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Inhibitors of serine protease, particularly hcv ns3-ns4a protease

a protease and serine technology, applied in the field of inhibitors of serine protease, can solve the problems of inability to broadly effective treat the debilitating progression of chronic hcv, inability to use interferons, and inability to achieve satisfactory anti-hcv agents or treatments, so as to reduce the risk of or severity of hcv infection, inhibit hcv replication, and improve the effect of anti-hcv

Inactive Publication Date: 2009-01-22
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention also relates to processes for preparing the above compounds and 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.
Furthermore, the current understanding of HCV has not led to any other 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 protease, particularly hcv ns3-ns4a protease
  • Inhibitors of serine protease, particularly hcv ns3-ns4a protease
  • Inhibitors of serine protease, particularly hcv ns3-ns4a protease

Examples

Experimental program
Comparison scheme
Effect test

embodiments

According to one embodiment of compounds of formula I, the

radical is,

wherein;

in R′, R10, and R10′, X and Y are both a bond and Z is hydrogen; and in R9′;

X is a bond;

Y is a bond, —CH2—, or —C(O)—; and

Z is (C1-C12)-aliphatic-,(C3-C10)-cycloalkyl- or -cycloalkenyl-,[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,(C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-,(C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,(C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;wherein up to three aliphatic carbon atoms in Z may be optionally replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)—, in a chemically stable arrangement;wherein any ring may be optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;wherein Z may be independently and optionally substituted with up to 3 substituents independently selected from J.

According to another embodiment, in R9′;

X is a bond;

Y is a bond; and

Z is (C1-C12)-aliphatic-,(C3-C10)-cyc...

example 1

Pyrazine-2-carboxylic acid (cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-3-isopropyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide (56)

To a stirring suspension of copper bromide-dimethylsulfide (9.1 g, 44.28 mmol) in 100 mL of dry ether at −20° C. was added isopropenyl magnesium bromide 0.09M (100 mL). After 15 min. of stirring, the temperature was lowered to −78° C. and enone 4a (4.0 g, 8.86 mmol, prepared according to procedure in JACS, 117, p. 10775, (1995)) in 50 mL of ether was added followed by TMSCl (2.25 mL, 18 mmol). The reaction mixture was stirred at −78° C. for 1 h and quenched with 100 mL of ammonium hydroxide-ammonium chloride solution (1:4). Extracted with ether and the organic phase was washed to remove all the copper salts. The ether layer was dried with sodium sulfate and concentrated in vacuo to an oil that was subjected to flash chromatography (ether-hexanes (2:3) to provide 3.5 g (73%) of the desired intermediate olefin.

1H NMR...

example 2

3-tert-Butyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (6a)

t-Butyl zinc bromide 0.5M solution in THF (3.7 mL, 1.83 mmol)was added to a solution of enone 4a (280 mg, 0.85 mmol) in THF containing BF3OEt2 (350 uL, 2.75 mmol) and TMSCl (465 uL) at −30° C. over a period of 5 minutes. The heterogeneous mixture was stirred at −30° C. for 3.5 h than quenched with sat'd NH4Cl solution. Extracted with ether (3×) and the combined extract were washed with brine, dried with sodium sulfate and concentrated in vacuo. Flash chromatography (10% ethyl acetate-hexanes) provided 210 mg (64%) of 6a. 1H NMR (CDCl3) δ 3.9 (s, 1H); 3.8 (dd, 1H); 3.5 (d, 1H); 2.8 (dd, 1H); 2.3 (d, 1H); 1.9 (d, 1H); 1.4 (s, 9H); 0.9 (s, 18H); 0.1 (s, 3H); 0.05 (s, 3H) ppm.

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Abstract

The present invention relates to compounds of formula I:or a pharmaceutically acceptable salt, or mixtures 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 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

TECHNICAL FIELD OF THE INVENTIONThe 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 compound of this invention.BACKGROUND OF THE INVENTIONInfection by hepatitis C virus (“HCV”) is a compelling human medical problem. HCV is recognized as the causative agent for most cases of non-A, non-B hepatitis, with an estimated human sero-prevalence of 3% globally [A. Alberti et al., “Natural History of Hepatitis C,”J. Hepatology, 31....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/21C07D403/12A61K31/497C07D413/12A61K31/5377A61K31/401A61K31/407A61K31/4155A61K31/425A61K31/4745A61K31/4965A61K38/04C07D417/12C07D471/02
CPCA61K38/00C07D403/12C07K5/0812C07K5/0804C07K5/0808C07D417/12A61P31/12A61P31/14A61P43/00
Inventor FARMER, LUC J.PERNI, ROBERT B.BHISETTI, GOVINDA RAOWILSON, KEITH P.
Owner VERTEX PHARMA INC
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