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

Abstract

This invention relates to compounds, pharmaceutical compositions, and methods of using compounds of the formula; A is O or S; R is C 1 -C 10 straight or branched chain alkyl, C 2 -C 10 straight or branched chain alkenyl, C 2 -C 10 straight or branched chain alkynyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a C 1 -C 3 straight or branched chain alkyl, C 2 -C 3 straight or branched chain alkenyl, C 2 -C 3 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.

We claim:  
     
         1 . A compound of formula (I):  
                   
       or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein 
 A is O or S;  
 R is C 1 -C 10  straight or branched chain alkyl, C 2 -C 10  straight or branched chain alkenyl, C 2 -C 10  straight or branched chain alkynyl, aryl, heteroaryl, carbocycle, or heterocycle;  
 D is a bond, or a C 1 -C 3  straight or branched chain alkyl, C 2 -C 3  straight or branched chain alkenyl, C 2 -C 3  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, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  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.  
 
     
     
         2 . The compound of    claim 1   , wherein R is a hydrophobic group.  
     
     
         3 . The compound of    claim 1   , wherein R is a C 1 -C 10  straight or branched chain alkyl.  
     
     
         4 . The compound of    claim 1   , wherein X is an aryl group.  
     
     
         5 . The compound of    claim 4   , wherein the aryl group is phenyl.  
     
     
         6 . The compound of    claim 4   , wherein said aryl group is substituted selected from the group consisting of halo, hydroxy, amino, nitro, lower alkyl, dimethylamino, acetamide, sulfonyl, aryl, aralkyl, arylthio, —COOR 1 , —OR 1  or —NHR 1 , where R 1  is hydrogen, lower alkyl, and aralkyl.  
     
     
         7 . The compound of    claim 1   , wherein D is a bond.  
     
     
         8 . The compound of    claim 1   , wherein said compound is selected from the group consisting of:  
                   
     
     
         9 . The compound of    claim 1   , wherein said compound is selected from the group consisting of compounds 1-102.  
     
     
         10 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I):  
                   
       or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein 
 A is O or S;  
 R is C 1 -C 10  straight or branched chain alkyl, C 2 -C 10  straight or branched chain alkenyl, C 2 -C 10  straight or branched chain alkynyl, aryl, heteroaryl, carbocycle, or heterocycle;  
 D is a bond, or a C 1 -C 3  straight or branched chain alkyl, C 2 -C 3  straight or branched chain alkenyl, C 2 -C 3  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, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  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.  
 
     
     
         11 . The pharmaceutical composition of    claim 10   , wherein said compound has an IC 50  of 100 μM or lower for inhibiting poly(ADP-ribose) polymerase in vitro.  
     
     
         12 . The pharmaceutical composition of    claim 10   , wherein said compound has an IC 50  of 25 μM or lower for inhibiting poly(ADP-ribose) polymerase in vitro.  
     
     
         13 . The pharmaceutical composition of    claim 10   , wherein the carrier is a sterile solution, suspension or emulsion, in a single or divided dose.  
     
     
         14 . The pharmaceutical composition of    claim 10   , wherein the carrier is a capsule or tablet containing a single or divided dose of said compound.  
     
     
         15 . The pharmaceutical composition of    claim 10   , wherein the carrier comprises a biodegradable polymer.  
     
     
         16 . The pharmaceutical composition of    claim 15   , wherein the biodegradable polymer releases the compound of formula I over a prolonged period of time.  
     
     
         17 . The pharmaceutical composition of    claim 10   , wherein the carrier is a solid implant.  
     
     
         18 . The pharmaceutical composition of    claim 10    for treating diseases and disorders, wherein the diseases or disorders are selected from the group consisting of tissue damage resulting from cell damage or death due to necrosis or apoptosis, neuronal mediated tissue damage or diseases, neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, vascular stroke, cardiovascular disorders, age-related macular degeneration, AIDS and other immune diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, nervous insult, peripheral nerve injury, renal failure, retinal ischemia, septic shock, and skin aging, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.  
     
     
         19 . The pharmaceutical composition of    claim 18   , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, stroke associated with brain damage, and demyelinating diseases.  
     
     
         20 . The pharmaceutical composition of    claim 18   , wherein the cardiovascular disorder is selected from the group consisting of cardiovascular tissue damage, coronary artery disease, myocardial infarction, angina pectoris and cardiogenic shock.  
     
     
         21 . 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 
 A is O or S;  
 R is C 1 -C 10  straight or branched chain alkyl, C 2 -C 10  straight or branched chain alkenyl, C 2 -C 10  straight or branched chain alkynyl, aryl, heteroaryl, carbocycle, or heterocycle;  
 D is a bond, or a C 1 -C 3  straight or branched chain alkyl, C 2 -C 3  straight or branched chain alkenyl, C 2 -C 3  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, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  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.  
 
     
     
         22 . The method of    claim 21   , wherein the diseases or disorders are selected from the group consisting of tissue damage resulting from cell damage or death due to necrosis or apoptosis, neuronal mediated tissue damage or diseases, neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, vascular stroke, cardiovascular disorders, age-related macular degeneration, AIDS and other immune diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, nervous insult, peripheral nerve injury, renal failure, retinal ischemia, septic shock, and skin aging, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.  
     
     
         23 . The method of    claim 22   , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, stroke associated with brain damage, and demyelinating diseases.  
     
     
         24 . The method of    claim 23   , wherein the demyelinating disease is multiple sclerosis.  
     
     
         25 . The method of    claim 22   , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and amyotropic lateral sclerosis.  
     
     
         26 . The method of    claim 22   , 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, breast cancer, cervix 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 (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary cancer, 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.  
     
     
         27 . The method of    claim 22   , wherein the bowel disorder is colitis.  
     
     
         28 . The method of    claim 22   , wherein the bowel disorder is Crohn's disease.  
     
     
         29 . The method of    claim 22   , wherein the cardiovascular disorder is selected from the group consisting of cardiovascular tissue damage, coronary artery disease, myocardial infarction, angina pectoris and cardiogenic shock.  
     
     
         30 . The method of    claim 22   , wherein the septic shock is endotoxic shock.  
     
     
         31 . The method of    claim 22   , wherein the disease or disease condition induced or exacerbated by cellular senescence is selected from the group consisting of skin aging, Alzheimer's disease, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, age-related macular degeneration, immune senescence, and AIDS.