2′-chloro nucleoside analogs for HCV infection

• US 10,513,534 B2
• Filed: 10/07/2013
• Issued: 12/24/2019
• Est. Priority Date: 10/08/2012
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Inventors: Gosselin, Gilles, Parsy, Christophe Claude, Alexandre, Francois-Rene, Rahali, Houcine, Griffon, Jean-Francois, Surleraux, Dominique, Dousson, Cyril B., Pierra, Claire, Moussa, Adel M., Mayes, Benjamin Alexander, Stewart, Alistair James
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US14/047,862
• Publication Number:
  US 20140099283A1
• Time in Patent Office: 2,269 Days
• Field of Search: None
• 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 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• 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 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 38/212 IFN-alpha
• 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 31/04 Antibacterial agents
• 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: 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 19/11 containing cyclic phosphate
• CPC Class Codes: C07H 19/12 Triazine radicals
• CPC Class Codes: C07H 19/14 : Pyrrolo-pyrimidine radicals
• 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: C07H 19/213 : containing cyclic phosphate
• 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 herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are 2′-chloro nucleosides according to Formula 2001:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein B, Z and PD are as described herein.

Claims

1. A compound according to Formula 2001:

2. The compound of claim 1 according to Formula II:

3. The compound of claim 2 wherein each X is independently an N-linked D-alanine ester.

4. The compound of claim 2, wherein said compound is according to one of the following the structures:

5. The compound according to claim 4, wherein said compound is selected from the group consisting of:

6. The compound of claim 1 according to Formula (2001) wherein PD is monophosphate, diphosphate, or triphosphate;

or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof.

7. The compound of claim 1 which is:

8. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, wherein:

PD is

9. The pharmaceutical composition of claim 8, wherein said compound is

10. The pharmaceutical composition of claim 9, wherein said compound is:

11. The pharmaceutical composition according to claim 8, wherein said compound is selected from the group consisting of:

12. The pharmaceutical composition according to claim 11, wherein said compound is a designated enantiomer selected from the group consisting of:

13. A method of treating an hepatitis C virus (HCV) in a human infected with an HCV, comprising administering to the human an effective amount of the compound of claim 1.

14. The method of claim 13 where said compound is according to one of the following structures:

15. The method according to claim 14, wherein said compound is according to one of the following structures:

16. The method of claim 13, wherein said compound is

17. The method of claim 13, wherein the compound is administered in combination or alternation with a second anti-viral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, and a cyclophilin inhibitor, or a combination thereof.

18. A compound according to Formula III:

19. The compound according to claim 18, wherein said compound is according to the structure:

20. The compound according to claim 19, wherein said compound is according to the structure:

21. The compound according to claim 19, wherein said compound is:

22. The compound according to claim 21, wherein said compound is:

23. The compound according to claim 18, wherein said compound is:

24. The compound of claim 23, wherein said compound is:

25. The compound according to claim 18, wherein said compound is according to the structure:

26. The compound according to claim 25, wherein said compound is according to the structure:

27. The compound according to claim 18, wherein said compound is:

28. The compound according to claim 27, wherein said compound is:

29. The compound according to claim 18, wherein said compound is:

30. The compound of claim 29, wherein said compound is:

31. The pharmaceutical composition according to claim 30, wherein said compound is a designated enantiomer, and said composition is substantially free of other stereoisomers of said compound.

32. A nucleoside composition comprising a compound selected from the group consisting of:

33. A nucleoside composition comprising a compound selected from the group consisting of:

34. A pharmaceutical composition comprising a compound according to the structure:

35. The pharmaceutical composition according to claim 34, wherein said compound is according to the structure:

36. The pharmaceutical composition according to claim 34, wherein said compound is:

37. The pharmaceutical composition according to claim 36, wherein said compound is:

38. A pharmaceutical composition comprising a compound according to the structure:

39. The pharmaceutical composition according to claim 38, wherein said compound is according to the structure:

40. The pharmaceutical composition according to claim 38, wherein said compound is:

41. The pharmaceutical composition according to claim 40, wherein said compound is:

42. The pharmaceutical composition according to claim 41, wherein said compound is a designated enantiomer, and said composition is substantially free of other stereoisomers of said compound.

43. A method of treating an hepatitis C virus (HCV) in a human infected with a an HCV, comprising administering to the human an effective amount of a compound according to the structure:

44. The method according to claim 43, wherein said compound is according to the structure:

45. The method according to claim 43, wherein said compound is:

46. The method according to claim 45, wherein said compound is:

47. The method according to claim 43, wherein said compound is:

48. The method according to claim 47, wherein said compound is:

49. The method of claim 43, wherein the compound is administered in combination with or in alternation with a second anti-viral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NSSA inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, and combinations thereof.

50. The method of claim 49, wherein said second anti-viral agent is an NS3 protease inhibitor.

51. The method of claim 49, wherein said second anti-viral agent is an NS5A inhibitor.

52. A method of treating an hepatitis C virus (HCV) in a human infected with a an HCV, comprising administering to the human an effective amount of a compound according to the structure:

53. The method according to claim 52, wherein said compound is according to the structure:

54. The method according to claim 52, wherein said compound is:

55. The method according to claim 54, wherein said compound is:

56. The method according to claim 52, wherein said compound is:

57. The method according to claim 56, wherein said compound is:

58. The method of claim 52, wherein the compound is administered in combination with or in alternation with a second anti-viral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, and combinations thereof.

59. The method of claim 58, wherein said second anti-viral agent is an NS3 protease inhibitor.

60. The method of claim 58, wherein said second anti-viral agent is an NS5A inhibitor.