3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections

• US 7,094,770 B2
• Filed: 04/13/2001
• Issued: 08/22/2006
• Est. Priority Date: 04/13/2000
• Status: Expired due to Fees

• Current Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Original Assignee: Pharmasset Ltd (Gilead Sciences Inc.)
• Inventors: Pai, S. Balakrishna, Watanabe, Kyoichi A.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): McIntosh, III, Traviss C.
• Application Number:
  US09/834,596
• Publication Number:
  US 20020055483A1
• Time in Patent Office: 1,957 Days
• Field of Search: 514/45, 514/46, 514/47, 514/48, 514/49, 514/50, 514/51, 536/28.1, 536/28.2, 536/28.4
• US Class Current: 514/49
• 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 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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

Abstract

The present invention relates to a composition for and a method of treating hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, hepatitis D virus (HDV) infection or a proliferative disorder in a patient using an effective amount of a compound selected from the group consisting of formulas [I]–[IV] below and mixtures of two or more thereof:

wherein the substituents are as defined herein. Pharmaceutical compositions comprising these compounds in combination with other HBV, HCV, or HDV agents is also disclosed.

Claims

1. A method for the treatment of hepatitis C virus (HCV) infection comprising administering to a host in need thereof an anti-HCV effective amount of a compound selected from the group consisting of formulas [I]–

[IV] below and mixtures of two or more thereof;

2. The method of claim 1, further comprising administering the compound in combination or alternation with one or more additional anti-HCV agents.

3. The method of claim 2, wherein the additional HCV agent is selected from the group consisting of interferon, macrokine, heptazyme, ribavarin, amantadine, ofloxacin, zadaxin and reticulose.

11. The method of claim 1, wherein the compound is Formula I.

12. The method of claim 1, wherein the compound is Formula II.

13. The method of claim 1, wherein the compound is Formula III.

14. The method of claim 1, wherein the compound is Formula IV.

15. The method of claim 11, wherein R is H.

16. The method of claim 12, wherein R is H.

17. The method of claim 13, wherein R is H.

18. The method of claim 14, wherein R is H.

4. A method for the treatment of hepatitis D virus (HDV) infection comprising administering to a host in need thereof an anti-HDV effective amount of a compound selected from the group consisting of formulas [I]–

[IV] below and mixtures of two or more thereof;

5. The method of claim 4, further comprising administering the compound in combination or alternation with one or more additional anti-HDV agents.

6. The method of claim 5, wherein the additional HDV agent is selected from the group consisting of FTC, L-FMAU, interferon, beta-D-dioxolanyl-guanine (DXG), beta-D-dioxolanyl-2,6-diaminopurine (DAPD), beta-D-dioxolanyl-6-chloropurine (ACP), beta-D-dioxolanyl-2-aminopurine (ADP), famciclovir, penciclovir, bis-POM PMEA (adefovir dipivoxil);

lobucavir, ganciclovir, ribavarin, lamivudine (3TC), L-thymidine (L-dT), L-2′

-deoxycytidine (L-dT), L-2′

-deoxycytidine-3′

, 5′

-diO-valyl (D or L), entecavir (BMS-200475), adefovir, L-D4FC, D-D4FC, and mycophenolic acid (an IMPDH inhibitor).

19. The method of claim 4, wherein the compound is Formula I.

20. The method of claim 4, wherein the compound is Formula II.

21. The method of claim 4, wherein the compound is Formula III.

22. The method of claim 4, wherein the compound is Formula IV.

23. The method of claim 19, wherein R is H.

24. The method of claim 20, wherein R is H.

25. The method of claim 21, wherein R is H.

26. The method of claim 22, wherein R is H.

7. A pharmaceutical composition for the treatment of HCV comprising an anti-HCV agent and an anti-HCV effective amount of a compound selected from the group consisting of formulas [I]–

[IV] below and mixtures of two or more thereof;

27. The pharmaceutical composition of claim 7, wherein the compound is Formula I.

28. The pharmaceutical composition of claim 7, wherein the compound is Formula II.

29. The pharmaceutical composition of claim 7, wherein the compound is Formula III.

30. The pharmaceutical composition of claim 7, wherein the compound is Formula IV.

31. The pharmaceutical composition of claim 27, wherein R is H.

32. The pharmaceutical composition of claim 28, wherein R is H.

33. The pharmaceutical composition of claim 29, wherein R is H.

34. The pharmaceutical composition of claim 30, wherein R is H.

8. A pharmaceutical composition for the treatment of HDV comprising an anti-HDV agent and an anti-HDV effective amount of a compound selected from the group consisting of formulas [I]–

[IV] below and mixtures of two or more thereof;

35. The pharmaceutical composition of claim 8, wherein the compound is Formula I.

36. The pharmaceutical composition of claim 8, wherein the compound is Formula II.

37. The pharmaceutical composition of claim 8, wherein the compound is Formula III.

38. The pharmaceutical composition of claim 8, wherein the compound is Formula IV.

39. The pharmaceutical composition of claim 35, wherein R is H.

40. The pharmaceutical composition of claim 36, wherein R is H.

41. The pharmaceutical composition of claim 37, wherein R is H.

42. The pharmaceutical composition of claim 38, wherein R is H.

9. A process for stereospecifically preparing a 5′

-modified pyrimidine β

-nucleoside comprising;

a. applying the Mitsunobu reaction to a chiral compound of the formula;

10. The process of claim 9, wherein the acid labile agent is selected from the group consisting of tetrahydropyranyl (THP), a trityl group, or dimethyl-t-butylsilyl (DBMS).