COMBINATION THERAPY FOR TREATMENT OF VIRAL INFECTIONS

• US 20080131398A1
• Filed: 08/21/2007
• Published: 06/05/2008
• Est. Priority Date: 08/21/2006
• Status: Abandoned Application

• Current Assignee: United Therapeutics Corporation, University of Oxford
• Original Assignee: United Therapeutics Corporation
• Inventors: Gotzkowsky, S. Karl, JEFFS, Roger, Zitzmann, Nicole, Dwek, Raymond Allen
• Application Number:
  US11/842,569
• Publication Number:
  US 20080131398A1
• Time in Patent Office: Days
• US Class Current: 424/85.4
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/45 having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• 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: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

One can treat a viral infection by first administering at least one first antiviral compound for a first time period and then, after the end of the first time period, concurrently or subsequently administering the at least one first antiviral compound and at least one second antiviral compound for a second period. In some cases, after the end of the second period, the same at least one second antiviral compound that was administered during the second time period may be administered for a third time period without concurrent or subsequent administration of the at least one first antiviral compound.

Claims

1. A method of treating a viral infection comprising

(A) administering to a subject in need thereof at least one first antiviral agent for a first time period, wherein said at least one first antiviral agent does not inhibit host α

-glucosidase; and

(B) after the first time period, sequentially or concurrently administering to the subject the at least one first antiviral agent and at least one second antiviral agent for a second time period, wherein the at least one second antiviral agent inhibits host α

-glucosidase.

2. The method of claim 1, further comprising evaluating a viral response of the subject to said administration after the first time period.

3. The method of claim 2, wherein the sequential or concurrent administration during the second time period occurs only in a subject exhibiting a negative viral load after the first time period based on the evaluation.

4. The method of claim 1, further comprising after the second time period, withdrawing administering the at least one first antiviral agent.

5. The method of claim 4, further comprising after the second time period, administering the at least one second antiviral agent for a third time period.

6. The method of claim 5, wherein the at least one second antiviral agent consists essentially of an α

-glucosidase inhibitor.

7. The method of claim 1, wherein the viral infection is an alphaviral infection.

8. The method of claim 1, wherein the viral infection is a viral infection caused by or associated with a virus belonging to a Flaviviridae family.

9. The method of claim 1, wherein the viral infection is a Hepatitis infection.

10. The method of claim 1, wherein the viral infection is a Hepatitis C infection.

11. The method of claim 1, wherein the at least one first antiviral agent comprises at least one agent selected from the group consisting of immunostimulators, immunomodulators, nucleoside antiviral agents, nucleotide antiviral agents, antifibrotics, caspase inhibitors, inosine 5′

-monophosphate dehydrogenase (IMPDH) inhibitors and viral enzyme inhibitors.

12. The method of claim 1, wherein the at least one first antiviral agent comprises an interferon receptor agonist.

13. The method of claim 1, wherein the interferon receptor agonist is an interferon.

14. The method of claim 13, wherein the interferon is selected from the group consisting of alpha interferons, beta interferons, gamma inteferons, pegylated alpha interferons, pegylated beta interferons, pegylated gamma interferons and mixtures of any two or more thereof.

15. The method of claim 13, wherein the at least one first antiviral agent further comprises at least one nucleoside or nucleotide antiviral agent.

16. The method of claim 15, wherein the at least one nucleoside or nucleotide antiviral agent is ribavirin or a derivative thereof.

17. The method of claim 1, wherein the viral infection is Hepatitis C infection and the at least one first antiviral agent comprises at least one HCV enzyme inhibitor.

18. The method of claim 17, wherein the at least one first antiviral agent comprises at least one of an HCV NS3 protease inhibitor, or an HCV NS5B polymerase inhibitor.

19. The method of claim 1, wherein the at least one second antiviral agent comprises a compound of formula II or a pharmaceutically acceptable salt thereof:

20. The method of claim 19, wherein R₁ is a substituted or unsubstituted alkyl group having from 1 to 16 carbon atoms and W, X, Y and Z are each hydrogen.

21. The method of claim 20, wherein R₁ has from 2 to 6 carbon atoms.

22. The method of claim 21, wherein R₁ is butyl.

23. The method of claim 20, wherein R₁ has from 7 to 12 carbon atoms.

24. The method of claim 23, wherein R₁ is nonyl.

25. The method of claim 1, wherein the at least one second antiviral agent comprises castanospermine or a derivative thereof.

26. The method of claim 1, wherein the viral infection is a Hepatitis C infection, wherein the administering in A) comprises administering interferon and ribavirin, wherein the administering in B) comprises administering interferon, ribavirin and N-butyl deoxynojirimycin and wherein the method further comprises, after the second time period, administering N-butyl deoxynojirimycin or a pharmaceutically acceptable salt thereof.

27. The method of claim 1, wherein the subject is a human.

28. A method of treating a viral infection comprising

(A) administering to a subject in need thereof at least one first antiviral agent for a first time period, wherein said at least first antiviral agent does not comprise an iminosugar;

and

(B) after the first time period, sequentially or concurrently administering to the subject the at least one first antiviral agent and at least one second antiviral agent for a second time period, wherein the at least one second antiviral agent comprises an iminosugar.

29. The method of claim 28, further comprising evaluating a viral response of the subject to said administration after the first time period.

30. The method of claim 29, wherein the sequential or concurrent administration during the second time period occurs only in a subject exhibiting a negative viral load after the first time period based on the evaluation.

31. The method of claim 28, further comprising after the end of the second time period, withdrawing administering the at least one first antiviral agent.

32. The method of claim 31, further comprising after the end of the second time period, administering the at least one second antiviral agent for a third time period.

33. The method of claim 28, wherein the at least one second antiviral agent consists essentially of the iminosugar.

34. The method of claim 28, wherein the viral infection is a viral infection caused by or associated with a virus belonging to a Flaviviridae family.

35. The method of claim 28, wherein the viral infection is a Hepatitis infection.

36. The method of claim 28, wherein the viral infection is a Hepatitis C infection.

37. The method of claim 28, wherein the at least one first antiviral agent comprises at least one agent selected from the group consisting of immunostimulators, immunomodulators, nucleoside antiviral agents, nucleotide antiviral agents, antifibrotics, caspase inhibitors, inosine 5′

-monophosphate dehydrogenase (IMPDH) inhibitors and viral enzyme inhibitors.

38. The method of claim 28, wherein the at least one first antiviral agent comprises at least one immunostimulator or immunomodulator and at least one nucleoside antiviral agent or nucleotide antiviral agent.

39. The method of claim 28, wherein the at least one first antiviral agent comprises an interferon receptor agonist.

40. The method of claim 39, wherein the interferon receptor agonist is an interferon.

41. The method of claim 40, wherein the interferon is selected from the group consisting of alpha interferons, beta interferons, gamma inteferons, pegylated alpha interferons, pegylated beta interferons, pegylated gamma interferons and mixtures of any two or more thereof.

42. The method of claim 41, wherein the at least one first antiviral agent further comprises ribavirin or a derivative thereof.

43. The method of claim 28, wherein the viral infection is Hepatitis C infection and the at least one first antiviral agent comprises at least one HCV enzyme inhibitor.

44. The method of claim 43, wherein the at least one first antiviral agent comprises at least one of an HCV NS3 protease inhibitor, or an HCV NS5B polymerase inhibitor.

45. The method of claim 28, wherein the iminosugar is a compound of formula TI or a pharmaceutically acceptable salt thereof:

46. The method of claim 45, wherein R₁ is alkyl and W, X, Y and Z are each hydrogen.

47. The method of claim 46, wherein R₁ is butyl.

48. The method of claim 46, wherein R₁ is nonyl.

49. The method of claim 28, wherein the iminosugar is a compound of Formula I or a pharmaceutically acceptable salt thereof:

50. The method of claim 49, wherein R is —

(CH₂)₆OCH₂CH₃.

51. The method of claim 28, wherein the at least one second antiviral agent comprises castanospermine or a derivative thereof.

52. The method of claim 28, wherein the subject is a human.

53. A method of treating a viral infection comprising

(A) administering to a subject in need thereof at least one first antiviral agent for a first time period, wherein said at least first antiviral agent does not inhibit an ion channel activity;

and

(B) after the first time period, sequentially or concurrently administering to the subject the at least one first antiviral agent and at least one second antiviral agent for a second time period, wherein the second antiviral agent inhibits an ion channel activity.

54. The method of claim 53, further comprising evaluating a viral response of the subject to said administration after the first time period.

55. The method of claim 53, wherein the sequential or concurrent administration during the second time period occurs only in a subject exhibiting a negative viral load after the first time period based on the evaluation.

56. The method of claim 53, further comprising after the end of the second time period, withdrawing administering the at least one first antiviral agent.

57. The method of claim 56, further comprising after the end of the second time period, administering the at least one second antiviral agent for a third time period.

58. The method of claim 57, wherein the at least one second antiviral agent consists essentially of an ion channel inhibitor.

59. The method of claim 53, wherein the viral infection is a viral infection caused by or associated with a virus belonging to a Flaviviridae family.

60. The method of claim 53, wherein the viral infection is a Hepatitis infection.

61. The method of claim 53, wherein the viral infection is a Hepatitis C infection.

62. The method of claim 53, wherein the at least one first antiviral agent comprises at least one agent selected from the group consisting of immunostimulators, immunomodulators, nucleoside antiviral agents, nucleotide antiviral agents, antifibrotics, caspase inhibitors, inosine 5′

-monophosphate dehydrogenase (IMPDH) inhibitors and viral enzyme inhibitors.

63. The method of claim 53, wherein the at least one first antiviral agent comprises at least one imminostimulator or immunomodulator and at least one nucleoside antiviral agent or nucleotide antiviral agent.

64. The method of claim 53, wherein the at least one first antiviral agent comprises an interferon receptor agonist.

65. The method of claim 64, wherein the interferon receptor agonist is an interferon.

66. The method of claim 65, wherein the interferon is selected from the group consisting of alpha interferons, beta interferons, gamma inteferons, pegylated alpha interferons, pegylated beta interferons, pegylated gamma interferons and mixtures of any two or more thereof.

67. The method of claim 65, wherein the at least one first antiviral agent further comprises ribavirin or a derivative thereof.

68. The method of claim 53, wherein the viral infection is a Hepatitis virus infection and the at least one first antiviral agent comprises at least one HCV enzyme inhibitor.

69. The method of claim 68, wherein the at least one HCV enzyme inhibitor comprises at least one of an HCV NS3 protease inhibitor, or an HCV NS5B polymerase inhibitor.

70. The method of claim 53, wherein the at least one second antiviral agent comprises a compound of Formula I or a pharmaceutically acceptable salt thereof:

71. The method of claim 70, wherein R is —

(CH₂)₆OCH₂CH₃.

72. The method of claim 53, wherein the least one second antiviral agent comprises a compound having formula

73. The method of claim 72, wherein R¹² is nonyl.

74. The method of claim 53, wherein the at least one second antiviral agent comprises a compound having formula

75. The method of claim 53, wherein the subject is a human.

76. A method of treating a viral infection comprising

(A) administering to a subject in need thereof at least one first antiviral agent for a first time period, wherein said at least one first antiviral agent does not comprise a nitrogen-containing compound of formula VIII;

and

(B) after the first time period, sequentially or concurrently administering to the subject the at least one first antiviral agent and at least one second antiviral agent for a second time period, wherein the at least one second antiviral agent comprises a nitrogen-containing compound of formula VIII or a pharmaceutically acceptable salt thereof;

77. The method of claim 76, further comprising evaluating a viral response of the subject to said administration after the first time period.

78. The method of claim 76, wherein the sequential or concurrent administration during the second time period occurs only in a subject exhibiting a negative viral load after the first time period based on the evaluation.

79. The method of claim 78, further comprising after the second time period, withdrawing administering the at least one first antiviral agent.

80. The method of claim 79, further comprising after the second time period, administering the at least one second antiviral agent for a third time period.

81. The method of claim 80, wherein the at least one second antiviral agent consists essentially of the compound of formula VIII.

82. The method of claim 76, wherein the viral infection is a viral infection caused by or associated with a virus belonging to a Flaviviridae family.

83. The method of claim 76, wherein the viral infection is a Hepatitis infection.

84. The method of claim 76, wherein the viral infection is a Hepatitis C infection.

85. The method of claim 76, wherein the at least one first antiviral agent comprises at least one agent selected from the group consisting of immunostimulators, immunomodulators, nucleoside antiviral agents, nucleotide antiviral agents, antifibrotics, caspase inhibitors, inosine 5′

-monophosphate dehydrogenase (IMPDH) inhibitors and viral enzyme inhibitors.

86. The method of claim 76, wherein the at least one first antiviral agent comprises at least one immunostimulator or immunomodulator and at least one nucleoside antiviral agent or nucleotide antiviral agent.

87. The method of claim 76, wherein the at least one first antiviral agent comprises an interferon receptor agonist.

88. The method of claim 87, wherein the interferon receptor agonist is an interferon.

89. The method of claim 88, wherein the interferon is selected from the group consisting of alpha interferons, beta interferons, gamma inteferons, pegylated alpha interferons, pegylated beta interferons, pegylated gamma interferons and mixtures of any two or more thereof.

90. The method of claim 87, wherein the at least one first antiviral agent further comprises ribavirin or a derivative thereof.

91. The method of claim 76, wherein the viral infection is Hepatitis C infection and the at least one first antiviral agent comprises at least one HCV enzyme inhibitor.

92. The method of claim 91, wherein the at least one first antiviral agent comprises at least one of an HCV NS3 protease inhibitor, or an HCV NS5B polymerase inhibitor.

93. The method of claim 76, wherein the nitrogen-containing compound has the formula

94. The method of claim 93, wherein the nitrogen containing compound has the formula

95. The method of claim 76, wherein the subject is a human.