Compounds and pharmaceutical compositions for the treatment of viral infections

• US 8,680,071 B2
• Filed: 03/31/2011
• Issued: 03/25/2014
• Est. Priority Date: 04/01/2010
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Surleraux, Dominique, Gosselin, Gilles
• Primary Examiner(s): OLSON, ERIC
• Application Number:
  US13/077,733
• Publication Number:
  US 20110243886A1
• Time in Patent Office: 1,090 Days
• Field of Search: None
• US Class Current: 514/52
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07F 9/24 Esteramides
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

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 of Formula I, wherein R⁷ and R⁸ are selected as follows:

i) R⁷ and R⁸ are each independently hydrogen, C₂-C₁₀ alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, alkylheterocyclyl or alkylheteroaryl, wherein alkyl is optionally substituted by alkoxy;

or

ii) R⁷ and R⁸ together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring.

3. The compound of claim 1, wherein

R¹ and R³ are each hydrogen;

R² is (G)_mC(O)Q¹; and

m is 1.

4. The compound of claim 1, wherein

R^l and R³ are each hydrogen;

R² is (G)_mC(O)Q¹; and

m is 2.

22. The compound of claim 1, wherein R is a moiety derivable by removal of a hydrogen from a hydroxy group of selected from ribavirin, viramidine, valopicitabine, PSI-6130, PSI-6206, PSI-35938 and R1479.

26. 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 of claim 1.

27. The method of claim 26, wherein the host is a human.

28. The method of claim 26, wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt or stereoisomer thereof to the liver of said host.

29. The method of claim 26, 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.

30. The compound of claim 1 where the antiviral drug is a nucleoside or nucleoside analog.

5. A compound of Formula II:

6. The compound of claim 5, wherein if R² is (G)_mC(O)Q¹, G is CR⁷R⁸, m is 1, and one of R⁷ or R⁸ is hydrogen;

the other of R⁷ and R⁸ is not methyl.

7. The compound of claim 5, wherein Y is OR⁹ and Z is OR¹⁰ or F.

8. The compound of claim 5, wherein W is alkyl.

9. The compound of claim 5, wherein W is ethynyl;

Y is OR⁹;

Z is F; and

R⁹ is hydrogen.

10. The compound of claim 5, wherein each R⁷ is hydrogen and each R⁸ is independently alkyl, aryl, aralkyl or alkylheteroaryl.

11. The compound of claim 10, wherein each R⁸ is C₂-C₁₀ alkyl.

12. The compound of claim 10, wherein each R⁸ is isobutyl, sec-butyl, phenyl or benzyl.

13. The compound of claim 5, wherein each R⁷ is hydrogen and each R⁸ is alkyl optionally substituted by alkoxy.

14. The compound of claim 13, wherein each R⁸ is t-butoxymethyl.

15. The compound of claim 5, wherein each of R⁷ and R⁸ is alkyl.

16. The compound of claim 15, wherein each of R⁷ and R⁸ is methyl.

17. The compound of claim 5, wherein R⁷ and R⁸ together with the carbon atom to which they are attached form a 5 membered cycloalkyl ring.

18. The compound of claim 5, wherein Base is adenine, cytosine, guanine, hypoxanthine, thymine or uridine.

19. The compound of claim 18, wherein Base is cytosine.

20. The compound of claim 18, wherein Base is guanine

21. The compound of claim 18, wherein Base is uridine.

23. The compound of claim 5 or a pharmaceutically acceptable salt, a stereoisomeric, tautomeric or polymorphic form thereof, selected from:

24. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable excipient, carrier or diluent.

25. The pharmaceutical composition of claim 24, wherein the composition is an oral formulation.