NUCLEOSIDE KINASE BYPASS COMPOSITIONS AND METHODS

摘要

The present invention relates to disulfide masked prodrug compounds, compositions 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 novel prodrugs for use as therapeutics.

主权项

1. A compound having Formula I: wherein, R1 is H, OH, C1-6 alkyl, C1-6 alkyl substituted with one or more hydroxyl groups, C1-6 alkyl substituted with one or more halo groups, C1-6 alkenyl, C1-6 alkenyl substituted with one or more hydroxyl groups, C1-6 alkenyl substituted with one or more halo groups, C1-6 alkynyl, C1-6 alkynyl substituted with one or more hydroxyl groups, C1-6 alkynyl substituted with one or more halo groups, C1-6 alkoxyl, C1-6 alkoxyl substituted with one or more hydroxyl groups, C1-6 alkoxyl substituted with one or more halo groups, aryl, heteroaryl, heterocyclyl, —NHC1-6 alkyl, arylC1-6 alkyl, heteroarylC1-6 alkyl, heterocyclylC1-6 alkyl, guanidinyl, C1-6alkylC(O)O—, arylC(O)O—, heterocyclylC(O)O—, O-propargyl, S-propargyl, O-allyl, S-allyl, or X-L-Y; wherein X is O, S, NH, C(O), S(O), C1-6 alkyl, C1-6 alkyl substituted with one or more hydroxyl groups, C1-6 alkyl substituted with one or more halo groups, C1-6 alkenyl, C1-6 alkenyl substituted with one or more hydroxyl groups, C1-6 alkenyl substituted with one or more halo groups, C1-6 alkynyl, C1-6 alkynyl substituted with one or more hydroxyl groups, C1-6 alkynyl substituted with one or more halo groups, C1-6 alkoxyl, C1-6 alkoxyl substituted with one or more hydroxyl groups, C1-6 alkoxyl substituted with one or more halo groups, aryl, heteroaryl, heterocyclyl, —NHC1-6 alkyl, arylC1-6 alkyl, heteroarylC1-6 alkyl, heterocyclylC1-6 alkyl, guanidinyl, C1-6alkylC(O)O—, arylC(O)O—, heterocyclylC(O)O—, O-propargyl, S-propargyl, O-allyl, S-allyl; L is a linker that is optionally present; and Y is a targeting agent, ligand and/or polymer that is optionally present; R4 is S or O; each R2, R3, R5, R6, R7 and R8 is independently halo or R1 as above; R9 is O-phenyl, O-naphthyl, or O-benzyl any of which can be substituted with one or more halo groups; or an amine, substituted amine, NH-benzyl, NHR12 or N(R12)2, wherein each R12 is independently H, C1-10 alkyl, or C1-10 alkyl substituted with one or more halo groups; R10 is S or O; and NUC is a nucleoside, nucleoside analog, nucleotide, nucleotide analog, or nucleobase analog thereof.