2′,4′-bridged nucleosides for HCV infection

• US 10,723,754 B2
• Filed: 10/21/2013
• Issued: 07/28/2020
• Est. Priority Date: 10/22/2012
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Mayes, Benjamin Alexander, Moussa, Adel M., Stewart, Alistair James
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US14/059,233
• Publication Number:
  US 20140112887A1
• Time in Patent Office: 2,472 Days
• Field of Search: None
• 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: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/11 containing cyclic phosphate
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/207 the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
• CPC Class Codes: C07H 19/213 containing cyclic phosphate
• CPC Class Codes: C07H 19/24 Heterocyclic radicals containing oxygen or sulfur as ring hetero atom

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′,4′-bridged nucleosides which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the 2′,4′-bridged nucleosides are of Formula 3001:

or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, where PD, B, W, X, R^A, R^B, R^C and R^D are as described herein.

Claims

1. A compound according to Formula 3001:

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

3. The compound of claim 2, wherein B cytosine, uracil, or 5′

-fluorouracil.

4. The compound of claim 1, according to any of formulas III or IV:

5. The compound of claim 4, wherein R³ is —

C(CH₃)₂CH₂OH.

6. The compound of claim 1, according to any of the following formulas:

7. The compound of claim 1 according to any of the following formulas:

8. The compound of claim 1, according to any of the following structures:

9. A pharmaceutical composition comprising the compound of claim 1 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 the compound of claim 1.

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

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

14. The method of claim 11, wherein the compound is administered in combination or alternation with a second anti-viral agent selected from the group consisting of 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, and combinations thereof.

15. The method of claim 14, wherein the second anti-viral agent is selected from the group consisting of telaprevir, bocepravir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, ribavirin, and combinations thereof.

16. The method of claim 14, wherein the second anti-viral agent is selected from the group consisting of telaprevir, bocepravir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, and combinations thereof;

and wherein the second anti-viral agent is administered in combination or alternation in the absence of ribavirin.