Ortho-diphenol compounds, methods and pharmaceutical compositions for inhibiting parp

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

• 38
• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein
• A is O or S;
• R is C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl, C2-C10 straight or branched chain alkynyl, aryl, heteroaryl, carbocycle, or heterocycle;
• D is a bond, or a C1-C3 straight or branched chain alkyl, C2-C3 straight or branched chain alkenyl, C2-C3 straight or branched chain alkynyl, wherein any of the carbon atoms of said alkyl, alkenyl, or alkynyl of D are optionally replaced with oxygen, nitrogen, or sulfur;
• and
• X is aryl, heteroaryl, carbocycle, or heterocycle;
• wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, or heterocycle of R, D, or X is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, amino, imino, alkylamino, arylamino, arylazo, arylthio, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, aryl, aralkyl, heteroaryl, carbocycle, or heterocycle;
• provided that when R is methyl, and D is a bond, then X is not phenyl, 4-nitrophenyl, 4-phenylazo-phenyl, or 3,5-dinitrophenyl;
• when R is a substituted benzopyran group, and D is a bond, ethenyl, or —NH—, then X is not phenyl, or 3,4,5-trihydroxyphenyl;
• when R is ethenyl, and D is ethenyl, then X is not 4-hydroxy-3-methoxyphenyl;
• when R is methyl, and D is ethenyl, then X is not 2-hydroxyphenyl;
• when R is 1-hydroxy-2-alkylamino-ethyl, and D is a bond, then X is not phenyl, methylphenyl, or 4-methoxyphenyl;
• and when R is propenyl, and D is a bond, then X is not phenyl.

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:
• 39
• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein
• A is O or S;
• R is C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl, C2-C10 straight or branched chain alkynyl, aryl, heteroaryl, carbocycle, or heterocycle;
• D is a bond, or a C1-C3 straight or branched chain alkyl, C2-C3 straight or branched chain alkenyl, C2-C3 straight or branched chain alkynyl, wherein any of the carbon atoms of said alkyl, alkenyl, or alkynyl of D are optionally replaced with oxygen, nitrogen, or sulfur;
• and
• X is aryl, heteroaryl, carbocycle, or heterocycle;
• wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, or heterocycle of R, D, or X is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, amino, imino, alkylamino, arylamino, arylazo, arylthio, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, aryl, aralkyl, heteroaryl, carbocycle, or heterocycle;
• provided that when R is methyl, and D is a bond, then X is not phenyl, 4-nitrophenyl, 4-phenylazo-phenyl, or 3,5-dinitrophenyl;
• when R is a substituted benzopyran group, and D is a bond, ethenyl, or —NH—, then X is not phenyl, or 3,4,5-trihydroxyphenyl;
• when R is ethenyl, and D is ethenyl, then X is not 4-hydroxy-3-methoxyphenyl;
• when R is methyl, and D is ethenyl, then X is not 2-hydroxyphenyl;
• when R is 1-hydroxy-2-alkylamino-ethyl, and D is a bond, then X is not phenyl, methylphenyl, or 4-methoxyphenyl;
• and when R is propenyl, and D is a bond, then X is not phenyl.