NOVEL INHIBITORS OF HEPATITIS C VIRUS REPLICATION

• US 20080019942A1
• Filed: 07/05/2007
• Published: 01/24/2008
• Est. Priority Date: 07/05/2006
• Status: Active Grant

• Current Assignee: Array Biopharma Incorporated (Pfizer Inc.), Intermune Incorporated (Roche Holding AG)
• Original Assignee: Intermune Incorporated (Roche Holding AG)
• Inventors: Beigelman, Leonid, Seiwert, Scott, Kennedy, April, Kercher, Timothy, Blatt, Lawrence, Andrews, Steven
• Granted Patent: US 7,781,474 B2
• Time in Patent Office: Days
• US Class Current: 424/85.5
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The embodiments provide compounds of the general Formula I, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments provide compounds of the general Formula II, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments provide compounds of the general Formula III, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

Claims

1. A compound of the formula (I):

2. The compound of claim 1, wherein R³ and R⁴ are each independently substituted or unsubstituted moieties selected from the group consisting of H and C_1-8 alkyl, or R³ and R⁴ taken together form a substituted or unsubstituted C_3-7 cycloalkyl ring.

3. The compound of claim 1, wherein R⁵ is H.

4. The compound of claim 1, wherein R⁵ is methyl.

5. The compound of claim 1, wherein R⁵ is —

C_1-8alkyl-NHC(O)OR^1a.

6. The compound of claim 5, wherein R⁵ is —

CH₂NHC(O)OR^1a.

7. The compound of claim 6, wherein R⁵ is —

CH₂NHC(O)O-tert-butyl.

8. The compound of claim 1, wherein Y has a formula selected from the group consisting of —

C(O)NHS(O)₂R^1a, —

C(O)NHS(O)₂NR^1aR^1b, —

C(O)C(O)NR^1aR^1b, C(O)C(O)OH, —

C(O)NHR^1a, and —

C(O)OH.

9. The compound of claim 1, wherein Y has a formula selected from the group consisting of —

C(O)NHS(O)₂R^1a, —

C(O)OR^1a, and —

C(O)OH.

10. The compound of claim 9, wherein R^1a is a substituted or unsubstituted group selected from the group consisting of H, C_1-6 alkyl, and C_3-7 cycloalkyl.

11. The compound of claim 9, wherein R^1a is a substituted or unsubstituted group selected from the group consisting of H, C_1-6 alkyl, and C_7-10 arylalkyl.

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

27. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to claim 1.

28. A method of inhibiting NS3/NS4 protease activity comprising contacting a NS3/NS4 protease with a compound according to claim 1.

29. The method of claim 28 in which the contacting is conducted in vivo.

30. The method of claim 29, further comprising identifying a subject suffering from a hepatitis C infection and administering the compound to the subject in an amount effective to treat the infection.

31. The method of claim 28, wherein the method further comprises administering to an individual an effective amount of a nucleoside analog.

32. The method of claim 31, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

33. The method of claim 30, wherein the method further comprises administering to the subject an effective amount of a human immunodeficiency virus 1 protease inhibitor.

34. The method of claim 33, wherein the protease inhibitor is ritonavir.

35. The method of claim 30, wherein the method further comprises administering to the subject an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

36. The method of claim 30, wherein the method further comprises administering to the subject an effective amount of interferon-gamma (IFN-γ

).

37. The method of claim 36, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

38. The method of claim 30, wherein the method further comprises administering to the subject an effective amount of interferon-alpha (IFN-α

).

39. The method of claim 38, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

40. The method of claim 38, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

41. The method of claim 38, wherein the IFN-α

is INFERGEN consensus IFN-α

.

42. The method of claim 30, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.

43. The method of claim 30, wherein a sustained viral response is achieved.

44. The method of claim 28, in which the contacting is conducted ex vivo.

45. A method of of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of a composition of claim 27.

46. The method of claim 45, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.

47. The method of claim 46, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

48. The method of claim 45, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.

49. The method of method of claim 48, wherein the protease inhibitor is ritonavir.

50. The method of claim 45, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

51. The method of claim 45, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ

).

52. The method of claim 51, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

53. The method of claim 45, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α

).

54. The method of claim 53, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

55. The method of claim 53, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

56. The method of claim 53, wherein the IFN-α

is INFERGEN consensus IFN-α

.

57. The method of claim 45, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.

58. A method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a composition of claim 27.

59. The method of claim 58, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.

60. The method of claim 59, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

61. The method of claim 58, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.

62. The method of method of claim 61, wherein the protease inhibitor is ritonavir.

63. The method of claim 58, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

64. The method of claim 58, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ

).

65. The method of claim 64, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

66. The method of claim 58, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α

).

67. The method of claim 66, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

68. The method of claim 66, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

69. The method of claim 66, wherein the IFN-α

is INFERGEN consensus IFN-α

.

70. The method of claim 58, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.

13. A compound of the formula (II):

14. The compound of claim 13 in which L consists of from 2 to 5 atoms.

15. The compound of claim 13 in which L comprises a —

W—

C(═

V)—

group, where V and W are each individually selected from O, S or NH.

16. The compound of claim 13 in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.

17. The compound of claim 13 in which P₂ is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, and Gln80.

71. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to claim 13.

72. A method of inhibiting NS3/NS4 protease activity comprising contacting a NS3/NS4 protease with a compound according to claim 13.

73. The method of claim 72 in which the contacting is conducted in vivo.

74. The method of claim 73, further comprising identifying a subject suffering from a hepatitis C infection and administering the compound to the subject in an amount effective to treat the infection.

75. The method of claim 72, wherein the method further comprises administering to an individual an effective amount of a nucleoside analog.

76. The method of claim 75, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

77. The method of claim 74, wherein the method further comprises administering to the subject an effective amount of a human immunodeficiency virus 1 protease inhibitor.

78. The method of claim 77, wherein the protease inhibitor is ritonavir.

79. The method of claim 74, wherein the method further comprises administering to the subject an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

80. The method of claim 74, wherein the method further comprises administering to the subject an effective amount of interferon-gamma (IFN-γ

).

81. The method of claim 80, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

82. The method of claim 74, wherein the method further comprises administering to the subject an effective amount of interferon-alpha (IFN-α

).

83. The method of claim 82, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

84. The method of claim 82, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

85. The method of claim 82, wherein the IFN-α

is INFERGEN consensus IFN-α

.

86. The method of claim 74, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.

87. The method of claim 74, wherein a sustained viral response is achieved.

88. The method of claim 72, in which the contacting is conducted ex vivo.

89. A method of of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of a composition of claim 71.

90. The method of claim 89, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.

91. The method of claim 90, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

92. The method of claim 89, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.

93. The method of method of claim 92, wherein the protease inhibitor is ritonavir.

94. The method of claim 89, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

95. The method of claim 89, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ

).

96. The method of claim 95, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

97. The method of claim 89, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α

).

98. The method of claim 97, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

99. The method of claim 97, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

100. The method of claim 97, wherein the IFN-α

is INFERGEN consensus IFN-α

.

101. The method of claim 89, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.

102. A method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a composition of claim 71.

103. The method of claim 102, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.

104. The method of claim 103, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

105. The method of claim 102, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.

106. The method of method of claim 105, wherein the protease inhibitor is ritonavir.

107. The method of claim 102, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

108. The method of claim 102, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ

).

109. The method of claim 108, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

110. The method of claim 102, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α

).

111. The method of claim 110, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

112. The method of claim 110, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

113. The method of claim 110, wherein the IFN-α

is INFERGEN consensus IFN-α

.

114. The method of claim 102, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.

18. A compound of the formula (III):

19. The compound of claim 18, wherein R³ and R⁴ are each independently substituted or unsubstituted moieties selected from the group consisting of H and C_1-8 alkyl, or R³ and R⁴ taken together form a substituted or unsubstituted C_3-7 cycloalkyl ring.

20. The compound of claim 18, wherein R^5a is H.

21. The compound of claim 18, wherein Y has a formula selected from the group consisting of —

C(O)NHS(O)₂R^1a, —

C(O)NHS(O)₂NR^1aR^1b, —

C(O)C(O)NR^1aR^1b, C(O)C(O)OH, —

C(O)NHR^1a, and —

C(O)OH.

22. The compound of claim 18, wherein Y has a formula selected from the group consisting of —

C(O)NHS(O)₂R^1a, —

C(O)OR^1a, and —

C(O)OH.

23. The compound of claim 22, wherein R^1a is a substituted or unsubstituted group selected from the group consisting of H, C_1-6 alkyl, and C_3-7 cycloalkyl.

24. The compound of claim 18, wherein Z is CH₂ or has a formula selected from the group consisting of —

NC(O)R^2a, —

NC(O)OR^2a, and —

NR^2a.

25. The compound of claim 24, wherein R^2a is a substituted or unsubstituted group selected from the group consisting of H, C_1-6 alkyl, and C_7-10 arylalkyl.

26. The compound of claim 18 selected from the group consisting of:

115. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to claim 18.

116. A method of inhibiting NS3/NS4 protease activity comprising contacting a NS3/NS4 protease with a compound according to claim 18.

117. The method of claim 116 in which the contacting is conducted in vivo.

118. The method of claim 117, further comprising identifying a subject suffering from a hepatitis C infection and administering the compound to the subject in an amount effective to treat the infection.

119. The method of claim 116, wherein the method further comprises administering to an individual an effective amount of a nucleoside analog.

120. The method of claim 119, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

121. The method of claim 118, wherein the method further comprises administering to the subject an effective amount of a human immunodeficiency virus 1 protease inhibitor.

122. The method of claim 121, wherein the protease inhibitor is ritonavir.

123. The method of claim 118, wherein the method further comprises administering to the subject an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

124. The method of claim 118, wherein the method further comprises administering to the subject an effective amount of interferon-gamma (IFN-γ

).

125. The method of claim 124, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

126. The method of claim 118, wherein the method further comprises administering to the subject an effective amount of interferon-alpha (IFN-α

).

127. The method of claim 126, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

128. The method of claim 126, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

129. The method of claim 126, wherein the IFN-α

is INFERGEN consensus IFN-α

.

130. The method of claim 118, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.

131. The method of claim 118, wherein a sustained viral response is achieved.

132. The method of claim 116, in which the contacting is conducted ex vivo.

133. A method of of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of a composition of claim 115.

134. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.

135. The method of claim 134, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

136. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.

137. The method of method of claim 136, wherein the protease inhibitor is ritonavir.

138. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

139. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ

).

140. The method of claim 139, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

141. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α

).

142. The method of claim 141, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

143. The method of claim 141, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

144. The method of claim 141, wherein the IFN-α

is INFERGEN consensus IFN-α

.

145. The method of claim 133, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.

146. A method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a composition of claim 115.

147. The method of claim 146, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.

148. The method of claim 147, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

149. The method of claim 146, wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor.

150. The method of method of claim 149, wherein the protease inhibitor is ritonavir.

151. The method of claim 146, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

152. The method of claim 146, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ

).

153. The method of claim 152, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

154. The method of claim 146, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α

).

155. The method of claim 154, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

156. The method of claim 154, wherein the IFN-α

is monoPEG-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

157. The method of claim 154, wherein the IFN-α

is INFERGEN consensus IFN-α

.

158. The method of claim 146, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.