N4-acylcytosine nucleosides for treatment of viral infections

• US 20040214844A1
• Filed: 12/13/2002
• Published: 10/28/2004
• Est. Priority Date: 12/14/2001
• Status: Active Grant

• Current Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Otto, Michael J., Watanabe, Kyoichi A., Shi, Junxing
• Granted Patent: US 7,105,527 B2
• Time in Patent Office: Days
• US Class Current: 514/269
• 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 31/22 for herpes viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

The present invention is directed to a method and composition of treating or preventing viral infections, in particular, human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections, in human patients or other animal hosts, comprising the administration of N⁴-acyl-2′,3′-dideoxy-5-fluorocytidine or N⁴-acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof.

Claims

1. A compound of the following formula:

2. A pharmaceutical composition that comprises an effective HIV treatment amount of a compound of claim 1 in a pharmaceutically acceptable carrier or diluent.

3. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

4. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

5. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

6. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier in combination with another anti-HBV agent.

7. The compound of claim 1 wherein R¹ is fluorine.

8. The compound of claim 1 wherein R³ and R^3′

is are H.

12. The compound of claim 1 selected from the group consisting of

β

-D-N⁴-p-bromobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-fluorobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-chlorobeenzoyl-2′

,3′

-didehydro-2′

3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-iodobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-ethylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine, and

β

-D-N⁴-p-t-butylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine.

14. The pharmaceutical composition of claim 2 wherein the compound is selected from the group consisting of

β

-D-N⁴-p-bromobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-fluorobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-chlorobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-iodobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-ethylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine, and

β

-D-N⁴-p-t-butylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine.

16. The method of claim 3 wherein the compound is selected from the group consisting of

β

-D-N⁴-p-bromobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-fluorobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-chlorobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-iodobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-ethylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine, and

β

-D-N⁴-p-t-butylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine.

28. The compound of claim 1 wherein R² is cycloalkyl.

29. The compound of claim 1 wherein R² is C₆H₄R⁶.

30. The compound of claim 29 wherein R⁶ is halogen.

31. The compound of claim 29 wherein R⁶ is alkyl.

32. The compound of claim 29 wherein R⁶ is NO₂.

33. The compound of claim 29 wherein R⁶ is alkoxy.

34. The compound of claim 1 wherein R¹ is hydrogen.

35. The compound of claim 1 wherein R¹ is halogen.

36. A pharmaceutical composition that comprises an effective HBV treatment amount of a compound of claim 1 in a pharmaceutically acceptable carrier or diluent.

39. The composition of one of claims 2 or 36-38 wherein the composition is suitable for oral administration.

40. The composition of one of claims 2 or 36-38 wherein the composition is suitable for intravenous administration.

41. The composition of one of claims 2 or 36-38 wherein the compound is in a dosage unit.

42. The composition of claim 41 wherein the dosage form is a tablet or capsule.

43. The composition of claim 41 wherein the dosage unit contains 70-1400 mg of active ingredient.

44. The composition of claim 41 wherein the dosage unit contains 50-1000 mg of active ingredient.

45. The composition of claim 2 or 37 further comprising another anti-HIV agent.

46. The composition of claim 36 or 38 further comprising another anti-HBV agent.

11. (Canceled)

13. (Canceled)

15. (Canceled)

17. A compound selected from the following, or its pharmaceutically acceptable salt:

9. The method of one of claims 3-6 or 18-21 wherein R¹ is hydrogen or fluorine.

10. The method of one of claims 3-6 or 18-21 wherein R³ and R^3′

are H.

18. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 17 in a pharmaceutically acceptable carrier.

19. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 17 in a pharmaceutically acceptable carrier.

20. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 17 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

21. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 17 in a pharmaceutically acceptable carrier in combination with another anti-HBV agent.

22. The method of claim 18 wherein the compound is selected from:

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine of the structure;

β

-D-N⁴-(4-chlorobenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-(4-bromobenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

or a pharmaceutically acceptable salt thereof.

23. The method of claim 18 wherein the compound is selected from:

β

-D-N⁴-p-anisoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(3-nitrobenzoyl)cytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-p-toluoylcytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-m-toluoylcytidine of the structure;

β

-D-N⁴-(4-t-butylbenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

or a pharmaceutically acceptable salt thereof.

24. The method of claim 18 wherein the compound is selected from:

β

-D-N⁴-cyclopentanecarbonyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-(cyclohexanecarbonyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

or a pharmaceutically acceptable salt thereof.

25. The method of claim 19 wherein the compound is selected from:

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine of the structure;

β

-D-N⁴-(4-chlorobenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-(4-bromobenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

or a pharmaceutically acceptable salt thereof.

26. The method of claim 19 wherein the compound is selected from:

β

-D-N⁴-p-anisoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(3-nitrobenzoyl)cytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-p-toluoylcytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-m-toluoylcytidine of the structure;

β

-D-N⁴-(4-t-butylbenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

or a pharmaceutically acceptable salt thereof.

27. The method of claim 19 wherein the compound is selected from:

β

-D-N⁴-cyclopentanecarbonyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-(cyclohexanecarbonyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition that comprises an effective HIV treatment amount of a compound of claim 17 in a pharmaceutically acceptable carrier or diluent.

38. A pharmaceutical composition that comprises an effective HBV treatment amount of a compound of claim 17 in a pharmaceutically acceptable carrier or diluent.