Hepatitis C virus inhibitors

A technology of cyclopropyl rings and compounds, applied in the field of antiviral compounds, can solve the problem of elusive regulation

Inactive Publication Date: 2013-10-09
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Genotype Modulation of Pathogenesis and Possible Therapy Remains Elusive

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0186]

[0187] (Biphenyl-4,4'-diylbis(1H-imidazole-4,2-diyl((2S,5S)-5-methyl-2,1-pyrrolidinediyl)((1S)-1 -((2R,6S)-2,6-Dimethyltetrahydro-2H-pyran-4-yl)-2-oxo-2,1-ethanediyl)))dicarbamate dimethyl

[0188] Embodiment 1 step a

[0189]

[0190] The above compound was synthesized according to the literature protocol (J.Med.Chem., 2006, 49, 3520), purified with the following modifications: Recrystallization of the crude material from EtOAc / hexane at ambient temperature afforded Example 1 step as white crystals a. 1 H NMR (400MHz, CDCl 3 )δppm4.32(br m,1H),3.89(br m,1H),2.40(brm,1H),2.00(m,2H),1.65(m,1H),1.45(s,9H),1.20(d ,J=5.6,3H). LC / MS: [M+Na] + C 11 h 20 NO 4 Analytical calculated for Na 252.12; found 252.21.

[0191] Embodiment 1 step b

[0192]

[0193] To Example 1 step a (7.12g, 31.1mmol) and 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethanone) (6.0g, 15mmol) in acetonitrile (100mL) Add i-Pr dropwise to the mixture in 2 EtN (5.56 mL, 31.8 mmol), and the rea...

Embodiment 2

[0206]

[0207] (Biphenyl-4,4'-diylbis(1H-imidazole-4,2-diyl((2S,5S)-5-methyl-2,1-pyrrolidinediyl)((1S)-1 -((2R,6R)-2,6-Dimethyltetrahydro-2H-pyran-4-yl)-2-oxo-2,1-ethanediyl)))dicarbamate dimethyl

[0208] HATU (63.6 mg, 0.167 mmol) was added to (S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonyl Amino)acetic acid (Cap-2) (41 mg, 0.17 mmol) and the hydrochloride salt (45.5 mg, 0.076 mmol) of step d of Example 1 in DMF (0.9 mL) and DIPEA (0.11 mL, 0.61 mmol) were stirred in solution. The reaction mixture was stirred at room temperature for 4 hours, then concentrated overnight under nitrogen flow. The residue was dissolved in MeOH, filtered and purified by preparative HPLC (Phenomenex Luna C18(2) 100 x 30 mm, 10 microns; MeOH / water) to give (biphenyl-4,4'- Diylbis(1H-imidazole-4,2-diyl((2S,5S)-5-methyl-2,1-pyrrolidinediyl)((1S)-1-((2R,6R)-2 , TFA salt of dimethyl 6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxo-2,1-ethanediyl))) dicarbamate (Example 2) (62.5...

Embodiment 3

[0223]

[0224] ((3-Methyl-biphenyl-4,4'-diyl)bis(1H-imidazol-4,2-diyl((2S,5S)-5-methyl-2,1-pyrrolidinyl )((1S)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxo-2,1-ethanediyl))) Dimethyl dicarbamate

[0225] Embodiment 3 step a

[0226]

[0227] To a solution of 4-bromo-2-methylbenzoic acid (10 g, 46.5 mmol) in DMF (150 mL) was added sequentially N,O-dimethylhydroxylamine hydrochloride (5.44 g, 55.8 mmol) at room temperature HOBT (8.55 g, 55.8 mmol). Then EDC (10.7 g, 55.8 mmol), DIPEA (24.4 mL, 140 mmol) were added sequentially and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then diluted with EtOAc (150 mL), washed with water (3 x 250 mL) and brine (150 mL), washed over Na 2 SO 4 Drying, filtration and concentration in vacuo afforded crude Example 3, step a (9.5 g), which was used as such in the next step. 1 H NMR (CDCl 3 ,δ=7.26ppm,400MHz):δ7.37(d,J=1.6Hz,1H),7.34(dd,J=8.0,1.6Hz,1H),7.14(d,J=8.0Hz,1H),3.47 ...

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Abstract

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application 61 / 467,602, filed March 25, 2011, and US Provisional Application 61 / 440,086, filed February 7, 2011. technical field [0003] The present invention is directed generally to antiviral compounds, and more particularly to compounds capable of inhibiting the function of the NS5A protein encoded by hepatitis C virus (HCV), compositions comprising said compounds and inhibiting the function of the NS5A protein Methods. Background technique [0004] HCV is a major human pathogen, infecting an estimated 170 million people worldwide - approximately five times the number infected by human immunodeficiency virus type 1. A significant proportion of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. [0005] The current standard of care for HCV utilizes a combination of pegylated interferon and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14A61K31/4178A61P31/14
CPCC07D309/06C07D405/14A61K45/06A61K31/4178A61P31/14A61P43/00A61K2300/00C07D403/14
Inventor J.A.本德O.D.洛佩兹G.王M.贝乐玛J.F.卡多
Owner BRISTOL MYERS SQUIBB CO
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