2'-SUBSTITUTED CARBA-NUCLEOSIDE ANALOGS FOR ANTIVIRAL TREATMENT

• US 20130243725A1
• Filed: 03/11/2013
• Published: 09/19/2013
• Est. Priority Date: 03/13/2012
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Clarke, Michael O'Neil Hanrahan
• Granted Patent: US 9,481,704 B2
• Time in Patent Office: Days
• US Class Current: 424/85.4
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04
• CPC Class Codes: A61M 2202/30 Vaccines
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/12 Triazine radicals
• CPC Class Codes: C07H 19/23 Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Abstract

Provided are compounds of Formula I,

as well as pharmaceutical compositions containing compounds of Formula I and methods for treating Orthomyxoviridae virus infections by administering these compounds. The compounds, compositions, and methods provided are particularly useful for the treatment of Human Influenza virus infections.

Claims

1. A compound of Formula I:

2. The compound of claim 1, represented by Formula II:

3. The compound of claim 2, wherein R¹ is H.

4. The compound of claim 3, wherein the compound is selected from the group consisting of

5. The compound of claim 1, wherein R¹ is H, CH₂OH, CH₂F, CHF₂, CH═

CH₂, C≡

CH, CN, CH₂CH═

CH₂, N₃, CH₃, or CH₂CH₃.

6. The compound of claim 5, wherein R¹ is H.

7. The compound of claim 1, wherein R² is OH or O-benzyl.

8. The compound of claim 7, wherein R² is OH.

9. The compound of claim 1, wherein R³ is F or N₃.

10. The compound of claim 9, wherein R³ is F.

11. The compound of claim 1, wherein R⁴ is NH₂ and R⁵ is H, F, Cl, Br, N₃, CN, CF₃, NH₂, SMe, or SO₂Me.

12. The compound of claim 1, wherein R⁵ is NH₂ and R⁴ is ═

O, OH, OMe, Cl, Br, I, NH₂, NHMe, NHcPr or SMe.

13. The compound of claim 1, wherein each of R⁴ and R⁵ is independently selected from the group consisting of H, NH₂, ═

O, NHMe, NHcPr, OH, OMe, Cl, Br, I, SMe, F, N₃, CN, CF₃, and SO₂Me.

14. The compound of claim 13, wherein R⁵ is H or NH₂.

15. The compound of claim 13, wherein R⁴ is ═

O or NH₂.

16. The compound of claim 1, wherein R⁶ is H, benzyl, or

17. The compound of claim 16, wherein R⁶ is H.

18. The compound of claim 1, wherein R⁷ is H or OH.

19. The compound of claim 18, wherein R⁷ is H.

20. The compound of claim 1, wherein R¹ is H, R² is OH and R³ is F.

21. The compound of claim 20, wherein R⁴ and R⁵ are NH₂, H or ═

O, and R⁶ and R⁷ are hydrogen.

22. The compound of claim 1, wherein R¹ is H, R² is O-benzyl or OH, R³ is F, R⁴ is SMe, NH₂ or ═

O, R⁵ is SMe, SO₂Me, H or NH₂, R⁶ is benzyl

23. The compound of claim 1, wherein the compound is

24. The compound of claim 1, wherein the compound is

25. A pharmaceutical composition comprising:

a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier or excipient.

26. The pharmaceutical composition of claim 25 further comprising at least one additional therapeutic agent.

27. The pharmaceutical composition of claim 26, wherein the at least one additional therapeutic agent is selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a β

2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline, an agent that inhibits migration of pro-inflammatory cells to the site of infection, and mixtures thereof.

28. The pharmaceutical composition of claim 27, wherein the at least one additional therapeutic agent is a viral haemagglutinin inhibitor, a viral neuramidase inhibitor, a M2 ion channel inhibitor, a Orthomyxoviridae RNA-dependent RNA polymerase inhibitor or a sialidase.

29. The pharmaceutical composition of claim 27, wherein the at least one additional therapeutic agent is an interferon, ribavirin, oseltamivir, zanamivir, laninamivir, peramivir, amantadine, rimantadine, CS-8958, favipiravir, AVI-7100, alpha-1 protease inhibitor or DAS181.

30. A method for treating an Orthomyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I:

31. The method of claim 30, wherein the compound of Formula I is represented by Formula II:

32. The method of claim 31, wherein R¹ is H.

33. The method of claim 30, wherein R¹ is H, CH₂OH, CH₂F, CHF₂, CH═

CH₂, C≡

CH, CN, CH₂CH═

CH₂, N₃, CH₃ or CH₂CH₃.

34. The method of claim 33, wherein R¹ is H.

35. The method of claim 30, wherein R² is OH or O-benzyl.

36. The method of claim 35, wherein R² is OH.

37. The method of claim 30, wherein R³ is F or N₃.

38. The method of claim 37, wherein R³ is F.

39. The method of claim 30, wherein R⁴ is NH₂ and R⁵ is H, F, Cl, Br, N₃, CN, CF₃, NH₂, SMe, or SO₂Me.

40. The method of claim 30, wherein R⁵ is NH₂ and R⁴ is ═

O, OH, OMe, Cl, Br, I, NH₂, NHMe, NHcPr or SMe.

41. The method of claim 30, wherein R⁴ and R⁵ are independently selected from the group consisting of H, NH₂, ═

O, NHMe, NHcPr, OH, OMe, Cl, Br, I, SMe, F, N₃, CN, CF₃, and SO₂Me.

42. The method of claim 41, wherein R⁵ is H or NH₂.

43. The method of claim 41, wherein R⁴ is ═

O or NH₂.

44. The method of claim 30, wherein R⁶ is H, benzyl, or

45. The method of claim 44, wherein R⁶ is H.

46. The method of claim 30, wherein R⁷ is H or OH.

47. The method of claim 46, wherein R⁷ is H.

48. The method of claim 30, wherein R¹ is H, R² is OH and R³ is F.

49. The method of claim 48, wherein R⁴ and R⁵ are NH₂, H or ═

O, and R⁶ and R⁷ are hydrogen.

50. The method of claim 30, wherein R¹ is H, R² is O-benzyl or OH, R³ is F, R⁴ is SMe, NH₂ or ═

O, R⁵ is SMe, SO₂Me, H or NH₂, R⁶ is benzyl or

51. The method of claim 30, wherein the compound is

52. The method of claim 51, wherein the compound is

53. The method of claim 30 wherein the compound is

54. The method of claim 30 further comprising administering a pharmaceutically acceptable carrier or excipient.

55. The method of claim 30 further comprising administering a therapeutically effective amount of at least one additional therapeutic agent or composition thereof selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a β

2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline, an agent that inhibits migration of pro-inflammatory cells to the site of infection, and mixtures thereof.

56. The method of claim 55, wherein the at least one additional therapeutic agent is a viral haemagglutinin inhibitor, a viral neuramidase inhibitor, a M2 ion channel inhibitor, a Orthomyxoviridae RNA-dependent RNA polymerase inhibitor or a sialidase.

57. The method of claim 55, wherein the at least one additional therapeutic agent is an interferon, ribavirin, oseltamivir, zanamivir, laninamivir, peramivir, amantadine, rimantadine, CS-8958, favipiravir, AVI-7100, alpha-1 protease inhibitor or DAS181.

58. The method of claim 55, wherein the compound of Formula I, Formula II and/or at least one therapeutic agent or mixtures thereof is administered by inhalation.

59. The method of claim 58, wherein the compound of Formula I, Formula II and/or at least one therapeutic agent or mixtures thereof is administered by nebulization.

60. The method of claim 30 wherein the Orthomyxoviridae infection is caused by an Influenza A virus.

61. The method of claim 30, wherein the Orthomyxoviridae infection is caused by an Influenza B virus.

62. The method of claim 30, wherein the Orthomyxoviridae infection is caused by an Influenza C virus.

63. The method of claim 30, wherein the Orthomyxoviridae infection is being treated by administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I compound, or a pharmaceutically acceptable salt, solvate or ester thereof, in combination with a pharmaceutically acceptable diluent or carrier.

64. The method of claim 30, wherein a Orthomyxoviridae RNA-dependent RNA polymerase is inhibited.