IP Library › Granted Patent US 6,946,450
Granted Patent B2
US 6,946,450 · App. 10/437,802 · Granted Sep 20, 2005

β-L-2′-deoxy-nucleosides for the treatment of hepatitis B

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Quick Facts
Patent No.
US 6,946,450
App. No.
10/437,802
Granted
Sep 20, 2005
Kind
B2
Abstract

This invention is directed to a method for treating a host infected with hepatitis B comprising administering an effective amount of an anti-HBV biologically active 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof, wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside has the formula: wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may be optionally substituted. The 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof may be administered either alone or in combination with another 2′-deoxy-β-L-erythro-pentofuranonucleoside or in combination with another anti-hepatitis B agent.

Claims (91)

1. A method for treating a human infected with hepatitis B virus comprising administering an effective amount of the β-L-nucleoside:

or a pharmaceutically acceptable salt thereof,

wherein R is selected from the group consisting of H, mono, di or tri phosphate, an amino acid acyl residue, acyl, alkyl, and a stabilized phosphate prodrug.

2. The method according to claim 1 , wherein the compound is

or a phannaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the R is a monophosphate.

4. The method of claim 1 , wherein the R is a diphosphate.

5. The method of claim 1 , wherein the R is a triphosphate.

6. The method of claim 1 , wherein the R is an amino acid acyl residue.

7. The method of claim 1 , wherein the R is acyl.

8. The method of claim 1 , wherein the R is alkyl.

9. The method of claim 1 , wherein the R is a stabilized phosphate prodrug.

10. The method according to claim 1 , wherein the compound is administered in a pharmaceutically acceptable carrier.

11. The method according to claim 1 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

12. The method according to claim 1 , wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.

13. The method according to claim 1 , wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.

14. The method according to claim 1 , wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.

15. The method according to claim 1 , wherein the pharmaceutically acceptable carrier is suitabie for subcutaneous delivery.

16. The method according to claim 1 , wherein the pharmaceutically acceptable carrier is suitable for topical delivery.

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

18. The method according to claim 17 , wherein the dosage unit contains 10 to 1500 mg of the compound.

19. The method according to claim 17 or 18 , wherein the dosage unit is a tablet or capsule.

20. A method for treating a human infected with hepatitis B virus comprising administering an effective amount of the β-L-nucleoside:

or a pharmaceutically acceptable salt or thereof, in alternation or combination with one or more other anti-hepatitis agents,

wherein R is selected from the group consisting of H, mono, di or tri phosphate, an amino acid acyl residue, acyl, ailcyl, and a stabilized phosphate prodrug.

21. The method according to claim 20 , wherein the anti-hepatitis agent is selected from the group consisting of β-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxatbiolane (FTC), βL-2″-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU), β-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclo-pentyl]-6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]-adenine (PMEA, adefovir, dipivoxil); 9-((1R,2R,3S)-2,3-bis(hydroxyinethyl)cyclo-butyl)guanine (lobucavir), ganciclovir, and ribavirin.

22. The method according to claim 20 , wherein the anti-hepatitis agent is β-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC).

23. The method according to claim 20 , wherein the anti-hepatitis agent is cis-2-hydroxymcthyl-5-(5-fluorocytosin-1-yl)-1,3-oxatbiolane (FTC).

24. The method according to claim 20 , wherein the anti-hepatitis agent is L-2′-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU).

25. The method according to claim 20 , wherein the anti-hepatitis agent is β-D-2,6-diaminopurine dioxolane (DAPD).

26. The method according to claim 20 , wherein the anti-hepatitis agent is famicilovir.

27. The method according to claim 20 , wherein the anti-hepatitis agent is penciclovir.

28. The method according to claim 20 , wherein the anti-hepatitis agent is 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclo-pentyl]-6H-purin-6-one (entecavir, BMS-200475).

29. The method according to claim 20 , wherein the anti-hepatitis agent is 9-[2-(phosphono-methoxy)ethyl]-adenine (PMEA, adefovir, dipivoxil).

30. The method according to claim 20 , wherein the anti-hepatitis agent is 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclo-butyl)guanine (lobucavir).

31. The method according to claim 20 , wherein the anti-hepatitis agent is ganciclovir.

32. The method according to claim 20 , wherein the anti-hepatitis agent is ribavirin.

33. The method according to claim 20 , wherein the compound is administered in a pharmaceutically acceptable carrier.

34. The method according to claim 20 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

35. The method according to claim 20 , wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.

36. The method according to claim 20 , wherein the pharmaceutically acceptable carrier is suitable for parentcral delivery.

37. The method according to claim 20 , wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.

38. The method according to claim 20 , wherein the pharmaceutically acceptable carrier is suitable for subcutaneous delivery.

39. The method according to claim 20 , wherein the pharmaceutically acceptable carrier is suitable for topical delivery.

40. The method according to claim 20 , wherein the compound is in the form of a dosage unit.

41. The method according to claim 40 , wherein the dosage unit contains 10 to 1500 mg of the compound.

42. The method according to claim 40 and 41 , wherein the dosage unit is a tablet or capsule.

43. A pharmaceutical composition for treating a human infected with hepatitis B virus comprising an effective amount of the B-L-nucleoside:

or a pharmaceutically acceptable salt or thereof,

wherein R is selected from the group consisting of H, mono, di or tri phosphate, an amino acid acyl residue, acyl, alkyl, and a stabilized phosphate prodrug;

with one or more other anti-hepatitis agents; optionally in a pharmaceutically acceptable carrier.

44. The pharmaceutical composition of claim 43 , wherein the β-L-nucleoside is

or a pharmaceutically acceptable salt thereof.

45. The pharmaceutical composition according claim 43 , wherein the compound is the form of a dosage unit.

46. The pharmaceutical composition according to claim 45 , wherein the dosage unit contains 10 to 1500 mg of the compound.

47. The pharmaceutical composition according claim 43 , wherein the composition is administered in a pharmaceutically acceptable carrier.

48. The pharmaceutical composition according claim 43 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

49. The pharmaceutical composition according claim 43 , wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.

50. The pharmaceutical composition according claim 43 , wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.

51. The pharmaceutical composition according claim 43 , wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.

52. The pharmaceutical composition according claim 43 , wherein the pharmaceutically acceptable carrier is suitable for subcutaneous delivery.

53. The pharmaceutical composition according claim 43 , wherein the pharmaceutically acceptable carder is suitable for topical delivery.

54. The method according to claim 20 , wherein the R is a monophosphate.

55. The method according to claim 20 , wherein the R is a diphospbate.

56. The method according to claim 20 , wherein the R is a triphosphate.

57. The method according to claim 20 , wherein the R is an amino acid acyl residue.

58. The method according to claim 20 , wherein the R is acyl.

59. The method according to claim 20 , wherein the R is alkyl.

60. The method according to claim 20 , wherein the R is a stabilized phosphate prodrug.

61. The pharmaceutical composition according to claim 43 , wherein the R is a monophosphate.

62. The pharmaceutical composition according to claim 43 , wherein the R is a diphosphate.

63. The pharmaceutical composition according to claim 43 , wherein the R is a triphosphate.

64. The pharmaceutical composition according to claim 43 , wherein the R is an amino acid acyl residue.

65. The pharmaceutical composition according to claim 43 , wherein the R is acyl.

66. The pharmaceutical composition according to ciaim 43 , wherein the R is alkyl.

67. The pharmaceutical composition according to claim 43 , wherein the R is a stabilized phosphate prodrug.

68. The pharmaceutical composition according to claim 45 or 46 , wherein the dosage unit is a tablet or capsule.

69. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is selected from the group consisting of β-L-2-hydroxymcthyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), β-L-2′-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU), β-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclo-pentyl]-6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]-adenine (PMEA, adefovir, dipivoxil); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclo-butyl)guanine (lobucavir), ganciclovir, and ribavirin.

70. The phannaceutical composition according to claim 43 , wherein the anti-hepatitis agent is β-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC).

71. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC).

72. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is L-2′-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU).

73. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is β-D-2,6-diaminopurine dioxolane (DAPD).

74. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is famicilovir.

75. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is penciclovir.

76. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is 2-amino-1,9dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylene-cyclopentyl]-6H-purin-6-one (entecavir, BMS-200475).

77. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is 9-[2-(phosphono-methoxy)ethy]-adenine (PMEA, adefovir, dipivoxil).

78. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclo-butyl)guanine (lobucavir).

79. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is ganciclovir.

80. The pharmaceutical composition according to claim 43 , wherein the anti-hepatitis agent is ribavirin.

81. The method of claim 20 , wherein the β-L-nucleoside is

or a pharmaceutically acceptable salt thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 26, 2014
From: IDENIX PHARMACEUTICALS, INC.
To: NOVARTIS AG
Reel/Frame 032535/0402 →