Nucleoside kinase bypass compositions and methods
View Patent ↗The present invention relates to disulfide masked prodrug compounds of Formula (I), nucleoside kinase bypass compositions thereof and methods that are amenable to bioactivation by a reducing agent such as glutathione: Such disulfide based compounds, compositions, and methods can be useful, for example, in providing prodrugs for use as therapeutics.
1. A compound having Formula I:
wherein,
R 1 is H, OH, C 1-6 alkyl, C 1-6 alkyl substituted with one or more hydroxyl groups, C 1-6 alkyl substituted with one or more halo groups, C 1-6 alkenyl, C 1-6 alkenyl substituted with one or more hydroxyl groups, C 1-6 alkenyl substituted with one or more halo groups, C 1-6 alkynyl, C 1-6 alkynyl substituted with one or more hydroxyl groups, C 1-6 alkynyl substituted with one or more halo groups, C 1-6 alkoxyl, C 1-6 alkoxyl substituted with one or more hydroxyl groups, C 1-6 alkoxyl substituted with one or more halo groups, aryl, heteroaryl, heterocyclyl, —NHC 1-6 alkyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, heterocyclylC 1-6 alkyl, guanidinyl, C 1-6 alkylC(O)O—, arylC(O)O—, heterocyclylC(O)O—, O-propargyl, S-propargyl, O-allyl, or S-allyl;
R 4 is S or O;
each R 2 , R 3 , R 5 , R 6 , R 7 and R 8 is independently halo or R 1 as above;
R 9 is O-phenyl, O-naphthyl, or O-benzyl any of which can be substituted with one or more halo groups; or NH-benzyl, NHR 12 or N(R 12 ) 2 , wherein each R 12 is independently H, C 1-10 alkyl, or C 1-10 alkyl substituted with one or more halo groups;
R 10 is S or O; and
NUC is selected from the group consisting of:
2. The compound of claim 1 having the following formula:
3. The compound of claim 1 having a structure selected from:
4. The compound of claim 3 , wherein R 10 is O.
5. A compound having Formula II:
wherein,
R 1 is OH, C 1-6 alkyl, C 1-6 alkyl substituted with one or more hydroxyl groups, C 1-6 alkyl substituted with one or more halo groups, C 1-6 alkenyl, C 1-6 alkenyl substituted with one or more hydroxyl groups, C 1-6 alkenyl substituted with one or more halo groups, C 1-6 alkynyl, C 1-6 alkynyl substituted with one or more hydroxyl groups; C 1-6 alkynyl substituted with one or more halo groups, C 1-6 alkoxyl, C 1-6 alkoxyl substituted with one or more hydroxyl groups, C 1-6 alkoxyl substituted with one or more halo groups, aryl, heteroaryl, heterocyclyl, —NHC 1-6 alkyl, arylC 1-6 alkyl; heteroarylC 1-6 alkyl, heterocyclylC 1-6 alkyl, guanidinyl, C 1-6 alykylC(O)O—; arylC(O)O—, heterocyclylC(O)O—, O-propargyl, S-propargyl, O- or S-allyl;
R 4 is S or O;
each R 2 , R 3 , R 5 , R 6 , R 7 and R 8 is independently halo or R 1 as above;
R 10 is S or O; and
is selected from the group consisting of:
6. The compound of claim 5 having the following formula:
7. The compound of claim 5 having a structure selected from:
8. The compound of claim 7 , wherein R 10 is O.
9. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof, and a pharmaceutically acceptable carrier or diluent.
10. A method for the treatment of a viral infection in a patient in need thereof, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof, to the patient, wherein the viral infection is HCV, HBV or HIV infection.
11. The compound of claim 1 , wherein R 9 is:
12. The compound of claim 1 , wherein R 9 is:
13. The compound of claim 1 , wherein R 9 is:
14. The compound of claim 1 , wherein R9 is:
15. The compound of claim 1 , wherein R9 is:
16. The compound of claim 1 having the following formula: