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

• US 20070015905A1
• Filed: 06/27/2003
• Published: 01/18/2007
• 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 7,662,798 B2
• Time in Patent Office: Days
• US Class Current: 530/322
• 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. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, of the formula:

11. A method for the treatment of a host infected with a Flaviviridae virus, comprising administering an effective treatment amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-10.

12. The method of claim 11, wherein the virus is hepatitis C.

13. The method of claim 11, wherein the compound or pharmaceutically acceptable salt thereof, is administered in combination or alternation with a second anti-viral agent.

14. The method of claim 13 wherein the second anti-viral agent is selected from the group consisting of an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenan-threnequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a phenan-threnequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

15. The method of claim 14, wherein the second ant-viral agent is an interferon.

16. The method of claim 15, 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, interferon gamma, interferon tau, interferon delta and interferon gamma-1b.

17. The method of claim 11, wherein the compound or pharmaceutically acceptable salt thereof, is in the form of a dosage unit.

18. The method of claim 17, wherein the dosage unit contains 50 to 1000 mg or 0.1 to 50 mg of the compound.

19. The method of claim 17, wherein the dosage unit is a tablet or capsule.

20. The method of claim 11, wherein the host is a human.

21. The method of claim 11, wherein the wherein the compound or pharmaceutically acceptable salt thereof, is in substantially pure form.

22. The method of claim 11, wherein the compound or stereoisomeric or tautomeric form thereof, or pharmaceutically acceptable salt thereof, is at least 90% by weight of the β

-D-isomer.

23. The method of claim 11, wherein the compound or stereoisomeric or tautomeric form thereof, or pharmaceutically acceptable salt thereof, is at least 95% by weight of the β

-D-isomer.

24. The method of claim 11, wherein the compound is in the form of a pharmaceutically acceptable salt selected from the group consisting of a tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorate, α

-ketoglutarate, α

-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, nitrate, bicarbonate, carbonate salts, hydrobromate, hydrochloride, di-hydrochloride, and phosphoric acid salt.

25. The method of claim 24, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

26. A pharmaceutical composition comprising a compound of any of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical composition of claim 26, further comprising a pharmaceutically acceptable carrier, diluent or excipient.

28. The pharmaceutical composition of claim 26 comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof, for the treatment of a host infected with a Flaviviridae virus.

29. The composition of claim 28, wherein the Flaviviridae virus is hepatitis C.

30. The pharmaceutical composition of claim 26, wherein the compound or a pharmaceutically acceptable salt thereof, is in the form of a dosage unit.

31. The composition of claim 30, wherein the dosage unit contains 50 to 1000 mg or 0.1 to 50 mg of the compound.

32. The composition of claim 30, wherein said dosage unit is a tablet or capsule.

33. The pharmaceutical composition of claim 26, further comprising a second anti-viral agent.

34. The pharmaceutical composition of claim 33, wherein the second anti-viral agent is selected from the group consisting of an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenan-threnequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a phenan-threnequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

35. The pharmaceutical composition of claim 34, wherein the second anti-viral agent is an interferon.

36. The pharmaceutical composition of claim 35, 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, interferon gamma, interferon tau, interferon delta and interferon gamma-1b.

37. The pharmaceutical composition of claim 26, or pharmaceutically acceptable salt thereof, is in substantially pure form.

38. The pharmaceutical composition of claim 26, wherein the compound or pharmaceutically acceptable salt thereof;

is at least 90% by weight of the β

-D-isomer.

39. The pharmaceutical composition of claim 26, wherein the compound or pharmaceutically acceptable salt thereof;

is at least 95% by weight of the β

-D-isomer.

40. The pharmaceutical composition of claim 26, further comprising a pharmaceutically acceptable carrier suitable for oral, parenteral, inhalant or intravenous delivery.

41. The pharmaceutical composition of claim 26, wherein the compound is in the form of a pharmaceutically acceptable salt selected from the group consisting of a tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorate, α

-ketoglutarate, α

-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, nitrate, bicarbonate, carbonate salts, hydrobromate, a hydrochloride, a di-hydrochloride, and phosphoric acid salt.

42. The pharmaceutical composition of claim 41, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

2. A compound of Formula II, or a pharmaceutically acceptable salt of the formula:

3. A compound of Formula III, or a pharmaceutically acceptable salt thereof:

4. A compound of Formula IV, or a pharmaceutically acceptable salt or prodrug thereof:

5. A compound of Formula V, or a pharmaceutically acceptable salt or prodrug thereof:

6. A compound of Formula VI or a pharmaceutically acceptable salt or prodrug thereof:

7. A compound selected from Formulas VII and VIII, or a pharmaceutically acceptable salt or prodrug thereof:

8. A compound of Formulas IX and X, or a pharmaceutically acceptable salt:

9. A compound selected from Formulas XI and XII, or a pharmaceutically acceptable salt thereof:

10. A compound of Formula XIII, or a pharmaceutically acceptable salt thereof: