Compounds useful for treating hepatitis C virus

Details Compounds useful for treating hepatitis C virus Compounds useful for treating hepatitis C virus

2003-08-27

2004-10-12

Richter, Johann (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S394000, C548S304700, C548S305100, C546S113000

Reexamination Certificate

active

06803374

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to compounds which inhibit the RNA-dependent RNA polymerase (RdRp) encoded by Hepatitis C virus (HCV). The compounds, or pharmaceutically acceptable salts or prodrugs thereof, are of value in the treatment and/or prevention of infection by HCV.
BACKGROUND OF THE INVENTION
The Field of the Invention. 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. (Lauer, G. M.; Walker, B. D.
N. Engl. J. Med
. (2001), 345, 41-52).
Presently, the most effective HCV therapy employs a combination of alpha-interferon and ribavirin, leading to sustained efficacy in 40% of patients. (Poynard, T. et al.
Lancet
(1998), 352, 1426-1432). Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy (Zeuzem, S. et al.
N. Engl. J. Med
. (2000), 343, 1666-1672). However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. In addition, the prospects for development of a prophylactic or therapeutic vaccine appear dim, in spite of intensive research efforts. Thus, there is a clear and long-felt need to develop effective therapeutics for treatment of HCV infection.
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. 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. The translated product contains the following proteins: core-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. This precursor protein is cotranslationally and posttranslationally processed into at least 10 viral structural (core, E1, E2) and nonstructural (NS2-NS5B) proteins by the action of host cell signal peptidase and by two distinct viral proteinase activities (NS2/3 and NS3).
Although the functions of the NS proteins are not completely defined, it is known that NS3 is a serine protease/RNA helicase, NS4A is a protease cofactor, and NS5B is an RNA dependent RNA polymerase involved in viral replication. It has recently been demonstrated that functional NS5B is required for virus infectivity in chimpanzees (Kolykhalov, A. A. et al.
J. Virol
. (2000), 74, 2046-2051). This result strongly suggests that inhibition of the NS5B RdRp is a viable approach for the development of HCV therapeutic agents.
Description of Related Art. Efforts toward the development of HCV NS5B RdRp inhibitors have resulted in the following disclosures:
Altamura et al. (Istituto Di Ricerche Di Biologia Molecolare) describe diketoacid RdRp inhibitors (WO 00/06529 and WO 02/06246 A1). Altamura et al. suggest that the diketoacids and dihydroxypyriridine carboxylic acids inhibit HCV RdRp by interfering with the binding of phosphoryl groups at the active site of the enzyme.
A series of three disclosures from Viropharma Inc. (Bailey, T. R. et al, WO 00/10573; Bailey, T. R. et al, WO 00/13708; Young, D. C. et al, WO 00/18231) describe HCV RdRp inhibitors. WO 00/10573 covers a series of rhodanine derivatives, WO 00/13708 covers a series of barbituric acid or thiobarbituric acid derivatives, and WO 0018231 covers a series of dihydrobenzothiophene derivatives.
R. Storer (Biochem Pharma, Inc.) has disclosed the use of a series of dioxolane nucleosides for treatment of HCV (WO 01/32153).
EP 1162196 (Japan Tobacco Inc.) discloses a series of fused ring heterocycles as inhibitors of HCV RdRp. These compounds may be distinguished from the applicants' compounds in the nature of the “A” substituent in applicants' Formula I compounds.
WO 02/04425 (Boehringer Ingelheim) discloses a series of HCV NS5B polymerase inhibitors which also may be distinguished from the applicants' compounds in the nature of the “A” substituent in applicants' Formula I compounds.
WO 01/85172 (Smithkline Beecham) discloses a series of 1-(alkyl)-3-(1,1-dioxo-2H-benzo-1,2,4-thiadiazin-3-yl)-4-hydroxy-2-quinolones as HCV inhibitors.
SUMMARY OF THE INVENTION
The present invention is directed to compounds according to Formula I:
wherein all represented groups are defined below.
The present invention is also directed to compounds of Formula I, or pharmaceutically acceptable salts or prodrugs thereof, which are useful as inhibitors of HCV NS5B RdRp. 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 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 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 inhibit the HCV NS5B RdRp.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds according to Formula I:
wherein: Q is CH or N; R
1
is tetrazolyl, MeCONHSO
2
—, PhCONHSO
2
—, R
5
O
2
C(CH
2
)
0-3
CONHSO
2
—,
—CH
2
Ar
1
, —CHPh
2
, —CH
2
CO(4-FPh), —CH
2
CO(4-CF
3
Ph), or —CH
2
CONp where Np is naphthyl; R
3
is C
5-7
cycloalkyl; R
4
is hydrogen, Ar
2
, or Ar
3
; Ar
1
is selected from the following group: phenyl, halophenyl,
Ar
2
is phenyl, naphthyl, or biphenyl, optionally substituted with 1-3 substituents selected from the group comprising halogen, C
1-6
alkyl, hydroxy C
1-6
alkyl, C
1-6
alkoxy, C
1-6
sulfoxy, C
1-2
perfluoroalkyl, hydroxy, formyl, C
1-6
alkylcarbonyl, cyano, nitro, C
1-6
alkylamido, CO
2
R
5
, CONR
5
R
5
, C
1-6
alkylsulfonamido, and dioxolane; Ar
3
is thienyl, furanyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, quinolinyl, or pyrimidinyl optionally substituted with 1-2 substituents selected from the group comprising C
1-6
alkyl, formyl, acetoxy, trifluoroacetoxy, and t-butoxycarbonyl; R
5
is hydrogen or C
1-6
alkyl; R
6
is halogen, methoxy, CO
2
R
5
or CONR
7
R
8
; R
7
and R
8
are independently hydrogen, C
1-6
alkyl, —CH(Me)CO
2
R
5
, —(CH
2
)
1-3
CO
2
R
5
, —(CH
2
)
1-3
CONR
5
R
5
, —(CH
2
)
1-3
OH,
or R
7
and R
8
taken together with the nitrogen to which they are attached form pyrrolidine, morpholine, piperidine, 4-hydroxypiperidine, piperazine, or 4-methylpiperazine; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
As used herein, the following terms shall be understood to have the meaning set forth in the following definitions.
The term “compounds of the invention”, and equivalent expressions, are meant to embrace compounds of formula I, and include prodrugs, pharmaceutically acceptable salts, and solvates

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