Compounds and methods for treating mitochondria-associated diseases

Abstract

Compounds, compositions and methods are disclosed for treating mitochondria-associated diseases, such as cancer, psoriasis, stroke, Alzheimer's Disease and diabetes. The compounds of this invention have structure (I) below, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein Ar and L are as defined herein. The methods of this invention are directed to treating a mitochondria-associated disease by administering to a warm-blooded animal in need thereof an effective amount of a compound of structure (I), typically in the form of a pharmaceutical composition.

1 . A method for treating a mitochondria-associated disease by administering to a warm-blooded animal in need thereof an effective amount of a compound having the following structure:  
       
         
           
           
               
               
           
         
       
       including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, 
 wherein: 
 Ar is phenyl or naphthyl optionally substituted with 1 to 5 R 2  groups;  
 L is an optional linker moiety selected from —(CH 2 ) n —, —(CH 2 ) n NH—, —(CH 2 ) n N(C 1-4 alkyl)—, —NHC(═NH)— and —(CH 2 ) n O(CH 2 ) n —, wherein n is 1-4 and each linker moiety is optionally substituted with 1 to 5 R 3  groups;  
 
 R 2  is hydroxy, C 1-12 alkyl, C 1-12 alkyloxy, halo, —NH 2 , —NHR, —NRR, cyano, nitro, —SR, —COOH, C 7-12 aralkyl or heterocycle; or C 1-2 alkyl, C 1-12 alkyloxy, —NH 2 , —NHR, —NRR, —SR, C 7-12 aralkyl or heterocycle substituted with 1 to 5 R 3  groups;  
 R 3  is hydroxy, halo, C 1-4 alkyl, —OR, —NH 2 , —NHR or —NRR; and  
 each occurrence of R is independently selected from C 1-4 alkyl.  
 
     
     
         2 . The method of  claim 1  wherein Ar is phenyl optionally substituted with 1 to 5 R 2  groups.  
     
     
         3 . The method of  claim 2  wherein Ar is phenyl, 3,5-di-t-butyl-4-hydroxyphenyl. 2-methoxy-4-carboxylphenyl, 2-chloro-4-carboxyl-5-methoxyphenyl, 3,5-di-tetrafluoromethylphenyl, 3,5-difluorophenyl, 3,4,5-trimethoxyphenyl, 4-n-hexoxyphenyl, 4-fluorophenyl, 3-trifluorophenyl, 2-carbinolphenyl, 2-chloro-5-methylphenyl, 3-carboxylphenyl, 3-carboxyl-4-hydroxyphenyl, 2-methyl-4-carboxylphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 4-(N-morphinol)phenyl, 3,4-dihydroxyphenyl, 2,4-dimethylphenyl, 2-methyl-4-hydroxyphenyl, 4-n-octylphenyl, 2-hydroxy-5-n-octylphenyl, 4-chlorophenyl, or 2-methyl-4-chlorophenyl,  
     
     
         4 . The method of  claim 1  wherein Ar is naphthyl optionally substituted with 1 to 5 R 2  groups.  
     
     
         5 . The method of  claim 4  wherein Ar is naphthyl or 4-bromonaphthyl.  
     
     
         6 . The method of  claim 1  wherein the L is not present.  
     
     
         7 . The method of  claim 1  wherein L is present.  
     
     
         8 . The method of  claim 7  wherein L is —CH 2 NH—, —CH 2 CH 2 , —CH(OH)CH 2 —, —CH 2 N(CH 3 )— or —NHC(═NH)—.  
     
     
         9 . The method of  claim 1  wherein the compound is administered in the form of a pharmaceutical composition.  
     
     
         10 . The method of  claim 1  wherein the mitochondria-associated disease is a disease in which free radical mediated oxidative injury leads to tissue degeneration.  
     
     
         11 . The method of  claim 1  wherein the mitochondria-associated disease is a disease in which cells inappropriately undergo apoptosis.  
     
     
         12 . The method of  claim 10  or  11  wherein the mitochondria-associated disease is Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, auto-immune disease, diabetes mellitus (Type I or Type II), congenital muscular dystrophy, fatal infantile myopathy, “later-onset” myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke), MIDD (mitochondrial diabetes and deafness), MERFF (myoclonic epilepsy ragged red fiber syndrome), arthritis, NARP (Neuropathy; Ataxia; Retinitis Pigmentosa), MNGIE (Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy), LHON (Leber's; Hereditary; Optic; Neuropathy), Kearns-Sayre disease, Pearson's Syndrome, PEO (Progressive External Ophthalmoplegia), Wolfram syndrome, DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness), Leigh's Syndrome, dystonia, or schizophrenia.  
     
     
         13 . The method of  claim 1  wherein the mitochondria-associated disease is a disease in which cells fail to undergo apoptosis.  
     
     
         14 . The method of  claim 13  wherein the mitochondria-associated disease is cancer.  
     
     
         15 . The method of  claim 1  wherein the mitochondria-associated disease is stroke.  
     
     
         16 . The method of  claim 1  wherein the mitochondria-associated disease is Alzheimer's Disease.  
     
     
         17 . The method of  claim 1  wherein the mitochondria-associated disease is diabetes.  
     
     
         18 . The method of  claim 1  wherein the mitochondria-associated disease is auto-immune disease.  
     
     
         19 . The method of  claim 1  wherein the mitochondria-associated disease is psoriasis.  
     
     
         20 . A pharmaceutical composition comprising a compound having the following structure:  
       
         
           
           
               
               
           
         
       
       including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, 
 wherein: 
 Ar is phenyl or naphthyl optionally substituted with 1 to 5 R 2  groups;  
 L is an optional linker moiety selected from —(CH 2 ) n —, —(CH 2 ) n NH—, —(CH 2 ) n N(C 1-4 alkyl)—, —NHC(═NH)— and —(CH 2 ) n O(CH 2 ) n —, wherein n is 1-4 and each linker moiety is optionally substituted with 1 to 5 R 3  groups;  
 R 2  is hydroxy, C 1-12 alkyl, C 1-12 alkyloxy, halo, —NH 2 , —NHR, —NRR, cyano, nitro, —SR, —COOH, C 7-12 aralkyl or heterocycle; or C 1-12 alkyl, C 1-12 alkyloxy, —NH 2 , —NHR, —NRR, —SR, C 7-12 aralkyl or heterocycle substituted with 1 to 5 R 3  groups;  
 R 3  is hydroxy, halo, C 1-4 alkyl, —OR, —NH 2 , —NHR or —NRR; and  
 each occurrence of R is independently selected from C 1-4 alkyl;  
 
 and a pharmaceutically acceptable carrier.