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Hepatitis C Virus Inhibitors

Inactive Publication Date: 2010-09-30
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0026]The compounds of the present disclosure can be effective to inhibit the function of the HCV NS5A protein. In particular, the compounds of the present disclosure can be effective to inhibit the HCV 1b genotype or multiple genotypes of HCV. Therefore, this invention also encompasses: (1) compositions comprising a com

Problems solved by technology

The current standard of care for HCV, which employs a combination of pegylated-interferon and ribavirin, has a non-optimal success rate in achieving sustained viral response and causes numerous side effects.
Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome due to the high error rate of the encoded RNA dependent RNA polymerase which lacks a proof-reading capability.
The possible modulator effect of genotypes on pathogenesis and therapy remains elusive.

Method used

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Examples

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examples

[0734]The present disclosure will now be described in connection with certain embodiments which are not intended to limit its scope. On the contrary, the present disclosure covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include specific embodiments, will illustrate one practice of the present disclosure, it being understood that the examples are for the purposes of illustration of certain embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

[0735]Solution percentages express a weight to volume relationship, and solution ratios express a volume to volume relationship, unless stated otherwise. Nuclear magnetic resonance (NMR) spectra were recorded either on a Bruker 300, 400, or 500 MHz spectrometer; the chemical shifts (8) are reported in parts per million.

[0736]Purity assessment and low ...

example qc-1a

[0784]

[0785]To a solution of bicyclohexanone (5.05 g, 26.0 mmol) and 2,6-diterbutyl phenol (11.75 g, 57.2 mmol) in 200 mL of dry dichloromethane was added triflic anhydride (9.10 mL, 54.6 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was taken up in hexanes and filtered. The filtrate was washed with 1 N HCl and brine. The organic layer was dried with potassium carbonate and concentrated. The crude product was purified by a flash chromatography (silica gel, 5% ethyl acetate / hexanes) to give Example QC-1a as a white solid (8.22 g, 69.0%, mixture of diastereomers). 1H NMR (500 MHz, CDCl3) δ ppm 1.35-1.64 (m, 4H) 1.81-2.07 (m, 4H) 210-2.53 (m, 6H) 5.66-5.80 (m, 2H). LC / MS: Anal. Calcd. for [M+H]+ C14H17F6O6S2: 459.37; found (molecule did not ionize well in mass spec chamber).

example qc-1b

[0786]

[0787]To a flask with bis(pinacolato)diboron (2.79 g, 11.0 mmol), potassium phenolate (1.98 g, 15.0 mmol), PdCl2(PPh3)2 (0.21 g, 0.3 mmol) and triphenylphosphine (0.16 g, 0.6 mmol) was added 50 mL of dry toluene and (1a) (2.29 g, 5.0 mmol). The resulting mixture was stirred at 50° C. for 3 h. The reaction was quenched with water and extracted with toluene. The organic layers were combined, washed with brine, dried with MgSO4 and concentrated. The crude product was purified by flash chromatography (silica gel, 5-80% ethyl acetate / hexanes) to give Example QC-1b as a white solid (1.14 g, 55%, mixture of diastereomers). 1H NMR (500 MHz, CDCl3) δ ppm 1.10-1.19 (m, 2H) 1.24 (s, 24H) 1.31-1.43 (m, 2H) 1.73-1.90 (m, 4H) 1.97-2.29 (m, 6H) 6.52-6.58 (n, 2H).

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Abstract

This disclosure concerns novel compounds of Formula (I) as defined in the specification and compositions comprising such novel compounds. These compounds are useful antiviral agents, especially in inhibiting the function of the NS5A protein encoded by Hepatitis C virus (HCV). Thus, the disclosure also concerns a method of treating HCV related diseases or conditions by use of these novel compounds or a composition comprising such novel compounds.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application Ser. No. 61 / 164,579 filed Mar. 30, 2009.FIELD OF THE INVENTION[0002]The present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS5A protein.BACKGROUND OF THE INVENTION[0003]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.[0004]The current standard of care for HCV, which employs a combination of pegylated-interferon and ribavirin, has a non-optimal success rate in achieving sustained viral ...

Claims

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Application Information

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IPC IPC(8): A61K31/454C07D403/14A61K31/4178A61P31/14C07D401/14C07D413/14A61K31/422
CPCC07D413/14C07D403/14A61P1/16A61P31/00A61P31/14A61P31/18A61P43/00A61K31/4178A61K47/10
Inventor LOPEZ, OMAR D.CHEN, QIBELEMA, MAKONENHAMANN, LAWRENCE G.
Owner BRISTOL MYERS SQUIBB CO
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