-quinolinyloxy)methyl]-1-Piperazineethanol (E)-2-butenedioate fumarate (1:1.5), C30 H31 N3 O3 . 3/2 C4 H4 O4
1-​Piperazineethanol, 4-​(diphenylacetyl)​-​α-​[(5-​quinolinyloxy)​methyl]​-​, (E)​-​2-​butenedioate (2:3)
1-​Piperazineethanol, 4-​(diphenylacetyl)​-​α-​[(5-​quinolinyloxy)​methyl]​-​, (E)​-​2-​butenedioate (2:3)

Figure
Dofequidar fumarate(MS-209 fumarate), an orally active quinoline compound, has been reported to overcome MDR by inhibiting ABCB1/P-gp, ABCC1/MDR-associated protein 1, or both.
Dofequidar fumarate(MS-209 fumarate), an orally active quinoline compound, has been reported to overcome MDR by inhibitingABCB1/P-gp, ABCC1/MDR-associated protein 1, or both.
IC50 value:
Target: P-gp
in vitro: MS-209 at 3 microM effectively overcame docetaxel resistance in MDR cancer cells, and this concentration was achieved in blood plasma for > 7 h without serious toxicity [1]. MS-209 restored chemosensitivity of SBC-3 / ADM cells to VP-16, ADM, and VCR in a dose-dependent manner in vitro [2]. dofequidar inhibits the efflux of chemotherapeutic drugs and increases the sensitivity to anticancer drugs in CSC-like side population (SP) cells isolated from various cancer cell lines. Dofequidar treatment greatly reduced the cell number in the SP fraction [3]. In 4-1St cells, which are extremely resistant to ADM and VCR, MS-209 at a concentration of 3 microM enhanced the cytotoxicity of ADM and VCR, 88- and 350-fold, respectively [4].
in vivo: Treatment with docetaxel alone at the maximal tolerated dose (MTD) showed an apparent antitumor activity to an intrinsically resistant HCT-15 tumor xenograft, and MS-209 additionally potentiated the antitumor activity of docetaxel. Against a MCF-7/ADM tumor xenograft expressing larger amounts of P-gp, docetaxel alone at the MTD showed no antitumor activity, whereas the MTD of docetaxel combined with MS-209 greatly reduced MCF-7/ADM tumor growth [1]. Intravenous injection with SBC-3 or SBC-3 / ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell-depleted severe combined immunodeficiency (SCID) mice, though SBC-3 / ADM cells more rapidly produced metastases than did SBC-3 cells. Treatment with VP-16 and ADM reduced metastasis formation by SBC-3 cells, whereas the same treatment did not affect metastasis by SBC-3 / ADM cells. Although MS-209 alone had no effect on metastasis by SBC-3 or SBC-3 / ADM cells, combined use of MS-209 with VP-16 or ADM resulted in marked inhibition of metastasis formation by SBC-3 / ADM cells to multiple organs [2].
Dofequidar fumarate is a multidrug resistance (MDR)-reversing quinoline derivative that interacts directly with P-glycoprotein and inhibits the efflux of antitumor agents. The agent had been in phase III clinical development by Nihon Schering (now Bayer) for the treatment of advanced and recurrent breast cancer and non-small lung cancer (NSCLC) and at the National Cancer Institute in combination with docetaxel for the treatment of solid tumors. In 2000, Schering AG obtained dofequidar fumarate when Nihon Schering acquired Mitsui Pharmaceuticals, originator of the compound.

PAPER

Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer
J Med Chem 1997, 40(13): 2047
5-[3-{4-(2,2-Diphenylacetyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline 1.5Fumarate (16, MS-209)
free form of 16 (7.37 g, 70%):  mp 161−162 °C; 1H-NMR (CDCl3) δ 2.2−2.8 (m, 6 H), 3.5−3.6 (m, 2H), 3.7−3.9 (m, 2H), 4.1−4.3 (m, 3H), 5.20 (s, 1H), 6.86 (d, 1H,J = 7.3 Hz), 7.2−7.4 (m, 11H), 7.59 (t, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 8.1 Hz), 8.54 (d, 1H, J = 7.3 Hz), 8.91 (dd, 1H, J = 2, 4 Hz); IR (KBr) 2954, 1630, 1587, 1268, 1091, 802, 748, 703 cm-1.
16 1.5Fumarate(1.0 g, 60%):  mp 210 °C dec; 1H-NMR (DMSO-d6) δ 2.2−2.6 (m, 6H), 3.4−3.6 (m, 4H), 4.0−4.2 (m, 3H), 5.53 (s, 1H), 6.63 (s, 3H), 7.03 (d, 1H, J = 8.1 Hz), 7.2−7.4 (m, 10H), 7.5−7.7 (m, 3H), 8.61 (d, 1H, J = 8.1 Hz), 8.89 (dd, 1H, J = 1.5, 4.4 Hz); IR (KBr) 3424, 1644, 1592, 1277, 1180, 1110, 799 cm-1.

Patent

WO 2004099151
A method for producing the purest rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyI] -piperazin-1-yl} -2,2-diphenylethan-1-one fumarate and the purest rac-1 – {4- [2-hydroxy-3- (5-quinoly loxy) propylene l] piperazin-1-yl} -2,2-diphenylethan-1 -one fumarate
The invention relates to a method for producing the purest rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1-one fumarate as well as rac -1- {4- [2- hydroxy-3- (5-quinolyloxy) propyl] piperazin-1-yl} -2,2-diphenylethan-1-one fumarate with a purity of at least 99.55%
The multidrug resistance modulator rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] – piperazin-1-yl} -2,2-diphenylethan-1 -one fumarate, its preparation and use as carcinostatic drug is described as well as other derivatives of this compound in EP 575,890.
According to the process described in EP 575 890 A process for the preparation of pure rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-dϊphenylethan-1-one fumarate is first by coupling the two modules epoxiline (B) (5- (2,3-epoxypropoxy) – quinoline) and Diphenpiperazid (C) (N- (2,2-Diphenylacetyl) piperazine), the free base 5- [3- {4- (2,2-diphenylacetyl) piperazin-1-yl} -2-hydroxypropoxy] quinoline isolated as a crude product. This implementation includes two sub-stages. First, the Epoxylat with hydroxyquinoline (A) is reacted. In the second step the epoxiline (B) (5- (2,3-epoxypropoxy) -quinolin) by Diphenpiperazid (C) (N- (2,2-Diphenylacetyl) piperazine) is opened, it gives the secondary alcohol (D). This reaction takes place in ethanol, water catalyzes the conversion. The workup / isolation is then carried out by precipitation from acetone / water and drying under vacuum at 60 ° C.
The overall reaction results from the following scheme:
Figure imgf000003_0001
On the isolation of the free base, the many impurities (purity of the crude product is typically about 80%), joins in the next step a very expensive cleaning procedures. After charcoal treatment of the free base and the formation of the fumarate in methanol, the free base is again prepared by treatment with dilute sodium hydroxide solution for purification. Subsequently, as the last step, repeated fumarate formation. The two fumarate formations are procedurally identical and differ only in the batch size (T. Suzuki et al., J. Med. Chem. (1997) 40, 2047) (JP 2000281653). Starting from the crude free base, the typical yield for this laboratory cleaning sequence 45% of theory.
A disadvantage of this method is not only the low yield (about 50% loss in the final stage), but also the complex technical implementation, which binds many operational capacities and thus caused increased costs. A particular disadvantage is the extremely poor filterability of the free base, the filter must be dried partially over several weeks.
Despite the high procedural expenses according to this known method, the extremely high purity requirements of rac-1 – {4- [2-hydroxy-3- (5- quinolyloxy) propyl] piperazine-1-yl} -2,2-diphenylethane-1 -one fumarate not always be achieved completely satisfactory.
. Furthermore provides the method described in EP 575 890 any reasonable results during scale-up an overview of the individual reactions are the following scheme:
Figure imgf000004_0001
It has now been found that these known disadvantages can be overcome with the process of this invention. In the process of this invention also the epoxiline (B) and Diphenpiperazid (C) is first coupled by opening of the epoxide. But is not the free base (D) but after the addition of solid fumaric acid directly the fumarate salt (E) is then isolated as a crude product.

The present application thus provides a process for the preparation of pure rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1 -one fumarate , which is characterized in that firstly
a) a Epoxytosylat of structure I
OTs
(0 with
Figure imgf000005_0001

b) 5-hydroxyquinoline (II)

(II) and cesium carbonate in a suitable solvent and at a suitable temperature to 5- (2,3-epoxypropoxy) -quinolin of formula III
Figure imgf000005_0002

allowed to react, and then the 5- (2,3-epoxypropoxy) -quinolin of formula III

c) with N- (2,2-Diphenylacefyl) piperazine of the formula IV
Figure imgf000005_0003

in a suitable solvent and at a suitable temperature followed by the addition of solid fumaric acid to the crude rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] – piperazin-1-yl} -2,2-diphenylethane 1-one fumarate of the formula V

Figure imgf000006_0001
And subsequently reacting (V)
d) the thus formed crude rac-1 – fumarate {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1 -one (V) is isolated and is dissolved in a solvent mixture of methanol and methylene chloride, is treated with activated carbon and subsequently filtered through a pressure filter having silica gel as column material, and the thus obtained pure rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1-one fumarate (V) is crystallized from a suitable alcohol.
Preparation Example
Preparation of rac-1 – 4- [2-Hy droxy-3- (5-quinolyloxy) propylene l] -piperazin-1 -yl> -2,2-diphenylethan-1-one fumarate
A) Under nitrogen, 44.2 g of 5-hydroxy-quinoline and 151.9 g of cesium carbonate with 560 ml acetone will give at room temperature together and stirred for 30 minutes at 60 ° C bath temperature. At 50 ° C internal temperature 73.0 g of 5- (2,3-epoxypropoxy) -quinolin dissolved in
153.3 g of dichloromethane, admit. The mixture is stirred at 50 ° C for two hours.The mixture is filtered at 50 ° C. The filter residue (inorganic salts) is washed with 560 ml of 50 ° C warmed acetone. 85.4 g are then N- (2,2-diphenyl-acetyl) piperazine admit and concentrated at a bath temperature of 40 ° C under vacuum to 374 g final weight. It will then add 374 g of demineralized water and 2
Stirred at 40 ° C hours. Then 255 g of acetone and 201 g of demineralized water will admit. The mixture is cooled to room temperature and 89.1 g of fumaric acid are in solid form to Gege-ben. It is stirred for 60 minutes at 60 ° C bath temperature and then stirred at 0 ° C for 2 hours. The solid is suction filtered and washed with 150 ml of ice-cold methanol. The filter residue is dried at 60 ° C under vacuum.
Yield: 65 – 85% of theory
B) 56.0 g of the thus prepared rac-1 – {4- [2-hydroxy-3- (5-quinolyIoxy) propyl] -piperazin-1-yl} – 2,2-diphenylethan-1-one fumarate were nitrogen and treated at room temperature with 5.6 g of activated carbon, Norit SX plus, 672 ml of methanol and 1008 ml of dichloromethane. The resulting suspension is stirred at a bath temperature of 75 ° C to warm to reflux temperature and refluxed for 30 min. At an internal temperature of 40 ° C is rac-1 – {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethan-1-one fumarate in solution. The mixture is then filtered hot through 300% silica gel and the silica gel with 560 ml of a mixture of 168 ml of methanol and 392 ml of dichloromethane at room temperature RT. The solution is concentrated at a bath temperature of 40 ° C and an initial vacuum of 400 mbar to a final volume of 517 ml. The ultimate vacuum of 350 mbar. The distilled volume is about the difference in volume (about 1, 7 I). There are 404 ml of methanol was added so that a final volume of 921 ml is achieved. The solution is cooled to 0 ° C, whereupon the product precipitates. The resulting suspension is stirred for 2 hours at 0 ° C and then filtered through a paper filter. The filter residue is washed with 56.0 ml of ice-cold methanol. The filter residue is dried at 60 ° C and under vacuum at 100 mbar for 10 hours.
Yield (. Uncorr): 47.29 g (84.45% FS)
Purity: 99.65% (HPLC, 100% method)

References on Dofequidar fumarate

///////////MS-209,  Dofequidar fumarate, PHASE 3

FK-3311



FK-3311
FK 3311; 116686-15-8; FK-3311; N-[4-acetyl-2-(2,4-difluorophenoxy)phenyl]methanesulfonamide; COX-2 Inhibitor V, FK3311; FK3311;
A prostaglandin receptor antagonist potentially for the treatment of rheumatoid arthritis.
cas 116686-15-8
Molecular Formula: C15H13F2NO4S
Molecular Weight: 341.329826 g/mol


This compound has been obtained by two different ways: 1) The oxidation of 4′-amino-3′-chloroacetophenone (I) with NaNO2 and HCl in water gives 3′-chloro-4-nitroacetophenone (II), which is condensed with 2,4-difluorophenol (III) by means of K2CO3 in xylene yielding 3′-(2,4-difluorophenyl)-4′-nitroacetophenone (IV). The reduction of (IV) with Fe and NH4Cl in ethanol affords the corresponding 4′-amino compound (V), which is finally treated with methanesulfonyl chloride and pyridine. 2) The reaction of 4′-aminoacetophenone (VI) with methanesulfonyl chloride as before gives the corresponding sulfonamide (VII), which is brominated with Br2 in acetic acid yielding N-(4-acetyl-3-bromophenyl)methanesulfonamide (VIII). Finally, this compound is condensed with 2,4-difluorophenol (III) by means of K2CO3 and CuCl as before.
Chem Pharm Bull 1992,40(9),2399



1 to 4 of 4

Patent Submitted Granted
METHODS TO TREAT INFECTIONS [US2014329777] 2014-04-22 2014-11-06
NOVEL NIMESULIDE COMPOSITIONS [US2012063996] 2011-07-28 2012-03-15
NANOPARTICULATE MELOXICAM FORMULATIONS [US2014141083] 2013-07-12 2014-05-22
Alkanesulfonanilide derivatives, processes for preparation thereof and pharmaceutical composition comprising the same [US4866091] 1989-09-12
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SEE........http://newdrugapprovals.org/2016/01/06/fk-3311/

Tuesday, 5 January 2016

Fluorofenidone


2(1H)-Pyridinone, 1-(3-fluorophenyl)-5-methyl-.png
Fluorofenidone
1- (3-fluorophenyl) -5-methyl – 2 (1H) pyridone
2(1H)​-​Pyridinone, 1-​(3-​fluorophenyl)​-​5-​methyl-
1- (3_ fluorophenyl) -5_ methylpyridine _2 (IH) – one
C12 H10 F N O, 203.2123
PRECLINICAL, IND Filing
An anti-inflammatory agent potentially for the treatment of organ fibrosis.

CAS No. 848353-85-5
Synthesis
str1

PATENT

WO 2006108354

PATENT

(Compound 1)
A. (3_ fluorophenyl) methyl pyridine _2 (IH) 1- -5_ – -one
9. 6gDMF, 45 0g (0 2mol.) Inter-fluoro-iodobenzene, 21 8g (0. 2mol) 5_ methylpyridine _2_ (IH) -.. -one, 28g of anhydrous potassium carbonate and 1. Og copper powder, 160 ° -170 °, the reaction was stirred at reflux for 20 hours, the natural cooling to 110~120 ° C, was slowly added to about 330ml 80~90 ° C hot water, cooled to 20 ° C. Suction filtered, the filter cake was washed with about 20ml of water, remove the cake, with about 300ml of ethyl acetate ultrasound 30min, suction filtered, the filter residue was washed with 20ml of ethyl acetate. The combined ethyl acetate, washed with water three times (50ml * 3), and the filtrate layers were separated and allowed to stand for 15min, ethyl acetate fraction was concentrated to a non-steamed, hot added under stirring for about 85ml of petroleum ether, cooling to 15~20 ° C insulation ~ 1.5 hours. Filtration, the filter cake was washed twice with petroleum ether (about 20ml * 2) used to give 34. 9g crude. Recrystallized from 20% ethanol to give the product 1- (3_ fluorophenyl) -5_ methylpyridine _2 (IH) – one as a white solid # 30. Ig0 Μ P.: 132 · 1 ~133 7 °.. C.
PATENT
http://www.google.co.in/patents/WO2009149188A1?cl=zh-CN

PATENT
CN 102241625
http://www.google.com/patents/CN102241625A?cl=zh
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009111947

PAPER

.
CN1386737A * Jun 11, 2002 Dec 25, 2002 中南大学湘雅医学院 Antifibrosis pyridinone medicine and its prepaing process
CN1846699A Apr 13, 2005 Oct 18, 2006 中南大学湘雅医院 Application of 1-(substituted phenyl)-5-methyl-2-(1H)-pyridone compound in preparing medicine for anti-other organifibrosis and tissue fibrosis except renal interstitial fibrosis
CN101235013A* Mar 10, 2008 Aug 6, 2008 广东东阳光药业有限公司;张中能 Crystallized 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridine and its preparation method composition and application
US20070203203 May 1, 2007 Aug 30, 2007 Tao Li J Composition and Method for Treating Fibrotic Diseases

Patent Submitted Granted
COMPOUNDS AND METHODS FOR TREATING INFLAMMATORY AND FIBROTIC DISORDERS [US2009318455] 2009-12-24
COMPOSITION AND METHOD FOR TREATING PROTEINURIA [US2010099719] 2010-04-22
COMPOSITION AND METHOD FOR TREATING FIBROTIC DISEASES [US2009258911] 2009-10-15
Composition and Method for Treating Fibrotic Diseases [US2008319027] 2008-12-25
METHODS FOR TREATING ACUTE MYOCARDIAL INFARCTIONS AND ASSOCIATED DISORDERS [US2010190731] 2010-07-29
Methods for Treating Acute Myocardial Infarctions and Associated Disorders [US2011218515] 2011-09-08
METHODS OF TREATING HIV PATIENTS WITH ANTI-FIBROTICS [US2012014917] 2012-01-19
Composition and Method for Treating Fibrotic Diseases Composition and Method for Treating Fibrotic Diseases [US2009005424] 2007-08-30
Crystalline 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridone, the preparation methods, compositions and applications thereof [US8232408] 2009-03-10 2012-07-31
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