2' and 3'-nucleoside prodrugs for treating Flaviviridae infections

• US 20070060498A1
• Filed: 12/06/2004
• Published: 03/15/2007
• Est. Priority Date: 06/28/2002
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.), Universite Montpellier II, University of Calgary
• Original Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.), Universite Montpellier II, University of Calgary
• Inventors: Sommadossi, Jean-Pierre, Gosselin, Gilles, Storer, Richard, LaColla, Paola
• Granted Patent: US 7,625,875 B2
• Time in Patent Office: Days
• US Class Current: 514/46
• 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 31/7068 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 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 31/12 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 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/067 with ribosyl as the saccharide radical
• CPC Class Codes: C07K 9/003 Peptides being substituted by heterocyclic radicals, e.g. bleomycin, phleomycin

Abstract

2′ and 3′-Prodrugs of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides, or their pharmaceutically acceptable salts and derivatives are described, which are useful in the prevention and treatment of Flaviviridae infections and other related conditions. These modified nucleosides provide superior results against flaviviruses and pestiviruses, including hepatitis C virus and viruses generally that replicate through an RNA dependent RNA reverse transcriptase. Compounds, compositions, methods and uses are provided for the treatment of Flaviviridae infection, including HCV infection, that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

Claims

1. (canceled)

2. A method for the treatment of a host infected with a Flaviviridae virus, comprising administering an effective treatment amount of a compound of formula

3. The method of claim 2, wherein the virus is hepatitis C.

4. The method of claim 2, wherein the compound or pharmaceutically acceptable salt, thereof, is administered in combination or alternation with a second anti-viral agent.

5. The method of claim 2 wherein the second anti-viral agent is selected from the group consisting of an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a HCV helicase inhibitor, a polymerase inhibitor, a nucleoside, and an inhibitor of IRES-dependent translation, and a ribozyme.

6. The method of claim 2, wherein the second anti-viral agent is an interferon.

7. The method of claim 6, wherein the second agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, and interferon gamma-1b.

8. The method of claim 2, wherein the compound or pharmaceutically acceptable salt thereof is in the form of a dosage unit.

9. The method of claim 8, wherein the dosage unit is a tablet or capsule.

10. The method of claim 2, wherein the host is a human.

11. The method of claim 2, wherein the compound is in substantially pure form.

12. The method of claim 2, wherein the compound is at least 90% by weight of the β

-D-isomer.

13. The method of claim 2, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with a pharmaceutically acceptable carrier to form a composition.

14. The of claim 13, comprising administering the composition in a form that is suitable for oral delivery.

15. The method of claim 13, wherein the composition is in the form of a dosage unit.

16. The method of claim 15, wherein the dosage unit contains 50 to 1000 mg of the compound.

17. The method of claim 16, wherein said dosage unit is a tablet or capsule.

19. The method of claim 13, wherein the compound or pharmaceutically acceptable salt thereof, is in substantially pure form.

20. The method of claim 13, wherein the pharmaceutically acceptable carrier is suitable for systemic, topical, parenteral, inhalant or intravenous delivery.

21. The method of claim 2, wherein R¹ is a mono, di or triphosphate.

22. The method of claim 2, wherein R² is acyl.

23. The method of claim 2, wherein R² is an amino acid ester.

24. The method of claim 2, wherein R² is a peptide.

25. The method of claim 2, wherein R² is a carbohydrate.

26. The method of claim 2, wherein R¹ is hydrogen.

27. The method of claim 2, wherein R¹ is H and R⁶ is alkyl.

28. The method of claim 21, wherein R⁶ is alkyl.

29. The method of claim 23, wherein R⁶ is alkenyl.

30. The method of claim 2, wherein R⁶ is alkynyl.

31. The method of claim 2, wherein R⁶ is —

CH═

CH₂.

32. The method of claim 30, wherein R⁶ is ethynyl.

33. The method of claim 28, wherein R⁶ is methyl, ethyl, or propyl.

34. The method of claim 22, wherein acyl is of the formula C(O)R′

, wherein R′

is a straight, branched, or cyclic alkyl.

35. The method of claim 22, wherein acyl is of the formula C(O)R′

, wherein R′

is aryl, alkaryl, aralkyl alkoxyalkyl or aryloxyalkyl.

36. The method of claim 22, wherein acyl is of the formula C(O)R′

wherein R′

is aryl.

37. The method of claim 22, wherein R² is acetyl.

38. The method of claim 22, wherein R² is propionyl, butyryl or hexanoyl.

39. The method of claim 31, wherein R² is 2-propenyl.

40. The method of claim-2, wherein the base is selected from the group consisting of N⁶-alkylpurine, N⁶-acylpurine, N⁶-benzylpurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-hydroxyalkylpurine, N⁶-alkylaminopurine, N⁶-thioalkylpurine, N²-alkylpurine, N²-alkyl-6-thiopurine and C⁵-hydroxyalkyl purine.

41. The method of any one of claims 2 or 14, wherein the base is adenine.

42. The method of claim 2, wherein the base is guanine.

43. The method of claim 2, wherein R² is an ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.

44. The method of claim 2, wherein R² is an ester of a naturally occurring or synthetic α

, β

, γ

, or δ

amino acid.

45. The method of claim 2, wherein R² is an ester of an amino acid in the L configuration.

46. The method of claim 2, wherein R² is an ester of valine.

47. The method of claim 2, wherein host is human.

48. The method of claim 23, 26 or 27 wherein host is human.

49. The method of claim 2, wherein:

R¹ is H, mono, di or triphosphate or a stabilized phosphate;

R² is acyl or an amino acid ester; and

R⁶ is methyl, ethyl or propyl.

50. The method of claim 49, wherein the base is selected from the group consisting of N⁶-alkylpurines, N⁶-acylpurines, N⁶-benzylpurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-hydroxyalkylpurine, N⁶-alkylaminopurine, N⁶-thioalkylpurine, N²-alkylpurine, N²-alkyl-6-thiopurines and C⁵-hydroxyalkyl purine.

51. The method of claim 49, wherein the base is adenine.

52. The method of claim 49, wherein the base is guanine.

53. The method of claim 49, wherein R² is an ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.

54. The method of claim 49, wherein R² is an ester of a naturally occurring or synthetic α

, β

, γ

, or δ

amino acid.

55. The method of claim 49, wherein R² is an ester of an amino acid in the L configuration.

56. The method of claim 49, wherein R² is an ester of valine.

57. The method of claim 49, wherein host is human.

58. The method of claim 49, wherein the compound or pharmaceutically acceptable salt, thereof, is administered in combination or alternation with a second anti-viral agent.

59. The method of claim 58 wherein the second anti-viral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a HCV helicase inhibitor, a polymerase inhibitor, a nucleoside, and an inhibitor of IRES-dependent translation.

60. The method of claim 59, wherein the second anti-viral agent is an interferon.

61. The method of claim 58, wherein the second agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha and interferon gamma-1b.

62. The method of claim 10, wherein the virus is hepatitis C.

63. The method of claim 2, wherein the base is hypoxanthine.

64. The method of claim 2, wherein the base is 2,6-diaminopurine.

65. The method of claim 2, wherein the base is 6-chloropurine.

66. The method of claim 58, wherein the virus is hepatitis C.

67. The method of claim 60, wherein the virus is hepatitis C.

68. The method of claim 66, wherein the host is human.

18. (canceled)