Nucleoside compounds for treating viral infections

• US 20050107312A1
• Filed: 10/20/2004
• Published: 05/19/2005
• Est. Priority Date: 10/27/2003
• Status: Active Grant

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Genelabs Technologies, Inc. (GlaxoSmithKline PLC)
• Inventors: Roberts, Christopher D., Dyatkina, Natalia B., Keicher, Jesse D.
• Granted Patent: US 7,157,434 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• 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 19/14 Pyrrolo-pyrimidine radicals

Abstract

Disclosed are compounds, compositions and methods for treating viral infections caused by a flaviviridae family virus, such as hepatitis C virus.

Claims

1. A compounds of Formula I:

2. The compound of claim 1 wherein Y is oxygen.

3. The compound of claim 1 wherein each of W, W¹, and W² is independently hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate, phosphate esters, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR²NH₂ where R² is selected from the group consisiting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted hetereoaryl, heterocyclic, substituted heterocyclic, and a sidechain of an amino acid.

4. The compound of claim 3 wherein W is hydrogen, or W¹ is hydrogen, or W² is hydrogen.

5. The compound of claim 3 wherein W and W¹ are hydrogen, or W and W² are hydrogen, or W¹ and W² are hydrogen.

6. The compound of claim 3 wherein W, W¹ and W² are hydrogen.

7. The compound of claim 5 wherein W¹ and W² are hydrogen and W is hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR²NH₂ where R² is selected from the group consisiting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted hetereoaryl, heterocyclic, substituted heterocyclic, and a sidechain of an amino acid.

8. The compound of claim 7 wherein W¹ and W² are hydrogen and W is represented by the formula:

9. The compound of claim 5 wherein W and W² are hydrogen and W¹ is represented by the formula:

20. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound or a mixture of one or more of such compounds as defined in any one of claims 1 to 19.

21. A pharmaceutical composition according to claim 20, wherein said composition further comprises a therapeutically effective amount of one or more agents active against HCV.

22. The pharmaceutical composition according to claim 21, wherein said one or more agents is/are selected from the group consisting of ribavirin, levovirin, thymosin alpha-1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha or pegylated interferon-alpha, either alone or in combination with ribavirin or levovirin.

23. The pharmaceutical composition according to claim 22, wherein said one or more agents is/are interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin.

24. A method for treating and/or inhibiting a viral infection in a mammal which infection is mediated at least in part by a virus in theflaviviridae family of viruses which method comprise administering to said mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a pharmaceutical composition according to claim 20.

25. The method according to claim 24 wherein said virus is hepatitis C virus.

26. The method according to claim 25 wherein said pharmaceutical composition further comprises a therapeutically effective amount of one or more agents active against HCV.

27. The method according to claim 26 wherein said one or more agents is/are selected from the group consisting of ribavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, pegylated interferon-alpha, alone or in combination with ribavirin or levovirin.

28. The method according to claim 27 wherein said one or more agents is/are interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin.

10. A compound of Formula II:

11. The compound of claim 10 wherein W is independently hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate, phosphate esters, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR²NH₂ where R² is selected from the group consisiting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted hetereoaryl, heterocyclic, substituted heterocyclic, and a sidechain of an amino acid.

12. The compound of claim 11 wherein W is represented by the formula:

13. 7-(2′

—

C-methyl-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine or pharmaceutically acceptable salts or partial salts thereof.

14. 7-(2′

—

C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine or pharmaceutically acceptable salts or partial salts thereof.

15. 7-(2′

—

C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine or pharmaceutically acceptable salts or partial salts thereof.

16. 7-(2′

—

C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine or pharmaceutically acceptable salts or partial salts thereof.

17. 7-(2′

-methyl-5′

-(phenoxy-L-alaninyl)phosphate-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl) -pyrrolo[2,3-d]pyrimidine or pharmaceutically acceptable salts or partial salts thereof.

18. 7-(2′

-methyl-3′

-O-L-valine ester-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl) -pyrrolo[2,3-d]pyrimidine or pharmaceutically acceptable salts or partial salts thereof.

19. 7-(2′

-methyl-3′

-O-L-alanin ester-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl) -pyrrolo[2,3-d]pyrimidine or pharmaceutically acceptable salts or partial salts thereof.