ASUNAPREVIR

ASUNAPREVIR
630420-16-5 CAS

THERAPEUTIC CLAIM Treatment of hepatitis C
CHEMICAL NAMES
1. Cyclopropanecarboxamide, N-[(1,1-dimethylethoxy)carbonyl]-3-methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxy-1-isoquinolinyl)oxy]-L-prolyl-1-amino-N-(cyclopropylsulfonyl)-2-ethenyl-, (1R,2S)-
2. 1,1-dimethylethyl [(1S)-1-{[(2S,4R)-4-(7-chloro-4methoxyisoquinolin-1-yloxy)-2-({(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)pyrrolidin-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate
MOLECULAR FORMULA C35H46ClN5O9S
MOLECULAR WEIGHT 748.3
SPONSOR Bristol-Myers Squibb
CODE DESIGNATION ...........BMS-650032
CAS REGISTRY NUMBER 630420-16-5


Asunaprevir (formerly BMS-650032) is an experimental drug candidate for the treatment of hepatitis C. It is undergoing development by Bristol-Myers Squibb and is currently inPhase III clinical trials.^[1]
In 2013, the company Bristol-Myers Squibb received breakthrough therapy designation in the U.S. for the treatment of chronic hepatitis C in combination with daclatasvir and BMS-791325.
Asunaprevir is an inhibitor of the hepatitis C virus enzyme serine protease NS3.^[2]
Asunaprevir is being tested in combination with pegylated interferon and ribavirin, as well as in interferon-free regimens with other direct-acting antiviral agents includingdaclatasvir^[3][4][5]
Asunaprevir is an antiviral agent originated by Bristol-Myers Squibb undergoing the registration in Japan for the treatment of chronic hepatitis C virus infection in combination with daclatasvir in patients who are non-responsive to interferon plus ribavirin and interferon based therapy ineligible naive/intolerant

1. "A Phase 3 Study in Combination With BMS-790052 and BMS-650032 in Japanese Hepatitis C Virus (HCV) Patients". ClinicalTrials.gov.
2. C. Reviriego (2012). Drugs of the Future 37 (4): 247–254.doi:10.1358/dof.2012.37.4.1789350.
3.  Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. Lok, A et al. New England Journal of Medicine. 366(3):216-224. January 19, 2012.
4.  "Bristol-Myers' Daclatasvir, Asunaprevir Cured 77%: Study". Bloomberg. Apr 19, 2012.
5. AASLD: Daclatasvir plus Asunaprevir Rapidly Suppresses HCV in Prior Null Responders. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
6. Bioorganic and Medicinal Chemistry Letters, 2011 ,  vol. 21,   7  pg. 2048 - 2054

patents
WO 2003099274, WO 2003099274, WO 2009085659

US8202996	6-20-2012	Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N- ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide
US8163921	4-25-2012	Hepatitis C Virus Inhibitors
US7915291	3-30-2011	HEPATITIS C VIRUS INHIBITORS
US7449479	11-12-2008	Hepatitis C virus inhibitors
US6995174	2-8-2006	Hepatitis C virus inhibitors

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Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated 170 million persons worldwide—roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.
Presently, the most effective HCV therapy employs a combination of alpha-interferon and ribavirin, leading to sustained efficacy in 40 percent of patients. Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy. However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Thus, there is a clear and unmet need to develop effective therapeutics for treatment of HCV infection.


http://www.google.com/patents/US8338606
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https://www.google.co.in/patents/WO2003099274A1?dq=WO+2003099274&ei=fje5Us3WBo3JrQfcsoHgAw&cl=en

Compound 277

Compound 277 was prepared by following Scheme 2 of Example 269 except that 3- (4-chloro-phenyl)-3-methoxy-acrylic acid was used in place of 2- trifluormethoxycinnamic acid in step 1.

Step 1:

Modifications: 4.24 g 3-(4-chloro-phenyl)-3-methoxy-acrylic acid used, 130 mg product obtained (3% yield) Product:

Data: 1H NMR(400 MHz, CD₃OD) δ ppm 3.96 (s, 3 H), 7.19 (dd, 7=8.80, 2.45 Hz, 1 H), 7.28 (d, 7=2.45 Hz, 1 H), 7.34 (s, 1 H), 8.25 (d, 7=9.05 Hz, 1 H); MS: (M+H)⁺ 210.

Step 2:

Modifications: 105 mg 7-chloro-4-methoxy-2H-isoquinolin-l-one used, 60 mg product obtained (71% yield). Product:

Data: Η NMR (400 Hz, CDC1₃) δ ppm 4.05 (s, 3 H), 7.67 (dd, 7=8.80, 1.96 Hz, 1 H), 7.80 (s, 1 H), 8.16 (d, 7=9.05 Hz, 1 H), 8.24 (d, 7=1.96 Hz, 1 H); MS: (M+H)⁺ 229.

Step 3:

Modifications: 46 mg l,7-dichloro-4-methoxy-isoquinoline and 113 mg { l-[2-(l- cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy- pyrrolidine-1 -carbon yl]-2,2-dimethyl-propyl} -carbamic acid tert-butyl ester used, 50 mg product obtained (31% yield). Product:

Compound 277

Data: 1H NMR (400 Hz, CD₃OD) δ ppm 1.06 (m, 11 H), 1.16 (s, 9 H), 1.24 (m, 2 H), 1.44 (dd, 7=9.54, 5.38 Hz, 1 H), 1.88 (dd, 7=8.07, 5.62 Hz, 1 H), 2.28 (m, 2 H), 2.59 (dd, 7=13.69, 6.85 Hz, 1 H), 2.94 (m, 1 H), 4.00 (s, 3 H), 4.05 (d, 7=11.74 Hz, 1 H), 4.19 (s, 1 H), 4.43 (d, 7=11.49 Hz, 1 H), 4.56 (dd, 7=10.03, 6.85 Hz, 1 H), 5.12 (d, 7=11.49 Hz, 1 H), 5.30 (d, 7=17.12 Hz, 1 H), 5.76 (m, 2 H), 7.57 (s, 1 H), 7.67 (d, 7=8.56 Hz, 1 H), 8.04 (s, 1 H), 8.08 (d, 7=8.80 Hz, 1 H); MS: (M+H)⁺ 749.

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https://www.google.co.in/patents/US6995174?dq=WO+2003099274&ei=1DW5Uoa0C4GTrgfy84HgBQ&cl=en





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WO 2003099274


https://www.google.co.in/patents/US6995174?dq=WO+2003099274&ei=fje5Us3WBo3JrQfcsoHgAw&cl=en
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https://www.google.co.in/patents/US20090202476?dq=WO+2009085659&ei=dzy5UpL_LMXXrQewxYG4Dw&cl=en





Preparation of Compound C

DMSO (264 ml) was added to a mixture of Compound A (6 g, 26.31 mmol, 1.0 eq, 96.5% potency), Compound B (6.696 g, 28.96 mmol, 1.1 eq) and KOtBu (8.856 g, 78.92 mmol, 3 eq) under nitrogen and stirred at 36° C. for 1 h. After cooling the dark solution to 16° C., it was treated with water (66 ml) and EtOAc (132 ml). The resulting biphasic mixture was acidified to pH 4.82 with 1N HCl (54 ml) at 11.2-14.6° C. The phases were separated. The aqueous phase was extracted once with EtOAc (132 ml). The organic phases were combined and washed with 25% brine (2×132 ml). Rich organic phase (228 ml) was distilled at 30-40° C./50 mbar to 37.2 ml. A fresh EtOAc (37.2 ml) was added and distilled out to 37.2 ml at 30-35° C./50 nm bar. After heating the final EtOAc solution (37.2 ml) to 50° C., heptane ((37.2 ml) was added at 46-51° C. and cooled to 22.5° C. over 2 h. It was seeded with 49 mg of Compound C and held at 23° C. for 15 min to develop a thin slurry. It was cooled to 0.5° C. in 30 min and kept at 0.2-0.5° C. for 3 h. After the filtration, the cake was washed with heptane (16.7 ml) and dried at 47° C./80 mm/15.5 h to give Compound C as beige colored solids (6.3717 g, 58.9% corrected yield, 99.2% potency, 97.4 AP).

Preparation of Compound E

DIPEA (2.15 ml, 12.3 mmol, 1.3 eq followed by EDAC (2 g, 10.4 mmol, 1.1 eq) were added to a mixture of Compound C (4 g, 9.46 mmol, 97.4% potency, 98.5 AP), Compound D (4.568 g, 11.35 mmol, 1.20 eq), HOBT-H2O (0.86 g, 4.18 mmol, 0.44 eq) in CH₂Cl₂ (40 ml) at 23-25° C. under nitrogen. The reaction was complete after 3 h at 23-25° C. It was then washed with 1N HCl (12 ml), water (12 ml) and 25% brine (12 ml). MeOH (80 ml) was added to the rich organic solution at 25° C., which was distilled at atmospheric pressure to ˜60 ml to initiate the crystallization of the product. The crystal slurry was then cooled from 64° C. to 60° C. in 5 min and stirred at 60° C. for 1 h. It was further cooled to 24° C. over 1.5 h and held at 24° C. for 2 h. After the filtration, the cake was washed with MeOH (12 ml) and dried at 51° C./20-40 nm i/18 h to give Compound E (5.33 g, 89% yield, 97.7% potency, 99.1 AP).

Preparation of Compound F

5-6N HCl in IPA (10.08 ml, 50.5 mmol, Normality: 5N) was added in four portions in 1 h to a solution of Compound E (8 g, 12.6 mmol, 97.7% potency, 99.1 AP) in IPA (120 ml) at 75° C. After stirring for 1 h at 75° C., the resulting slurry was cooled to 21° C. in 2 h and stirred at 21° C. for 2 h. It was filtered and the cake was washed with IPA (2×24 ml). The wet cake was dried at 45° C./House vacuum/16 h to give Compound F as an off-white solid (6.03 g, 84.5% yield, 98.5% potency, 100 AP).

Preparation of Compound (I)

DIPEA (9.824 ml) followed by HATU (7.99 g) were added to a stirred mixture of Compound F (10 g, 99.2% potency, 99.6 AP) and Compound G (4.41 g) in CH₂Cl₂ (100 ml) at 2.7-5° C. under nitrogen. The resulting light brown solution was stirred at 0.2-3° C. for 1.5 h, at 3-20° C. in 0.5 h and at 20-23° C. for 15.5 h for a reaction completion. It was quenched with 2N HCl (50 ml) at 23° C. and stirred for 20 min at 23-24° C. The biphasic mixture was polish filtered through diatomaceous earth (Celite®) (10 g) to remove insoluble solids of HOAT and HATU. The filter cake was washed with 20 ml of CH₂Cl₂. After separating the organic phase from the filtrates, it was washed with 2N HCl (5×50 ml) and water (2×50 ml). The organic phase (115 ml) was concentrated to ˜50 ml, which was diluted with absolute EtOH (200 proof, 100 ml) and concentrated again to ˜50 ml. Absolute EtOH (50 ml) was added to bring the final volume to 100 ml. It was then warmed to 50° C. to form a clear solution and held at 50° C. for 35 min. The ethanolic solution was cooled from 50 to 23° C. over 15 min to form the crystal slurry. The slurry was stirred at 23 CC for 18 h, cooled to 0.3° C. over 30 min and kept at 0.2-0.3° C. for 2 h. After the filtration, the cake was washed with cold EtOH (2.7° C., 2×6 ml) and dried at 53° C./72 mm/67 h to give Compound (I) in Form T1F-1/2 as an off white solid (10.49 g, 80.7% yield, 99.6 AP).https://www.google.co.in/patents/US20090202476?dq=WO+2009085659&ei=dzy5UpL_LMXXrQewxYG4Dw&cl=en

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extra info

Hepatitis C virus (HCV) infection is the principal cause of chronic liver disease that can lead to cirrhosis, carcinoma and liver failure.¹ More than 200 million people worldwide are chronically infected by this virus. Currently, the most effective treatment for HCV infection is based on a combination therapy of injectable pegylated interferon-α (PEG IFN-α) and antiviral drug ribavirin. This treatment, indirectly targeting the virus, is associated with significant side effects often leading to treatment discontinuation in certain patient populations.² In addition, this treatment regimen cures only less than 50% of patients infected with genotype-1 which is the predominant genotype (while genotype 1a is most abundant in the US, the majority of sequences in Europe and Japan are from genotype 1b).³ Limited efficacy and adverse side effects of current treatment, and high prevalence of infection worldwide highlight an urgent need for more effective, convenient, and well-tolerated treatments.⁴

HCV NS3 serine protease plays a critical role in the HCV replication by cleaving downstream sites (with the assistance of the cofactor NS4A) along the HCV viral polyprotein to produce functional proteins. Recently, NS3/4A protease inhibitors have emerged as a promising treatment for HCV infection.⁵ There are two distinct classes of NS3 protease inhibitors in clinical development. The first class is comprised of serine-trap inhibitors, exemplified by VX-950 (telaprevir)⁶ and SCH-503034 (boceprevir).⁷ The second class is represented by reversible noncovalent inhibitors such as macrocyclic inhibitors BILN-2061 (ciluprevir),⁸ ITMN-191 (danoprevir),⁹ TMC-435350¹⁰ and MK-7009 (vaniprevir).¹¹ Due to concern over cardiac issues in animals treated with macrocyclic BILN-2061,¹² newer acyclic inhibitors have recently been developed exemplified by BI-201335¹³ and BMS-650032.¹⁴ However, a rapid development of viral resistance has been observed for patients treated with HCV NS3 protease inhibitors.¹⁵ Therefore, the discovery of new NS3 protease inhibitors with novel binding paradigm and thus potentially differentiated resistance profile is highly desirable.

References and notes

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13. • M. Llinàs-Brunet, M.D. Bailey, N. Goudreau, P.K. Bhardwaj, J. Bordeleau, M. Bös, Y. Bousquet, M.G. Cordingley, J. Duan, P. Forgione, M. Garneau, E. Ghiro, V. Gorys, S. Goulet, T. Halmos, S.H. Kawai, J. Naud, M.A. Poupart, P.W. White
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14. • (a)Chemical and Engineering News (April 12, 2010 issue), 88, pp 30–33.
    • (b)Perrone, R.K.; Wang, C.; Ying, W.; Song, A.I. WO 2009085659
• L. Rong, H. Dahari, R.M. Ribeiro, A.S. Perelson
• Sci. Transl. Med., 2 (2010), p. 30ra32

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