Nucleoside compounds for treating viral infections

• US 20060079468A1
• Filed: 06/04/2004
• Published: 04/13/2006
• 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 7,202,223 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• 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 Ia:

2. A 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)CHR³NH₂, where R³ is a sidechain of an amino acid, or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

4. 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 to 3.

5. The pharmaceutical composition according to claim 4 wherein said composition comprises one or more antiviral agents.

6. 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 4.

7. 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 4.

3. A compound selected from the group consisting of:

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-5′

-monophospho-β

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

7-(2′

-C-methyl-5′

-diphospho-β

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

7-(2′

-C-methyl-5′

-triphospho-β

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

7-(2′

-C-methyl-5′

-monophospho-β

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

7-(2′

-C-methyl-5′

-diphospho-β

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

7-(2′

-C-methyl-5′

-triphospho-β

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

or pharmaceutically acceptable salts or partial salts thereof.

8. A compound of formula II:

9. A compound according to claim 8, 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)CHR³NH₂, where R³ is a sidechain of an amino acid, or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

10. A compound selected from the group consisting of:

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-5′

-phospho-β

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

7-(2′

-C-methyl-5′

-diphospho-β

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

7-(2′

-C-methyl-5′

-triphospho-β

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

or pharmaceutically acceptable salts or partial salts thereof.

11. 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 8 to 10.

12. The pharmaceutical composition according to claim 11 wherein said composition comprises one or more antiviral agents.

13. 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 11.

14. 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 11.

15. A compound of formula III:

16. A compound according to claim 15, 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)CHR³NH₂, where R³ is a sidechain of an amino acid, or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

18. 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 15 to 17.

19. The pharmaceutical composition according to claim 18 wherein said composition comprises one or more antiviral agents.

20. 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 18.

21. 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 18.

17. A compound selected from the group consisting of:

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-5′

-phospho-β

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

7-(2′

-C-methyl-5′

-phospho-β

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

7-(2′

-C-methyl-5′

-diphospho-β

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

7-(2′

-C-methyl-5′

-diphospho-β

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

7-(2′

-C-methyl-5′

-triphospho-β

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

7-(2′

-C-methyl-5′

-triphospho-β

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

or pharmaceutically acceptable salts or partial salts thereof.

22. A compound of formula IV:

23. A compound according to claim 22, 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)CHR³NH₂, where R³ is a sidechain of an amino acid, or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

25. 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 22 to 24.

26. The pharmaceutical composition according to claim 25 wherein said composition comprises one or more antiviral agents.

27. 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 25.

28. 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 25.

24. A compound selected from the group consisting of:

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-5′

-phospho-β

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

7-(2′

-C-methyl-5′

-diphospho-β

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

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.

29. A compound of formula V:

30. A compound according to claim 29, 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)CHR³NH₂, where R³ is a sidechain of an amino acid, or where W and W¹ may optionally join together to form a cyclic phosphonamidate.

32. 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 29 to 31.

33. The pharmaceutical composition according to claim 32 wherein said composition comprises one or more antiviral agents.

34. 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 32.

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 32.

31. A compound selected from the group consisting of:

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-β

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

7-(2′

-C-methyl-5′

-phospho-β

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

7-(2′

-C-methyl-5′

-phospho-β

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

7-(2′

-C-methyl-5′

-phospho-β

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

7-(2′

-C-methyl-5′

-diphospho-β

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

7-(2′

-C-methyl-5′

-diphospho-β

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

7-(2′

-C-methyl-5′

-diphosphol-β

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

7-(2′

-C-methyl-5′

-triphosphol-β

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

7-(2′

-C-methyl-5′

-triphosphol-β

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

7-(2′

-C-methyl-5′

-triphosphol-β

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

or pharmaceutically acceptable salts or partial salts thereof.

36. 7-(2′

-C-methyl-β

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

37. 7-(2′

-C-methyl-β

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

38. 7-(2′

-C-methyl-β

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

39. 7-(2′

-C-methyl-β

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

40. 7-(2′

-C-methyl-β

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

41. 7-(2′

-C-methyl-β

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

42. 7-(2′

-C-methyl-β

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

43. 7-(2′

-C-methyl-β

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

44. 7-(2′

-C-methyl-β

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