Ortho-diphenol compounds, methods and pharmaceutical compositions for inhibiting parp
AssigneeGuilford Pharmaceuticals Inc.
InventorsJie Zhang, Larisa E. Serdyuk, Jia-He Li
Life of this patent
Estimating the term…
Abstract
This invention relates to compounds, pharmaceutical compositions, and methods of using compounds of the formula: 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.
Claims31
A compound of formula (I):
- or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, 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, aryl, or carbocycle;
- 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, or carbocycle;
- wherein said alkyl, alkenyl, alkynyl, aryl, or carbocycle 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, or carbocycle;
- provided that when R is methyl, and D is a bond or C2-C3 straight chain alkenyl, then X is not phenyl, 4-nitrophenyl, 4-phenylazo-phenyl, or 3,5-dinitrophenyl;
- when R is methyl, and D is C2-C3 straight chain alkenyl, X is not hydroxy substituted phenyl;
- 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 pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I):
- or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, stercoisomer, or a mixture 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, or carbocycle;
- 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, or carbocycle;
- wherein said alkyl, alkenyl, alkynyl, aryl, or carbocycle 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, or carbocycle;
- 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 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 or treating diseases or disorders, or radiosensitizing, comprising:
- administering a therapeutically effective amount of a compound of formula I:
- or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, 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, or carbocycle;
- 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, or carbocycle;
- wherein said alkyl, alkenyl, alknyl, aryl, or carbocycle 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, or carbocycle;
- 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 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 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.
The method of 21, wherein the cancer is selected from the group consisting of ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breat cancer, cervic cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head & neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer, malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary germ cell cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, cancer of the uterus, vaginal cancer, cancer of the vulva and Wilm's tumor.
Dependencies are inferred from the claim text.