Thionucleoside derivatives as inhibitors of rna-dependent rna viral polymerase

• US 20060122154A1
• Filed: 07/18/2003
• Published: 06/08/2006
• Est. Priority Date: 07/24/2002
• Status: Active Grant

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.), Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Bhat, Balkrishen, Olsen, David B., Cook, Philip Dan
• Granted Patent: US 7,323,449 B2
• Time in Patent Office: Days
• US Class Current: 514/81
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals

Abstract

The present invention provides thionucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such thionucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the thionucleoside compounds of the present invention.

Claims

1. A compound of the structural formula I:

2. The compound of claim 1 of the structural formula II:

3. The compound of claim 2 wherein

R¹ is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R² is hydroxy, fluoro, or methoxy;

R³ is hydrogen, fluoro, hydroxy, amino, or methoxy;

R⁵ is hydrogen or P₃O₉H₄;

R⁸ is hydrogen or amino;

R⁹ is hydrogen, cyano, methyl, halogen, or CONH₂; and

R¹⁰ and R¹¹ are each independently hydrogen, fluoro, hydroxy, or amino.

4. The compound of claim 3 which is 4-amino-7-(2-C-methyl-4-thio-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine or 2-amino-7-(2-C-methyl-4-thio-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one;

and the corresponding 5′

-triphosphates;

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 5 useful for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA replication, and/or treating RNA-dependent RNA viral infection.

7. The pharmaceutical composition of claim 6 wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase, said RNA-dependent RNA viral replication is HCV replication, and said RNA-dependent RNA viral infection is HCV infection.

8. A method of inhibiting RNA-dependent RNA viral polymerase and/or inhibiting RNA-dependent RNA viral replication comprising administering to a mammal in need of such inhibition an effective amount of a compound according to claim 1.

9. The method of claim 8 wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase and said RNA-dependent RNA viral replication is HCV viral replication.

10. A method of treating RNA-dependent RNA viral infection comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1.

11. The method of claim 10 wherein said RNA-dependent RNA viral infection is HCV infection.

12. The method of claim 11 in combination with a therapeutically effective amount of another agent active against HCV.

13. The method of claim 12 wherein said agent active against HCV is ribavirin;

levovirin;

thymosin alpha-1;

interferon-β

;

an inhibitor of NS3 serine protease;

an inhibitor of inosine monophosphate dehydrogenase;

interferon-α

or pegylated interferon-α

, alone or in combination with ribavirin or levovirin.

14. The method of claim 13 wherein said agent active against HCV is interferon-α

or pegylated interferon-α

, alone or in combination with ribavirin.

15-20. -20. (canceled)