Compounds and pharmaceutical compositions for the treatment of viral infections

• US 9,243,025 B2
• Filed: 03/30/2012
• Issued: 01/26/2016
• Est. Priority Date: 03/31/2011
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Surleraux, Dominique, Gosselin, Gilles
• Primary Examiner(s): Lewis, Patrick
• Application Number:
  US13/436,587
• Publication Number:
  US 20120251487A1
• Time in Patent Office: 1,397 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7042 Compounds having saccharide radicals and heterocyclic rings
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• 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 31/7076 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: 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: C07H 19/167 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical

Abstract

Provided herein are compounds, compositions and methods for the treatment of liver disorders, including HCV infections. In one embodiment, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

Claims

1. A compound of Formula I:

2. The compound of claim 1 of Formula I, wherein R⁷ and R⁸ are selected as follows:

i) R⁷ and R⁸ are each independently hydrogen, C₂-C₁₀ alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, wherein alkyl is optionally substituted by alkoxy;

or

ii) R⁷ and R⁸ together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring.

3. The compound of claim 1, wherein one of R⁷ or R⁸ is C₂-C₆ alkyl.

4. The compound of claim 1, wherein

R¹ and R³ are each hydrogen;

R² is (G)_mC(O)Q¹; and

m is 1.

5. The compound of claim 1, wherein

R¹ and R³ are each hydrogen;

R² is (G)_mC(O)Q¹; and

m is 2.

6. The compound of claim 1, wherein Q and Q¹ are each OR⁴ and each R⁴ is alkyl.

7. The compound of claim 1, wherein

R¹ and R³ are each hydrogen;

R² is (G)_mC(O)Q¹;

m is 1;

Q¹ is OR⁴; and

R⁴ is alkyl.

8. The compound of claim 1, wherein

R¹ and R³ are each hydrogen;

R² is (G)_mC(O)Q¹;

m is 1;

Q¹ is OR⁴; and

R⁴ is alkyl;

each R⁷ is hydrogen; and

each R⁸ is alkyl, alkylaryl or alkylheteroaryl.

9. The compound of claim 1, wherein;

n is 1;

R³ and R⁷ together with the nitrogen and carbon atoms to which they are attached form a 5 membered heterocyclic ring substituted by C(O)Q¹;

each Q¹ is OR⁴;

each R⁴ is alkyl; and

each R⁸ is alkyl, alkylaryl or alkylheteroaryl.

10. The compound of claim 1, wherein X is O.

40. The compound of claim 1, wherein, when E, Q, Q¹, R¹, R², R⁵, R⁶, n and m form at least one amino acid group, the amino acid is in the L-configuration.

52. The compound of claim 1, wherein R is a moiety derivable by removal of a hydrogen from a hydroxy group of selected from ribavirin, viramidine, valopicitabine, PSI-6130, PSI-6206, PSI-35938 and R1479.

53. A compound of claim 1, or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof, of the formula:

54. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.

55. The pharmaceutical composition of claim 54, wherein the composition is an oral formulation.

56. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound or composition of claim 1.

57. The method of claim 56, wherein the host is a human.

58. The method of claim 56, wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt or stereoisomer thereof to the liver of said host.

59. The method of claim 56, wherein said compound or composition is administered in combination or alternation with a second anti-viral agent selected from an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, or a ribozyme.

60. The method of claim 59, wherein the second agent is pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta or interferon γ

-1b.

11. A compound of Formula II:

12. The compound of claim 11, wherein if R² is (G)_mC(O)Q¹, G is CR⁷R⁸, m is 1, and one of R⁷ or R⁸ is hydrogen;

the other of R⁷ and R⁸ is not methyl.

13. The compound of claim 11, wherein Y is OR⁹ and Z is OR¹⁰ or F.

14. The compound of claim 11, wherein W is alkyl, alkenyl or alkynyl.

15. The compound of claim 14, wherein W is alkyl.

16. The compound of claim 11, wherein W is ethynyl;

Y is OR⁹;

Z is F; and

R⁹ is hydrogen.

17. The compound of claim 11, wherein W is methyl;

Y is OR⁹;

Z is F; and

R⁹ is hydrogen.

18. The compound of claim 11, wherein W is methyl;

Y is OR⁹;

Z is OR¹⁰; and

R⁹ and R¹⁰ are each hydrogen.

19. The compound of claim 11, wherein R¹ and R³ are each hydrogen;

and R² is (G)_mC(O)Q¹.

20. The compound of claim 11, wherein Q and Q¹ are each OR⁴.

21. The compound of claim 11, wherein Q and Q¹ are each SR⁴.

22. The compound of claim 11, wherein each R⁴ is alkyl.

23. The compound of claim 11, wherein Q and Q¹ are each NR⁵R⁶.

24. The compound of claim 11, wherein X is O.

25. The compound of claim 11, wherein m is 1.

26. The compound of claim 11, wherein n is 1.

27. The compound of claim 11, wherein m is 2.

28. The compound of claim 11, wherein n is 2.

29. The compound of claim 11, wherein each R⁷ is hydrogen;

and each R⁸ is independently alkyl, aryl, aralkyl or alkylheteroaryl.

30. The compound of claim 29, wherein each R⁸ is C₂-C₁₀ alkyl.

31. The compound of claim 29, wherein each R⁸ is C₂-C₆ alkyl.

32. The compound of claim 29, wherein each R⁸ is C₃-C₆ alkyl.

33. The compound of claim 29, wherein each R⁸ is isobutyl.

34. The compound of claim 29, wherein each R⁸ is sec-butyl.

35. The compound of claim 29, wherein each R⁸ is phenyl.

36. The compound of claim 29, wherein each R⁸ is benzyl.

37. The compound of claim 29, wherein each R⁸ is 1-H-indol-3-ylmethyl.

38. The compound of claim 11, wherein each of R⁷ and R⁸ is alkyl.

39. The compound of claim 11, wherein R⁷ and R⁸ together with the carbon atom to which they are attached form a 5 membered cycloalkyl ring.

41. The compound of claim 11, wherein Base is adenine, cytosine, guanine, hypoxanthine, thymine or uridine.

42. The compound of claim 41, wherein Base is cytosine.

43. The compound of claim 41, wherein Base is guanine.

44. The compound of claim 41, wherein Base is uridine.

45. The compound of claim 11, wherein Base is selected from one of formulae (i) to (xxvi):

46. The compound of claim 45, wherein R^L is hydrogen, alkyl or cycloalkyl.

47. The compound of claim 45, wherein R^L is cyclopropyl or cyclopentyl.

48. The compound of claim 45, wherein R^L is methyl, ethyl, propyl, or isopropyl.

49. The compound of claim 45, wherein R^M is hydrogen.

50. The compound of claim 45, wherein R^M is methyl.

51. The compound of claim 45, wherein Base is selected from