Compounds and pharmaceutical compositions for the treatment of viral infections

• US 8,951,985 B2
• Filed: 09/11/2012
• Issued: 02/10/2015
• Est. Priority Date: 09/12/2011
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Surleraux, Dominique, Dousson, Cyril B., Dukhan, David, Pierra, Claire
• Primary Examiner(s): LEWIS, PATRICK T
• Application Number:
  US13/610,574
• Publication Number:
  US 20130064793A1
• Time in Patent Office: 882 Days
• Field of Search: None
• US Class Current: 514/47
• 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: C07H 19/207 the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Abstract

Provided herein are compounds, compositions and methods for the treatment of liver disorders, including HCV infections. In one embodiment, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein each R¹⁰ and R¹¹ is hydrogen.

3. The compound of claim 1, wherein each X is O.

4. The compound of claim 1, wherein Base is adenine, cytosine, guanine, hypoxanthine, thymine or uridine.

5. The compound of claim 1, wherein Base is selected from one of formulae (i) to (xxvi):

6. The compound of claim 1, or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof, of the formula:

7. The compound of claim 1, or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof, of the formula:

8. The compound of claim 1, or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof, of the formula Ia:

9. A compound of claim 8, wherein R¹ is OH or F;

and R⁸ is hydrogen, alkyl or benzyl.

10. A compound of claim 8, wherein R⁸ is methyl, isopropyl, isobutyl or benzyl.

11. A compound of claim 8, wherein R² is methoxy, ethoxy or isopropoxy.

12. A compound of claim 11, wherein R⁸ is methyl, isopropyl, isobutyl or benzyl.

13. A compound of claim 12, wherein R⁸ is isobutyl.

14. A compound of claim 13, wherein R⁹ is methyl, ethyl or isopropyl.

15. A compound of claim 1, or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof, wherein the compound is selected from the group consisting of:

16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.

17. The pharmaceutical composition of claim 16, wherein the composition is an oral formulation.

18. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound or composition of claim 1.

19. The method of claim 18, wherein the host is a human.

20. The method of claim 18, wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt or stereoisomer thereof to the liver of said host.

21. The method of claim 18, wherein said compound or composition is administered in combination or alternation with a second anti-viral agent optionally selected from the group consisting of an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

22. The method of claim 21, wherein the second agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta and interferon γ

-1b.