Phenazine compounds, methods and pharmaceutical compositions for inhibiting PARP

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof where R1-R9 and Z are independently hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, cyano, nitro, amino, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, alkylsulfonyl, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C2-C9 straight or branched chain alkynyl, C1-C6 straight or branched chain alkoxy, C2-C6 straight or branched chain alkenoxy, C2-C6 straight or branched chain alkynoxy, aryl, carbocycle, heterocycle, aralkyl, alkylaryl, alkylaryloxy, aryloxy, aralkyloxy, aralkylsulfonyl, aralkylamino, arylamino, arylazo, arylthio, or aralkylthio;
• or Z is
• wherein U is C or N, and R7 and R8 are defined above;
• and X and Y are independently aryl, carbocycle, or heterocycle;
• wherein said alkyl, alkenyl, alkynyl, imino, aryl, carbocycle, heterocycle, aralkyl, alkylaryl, alkylaryloxy, aryloxy, aralkyloxy, aralkylsulfonyl, aralkylamino, arylamino, arylazo, arylthio, aralkylthio of R1-R8, X, Y, or Z is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, haloalkylamide, thiocarbonyl, double-bonded oxygen to form carbonyl, carboxy, alkoxy, alkenoxy, cyano, nitro, amino, imino, amide, —NHCOR9 or —COOR9 where R9 is defined above, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, aryl, aralkyl, aryloxy, arylamino, arylazo, arylthio, carbocycle, or heterocycle.

A method of inhibiting PARP activity, treating or preventing diseases or disorders, altering gene expression, or radiosensitizing, comprising:

• administering a therapeutically effective amount of a compound of formula I:
• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein R1-R9 and Z are independently hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, cyano, nitro, amino, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, alkylsulfonyl, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C2-C9 straight or branched chain alkynyl, C1-C6 straight or branched chain alkoxy, C2-C6 straight or branched chain alkenoxy, C2-C6 straight or branched chain alkynoxy, aryl, carbocycle, heterocycle, aralkyl, alkylaryl, alkylaryloxy, aryloxy, aralkyloxy, aralkylsulfonyl, aralkylamino, arylamino, arylazo, arylthio, or aralkylthio;
• or Z is
• wherein U is C or N, and R7 and R8 are defined above;
• and X and Y are independently aryl, carbocycle, or heterocycle;
• wherein said alkyl, alkenyl, alkynyl, imino, aryl, carbocycle, heterocycle, aralkyl, alkylaryl, alkylaryloxy, aryloxy, aralkyloxy, aralkylsulfonyl, aralkylamino, arylamino, arylazo, arylthio, aralkylthio of R1-R8, X, Y, or Z is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, haloalkylamide, thiocarbonyl, double-bonded oxygen to form carbonyl, carboxy, alkoxy, alkenoxy, cyano, nitro, amino, imino, amide, —NHCOR9 or —COOR9 where R9 is defined above, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, aryl, aralkyl, aryloxy, arylamino, arylazo, arylthio, carbocycle, or heterocycle.