Nucleoside kinase bypass compositions and methods
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: