Methods and compositions for treating hepatitis C virus

• US 7,169,766 B2
• Filed: 06/20/2003
• Issued: 01/30/2007
• Est. Priority Date: 05/23/2000
• Status: Expired due to Term

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.), Universita' Degli Studi Di Bari (Repubblica Italiana)
• Inventors: Sommadossi, Jean-Pierre, LaColla, Paulo
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): OWENS JR, HOWARD V
• Application Number:
  US10/602,976
• Publication Number:
  US 20040101535A1
• Time in Patent Office: 1,320 Days
• Field of Search: 514/49, 514/25, 514/50, 514/44, 514/28.1, 536/28.1, 536/28.2, 536/27.1, 568/833, 549/5, 549/6
• US Class Current: 514/49
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: G03C 1/0051 Tabular grain emulsions

Abstract

A method and composition for treating a host infected with hepatitis C comprising administering an effective hepatitis C treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

Claims

1. A method for the treatment of a hepatitis C virus infection in a host, comprising administering an anti-virally effective amount of a β

-D nucleoside compound of formula;

2. The method of claim 1 for the treatment of a hepatitis C virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula:

3. The method of claim 1 for the treatment of a hepatitis C virus infection in a host, wherein, in the compound of Formula XVII:

R¹ is H, alkyl, chlorine, bromine or iodine;

R⁷ and R⁹ are independently OR¹, alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂;

R⁶ is alkyl, lower alkyl, chlorine, bromine or iodine; and

X is O, S, SO₂ or CH₂.

4. The method of claim 1 wherein R¹ is hydrogen or phosphate.

5. The method of claim 1 wherein R¹ is hydrogen, acyl or alkyl.

6. The method of claim 1 wherein R⁶ is alkyl or lower alkyl.

7. The method of claim 1 wherein R⁷ and R⁹ are independently OR¹ or hydroxy.

8. The method of claim 1 wherein R⁷ is hydroxy.

9. The method of claim 1 wherein R⁹ is hydroxy.

10. The method of claim 1 wherein R⁷ and R⁹ are hydroxy.

11. The method of claim 1 wherein R¹⁰ is hydrogen.

12. The method of claim 1 wherein X is O.

13. The method of claim 1 wherein

R¹ is hydrogen, alkyl, acyl, or phosphate;

R⁶ is alkyl or lower alkyl;

R⁷ and R⁹ are independently OR¹ or hydroxy;

R¹⁰ is hydrogen; and

X is O.

14. The method of claim 1, wherein the method comprises administering the compound or a pharmaceutically acceptable salt or ester thereof in combination or alternation with a second anti-hepatitis C virus agent.

15. The method of claim 14, wherein the second anti-hepatitis C virus agent is selected from the group consisting of consisting of interferon, ribavirin, a protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, and a helicase inhibitor.

16. The method of claim 15, wherein the second anti-hepatitis C virus agent is interferon.

17. The method of claim 15, wherein the second anti-hepatitis C virus agent is a protease inhibitor.

18. The method of claim 15, wherein the second anti-hepatitis C virus agent is ribavirin.

19. The method of claim 1, wherein the compound is in the form of a dosage unit.

20. The method of claim 19, wherein the dosage unit contains 50 to 1000 mg of said compound.

21. The method of claim 19, wherein said dosage unit is a tablet or capsule.

22. The method of claim 1, wherein the host is a human.

23. The method of claim 1, wherein the compound nucleoside is in substantially pure form.

24. The method of claim 1, wherein compound is at least 90% by weight of the β

-D-isomer.

25. The method of claim 1, wherein the compound is at least 95% by weight of the β

-D-isomer.

26. The method of claim 1, wherein the compound is at least 85% by weight of the β

-D-isomer.

27. The method of claim 1, wherein R⁶ is methyl.

28. The method of claim 13, wherein R⁶ is methyl.

29. The method of claim 1, wherein R⁶ is methyl, and R⁷ and R⁹ hydroxy.

30. The method of claim 1, wherein R⁶ is methyl, R⁷ and R⁹ are hydroxy;

and R¹⁰ is hydrogen.

31. The method of claim 1, wherein X is O;

R⁶ is methyl;

R⁷ and R⁹ are hydroxy; and

R¹⁰ is hydrogen.

32. The method of claim 31, wherein R¹ is H.

33. The method of claim 31, wherein R¹ is an acyl.

34. The method of claim 31, wherein R¹ is a phosphate.

35. The method of claim 31, wherein R¹ is an amino acid.

36. The method of claim 1, wherein the base is triazolopyridine.

37. The method of claim 1, wherein the base is imidazolopyridine.

38. The method of claim 1, wherein the base is pyrazolopyrimidine.

39. The method of any one of claims 31–

35, wherein the base is triazolopyridine.

40. The method of any one of claims 31–

35, wherein the base is imidazolopyridine.

41. The method of any one of claims 31–

35, wherein the base is pyrazolopyrimidine.

42. The method any one of claims 39–

41, wherein the method of comprises administering the compound or a pharmaceutically acceptable salt or ester thereof in combination or alternation with a second anti-hepatitis C virus agent.

43. The method of claim 42, wherein the second anti-hepatitis C virus agent is selected from the group consisting of consisting of interferon, ribavirin, a protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, and a helicase inhibitor.

44. The method of claim 42, wherein the second anti-hepatitis C virus agent is interferon.

45. The method of claim 42, wherein the second anti-hepatitis C virus agent is a protease inhibitor.

46. The method of claim 42, wherein the second anti-hepatitis C virus agent is ribavirin.

47. The method of any one of claims 39–

46, wherein the host is a human.

48. The method of any one of claims 39–

46, wherein the host is a cell.

49. The method of claim 1, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

50. The method of claim 1, wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.

51. The method of claim 1, wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.

52. The method of claim 1, wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.

53. The method of claim 1, wherein the pharmaceutically acceptable carrier is suitable for subcutaneous delivery.

54. The method of claim 1, wherein the pharmaceutically acceptable carrier is suitable for topical delivery.

55. The method of claim 1, wherein the host is a cell.