Derivatives of uridine 5′-cyclophosphate useful to treat hepatitis C viral infections

Patent metadata

Field	Value
Publication number	US-9676809-B2
Application number	US-201415034757-A
Country	US
Kind code	B2
Filing date	Nov 19, 2014
Priority date	Nov 22, 2013
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

Some embodiments of the present invention include nucleoside 5′-monophosphate derivative compounds, their preparation and their uses. In some embodiments, such compounds are useful to treat hepatitis C viral infections.

First claim

What is claimed is:

1. A compound of Formula IB:

and pharmaceutically acceptable salts thereof,
wherein:
R is an optionally substituted phenyl or an optionally substituted pyridyl;
R 1B is selected from:
C 1 -C 8 alkyl substituted with one or more R 1BA ,
C 1 -C 8 alkoxy optionally substituted with one or more R 1BA , and
—N(R 1C ) 2 ;

each R 1C is independently hydrogen or C 1 -C 8 alkyl;
each R 1BA is independently hydroxy, halo, —N(R 1CC ) 2 or —OR 1BB ;
R 1BB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl; and
each R 1CC is independently hydrogen or C 1 -C 8 alkyl.

2. The compound of claim 1 , wherein R is selected from the group consisting of:

3. The compound of claim 1 , wherein R is selected from the group consisting of

4. The compound of claim 1 , wherein R 1B is C 1 -C 6 haloalkyl.

5. The compound of claim 1 , wherein R 1B is C 1 -C 8 alkyl substituted with —N(R 1CC ) 2 .

6. The compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

7. A compound having the structure of Formula I-A:

and pharmaceutically acceptable salts thereof,
wherein:
R is an optionally substituted phenyl or an optionally substituted pyridyl;
R 1A is selected from hydroxyl, —O—C(═)CH 3 , and C 1 -C 8 alkyl optionally substituted with one or more R 1AA ;
each R 1AA is independently hydroxy, halo, or —O—C(═O)R 1AB ; and
R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

8. The compound of claim 7 , wherein R 1A is C 1 -C 8 alkyl substituted with one or more R 1AA ;
each R 1AA is independently hydroxy, or halo; and
R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

9. The compound of claim 7 , wherein R 1A is C 1 -C 8 alkyl substituted with one or more R 1AA ;
each R 1AA is independently —O—C(═O)R 1AB ; and
R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

10. The compound of claim 1 , wherein R 1B is C 1 -C 8 alkyl or C 1 -C 8 alkoxy each optionally substituted with one or more R 1BA ;
each R 1BA is independently hydroxy, halo, —N(R 1CC ) 2 or —OR 1BB ;
R 1BB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl; and
each R 1CC is independently hydrogen or C 1 -C 6 alkyl.

11. The compound of claim 1 , wherein R 1B is —N(R 1C ) 2 ; and
each R 1C is independently hydrogen or C 1 -C 6 alkyl.

12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

13. A method of treating a viral infection in a subject comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

14. The method of claim 13 , further comprising administering an effective amount of an additional therapeutic agent to the subject wherein the additional therapeutic agent is selected from the group consisting of thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, an inhibitor of HCV helicase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, ribavirin, interferon-α, and pegylated interferon-α.

15. The method of claim 13 , wherein the viral infection comprises hepatitis C (HCV).

16. A method of inhibiting viral replication in a cell comprising contacting the cell with the compound of claim 1 .

17. The method of claim 16 , wherein the viral replication is RNA-dependent.

18. The method of claim 16 , further comprising contacting the cell with an additional antiviral agent(s) selected from the group consisting of ribavirin, thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, ribavirin, interferon-α, and pegylated interferon-α.

19. The method of claim 16 , wherein the cell is a hepatocyte.

20. The compound of claim 7 selected from the group consisting of:

21. A method of treating a viral infection in a subject comprising administering an effective amount of a compound of claim 7 to a subject in need thereof.

Assignees

• Ligand Pharm Inc

Inventors

• Zhi Lin

Classifications

• C07H19/11

  containing cyclic phosphate · CPC title

• C07H19/10 Primary

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• A61P31/14

  for RNA viruses · CPC title