Nucleoside compounds for treating viral infections

• US 20050090463A1
• Filed: 06/04/2004
• Published: 04/28/2005
• 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., Keicher, Jesse D.
• Granted Patent: US 7,144,868 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof

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 compound of formula I:

2. The compound according to 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 esters, phosphate, phospho, diphospho, triphospho, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR⁴NH₂ where R⁴ is a sidechain of an amino acid;

or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

18. A compound according to any of claims 1, 3, 5, 7, 9, 11, 13, 15 and 17 wherein R is selected from the group consisting of —

C(O)NH₂, —

Si(CH₃)₃, pyrid-2-yl, 4-methoxyphenyl, and —

CH(OCH₂CH₃)₂.

28. 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 according to any one of claims 1-17, or 19-27.

29. The pharmaceutical composition according to claim 28 wherein said composition comprises one or more antiviral agents.

30. The pharmaceutical composition according to claim 29 wherein said antiviral agent is an agent active against RNA-dependent RNA virus.

31. A method for treating a viral infection in a mammal which infection is mediated at least in part by a virus in the flaviviridae family of viruses which method comprises 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 28.

32. A method for treating a viral infection in a mammal which infection is mediated at least in part by a virus in the flaviviridae family of viruses which method comprises 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 29.

33. A method for treating a viral infection in a mammal which infection is mediated at least in part by a virus in the flaviviridae family of viruses which method comprises 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 30.

34. A method for treating HCV in a mammalian patient suffering from HCV which method comprises administering to said mammal a pharmaceutical composition according to claim 28.

35. A method for treating HCV in a mammalian patient suffering from HCV which method comprises administering to said mammal a pharmaceutical composition according to claim 29.

36. A method for treating HCV in a mammalian patient suffering from HCV which method comprises administering to said mammal a pharmaceutical composition according to claim 30.

37. The method of claim 36 in combination with the administration of a therapeutically effective amount of one ore more agents active against HCV.

38. The method of claim 37 wherein said agent is ribavirin, levovirin, 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.

39. The method of claim 38 wherein said agent is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin.

3. A compound represented by Formula II:

4. The compound according to claim 3, 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 esters, phosphate, phospho, diphospho, triphospho, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR⁴NH₂ where R⁴ is a sidechain of an amino acid;

or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

5. A compound represented by Formula III:

6. The compound according to claim 5, wherein each of W and W¹ is independently hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phospho, diphospho, triphospho, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR⁴NH₂ where R⁴ is a sidechain of an amino acid;

or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

7. A compound represented by Formula IV:

8. The compound according to claim 7, wherein each of W and W² is independently hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phospho, diphospho, triphospho, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR⁴NH₂ where R⁴ is a sidechain of an amino acid;

or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

9. A compound represented by Formula V:

10. The compound according to claim 9, wherein each of W¹ and W² is independently hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phospho, diphospho, triphospho, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR⁴NH₂ where R⁴ is a sidechain of an amino acid.

11. A compound represented by Formula VI:

12. The compound according to claim 11, wherein W¹ is hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phospho, diphospho, triphospho, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR⁴NH₂ where R⁴ is a sidechain of an amino acid.

13. A compound represented by formula VII:

14. The compound according to claim 13, wherein W² is hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phospho, diphospho, triphospho, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR⁴NH₂ where R⁴ is a sidechain of an amino acid.

15. A compound represented by Formula VIII:

16. The compound according to claim 15, wherein W is hydrogen or a pharmaceutically acceptable prodrug selected from the group consisting of acyl, oxyacyl, phosphonate, phosphate esters, phosphate, phospho, diphospho, triphospho, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, and —

C(O)CHR⁴NH₂ where R⁴ is a sidechain of an amino acid.

17. A compound represented by Formula IX:

19. A compound selected from the group consisting of:

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2′

-trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-2-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-4-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methoxyphenyl)-ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-carboxamidoethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5[(3,3-diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5[(N,N-dimethyl-2-carboxamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5[(N-amino-2-carboxamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2′

-trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-2-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-4-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methoxyphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxamidoethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[(3,3-diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[2-(N,N-dimethylcarboxyamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[2-(N-aminocarboxyamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2′

-trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-2-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-4-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methoxyphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxyamidoethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5[(3,3-diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-[(N,N-dimethyl-2-carboxyamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5[(N-amino-2-carboxyamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2′

-trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-2-yl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-[2-(pyrid-4-yl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methoxyphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxyamidoethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5[(3,3-diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5[(N,N-dimethylcarboxylamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine; and

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5[(N-aminocarboxylamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

or pharmaceutically acceptable salts or partial salts thereof.

20. 7-(2′

-C-methyl-β

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

21. 7-(2′

-C-methyl-β

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

22. 7-(2′

-C-methyl-β

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

23. 7-(2′

-C-methyl-β

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

24. 7-(2′

-C-methyl-β

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

25. 7-(2′

-C-methyl-β

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

26. 7-(2′

-C-methyl-β

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

27. 7-(2′

-C-methyl-β

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