D-amino acid compounds for liver disease

• US 10,717,758 B2
• Filed: 05/16/2018
• Issued: 07/21/2020
• Est. Priority Date: 05/22/2012
• 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, Dukhan, David
• Primary Examiner(s): Alstrum-Acevedo, James H
• Assistant Examiner(s): Yang, Kaipeen E
• Application Number:
  US15/981,813
• Publication Number:
  US 20180258130A1
• Time in Patent Office: 797 Days
• 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 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• 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 31/7076 containing purines, e.g. adenosine, adenylic acid
• 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 38/55 Protease inhibitors
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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

Abstract

Provided herein are compounds, compositions and methods for the treatment of liver disease and conditions, 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 according to formula (IIa) or (IIb), or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, according to formula (IIa).

3. The compound of claim 1, according to formula (IIb).

4. The compound of claim 1 wherein

Y is —

OR¹;

R¹ is phenyl; and

R^b2 is —

OH or —

F.

5. The compound of claim 1 which is according to

6. A nucleoside composition comprising a compound according to Formula IIa or IIb:

7. The nucleoside composition of claim 6, wherein

Y is —

OR¹;

R^d is —

H;

R¹ is phenyl; and

R^b2 is —

OH or —

F.

8. The nucleoside composition of claim 7, wherein the composition provides a therapeutically effective amount of the compound for treating a human infected with HCV.

9. The nucleoside composition of claim 6, wherein the compound is according to Formula (IIa).

10. The nucleoside composition of claim 6, wherein the compound is according to Formula (IIb).

11. The nucleoside composition of claim 6, wherein the compound is at least 90% by weight the compound according to Formula (IIa).

12. The nucleoside composition of claim 6, wherein the compound is at least 90% by weight the compound according to Formula (IIb).

13. The nucleoside composition of claim 6, comprising the compound

14. The nucleoside composition of claim 6, comprising the compound

15. A pharmaceutical composition comprising a compound according to formula (II) or a pharmaceutically acceptable salt thereof:

16. The pharmaceutical composition of claim 15 wherein

Y is —

OR¹;

R¹ is phenyl; and

R^b2 is —

F or —

OH.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition provides a therapeutically effective amount of the compound for treating a human infected with HCV.

18. A method for the treatment of a human infected with a hepatitis C virus, comprising the administration to the human an effective amount of a nucleoside composition comprising a compound according to formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof:

19. The method of claim 18, wherein

Y is —

OR¹;

R¹ is phenyl; and

R^b2 is —

OH or —

F.

20. The method of claim 18, 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.

21. The method of claim 20, wherein the second anti-viral agent is an HCV NS3 protease inhibitor.

22. The method of claim 20, wherein the second anti-viral agent is an HCV NS5A inhibitor.

23. The method of claim 18, wherein the nucleoside composition comprises the compound

24. The method of claim 18, wherein the nucleoside composition comprises the compound