2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections

• US 20070275883A1
• Filed: 09/06/2006
• Published: 11/29/2007
• 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, LaColla, Paolo
• Granted Patent: US 7,582,618 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses

Abstract

The 3′-L-valine ester of β-D-2′-C-methyl-ribofuranosyl cytidine provides superior results against flaviviruses and pestiviruses, including hepatitis C virus. Based on this discovery, compounds, compositions, methods and uses are provided for the treatment of flaviviridae, including HCV, that include the administration of an effective amount of val-mCyd or its salt, ester, prodrug or derivative, optionally in a pharmaceutically acceptable carrier. In an alternative embodiment, val-mCyd is used to treat any virus that replicates through an RNA-dependent RNA polymerase.

Claims

1-18. -18. (canceled)

19. A method of treating a host infected with a Flaviviridae virus, comprising administering to the host in need thereof an effective amount of a compound having the structure of the formula:

20. The method according to claim 19, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

21. The method according to claim 19, wherein the pharmaceutically acceptable salt is a dihydrochloride salt.

22. The method according to claim 19, further comprising administering the compound in a pharmaceutically acceptable carrier, diluent or excipient.

23. The method according to claim 19, wherein the compound is administered in combination or alternation with a second anti-viral agent.

24. The method according to claim 23, wherein the second antiviral agent is selected from the group consisting of interferon, ribavirin, interleukin, an NS3 protease inhibitor, cysteine protease inhibitor, thiazolidine derivative, thiazolidine, benzanilide, phenan-threnequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, gliotoxin, cerulenin, antisense phosphorothioate oligodeoxynucleotides, inhibitor of IRES-dependent translation, and a ribozyme.

25. The method according to claim 23, wherein the second antiviral agent is an interferon.

26. The method according to claim 19, wherein the second antiviral 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, interferon gamma, interferon tau, interferon delta and interferon gamma-1b.

27. The method of claim 26, wherein the second antiviral agent is interferon alpha 2.

28. The method of claim 19, wherein the host is a human.

29. The method of claim 19, wherein the compound is in the form of a dosage unit.

30. The method of claim 29, wherein the dosage unit contains 70 to 1400 mg of the compound.

31. The method of claim 29, wherein said dosage unit is a tablet or capsule.

32. The method of any one of claim 19, wherein the pharmaceutically acceptable carrier is suitable for oral or intravenous delivery.

33. The method of any one of claim 19, wherein the compound is in administered in substantially pure form.

34. The method of any one of claim 19, wherein the compound is at least 90% by weight of the β

-D-isomer.

35. The method of any one of claim 19, wherein the compound is at least 95% by weight of the β

-D-isomer.

36. The method of any one of claim 19, wherein the virus is HCV hepatitis C.

45. The method of claim 19, wherein the pharmaceutically acceptable salt is selected from tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α

-ketoglutarate, and α

-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicyate, sulfate, sulfonate, nitrate, hydrobromate, hydrobromide, hydroiodide, and phosphoric acid salts.

52. The method of claim 29 or 48, wherein the dosage unit contains 50 mg to 1000 mg of the compound.

53. The method of claim 29 or 48, wherein the dosage unit contains 100 mg of the compound.

54. The method of claim 29 or 48, wherein the dosage unit contains 200 mg of the compound.

55. The method of claim 29 or 48, wherein the dosage unit contains 400 mg of the compound.

56. The method of claim 29 or 48, wherein the dosage unit contains 800 mg of the compound.

57. The method of claim 29 or 48, wherein the dosage unit contains 1000 mg of the compound.

37-38. -38. (canceled)

39. A method for treating a host infected with an RNA-dependant RNA polymerase virus, comprising administering an effective amount of the compound of Formula I or its mono or dihydrochloride salt in a pharmaceutically acceptable carrier, wherein the 5′

-hydroxyl group is replaced with a 5′

-OR, wherein R is hydrogen, phosphate;

a stabilized phosphate prodrug;

acyl;

an amino acid;

a carbohydrate;

a peptide;

or other pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R is independently H or phosphate.

40. The method of claim 39 wherein the virus is a Flaviviridae virus.

41. The method of claim 39 or 40 wherein the Flaviviridae virus is hepatitis C.

42. The method of claims 39, 40 or 41 wherein the host is human.

46. The method of claim 39, wherein the compound or a pharmaceutically acceptable salt thereof, is administered in combination with a pharmaceutically acceptable carrier.

47. The method of claim 46, wherein the carrier is suitable for oral or intravenous delivery.

48. The method of claim 39, wherein the compound is in the form of a dosage unit.

49. The method of claim 39, wherein the compound is administered in substantially pure form.

50. The method of claim 39, wherein the compound is at least 90% by weight of the β

-D-isomer.

51. The method of claim 39, wherein the compound is at least 95% by weight of the β

-D-isomer.

43-44. -44. (canceled)