METHODS AND COMPOSITIONS FOR TREATING HEPATITIS C VIRUS

• US 20130149283A1
• Filed: 12/28/2012
• Published: 06/13/2013
• Est. Priority Date: 05/23/2000
• Status: Active Grant

• 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, Paolo
• Granted Patent: US 10,363,265 B2
• Time in Patent Office: Days
• US Class Current: 424/85.4
• 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 to the host an anti-virally effective amount of a compound of Formula XVII:

2. The method of claim 1, wherein R¹ and R² are each independently H;

phosphate;

a stabilized phosphate prodrug;

acyl;

or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R¹ and R² are each independently H or phosphate.

3. The method of claim 1, wherein R¹ is hydrogen, acyl, or phosphate.

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

5. The method of claim 1, wherein R¹ is phosphate.

6. The method of claim 1, wherein R² is hydrogen or acyl.

7. The method of claim 1, wherein R² is hydrogen.

8. The method of claim 1, wherein R⁶ is alkyl.

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

10. The method of claim 1, wherein R⁷ and R⁹ are each independently hydrogen, OR², hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —

C(O)O(alkyl), —

C(O)O(lower alkyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), chloro, bromo, iodo, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂.

11. The method of claim 1, wherein R⁷ and R⁹ are each independently hydrogen, OR², alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —

O(alkenyl), chloro, bromo, iodo, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂.

12. The method of claim 1, wherein R⁷ and R⁹ are each independently hydrogen, OR², hydroxy, azido, cyano, alkynyl, chloro, bromo, iodo, or NH₂.

13. The method of claim 1, wherein R⁷ is hydroxy.

14. The method of claim 1, wherein R⁷ is azido.

15. The method of claim 1, wherein R⁷ is cyano.

16. The method of claim 1, wherein R⁷ is alkynyl.

17. The method of claim 16, wherein R⁷ is ethynyl.

18. The method of claim 1, wherein R⁷ is halo.

19. The method of claim 1, wherein R⁷ is chloro, bromo, or iodo.

20. The method of claim 1, wherein R⁷ is chloro.

21. The method of claim 1, wherein R⁷ is NH₂.

22. The method of claim 1, wherein R⁹ is hydroxy.

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

24. The method of claim 1, wherein R¹⁰ is H, alkyl, chloro, bromo, or iodo.

25. The method of claim 1, wherein R¹⁰ is hydrogen.

26. The method of claim 1, wherein X is O.

27. The method of claim 1, wherein Base is selected from the group consisting of cytosinyl, 5-azacytocinyl, 6-azacytosinyl, 5-fluorocytosinyl, 5-methylcytosinyl, 6-azapyrimidinyl, 2-mercaptopyrmidinyl, 4-mercaptopyrmidinyl, C⁵-alkylpyrimidinyls, C⁵-benzylpyrimidinyls, C⁵-halopyrimidinyls, C⁵-vinylpyrimidinyl, C⁵-acetylenic pyrimidinyl, C⁵-acyl pyrimidinyl, C⁵-amidopyrimidinyl, C⁵-cyanopyrimidinyl, C⁵-nitropyrimidinyl, C⁵-aminopyrimidinyl, thyminyl, uracilyl, 5-halouracilyl, 5-fluorouracilyl, and 5-azauracilyl.

28. The method of claim 1, wherein Base is cytosinyl, N-acetylcytosinyl, N,N-diacetyl)cytosinyl, N-methylcytosinyl, N-ethylcytosinyl, N-cyclopropylcytosinyl, thyminyl, 2,4-O-diacetylthyminyl, uracilyl, 5-fluorouracilyl, 4-O-acetyluracilyl, 2,4-O-diacetyluracilyl, 4-O-methyluracilyl, 4-O-ethyluracilyl, or 4-O-cyclopropyluracilyl.

29. The method of claim 1, wherein Base is cytosinyl, thyminyl, or uracilyl.

30. The method of claim 1, wherein Base is cytosinyl.

31. The method of claim 1, wherein Base is thyminyl.

32. The method of claim 1, wherein Base is uracilyl.

33. The method of claim 1, wherein Base is selected from the group consisting of:

34. The method of claim 1, wherein Base is selected from the group consisting of:

35. The method of claim 1, wherein:

Base is a pyrimidine base;

R¹ and R² are each independently H;

phosphate;

a stabilized phosphate prodrug;

acyl;

or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R¹ and R² are each independently H or phosphate;

R⁶ is alkyl;

R⁷ and R⁹ are each independently hydrogen, OR², hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —

C(O)O(alkyl), —

C(O)O(lower alkyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), chloro, bromo, iodo, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂;

R¹⁰ is H, alkyl, chloro, bromo, or iodo;

alternatively, R⁷ and R⁹, or R⁷ and R¹⁰ can come together to form a bond; and

X is O.

36. The method of claim 1, wherein:

Base is a pyrimidine base;

R¹ is hydrogen or phosphate;

R² is hydrogen or acyl;

R⁶ is alkyl;

R⁷ and R⁹ are each independently hydrogen, OR², hydroxy, azido, cyano, alkynyl, chloro, bromo, or iodo;

R¹⁰ is hydrogen; and

X is O.

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

73. The method of claim 72, wherein the second anti-hepatitis C virus agent is selected from the group consisting of interferon, ribavirin, a protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, and a helicase inhibitor.

74. The method of claim 72, wherein the second anti-hepatitis C virus agent is interferon.

75. The method of claim 72, wherein the second anti-hepatitis C virus agent is a protease inhibitor.

76. The method of claim 72, wherein the second anti-hepatitis C virus agent is ribavirin.

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

78. The method of claim 77, wherein the dosage unit contains from about 50 to about 1000 mg of the compound.

79. The method of claim 77, wherein the dosage unit is a tablet or capsule.

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

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

82. The method of claim 1, wherein the compound is at least 90% by weight of the 13-D-isomer.

83. The method of claim 1, wherein the compound is at least 95% by weight of the 13-D-isomer.

37. A method for the treatment of a hepatitis C virus infection in a host, comprising administering to the host an anti-virally effective amount of a compound of Formula X or XI:

38. The method of claim 37, wherein the compound has the structure of Formula V:

39. The method of claim 38, wherein:

R¹, R², and R³ are each independently H;

phosphate;

a stabilized phosphate prodrug;

acyl;

or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R¹, R², and R³ are each independently H or phosphate;

Y is hydrogen, bromo, chloro, fluoro, iodo, OR⁴, NR⁴R⁵, or SR⁴;

X¹ is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR⁴, NR⁴NR⁵, and SR⁵; and

each R⁴ and R⁵ is independently hydrogen, acyl, or alkyl.

40. The method of claim 37, wherein:

Base is a pyrimidine base;

R¹, R², and R³ are each independently H, phosphate, a stabilized phosphate prodrug, acyl, or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R¹ and R² are each independently H or phosphate;

R⁶ is hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —

C(O)O(alkyl), —

C(O)O(lower alkyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), chloro, bromo, fluoro, iodo, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂;

R⁷ is hydrogen, OR³, hydroxyl, azido, cyano, alkynyl, halo, or NH₂; and

X is O.

41. The method of claim 37, wherein R¹ and R² are each independently H;

phosphate;

a stabilized phosphate prodrug;

acyl;

or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R¹ and R² are each independently H or phosphate.

42. The method of claim 37, wherein R¹ is hydrogen, acyl, or phosphate.

43. The method of claim 37, wherein R¹ is hydrogen or phosphate.

44. The method of claim 37, wherein R¹ is phosphate.

45. The method of claim 37, wherein R² is hydrogen or acyl.

46. The method of claim 37, wherein R² is hydrogen.

47. The method of claim 37, wherein R⁶ is alkyl.

48. The method of claim 37, wherein R⁶ is methyl.

49. The method of claim 37, wherein R⁷ is hydrogen, OR², hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —

C(O)O(alkyl), —

C(O)O(lower alkyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), chloro, bromo, iodo, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂.

50. The method of claim 37, wherein R⁷ is hydrogen, OR², alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —

O(alkenyl), chloro, bromo, iodo, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂.

51. The method of claim 37, wherein R⁷ is hydrogen, OR², hydroxy, azido, cyano, alkynyl, chloro, bromo, iodo, or NH₂.

52. The method of claim 37, wherein R⁷ is hydroxy.

53. The method of claim 37, wherein R⁷ is azido.

54. The method of claim 37, wherein R⁷ is cyano.

55. The method of claim 37, wherein R⁷ is alkynyl.

56. The method of claim 55, wherein R⁷ is ethynyl.

57. The method of claim 37, wherein R⁷ is halo.

58. The method of claim 37, wherein R⁷ is chloro, bromo, or iodo.

59. The method of claim 37, wherein R⁷ is chloro.

60. The method of claim 37, wherein R⁷ is NH₂.

61. The method of claim 37, wherein X is O.

62. The method of claim 37, wherein Base is selected from the group consisting of cytosinyl, 5-azacytocinyl, 6-azacytosinyl, 5-fluorocytosinyl, 5-methylcytosinyl, 6-azapyrimidinyl, 2-mercaptopyrmidinyl, 4-mercaptopyrmidinyl, C⁵-alkylpyrimidinyls, C⁵-benzylpyrimidinyls, C⁵-halopyrimidinyls, C⁵-vinylpyrimidinyl, C⁵-acetylenic pyrimidinyl, C⁵-acyl pyrimidinyl, C⁵-amidopyrimidinyl, C⁵-cyanopyrimidinyl, C⁵-nitropyrimidinyl, C⁵-aminopyrimidinyl, thyminyl, uracilyl, 5-halouracilyl, 5-fluorouracilyl, and 5-azauracilyl.

63. The method of claim 37, wherein Base is cytosinyl, N-acetylcytosinyl, N,N-diacetyl)cytosinyl, N-methylcytosinyl, N-ethylcytosinyl, N-cyclopropylcytosinyl, thyminyl, 2,4-O-diacetylthyminyl, uracilyl, 5-fluorouracilyl, 4-O-acetyluracilyl, 2,4-O-diacetyluracilyl, 4-O-methyluracilyl, 4-O-ethyluracilyl, or 4-O-cyclopropyluracilyl.

64. The method of claim 37, wherein Base is cytosinyl, thyminyl, or uracilyl.

65. The method of claim 37, wherein Base is cytosinyl.

66. The method of claim 37, wherein Base is thyminyl.

67. The method of claim 37, wherein Base is uracilyl.

68. The method of claim 37, wherein Base is selected from the group consisting of:

69. The method of claim 39, wherein Base is selected from the group consisting of:

70. The method of claim 37, wherein:

Base is a pyrimidine base;

R¹, R², and R³ are each independently H;

phosphate;

a stabilized phosphate prodrug;

acyl;

or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R¹ and R² are each independently H or phosphate;

R⁶ is alkyl;

R⁷ is hydrogen, OR³, hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —

C(O)O(alkyl), —

C(O)O(lower alkyl), —

O(acyl), —

O(lower acyl), —

O(alkyl), —

O(lower alkyl), —

O(alkenyl), chloro, bromo, iodo, NO₂, NH₂, —

NH(lower alkyl), —

NH(acyl), —

N(lower alkyl)₂, or —

N(acyl)₂; and

X is O.

71. The method of claim 37, wherein:

Base is a pyrimidine base;

R¹ is hydrogen or phosphate;

R² is hydrogen or acyl;

R⁶ is alkyl;

R⁷ is hydrogen, OR², hydroxy, azido, cyano, alkynyl, chloro, bromo, iodo, or NH₂;

R¹⁰ is hydrogen; and

X is O.

84. A method for inhibiting the replication of a hepatitis C virus in a host, comprising contacting the host with an anti-virally effective amount of a compound of Formula XVII:

85. The method of claim 84, wherein the host is a cell.

86. A method for inhibiting the replication of a hepatitis C virus in a host, comprising contacting the host with an anti-virally effective amount of a compound of Formula X or XI:

87. The method of claim 86, wherein the host is a cell.

88. A method for inhibiting the replication of a hepatitis C virus in a host, comprising contacting a polymerase of the host with an anti-virally effective amount of a compound of Formula XVII:

89. The method of claim 88, wherein the host is a cell.

90. A method for inhibiting the replication of a hepatitis C virus in a host, comprising contacting a polymerase of the host with an anti-virally effective amount of a compound of Formula X or XI:

91. The method of claim 90, wherein the host is a cell.