5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases

• US 9,416,154 B2
• Filed: 07/10/2012
• Issued: 08/16/2016
• Est. Priority Date: 07/13/2011
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Verma, Vishal A., Arasappan, Ashok, Njoroge, F. George, Girijavallabhan, Vinay, Bogen, Stephane L., Dang, Qun, Olsen, David B.
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US14/232,540
• Publication Number:
  US 20140235567A1
• Time in Patent Office: 1,498 Days
• US Class Current: 1/1
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals

Abstract

The present invention relates to 5′-Substituted Nucleoside Derivatives of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein X, Y, Z, R¹, R² and R³ are as defined herein and B is a 7-deaza-9-purinyl moiety. The present invention also relates to compositions comprising at least one 5′-Substituted Nucleoside Derivative, and methods of using the 5′-Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.

Claims

1. A compound having the structure:

2. The compound of claim 1, wherein X is O.

3. The compound of claim 1, wherein Z is C₁-C₆ alkyl.

4. The compound of claim 1, wherein R³ is C_1-6 alkyl.

5. The compound of claim 1 having the formula (Ia):

6. The compound of claim 5, wherein B is:

7. The compound of claim 5, wherein Y is H and Z is methyl.

8. The compound of claim 5, wherein Y is H and Z is ethyl.

9. The compound of claim 5, wherein R¹ is H.

10. The compound of claim 5, wherein R¹ is:

11. The compound of claim 5, wherein R^3′

is F or —

OH.

12. The compound of claim 5, wherein R^3′

is F.

13. The compound of claim 1 having the structure:

14. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14 further comprising an additional therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

16. The pharmaceutical composition of claim 15, further comprising wherein said additional therapeutic agent is selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

17. A method of treating a patient infected with HCV comprising administering an amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, effective to prevent and/or treat infection by HCV in said patient.

18. The method of claim 17, further comprising the step of administering an HCV protease inhibitor to said patient.

19. The method of claim 17, further comprising the step of administering ribavirin to said patient.