Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections

• US 8,507,460 B2
• Filed: 10/12/2012
• Issued: 08/13/2013
• Est. Priority Date: 10/14/2011
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Surleraux, Dominique, Dousson, Cyril B., Parsy, Christophe Claude
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US13/650,739
• Publication Number:
  US 20130095064A1
• Time in Patent Office: 305 Days
• Field of Search: None
• US Class Current: 514/48
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/213 containing cyclic phosphate

Abstract

Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, 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 R¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.

3. The compound of claim 1 wherein R² is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, cyclopentyl, cyclobutyl, cyclopropyl or t-butyl.

4. The compound of claim 1 according to formula Ia or Ib:

5. The compound of claim 1 according to formula II:

6. The compound of claim 1 according to formula IIa or IIb:

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

8. The pharmaceutical composition of claim 7, wherein the composition is an oral formulation.

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

10. The pharmaceutical composition of claim 9, wherein the composition is an oral formulation.

11. 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.

12. The method of claim 11, wherein the host is a human.

13. The method of claim 11, wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt or stereoisomer thereof to the liver of said host.

14. The method of claim 11, wherein said compound 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.

15. The method of claim 14, wherein the second agent is selected from the group consisting of telaprevir, bocepravir, 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.

16. 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 5.

17. The method of claim 16, wherein the host is a human.

18. The method of claim 16, wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt or stereoisomer thereof to the liver of said host.

19. The method of claim 16, wherein said compound 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.

20. The method of claim 19, wherein the second agent is selected from the group consisting of telaprevir, bocepravir, 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.