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

Patent metadata

Field	Value
Publication number	US-10000522-B2
Application number	US-201715590813-A
Country	US
Kind code	B2
Filing date	May 9, 2017
Priority date	Nov 22, 2013
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

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 method of preparing a compound of Formula I:

and pharmaceutically acceptable salts thereof,
wherein:
R is an optionally substituted phenyl or an optionally substituted pyridyl;
R 1 is selected from —CH 2 R 1A and —C(═O)R 1B ;
R 1A is selected from hydroxyl, —O—C(═OCH 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;

R 1B is selected from C 1 -C 8 alkyl optionally 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;

the method comprising:
(a) phosphorylating 2′-deoxy-2′-fluoro-2′-C-methyluridine or a derivative thereof at the 5′ hydroxyl group; and
(b) performing nucleophilic substitution at the 3′ hydroxyl group of the 2′-deoxy-2′-fluoro-2′-C-methyluridine or derivative thereof.

2. The method of claim 1 , protecting the 3′ hydroxyl group of the 2′-deoxy-2′-fluoro-2′-C-methyluridine or a derivative thereof prior to step (a).

3. The method of claim 2 , deprotecting the phosphorylated 2′-deoxy-2′-fluoro-2′-C-methyluridine derivative prior to step (b).

4. The method of claim 1 , wherein step (b) is performed before step (a).

5. The method of claim 1 , wherein the phosphorylating comprises reaction with:

6. The method of claim 1 , wherein the nucleophilic substitution comprises reaction with LG-R1, wherein LG is a leaving group.

7. The method of claim 1 , wherein R is selected from the group consisting of:

8. The method of claim 1 , wherein R is selected from the group consisting of

9. The method of claim 1 , wherein R 1 is —CH 2 R 1A .

10. The method of claim 9 , wherein R 1A is C 1 -C 8 alkyl substituted with one or more R 1AA .

11. The method of claim 10 , wherein R 1AA is hydroxy.

12. The method of claim 10 , wherein R 1AA is halo.

13. The method of claim 10 , wherein R 1AA is —O—C(═O)R 1AB .

14. The method of claim 9 , wherein R 1A is selected from —OH, —CH 3 , and —O—C(═O)CH 3 .

15. The method of claim 1 , wherein R 1 is —C(═O)R 1B .

16. The method of claim 15 , wherein R 1B is C 1 -C 8 alkyl optionally substituted with one or more R 1BA .

17. The method of claim 15 , wherein R 1B is C 1 -C 8 alkoxy optionally substituted with one or more R 1BA .

18. The method of claim 15 , wherein R 1B is —N(R 1C ) 2 .

19. The method of claim 15 , wherein R 1B is selected from —C(NH 2 )C 1-6 alkyl and —OCH 2 CH 3 .

20. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Assignees

• Ligand Pharm Inc

Inventors

• Zhi Lin

Classifications

• A61P31/14

  for RNA viruses · CPC title

• C07H19/11

  containing cyclic phosphate · CPC title

• C07H19/10 Primary

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