Inhibitors of hepatitis C virus NS3 protease

Details Inhibitors of hepatitis C virus NS3 protease Inhibitors of hepatitis C virus NS3 protease

2001-12-12

2003-11-25

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Boron containing doai

C514S183000, C514S256000, C514S258100, C514S259100, C514S259500, C544S229000, C544S253000, C544S315000, C544S322000, C544S335000

Reexamination Certificate

active

06653295

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to a novel class of pyrimidinones that are useful as serine protease inhibitors, and more particularly as Hepatitis C virus NS3 protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) is the major cause of transfusion and community-acquired non-A, non-B hepatitis worldwide. Approximately 2% of the world's population are infected with the virus. In the Unites States, hepatitis C represents approximately 20% of cases of acute hepatitis. Unfortunately, self-limited hepatitis is not the most common course of acute HCV infection. In the majority of patients, symptoms of acute hepatitis resolve, but alanine aminotransferase (a liver enzyme diagnostic for liver damage) levels often remain elevated and HCV RNA persists. Indeed, a propensity to chroninicity is the most distinguishing characteristic of hepatitis C, occurring in at least 85% of patients with acute HCV infection. The factors that lead to chronicity in hepatitis C are not well defined. Chronic HCV infection is associated with increased incidence of liver cirrhosis and liver cancer. No vaccines are available for this virus, and current treatment is restricted to the use of alpha interferon, which is effective in only 15-20% of patients. Recent clinical studies have shown that combination therapy of alpha interferon and ribavirin leads to sustained efficacy in 40% of patients (Poynard et al.
Lancet
1998, 352, 1426-1432.). However, a majority of patients still either fail to respond or relapse after completion of therapy. Thus, there is a clear need to develop more effective therapeutics for treatment of HCV-associated hepatitis.
HCV is a positive-stranded RNA virus. Based on comparison of deduced amino acid sequence and the extensive similarity in the 5′ untranslated region, HCV has been classified as a separate genus in the Flaviviridae family, which also includes flaviviruses such as yellow fever virus and animal pestiviruses like bovine viral diarrhea virus and swine fever virus. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.
The RNA genome is about 9.6 Kb in length, and encodes a single polypeptide of about 3000 amino acids. The 5′ untranslated region contains an internal ribosome entry site (IRES), which directs cellular ribosomes to the correct AUG for initiation of translation. As was determined by transient expression of cloned HCV cDNAs, the precursor protein is cotranslationally and posttranslationally processed into at least 10 viral structural and nonstructural (NS) proteins by the action of a host signal peptidase and by two distinct viral proteinase activities. The translated product contains the following proteins: core-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B.
The N-terminal portion of NS3 functions as a proteolytic enzyme that is responsible for the cleavage of sites liberating the nonstructural proteins NS4A, NS4B, NS5A, and NS5B. NS3 has further been shown to be a serine protease. Although the functions of the NS proteins are not completely defined, it is known that NS4A is a protease cofactor and NS5B is an RNA polymerase involved in viral replication. Thus agents that inhibit NS3 proteolytic processing of the viral polyprotein are expected to have antiviral activity.
There are several patents that disclose HCV NS3 protease inhibitors. WO98/17679 describes peptide and peptidomimetic inhibitors with the following formula: U—E
8
—E
7
—E
6
—E
5
—E
4
—NH—CH(CH
2
G
1
)—W
1
, where W is one of a variety of electrophilic groups, including boronic acid or ester. E4 represents either an amino acid or one of a series of peptidomimetic groups, the sythesis of which are not exemplified. HCV protease inhibitors described in the present case are not covered.
Based on the large number of persons currently infected with HCV and the limited treatments available, it is desirable to discover new inhibitors of HCV NS3 protease.
SUMMARY OF THE INVENTION
One object of the present invention is to provide compounds, or pharmaceutically acceptable salt forms or prodrugs thereof, which are useful as inhibitors of hepatitis C virus protease, more specifically, the NS3 protease.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt form or prodrug thereof.
It is another object of the present invention to provide a method for the treatment or prevention of HCV comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt form or prodrug thereof.
These and other objects of the invention, which will become apparent during the following detailed description, have been achieved by the discovery that compounds of Formula (I):
or pharmaceutically acceptable salt forms or prodrugs thereof, wherein R
1
, R
2
, R
3
, R
6
, R
13
, W, A
1
and A
3
are defined below, are effective inhibitors of HCV NS3 protease.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HCV NS3 protease, HCV growth, or both.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of HCV.
DETAILED DESCRIPTION OF THE INVENTION
[1] Thus, in one embodiment, the present invention provides a compound of Formula (I):
or a stereoisomer, pharmaceutically acceptable salt form or prodrug thereof, wherein:
A
1
is —CH
2
—, —CH
2
CH
2
—, —CH
2
CH
2
CH
2
—, —CR
5
R
5a
—, —CH
2
—CR
5
R
5a
—, —CH
2
—CH
2
—CR
5
R
5a
—, —A
2
—CH
2
—, —A
2
—CH
2
CH
2
—, or —CH
2
—A
2
—CH
2
—;
A
2
is O, S, or NR
7
;
A
3
is H, —C(═O)R
9a
, —OR
9a
, —SR
9a
, —S(═O)R
9a
, —S(═O)
2
R
9a
, —NHCOR
9a
, —CONHR
9a
, —NHS(═O)
2
R
9a
, —S(═O)
2
NHR
9a
, —NHC(═O)OR
9a
, —OC(═O)NHR
9a
, —C(═O)OR
9a
, —O—C(═O)R
9a
, —NR
8
R
9a
; —NH—A
4
—R
9b
; —NH—A
4
—A
5
—R
9b
; or —NH—A
4
—A
5
—A
6
R
9b
;
W is selected from the group:
—B(OR
26
)(OR
27
),
—C(═O)C(═O)—Q,
—C(═O)C(═O)NH—Q,
—C(═O)C(═O)—O—Q,
—C(═O)CF
2
C(═O)NH—Q,
—C(═O)Q
3
,
—C(═O)CF
3
,
—C(═O)CF
2
CF
3
, and
—C(═O)H;
Q is selected from the group:
—(CR
10
R
10c
)
m
—Q
1
,
—(CR
10
R
10c
)
m
—Q
2
,
C
1
-C
4
alkyl substituted with Q
1
,
C
2
-C
4
alkenyl substituted with Q
1
,
C
2
-C
4
alkynyl substituted with Q
1
,
an amino acid residue,
—A
7
—A
8
, and
—A
7
—A
8
—A
9
;
m is 1, 2, 3, or 4;
Q
1
is selected from the group:
—CO
2
R
11
, —SO
2
R
11
, —SO
3
R
11
, —P(O)
2
R
11
, —P(O)
3
R
11
;
aryl substituted with 0-4 Q
1a
; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 Q
1a
;
Q
1a
is H, F, Cl, Br, I, —NO
2
, —CN, —NCS, —CF
3
, —OCF
3
, —CO
2
R
19
, —C(&bo

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