Mitochondrially targeted antioxidants

Abstract

The invention provides mitochondrially targeted antioxidant compounds. A compound of the invention comprises a lipophilic cation covalently coupled to an antioxidant moiety. In preferred embodiments, the lipophilic cation is the triphenyl phosphonium cation, and the compound is of the formula P(Ph 3 ) + XR.Z- where X is a linking group, Z is an anion and R is an antioxidant moiety. Also provided are pharmaceutical compositions containing the mitochondrially targeted antioxidant compounds, and methods of therapy or prophylaxis of patients who would benefit from reduced oxidative stress, which comprise the step of administering the compounds of the invention.

1 . A mitochondrially-targeted antioxidant compound comprising a lipophilic cation covalently coupled to an antioxidant moiety, wherein the antioxidant moiety is capable of being transported through the mitochondrial membrane and accumulated within the mitochondria of intact cells, with the proviso that the compound is not thiobutyltriphenylphosphonium bromide.  
     
     
         2 . A compound as claimed in  claim 1  wherein the lipophilic cation is the triphenylphosphonium cation.  
     
     
         3 . A mitochondrially-targeted antioxidant compound as claimed in  claim 1 , wherein said compound has the formula  
       
         
           
           
               
               
           
         
       
       wherein X is a linking group, Z is an anion, and R is an antioxidant moiety.  
     
     
         4 . A compound as claimed in  claim 3 , wherein X is a C 1  to C 30  carbon chain, optionally including one or more double or triple bonds, and optionally including one or more substituents and/or unsubstituted or substituted alkyl, alkenyl or alkynyl side chains.  
     
     
         5 . A compound as claimed in  claim 4 , wherein X is (CH 2 ), where n is an integer of from 1 to 20.  
     
     
         6 . A compound as claimed in  claim 5  wherein X is an ethylene, propylene, butylene, pentylene or decylene group.  
     
     
         7 . A compound as claimed in  claim 3  wherein said compound has the formula  
       
         
           
           
               
               
           
         
       
       including all stereoisomers thereof.  
     
     
         8 . A compound as claimed in  claim 7  wherein Z is Br.  
     
     
         9 . A compound as claimed in  claim 3 , having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z is a pharmaceutically acceptable anion,  
 m is an integer of from 0 to 3,  
 each Y is independently selected from groups, chains and aliphatic and aromatic rings having electron donating and accepting properties,  
 (C) n  represents a carbon chain optionally including one or more double or triple bonds, and optionally including one or more substituents and/or unsubstituted or substituted alkyl, alkenyl or alkynyl side chains; and  
 n is an integer of from 1 to 20.  
 
     
     
         10 . A compound as claimed in  claim 9 , wherein (C) n  is an alkyl chain of the formula (CH 2 ), wherein n is an integer of from 1 to 20.  
     
     
         11 . A compound as claimed in  claim 10 , wherein each Y is independently selected from the group consisting of alkoxy, thioalxyl, alkyl, haloalkyl, halo, amino, nitro and optionally substituted aryl, or when m is 2 or 3, two Y groups, together with the carbon atoms to which they are attached, form an aliphatic or aromatic carbocyclic or heterocyclic ring fused to the aryl ring.  
     
     
         12 . A compound as claim in  claim 11  wherein each Y is independently selected from methoxy and methyl.  
     
     
         13 . A compound as claimed in  claim 9  wherein said compound has the formula  
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound as claimed in  claim 13  wherein Z is Br.  
     
     
         15 . A pharmaceutical composition suitable for the treatment of a patient who would benefit from reduced oxidative stress, which comprises an effective amount of a mitochondrially-targeted antioxidant as defined in  claim 1  in combination with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         16 . A pharmaceutical composition as claimed in  claim 15  wherein the mitochondrially-targeted antioxidant has the formula I  
       
         
           
           
               
               
           
         
       
       wherein X is a linking group, Z is an anion and R is an antioxidant moiety.  
     
     
         17 . A pharmaceutical composition as claimed in  claim 16  wherein the mitochondrially targeted antioxidant compound is  
       
         
           
           
               
               
           
         
       
     
     
         18 . A pharmaceutical composition as claimed in  claim 15  wherein the mitochondrially targeted antioxidant compound has the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z is a pharmaceutically acceptable anion,  
 m is an integer of from 0 to 3,  
 each Y is independently selected from groups, chains and aliphatic and aromatic rings having electron donating and accepting properties,  
 (C) n  represents a carbon chain optionally including one or more double or triple bonds, and optionally including one or more substituents and/or unsubstituted or substituted allyl, alkenyl or alkynyl side chains; and  
 n is an integer of from 1 to 20.  
 
     
     
         19 . A pharmaceutical composition as claimed in  claim 18 , wherein (C) n  is an alkyl chain of the formula (CH 2 ) n  wherein n is an integer of from 1 to 20.  
     
     
         20 . A pharmaceutical composition as claimed in  claim 18 , wherein each Y is independently selected from the group consisting of alkoxy, thioalkyl, alkyl, haloalkyl, halo, amino, nitro and optionally substituted aryl, or, when m is 2 or 3, two Y groups, together with the carbon atoms to which they are attached, form an aliphatic or aromatic carbocyclic or heterocyclic ring fused to the aryl ring.  
     
     
         21 . A pharmaceutically composition as claimed in  claim 20 , wherein each Y is independently selected from methoxy and methyl.  
     
     
         22 . A pharmaceutical composition as claimed in  claim 17  wherein the mitochondrially targeted antioxidant compound is:  
       
         
           
           
               
               
           
         
       
     
     
         23 . A method of therapy or prophylaxis of a patient who would benefit from reduced oxidative stress, which comprises the step of administering to the patient a mitochondrially-targeted antioxidant as defined in  claim 1 .  
     
     
         24 . A method of reducing oxidative stress in a cell which comprises the step of administering to the cell a mitochondrially-targeted antioxidant as defined in  claim 1.