Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-29
2003-08-19
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S085000, C514S616000, C544S337000, C544S406000, C546S298000, C564S153000
Reexamination Certificate
active
06608067
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to compounds that are useful as protease inhibitors, particularly as serine protease inhibitors, and more particularly as hepatitis C NS3 protease inhibitors. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HCV NS3 protease activity and consequently, may be advantageously used as therapeutic agents against the hepatitis C virus and other viruses that are dependent upon a serine protease for proliferation. This invention also relates to methods for inhibiting the activity of proteases, including hepatitis C virus NS3 protease and other serine proteases, using the compounds of this invention and related compounds.
BACKGROUND OF THE INVENTION
Infection 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 seroprevalence of 1% globally [Purcell, R. H., “Hepatitis C virus: Historical perspective and current concepts”
FEMS Microbiology Reviews
14, pp. 181-192 (1994); Van der Poel, C. L., “Hepatitis C Virus. Epidemiology, Transmission and Prevention in Hepatitis C Virus. Current Studies in Hematology and Blood Transfusion, H. W. Reesink, Ed., (Basel: Karger), pp. 137-163 (1994)]. Four million individuals may be infected in the United States alone [Alter, M. J. and Mast, E. E., “The Epidemiology of Viral Hepatitis in the United States,
Gastroenterol. Clin. North Am
. 23, pp. 437-455 (1994)].
Upon first exposure to HCV only about 20% of infected individuals develop acute clinical hepatitis while others appear to resolve the infection spontaneously. In most instances, however, the virus establishes a chronic infection that persists for decades [Iwarson, S. “The Natural Course of Chronic Hepatitis”
FEMS Microbiology Reviews
14, pp. 201-204 (1994)]. This usually results in recurrent and progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma [Kew, M. C., “Hepatitis C and Hepatocellular Carcinoma”,
FEMS Microbiology Reviews
, 14, pp. 211-220 (1994); Saito, I., et al. “Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carcinoma”
Proc. Natl. Acad. Sci. USA
87, pp. 6547-6549 (1990)]. Unfortunately, there are no broadly effective treatments for the debilitating progression of chronic HCV.
The HCV genome encodes a polyprotein of 3010-3033 amino acids [Choo, Q. -L., et al. “Genetic organization and Diversity of the Hepatitis C Virus”,
Proc. Natl. Acad. Sci. USA
, 88, pp. 2451-2455 (1991); Kato, N. et al., Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis”,
Proc. Natl. Acad. Sci. USA
, 87, pp. 9524-9528 (1990); Takamizawa, A. et al., “Structure and organization of the Hepatitis C Virus Genome Isolated From Human Carriers”,
J. Virol
., 65, pp. 1105-1113 (1991)]. The HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication. The NS proteins are derived by proteolytic cleavage of the polyprotein [Bartenschlager, R. et al., “Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions”,
J. Virol
., 67, pp. 3835-3844 (1993); Grakoui, A. et al. “Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Cleavage Sites”,
J. Virol
., 67, pp. 2832-2843 (1993); Grakoui, A. et al., Expression and Identification of Hepatitis C Virus Polyprotein Cleavage Products”,
J. Virol
., 67, pp. 1385-1395 (1993); Tomei, L. et al., “NS3 is a serine protease required for processing of hepatitis C virus polyprotein”,
J. Virol
., 67, pp. 4017-4026 (1993)].
The HCV NS protein 3 (NS3) contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. It is known that mutations in the yellow fever virus NS3 protease decreases viral infectivity [Chambers, T. J. et. al., “Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein”,
Proc. Natl. Acad. Sci. USA
, 87, pp. 8898-8902 (1990)]. The first 181 amino acids of NS3 (residues 1027-1207 of the viral polyprotein) have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein [C. Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and Processing Kinetics”,
J. Virol
., 68, pp. 8147-8157 (1994)].
The HCV NS3 serine protease and its associated cofactor, NS4A, helps process all of the viral enzymes, and is thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing HIV protease inhibitors, which inhibit viral protein processing are potent antiviral agents in man, indicating that interrupting this stage of the viral life cycle results in therapeutically active agents. Consequently it is an attractive target for drug discovery. Unfortunately, there are no serine protease inhibitors available currently as anti-HCV agents.
Furthermore, the current understanding of HCV has not led to any other satisfactory anti-HCV agents or treatments. The only established therapy for HCV disease is interferon treatment. However, interferons have significant side effects (Janssen et al., 1994; Renault and Hoofnagle, 1989) [Janssen, H. L. A., et al. “Suicide Associated with Alfa-Interferon Therapy for Chronic Viral Hepatitis”
J. Hepatol
., 21, pp. 241-243 (1994)]; Renault, P. F. and Hoofnagle, J. H., “Side effects of alpha interferon. Seminars in Liver Disease 9, 273-277. (1989)] and induce long term remission in only a fraction (~25%) of cases [Weiland, O. “Interferon Therapy in Chronic Hepatitis C Virus Infection”,
FEMS Microbiol. Rev
., 14, PP. 279-288 (1994)]. Moreover, the prospects for effective anti-HCV vaccines remain uncertain.
Thus, there is a need for more effective anti-HCV therapies. Such inhibitors would have therapeutic potential as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS3 protease inhibitors. Specifically, such compounds may be useful as antiviral agents, particularly as anti-HCV agents.
SUMMARY OF THE INVENTION
The present invention provides compounds, and pharmaceutically acceptable derivatives thereof, that are useful as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS3 protease inhibitors. These compounds can be used alone or in combination with immunomodulatory agents, such as &agr;-, &bgr;- or &ggr;-interferons; other antiviral agents such as ribavirin and amantadine; other inhibitors of hepatitis C protease; inhibitors of other targets in the HCV life cycle including the helicase, polymerase, metalloprotease, or internal ribosome entry; or combinations thereof.
The present invention also provides methods for inhibiting proteases, particularly serine proteases, and more particularly HCV NS3 protease.
The present invention also provides pharmaceutical compositions comprising the compounds of this invention, as well as multi-component compositions comprising additional immunomodulatory agents, such as &agr;-, &bgr;- or &ggr;-interferons; other antiviral agents such as ribavirin and amantadine; other inhibitors of hepatitis C protease; inhibitors of other targets in the HCV life cycle including the helicase, polymera
Bhisetti Govinda Rao
Farmer Luc J.
Tung Roger D.
Coleman Brenda
Dixon Lisa A.
Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
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