4′-fluoro nucleosides for the treatment of HCV

• US 9,211,300 B2
• Filed: 12/17/2013
• Issued: 12/15/2015
• Est. Priority Date: 12/19/2012
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Original Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals LLC (Merck & Co., Inc.), Universite Montpellier II
• Inventors: Mayes, Benjamin Alexander, Moussa, Adel M., Stewart, Alistair James, Gosselin, Gilles
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US14/109,463
• Publication Number:
  US 20140178338A1
• Time in Patent Office: 728 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• 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 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• 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: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• 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. In certain embodiments, the compounds are according to Formula 1501:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein B, PD, R^A, R^B, R^C, L, M and Z are as described herein.

Claims

1. A compound according to Formula 1501:

2. The compound of claim 1 according to Formula 1502:

3. The compound of claim 1 according to Formula 1503:

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

5. The compound of claim 1 according to any of Formulas 1504, 1505, or 1506:

6. The compound of claim 5, wherein R³ is branched hydroxyalkyl.

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

8. The compound of claim 1 according to any of Formulas 3002 or 3003:

9. The compound of claim 1 according to any of Formulas XII-XVII:

10. The compound of claim 1, wherein Y is an N-linked or O-linked amino acid residue or an N-linked or O-linked residue of an amino acid derivative.

11. The compound of claim 1 according to Formula 1507:

12. The compound of claim 1, wherein R^A is hydroxyl and R^B is hydrogen or methyl.

13. The compound of claim 1 according to any of Formulas 1-3, 101, 103, 104, or 106:

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 an effective amount of a compound of claim 1.

17. The method of claim 16, wherein the administration comprises directing the compound, or pharmaceutically acceptable salt thereof, to a liver of the host.

18. The method of claim 16, wherein the compound is administered in combination or alternation with a second anti-viral agent selected from 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 combination thereof.

20. The compound of claim 1, wherein:

B is

19. A method for the treatment of a host infected with a hepatitis C virus comprising administering an effective amount of a compound according to Formula 1501:

21. The method of claim 19, wherein:

B is

22. A compound according to Formula 1501:

23. The compound of claim 22, wherein:

B is