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Inhibitors of hepatitis c virus

An alkyl compound technology, applied in the field of antiviral compounds, can solve the problem that the viral load does not continue to decrease

Inactive Publication Date: 2009-11-11
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even with an experimental treatment regimen that included a combination of pegylated interferon-alpha and ribavirin, a significant proportion of patients did not experience sustained reductions in viral load

Method used

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  • Inhibitors of hepatitis c virus
  • Inhibitors of hepatitis c virus
  • Inhibitors of hepatitis c virus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] Racemic (1R,2S) / (1S,2R)-1-amino-2-vinylcyclopropanecarboxylate ethyl ester hydrochloride Preparation (Method A and Method B)

[0179]

[0180] The compounds were racemized by each of Methods A and B below.

[0181] Method A

[0182] Preparation of N-benzyl imine of ethyl glycine ester

[0183]

[0184] Glycine ethyl ester hydrochloride (303.8 g, 2.16 mol) was suspended in tert-butyl methyl ether (1.6 L). Benzaldehyde (231 g, 2.16 mol) and anhydrous sodium sulfate (154.6 g, 1.09 mol) were added and the mixture was cooled to 0°C using an ice-water bath. Triethylamine (455 mL, 3.26 mol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 48 hours. The reaction was then quenched by addition of ice-cold water (1 L) and the organic layer was separated. The aqueous phase was extracted with tert-butyl methyl ether (0.5 L) and the combined organic phases were washed with a mixture of saturated aqueous NaHCO3 (1 L) and brine (...

Embodiment 2

[0196] Resolution of ethyl N-Boc-(1R,2S) / (1S,2R)-1-amino-2-vinylcyclopropanecarboxylate

[0197]

[0198] Split A

[0199] To an aqueous sodium phosphate buffer solution (0.1 M, 4.25 liters ("L"), pH 8) in a 12 liter jacketed reactor, maintained at 39°C and stirred at 300 rpm, was added 511 grams of Alcalase 2.4 L (approx. 425 ml) (Novozymes North America Inc.). When the temperature of the mixture reached 39°C, the pH was adjusted to 8.0 by adding 50% NaOH in water. A solution of racemic ethyl N-Boc-(1R,2S) / (1S,2R)-1-amino-2-vinylcyclopropanecarboxylate (85 g) in 850 mL DMSO was then added over 40 minutes. The reaction temperature was then maintained at 40°C for 24.5 hours, during which time the pH of the mixture was adjusted to 8.0 with 50% NaOH in water at time points 1.5 and 19.5 hours. After 24.5 hours, the enantiomeric excess of the ester was determined to be 97.2%, the reaction was cooled to room temperature (26°C) and stirred overnight (16 hours), after which ...

Embodiment 3

[0247] Step 1: Preparation of ethyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate hydrochloride

[0248]

[0249] Ethyl 1(R)-tert-butoxycarbonylamino-2(S)-vinylcyclopropanecarboxylate (8.5 g, 33.3 mmol) was treated with 200 mL of 4N HCl / dioxane ( Aldrich) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure keeping the temperature below 40°C. This yielded 6.57 g (-100%) ethyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate hydrochloride as a light brown (tan) solid. 1 H NMR (300MHz, CD 3 OD)δ1.31(t, J=7.0Hz, 3H), 1.69-1.82(m, 2H), 2.38(q, J=8.8Hz, 1H), 4.29(q, J=7.0Hz, 2H), 5.22 (d, J=10.3 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.69-5.81 (m, 1H). MS m / z 156 (M++1).

[0250] Step 2: 1(R)-[1-tert-Butoxycarbonyl-4(R)-hydroxypyrrolidine-2(S)-carboxamido Preparation of (carboxamido)]-2(S)-ethyl vinylcyclopropanecarboxylate

[0251]

[0252] N-methylmorpholine (9.3 mL, 84.7 mmol), HATU (19.5 g, 51.3 mmol) and ethyl 1(R)-amino-2(S)-viny...

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Abstract

Macrocyclic peptides are disclosed having the general formula: wherein R3, R3', R, R6, R', X, Q and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of US Provisional Application Serial No. 60 / 863,857, filed November 1, 2006. Field of Invention [0003] The present disclosure relates generally to antiviral compounds, and more particularly to compounds that inhibit the function of the NS3 protease (also referred to herein as "serine protease") encoded by hepatitis C virus (HCV), compositions comprising such compounds and inhibition of NS3 Methods of Protease Function. Background of the Invention [0004] HCV is the major human pathogen, infecting an estimated 170 million people worldwide - roughly five times the number infected by human immunodeficiency virus type 1. A substantial proportion of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. [0005] Currently, the most effective HCV therapy employs a combination of alpha-interferon and ribavirin, produci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/08C07K5/06A61K38/06A61P31/14
CPCC07K5/0804A61P31/12A61P31/14A61P43/00
Inventor S·丹德里P·M·斯科拉
Owner BRISTOL MYERS SQUIBB CO
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