Nucleotide prodrug compounds and use
View Patent ↗Embodiments of the present invention include nucleoside 5′-monophosphate derivative compounds, their preparation and their uses. In some embodiments, nucleoside 5′-monophosphate derivative compounds are useful to treat viral infections.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is an optionally substituted phenyl;
R 2 is
R 2A is selected from the group consisting of H, a C 1 -C 6 alkyl, a C 1 -C 6 heteroalkyl, and a C 1 -C 6 acyl;
R 2B is selected from the group consisting of H, a C 1 -C 6 alkyl, a C 1 -C 6 heteroalkyl, and a C 1 -C 6 acyl;
R 3 and R 4 are each independently selected from the group consisting of H, acyl, and heteroacyl; or R 3 and R 4 can be optionally linked to form a carbonyl; and
X is O, S, or NH.
2. The compound of claim 1 , wherein R 1 is selected from the group consisting of:
3. The compound of claim 2 , wherein R 2 is
4. The compound of claim 3 , wherein X is O.
5. The compound of claim 4 , wherein R 2A is selected from the group consisting of H and C 1 -C 6 alkyl.
6. The compound of claim 5 , wherein R 3 and R 4 are each H, or R 3 and R 4 can be optionally linked to form a carbonyl.
7. The compound of claim 2 , wherein R 2 is
8. The compound of claim 7 , wherein X is O.
9. The compound of claim 8 , wherein R 2A is of H.
10. The compound of claim 9 , wherein R 2B is C 1 -C 6 alkyl.
11. The compound of claim 10 , wherein R 3 and R 4 are each independently selected from the group consisting of H, acyl, and heteroacyl.
12. The compound of claim 1 selected from the group consisting of
2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinanyloxymethyl)-3R,4R-dihydroxytetrahydrofuran,
2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-5R-(4R-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinanyloxymethyl)-3R,4R-dihydroxytetrahydrofuran,
2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-3R,4R-dihydroxytetrahydrofuran,
2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-4R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-7-oxo-3,6,8-trioxa-cis-bicyclo[3.3.0]octane,
2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-3R,4R-diacetyloxytetrahydrofuran,
2R-(3-(1-Ethoxy-1-iminomethyl)-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-3R,4R-diacetyloxytetrahydrofuran,
2R-(3-Ethylaminocarbonyl-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-3R,4R-diacetyloxytetrahydrofuran, and
(2R,3R,4R,5R)-2-(3-Carbamoyl-1H-1,2,4-triazol-1-yl)-5-((((2R,4S)-4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy)methyl)tetrahydrofuran-3,4-diyl dipropionate, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein R 1 is phenyl substituted with halogen.
14. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier.
15. A method of treating a viral infection comprising administering an effective amount of a compound claim 1 to a subject in need thereof.
16. The method of claim 15 , further comprising administering an effective amount of a second therapeutic agent in combination with the compound claim 1 to the subject in need thereof, wherein the second 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, interferon-α, and pegylated interferon-α.
17. The method of claim 15 , wherein the viral infection is an infection of the liver.
18. The method of claim 15 , wherein the viral infection is HCV.
19. A method of inhibiting viral replication in a cell comprising contacting the cell with the compound of claim 1 .
20. The method of claim 19 , wherein the viral replication is HCV replication.
21. The method of claim 19 , further comprising contacting the cell with a second antiviral agent 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, interferon-α, and pegylated interferon-α.
22. The method of claim 19 , wherein the cell is a hepatocyte.