Derivatives of uridine 5′-cyclophosphate useful to treat hepatitis C viral infections
View Patent ↗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.
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.