1′,4′-thio nucleosides for the treatment of HCV

• US 10,005,779 B2
• Filed: 06/04/2014
• Issued: 06/26/2018
• Est. Priority Date: 06/05/2013
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Inventors: Dukhan, David, Gosselin, Gilles, Dousson, Cyril B.
• Primary Examiner(s): Jarrell, Noble E
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US14/296,122
• Publication Number:
  US 20140364446A1
• Time in Patent Office: 1,483 Days
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07H 19/067 with ribosyl as the saccharide radical

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. In certain embodiments, the compounds are 1′,4′-thio nucleoside compounds which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the compounds are of Formula 3001:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof; wherein Base, R^A, R^B, W, X, Y, and Z are as described herein.

Claims

1. A compound according to Formula 3001:

2. The compound of claim 1, wherein:

X is —

NH-G(S_C)—

C(O)-Q¹; and

S_C is a side chain of a naturally occurring amino acid.

3. The compound of claim 1, wherein:

X is —

OR¹; and

R¹ is unsubstituted -alkyl-S—

C(O)-alkyl.

4. The compound of claim 1, wherein:

Y is hydrogen, —

OR¹, —

SR¹, —

NR¹R², or an N-linked or O-linked amino acid residue, or derivative thereof; and

Z is hydrogen, hydroxyl, or halo.

5. The compound of claim 1, wherein W is O.

6. The compound of claim 1 according to any of Formulas II-IV, or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof:

7. The compound of claim 1, wherein Base is:

8. The compound of claim 7 wherein Base is:

9. The compound of claim 1, wherein Base is uracil.

10. The compound of claim 1, wherein R^A is hydrogen or methyl.

11. The compound of claim 1, wherein Z is hydroxyl.

12. The compound of claim 1, wherein R^B is hydroxyl.

13. The compound of claim 1 according to any of Formulas 1-4, or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof:

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

15. The pharmaceutical composition of claim 14, wherein the composition is an oral formulation.

16. A method for the treatment of a human host infected with a hepatitis C virus, comprising administering to the host an effective amount of a compound of claim 1.

17. The method of claim 16 comprising administering a second anti-viral agent in combination or alternation with the compound, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof.

18. The method of claim 17, wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof.

19. The method of claim 17, wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof, and further wherein the administration is not in combination or alternation with ribavirin.

20. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable excipient, carrier, or diluent.

21. The pharmaceutical composition of claim 20, wherein the composition is an oral formulation.

22. A method for the treatment of a human host infected with a hepatitis C virus, comprising administering to the host an effective amount of a compound of claim 8.

23. The method of claim 22 comprising administering a second anti-viral agent in combination or alternation with the compound, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof.

24. A compound according to Formula (3001)