Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase

• US 20040067901A1
• Filed: 10/17/2003
• Published: 04/08/2004
• Est. Priority Date: 01/22/2001
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Anne B. Eldrup, Balkrishen Bhat, David B. Olsen, Malcolm Maccoss, Marija Prhavc, Neelima Bhat, Phillip Dan Cook, Quanlai Song, Steven S. Carroll, Thazha P. Prakash
• Inventors: Bhat, Balkrishen, Olsen, David B., Prakash, Thazha P., Cook, Phillip Dan, Song, Quanlai, Eldrup, Anne B., Maccoss, Malcolm, Prhavc, Marija, Carroll, Steven S., Bhat, Neelima
• Granted Patent: US 7,125,855 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• 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 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• 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
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/12 Triazine radicals
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: Y02P 20/582 : Recycling of unreacted starting or intermediate materials

Abstract

The present invention provides nucleoside 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 nucleoside 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 nucleoside compounds of the present invention.

Claims

1. A compound of the structural formula:

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

3. The compound of claim 2 wherein

R^b is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R^c is hydroxy, fluoro, or methoxy;

R^a is hydrogen, fluoro, hydroxy, amino, or methoxy;

Rⁱ is hydrogen or P₃O₉H_4;

R^g is hydrogen or amino;

R^d is hydrogen, cyano, methyl, halogen, or CONH₂; and

R^e and R^f are each independently hydrogen, fluoro, hydroxy, or amino;

with the proviso that when R^b is β

-methyl, R^a and R^c are α

-hydroxy, R^e is amino, and R^f, R^g, and Rⁱ are hydrogen, then R^d is not cyano or CONH₂.

4. The compound of claim 1 selected from the group consisting of:

4-amino-7-(2-C-methyl-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-methylamino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-dimethylamino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-cyclopropyl amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo [2,3-d]pyrimidine,

4-amino-7-(2-C-vinyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(2-C-hydroxymethyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(2-C-fluoromethyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-methyl-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,

4-amino-5-bromo-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-chloro-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-fluoro-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2,4-diamino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-4-cyclopropylamino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

2-amino-7-(2-C-methyl-β

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

4-amino-7-(2-C-ethyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(2-C,2-O-dimethyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

7-(2-C-methyl-β

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

2-amino-5-methyl-7-(2-C, 2-O-dimethyl-β

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

4-amino-7-(3-deoxy-2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-deoxy-2-C-methyl-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidine,

4-amino-2-fluoro-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(3-C-methyl-β

-D-xylofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(2,4-di-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and

4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;

and the corresponding 5′

-triphosphates;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 selected from the group consisting of:

4-amino-7-(2-C-methyl-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-7-(2-C-fluoromethyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-methyl-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-bromo-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

4-amino-5-chloro-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo [2,3-d]pyrimidine,

4-amino-5-fluoro-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and

4-amino-7-(2-C,2-O-dimethyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,

and the corresponding 5′

-triphosphates;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 which is

4-amino-7-(2-C-methyl-β

-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5 which is

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 5 which is

4-amino-7-(2-C-fluoromethyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 5 which is

4-amino-5-chloro-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 5 which is

4-amino-5-bromo-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 5 which is

4-amino-5-fluoro-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;

or a pharmaceutically acceptable salt thereof.

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

13. The pharmaceutical composition of claim 12 useful for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA replication, and/or treating RNA-dependent RNA viral infection.

14. The pharmaceutical composition of claim 13 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.

15. 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.

16. The method of claim 15 wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase and said RNA-dependent RNA viral replication is HCV viral replication.

17. 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.

18. The method of claim 17 wherein said RNA-dependent RNA viral infection is HCV infection.

19. The method of claim 18 in combination with a therapeutically effective amount of another agent active against HCV.

20. The method of claim 19 wherein said agent active against HCV is ribavirin;

levovirin;

thymosin alpha-1;

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.

21. The method of claim 20 wherein said agent active against HCV is interferon-α

or pegylated interferon-α

, alone or in combination with ribavirin or levovirin.