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Inhibitors of serine proteases, particularly HCV NS3-NS4A protease

Inactive Publication Date: 2005-06-02
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] The invention also relates to compositions that comprise the above compounds and the use thereof. Such compositions may be used to pre-treat invasive devices to be inserted into a patient, to treat biological samples, such as blood, prior to administration to a patient, and for direct administration to a patient. In each case the composition will be used to inhibit HCV replication and to lessen the risk of or the severity of HCV infection.

Problems solved by technology

Infection by hepatitis C virus (“HCV”) is a compelling human medical problem.
Unfortunately, there are no broadly effective treatments for the debilitating progression of chronic HCV.
There are not currently any satisfactory anti-HCV agents or treatments.
However, interferons have significant side effects [M. A. Wlaker et al., “Hepatitis C Virus: An Overview of Current Approaches and Progress,”DDT, 4, pp.
Moreover, the prospects for effective anti-HCV vaccines remain uncertain.

Method used

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  • Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
  • Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
  • Inhibitors of serine proteases, particularly HCV NS3-NS4A protease

Examples

Experimental program
Comparison scheme
Effect test

embodiments

[0266] According to one embodiment for compounds of formula I or formula I-1, the

radical is:

wherein: [0267] R12, R12′, and R13 are as defined in any of the embodiments herein.

[0268] According to another embodiment for compounds of formula I or formula I-1, the

radical is:

wherein: [0269] R12′ is hydrogen; [0270] R12 is: [0271] (C1-C12)-aliphatic-; [0272] (C6-C10)-aryl-, [0273] (C6-C10)-aryl-(C1-C12)aliphatic-, [0274] (C3-C10)-cycloalkyl or -cycloalkenyl-, [0275] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, [0276] (C3-C10)-heterocyclyl-, [0277] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, [0278] (C5-C10)-heteroaryl-, or [0279] (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; [0280] wherein up to 3 aliphatic carbon atoms in R12 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO2 in a chemically stable arrangement; [0281] wherein R12 is optionally substituted with up to 3 substituents independently selected from J; and [0282] R13 is as defined in any o...

example 1

N-Phenyl Oxalamic Acid (84)

[0717] Ethyl oxanilate 83 (Aldrich, 1.0 g, 1.0 eq) in 12 mL of THF was treated dropwise with a 1N NaOH solution (5.70 mL, 1.1 eq) resulting in a white precipitate. After stirring for 3 hours at RT, 0.5N HCl and ethyl acetate were added, the organic layer separated, washed with 0.5N HCl and brine and then dried over sodium sulfate, filtered, and concentrated to give 712 mg (68%) of N-phenyl oxalamic acid 84 as a white solid with consistent analytical data. FIA M+H=166.0, M−H=163.9; 1H NMR (DMSO-d6) δ 10.70 (s,1H), 7.75 (m,2H), 7.35 (m,2H), 7.15 (m,1H) ppm.

example 2

N-(Cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-octahydro-indole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-N′-phenyl-oxalamide (1)

[0718] Octahydro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 89 (Bachem, 1.6 g, 1.0 eq) in DMF (20 mL) was treated with PyBOP (3.41 g, 1.1 eq) and NMM (1.97 mL, 3.0 eq). To this was added 3-amino-2-hydroxy-hexanoic acid cyclopropylamide 90 (1.22 g, 1.1 eq, prepared according to the procedure of U. Schoellkogf et al., Justus Liebigs Ann. Chem. GE, pp. 183-202 (1976) and J. Semple et al., Org. Letters, 2, pp. 2769-2772 (2000) and NMM (1.97 mL, 3.0 eq) in DMF (3 mL) and the mixture stirred at rt overnight. The mixture was evaporated in vacuo, diluted with ethyl acetate, the organic phase washed with 0.5N HCl, sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give 2-[1-cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indole-1-carboxylic acid tert-butyl ester 91 which was used w...

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Abstract

The present invention relates to compounds of formula I: or a pharmaceutically acceptable salts thereof that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are useful as antiviral agents. The invention further relates to pharmaceutically acceptable compositions comprising said compounds either for ex vivo use or for administration to a patient suffering from HCV infection and to processes for preparing the compounds. The invention also relates to methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a compound of this invention.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application claims the benefit, under 35 U.S.C. § 119, of U.S. Provisional patent application No. 60 / 504,405, filed Sep. 18, 2003, entitled “Inhibitors of Serine Proteases, Particularly HCV NS3-NS4A Protease”, the entire contents of which is hereby incorporated by reference.TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The invention further relates to pharmaceutical compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection. The invention also relates to processes for preparing the compounds and methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a...

Claims

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Application Information

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IPC IPC(8): A61K38/04A61K38/05A61K38/07A61P31/12C07K5/04C07K5/06C07K5/08C07K5/10C07K7/06
CPCC07K5/10C07K7/06A61P1/16A61P31/12A61P31/14A61P43/00
Inventor COTTRELL, KEVINPERNI, ROBERTPITLIK, JANOSSCHAIRER, WAYNE
Owner VERTEX PHARMA INC
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