Amino acid phosphoramidate pronucleotides of 2′-cyano, azido and amino nucleosides for the treatment of HCV

• US 10,231,986 B2
• Filed: 09/25/2015
• Issued: 03/19/2019
• Est. Priority Date: 03/13/2013
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Dukhan, David, Parsy, Christophe Claude, Gosselin, Gilles, Griffon, Jean-Francois, Brandt, Guillaume, Dousson, Cyril B., Moussa, Adel M., Mayes, Benjamin Alexander, Stewart, Alistar James
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US14/866,759
• Publication Number:
  US 20160113956A1
• Time in Patent Office: 1,271 Days
• Field of Search: None
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 19/073 with 2-deoxyribosyl as the saccharide radical
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/173 with 2-deoxyribosyl as the saccharide radical
• 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 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 2′-cyano, azido or amino nucleosides according to Formula 1001 or 2001:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R¹ and R² are as described herein.

Claims

1. A compound according to Formula I:

2. The compound of claim 1 according to Formula Ia or Ib:

3. The compound of claim 1 according to Formula II:

4. The compound of claim 3 according to Formula IIa or IIb:

5. The compound of claim 1 according to Formula III:

6. The compound of claim 5 according to Formula IIIa or IIIb:

7. The compound of claim 1 according to Formula IV:

8. The compound of claim 3 according to Formula IVa or IVb:

9. The compound of claim 1 wherein:

Base is

10. The compound of claim 9 according to any of Formulas (V)-(XVI):

11. The compound of claim 1, wherein R² is hydrogen, methyl, or halo.

12. The compound of claim 1 according to any of Formulas 1-3:

13. The compound of claim 1, wherein:

Base is

14. The compound of claim 1 according to Formula 4:

15. The compound of claim 1 according to Formula 7:

16. The compound of claim 1 according to Formula 8:

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

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

26. A method for the treatment of a host infected with a hepatitis C virus, comprising the administering 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 the administering directs a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host.

29. The method of claim 26, further comprising administering the compound or composition in combination or alternation with a second anti-viral agent, wherein the second antiviral 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.

17. A compound according to Formula 4001:

18. The compound of claim 17 according to Formula 4001a or 4001b:

19. The compound of claim 17 according to Formula 4002:

20. The compound of claim 17 according to Formula 4003:

21. The compound of claim 17 according to Formula 4004:

22. The compound of claim 17 according to any of Formulas 1005-1012:

23. The compound of claim 17 selected from the group consisting of:

30. A method of inhibiting the activity of a polymerase, comprising contacting the polymerase with a compound according to Formula I:

31. A method of treating a host infected with a pestivirus, comprising the administering of an effective treatment amount of a compound according to Formula I: