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

• US 7,456,155 B2
• Filed: 06/27/2003
• Issued: 11/25/2008
• 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.), Universita' Degli Studi Di Bari (Repubblica Italiana)
• Inventors: Sommadossi, Jean-Pierre, Gosselin, Gilles, LaColla, Paolo
• Primary Examiner(s): Jiang; Shaojia Anna
• Assistant Examiner(s): McIntosh, III; Traviss C
• Application Number:
  US10/607,909
• Publication Number:
  US 20040077587A1
• Time in Patent Office: 1,978 Days
• Field of Search: 514/43, 514/49, 536/28.5
• 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 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

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. A compound of the formula:

2. The compound of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

3. The compound of claim 1, wherein the pharmaceutically acceptable salt is the dihydrochloride salt.

4. A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to treat a Flaviviridae infection, in a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4 wherein the pharmaceutically acceptable salt is a hydrochloride salt.

6. The pharmaceutical composition of claim 4 wherein the pharmaceutically acceptable salt is a dihydrochloride salt.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

8. The pharmaceutical composition of claim 6, wherein the compound is in the form of a dosage unit.

9. The composition of claim 8, wherein the dosage unit contains 50 mg to 1000 mg of the compound.

10. The composition of claim 8, wherein said dosage unit is a tablet or capsule.

11. The composition of claim 6, wherein the compound is in substantially pure form.

12. The compound of any of claims 1–

3, wherein the compound is at least 90% by weight the β

-D-isomer.

13. The compound of any of claims 1–

3, wherein the compound is at least 95% by weight of the β

-D-isomer.

15. A pharmaceutical composition that comprises the compound of claim 1, 2, or 3 in a pharmaceutically acceptable carrier, wherein the 5′

-hydroxyl group is replaced with a 5′

-OR group, wherein R is mono, di or triphosphate;

a stabilized phosphate prodrug;

acyl;

sulfonate ester;

or benzyl, wherein the phenyl group is optionally substituted;

an amino acid;

a carbohydrate;

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

16. The compound of claim 1, 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.

17. The composition of claim 4, 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.

18. The composition of claim 8, wherein the dosage unit contains 70 mg to 1400 mg of the compound.

19. The composition of claim 8, wherein the dosage unit contains 50 mg of the compound.

20. The composition of claim 8, wherein the dosage unit contains 100 mg of the compound.

21. The composition of claim 8, wherein the dosage unit contains 200 mg of the compound.

22. The composition of claim 8, wherein the dosage unit contains 400 mg of the compound.

23. The composition of claim 8, wherein the dosage unit contains 800 mg of the compound.

24. The composition of claim 8, wherein the dosage unit contains 1000 mg of the compound.

25. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

26. The pharmaceutical composition of claim 4, wherein the compound is in the form of a dosage unit.

27. The composition of claim 4, wherein the compound is in substantially pure form.

28. The composition of claim 4, wherein the dosage unit contains 50 mg to 1000 mg of the compound.

29. The composition of claim 4, wherein the dosage unit contains 70 mg to 1400 mg of the compound.

30. The composition of claim 4, wherein the dosage unit contains 50 mg of the compound.

31. The composition of claim 4, wherein the dosage unit contains 100 mg of the compound.

32. The composition of claim 4, wherein the dosage unit contains 200 mg of the compound.

33. The composition of claim 4, wherein the dosage unit contains 400 mg of the compound.

34. The composition of claim 4, wherein the dosage unit contains 800 mg of the compound.

35. The composition of claim 4, wherein the dosage unit contains 1000 mg of the compound.

36. The pharmaceutical composition of claim 4, wherein the Flaviviridae infection is hepatitis C.

37. The pharmaceutical composition of claim 5, wherein the Flaviviridae infection is hepatitis C.

38. The pharmaceutical composition of claim 6, wherein the Flaviviridae infection is hepatitis C.

39. The pharmaceutical composition of claim 7, wherein the Flaviviridae infection is hepatitis C.

14. A compound of the formula: