Details for Patent: 7,012,066

Title:	Peptides as NS3-serine protease inhibitors of hepatitis C virus
Abstract:	The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.
Inventor(s):	Saksena; Anil K. (Upper Montclair, NJ), Girijavallabhan; Viyyoor Moopil (Parsippany, NJ), Lovey; Raymond G. (West Caldwell, NJ), Jao; Edwin (Warren, NJ), Bennett; Frank (Piscataway, NJ), Mc Cormick; Jinping L. (Edison, NJ), Wang; Haiyan (Cranbury, NJ), Pike; Russell E. (Stanhope, NJ), Bogen; Stephane L. (Somerset, NJ), Chan; Tin-Yau (Edison, NJ), Liu; Yi-Tsung (Morris Township, NJ), Zhu; Zhaoning (East Windsor, NJ), Njoroge; F. George (Warren, NJ), Arasappan; Ashok (Bridgewater, NJ), Parekh; Tejal (Mountain View, CA), Ganguly; Ashit K. (Upper Montclair, NJ), Chen; Kevin X. (Iselin, NJ), Venkatraman; Srikanth (Fords, NJ), Vaccaro; Henry A. (South Plainfield, NJ), Pinto; Patrick A. (Morris Plains, NJ), Santhanam; Bama (Bridgewater, NJ), Kemp; Scott Jeffrey (San Diego, CA), Levy; Odile Esther (San Diego, CA), Lim-Wilby; Marguerita (La Jolla, CA), Tamura; Susan Y. (Santa Fe, NM), Wu; Wanli (Edison, NJ), Hendrata; Siska (Edison, NJ), Huang; Yuhua (Scotch Plains, NJ)
Assignee:	Schering Corporation (Kenilworth, NJ) Dendreon Corporation (Seattle, WA)
Filing Date:	Jul 19, 2001
Application Number:	09/908,955
Claims:	1. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being selected from the compounds of structures listed below: ##STR01939## ##STR01940## ##STR01941## ##STR01942## ##STR01943## ##STR01944## ##STR01945## ##STR01946## ##STR01947## ##STR01948## ##STR01949## ##STR01950## ##STR01951## ##STR01952## ##STR01953## ##STR01954## ##STR01955## ##STR01956## ##STR01957## ##STR01958## ##STR01959## ##STR01960## ##STR01961## ##STR01962## ##STR01963## ##STR01964## ##STR01965## ##STR01966## ##STR01967## ##STR01968## ##STR01969## ##STR01970## ##STR01971## ##STR01972## ##STR01973## ##STR01974## ##STR01975## ##STR01976## ##STR01977## ##STR01978## ##STR01979## ##STR01980## ##STR01981## ##STR01982## ##STR01983## ##STR01984## ##STR01985## ##STR01986## ##STR01987## ##STR01988## ##STR01989## ##STR01990## ##STR01991## ##STR01992## ##STR01993## ##STR01994## ##STR01995## ##STR01996## ##STR01997## ##STR01998## ##STR01999## ##STR02000## ##STR02001## ##STR02002## ##STR02003## ##STR02004## ##STR02005## ##STR02006## ##STR02007## 2. A pharmaceutical composition for treating disorders associated with hepatitis C virus (HCV), said composition comprising therapeutically effective amount of one or more compounds in claim 1 and a pharmaceutically acceptable carrier. 3. The pharmaceutical composition of claim 2, additionally containing an antiviral agent. 4. The pharmaceutical composition of claim 3, further containing an interferon or pegylated-interferon alpha conjugate. 5. The pharmaceutical composition of claim 4, wherein said antiviral agent is ribavirin and said interferon is .alpha.-interferon. 6. A method of treatment of a hepatitis C virus associated disorder, comprising administering an effective amount of one or more compounds of claim 1. 7. A method of modulating the activity of hepatitis C virus (HCV) protease, comprising contacting HCV protease with one or more compounds of claim 1. 8. A method of treating, or ameliorating one or more symptoms of hepatitis C, comprising administering an effective amount of one or more compounds of claim 1. 9. The method of claim 7, wherein the HCV protease is the NS3/NS4a protease. 10. The method of claim 9, wherein the compound or compounds inhibit HCV NS3/NS4a protease. 11. A method of modulating the processing of hepatitis C virus (HCV) polypeptide, comprising contacting a composition containing the HCV polypeptide under conditions in which the polypeptide is processed with one or more compounds of claim 1. 12. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02008## 13. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02009## 14. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being compound of structure shown below: ##STR02010## 15. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02011## 16. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02012## 17. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02013## 18. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02014## 19. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02015## 20. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02016## 21. A compound exhibiting hepatitis C virus (HCV) protease inhibitory activity, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being the compound of structure shown below: ##STR02017## 22. A pharmaceutical composition comprising as an active ingredient a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being compound of structure shown below: ##STR02018## ##STR02019## 23. The pharmaceutical composition of claim 22, additionally containing an antiviral agent. 24. The pharmaceutical composition of claim 23, further containing an interferon or pegylated-interferon alpha conjugate. 25. The pharmaceutical composition of claim 24, wherein said antiviral agent is ribavirin and said interferon is .alpha.-interferon. 26. A compound of claim 12, which has the formula shown below: ##STR02020## 27. A compound of claim 12, which has the formula shown below: ##STR02021## 28. A compound of claim 13, which has the formula shown below: ##STR02022## 29. A compound of claim 13, which has the formula shown below: ##STR02023## 30. A compound of claim 14, which has the formula shown below: ##STR02024## 31. A compound of claim 14, which has the formula shown below: ##STR02025## 32. A compound of claim 15, which has the formula shown below: ##STR02026## 33. A compound of claim 15, which has the formula shown below: ##STR02027## 34. A compound of claim 16, which has the formula shown below: ##STR02028## 35. A compound of claim 16, which has the formula shown below: ##STR02029## 36. A compound of claim 17, which has the formula shown below: ##STR02030## 37. A compound of claim 17, which has the formula shown below: ##STR02031## 38. A compound of claim 18, which has the formula shown below: ##STR02032## 39. A compound of claim 18, which has the formula shown below: ##STR02033## 40. A compound of claim 19, which has the formula shown below: ##STR02034## 41. A compound of claim 19, which has the formula shown below: ##STR02035## 42. A compound of claim 20, which has the formula shown below: ##STR02036## 43. A compound of claim 20, which has the formula shown below: ##STR02037## 44. A compound of claim 21, which has the formula shown below: ##STR02038## 45. A compound of claim 21, which has the formula shown below: ##STR02039## 46. The pharmaceutical composition of claim 22, wherein said compound is selected from the following: ##STR02040## ##STR02041## ##STR02042## ##STR02043## 47. The pharmaceutical composition of claim 46, additionally containing an antiviral agent. 48. The pharmaceutical composition of claim 47, additionally containing an interferon or pegylated-interferon alpha conjugate. 49. The pharmaceutical composition of claim 48, wherein said antiviral agent is ribavirin and said interferon is alpha-interferon. 50. A method of treating disorders associated with the HCV, said method comprising administering to a patient in need of such treatment, a pharmaceutical composition which comprises therapeutically effective amounts of a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound being selected from the following: ##STR02044## ##STR02045## 51. The method of claim 50, wherein said compound is selected from the following: ##STR02046## ##STR02047## ##STR02048## ##STR02049## 52. A method of treating disorders associated with the hepatitis C virus (HCV), said method comprising administering to a patient in need of such treatment, a compound of claim 1 and an interferon. 53. The method of claim 52, wherein said interferon is alpha-interferon or pegylated interferon. 54. The method of claim 53, wherein said administration is oral or subcutaneous. 55. A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment, a compound of claim 1 and an interferon. 56. The method of claim 55, wherein said interferon is alpha-interferon or pegylated interferon. 57. The method of claim 56, wherein said administration is oral or subcutaneous. 58. A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 22 and an interferon. 59. The method of claim 58, wherein said interferon is alpha-interferon or pegylated interferon. 60. The method of claim 59, wherein said administration is oral or subcutaneous. 61. The method of claim 52 wherein said treatment further comprising administering an antiviral agent. 62. A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a compound of any one of claims 26-45 and an interferon. 63. A method of treating disorders associated with the hepatitis C virus (HCV), comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 46 and an interferon. 64. The method of claim 51, further comprising administering an interferon.