Mitoquinone derivatives used as mitochondrially targeted antioxidants

Abstract

This invention relates to pharmaceutically acceptable amphiphilic antioxidant compounds, compositions and dosage forms comprising said compounds, and methods and uses reliant on said compounds. The exemplified compounds are all mitoquinone derivatives, being methoxyphenyl alkyl triphenylphosphonium or methoxy dioxocyclohexadiene alkyl triphenylphosphonium derivatives. The compounds, compositions, dosage forms, uses and methods are useful in, for example, the treatment of diseases or conditions associated with oxidative stress.

1 .- 119 . (canceled) 
     
     
         120 . A chemically stable antioxidant compound, comprising:
 a lipophilic cationic moiety linked by a linking moiety to an antioxidant moiety; and   an anionic complement for said cationic moiety,   wherein the cationic moiety is capable of mitochondrially targeting the antioxidant moiety and is selected from the group consisting of a substituted or unsubstituted triphenylphosphonium cation, tribenzylammonium cation and phosphonium cation,   wherein the linking moiety has a length equivalent to a linear saturated carbon chain of from 1 to 30 carbon atoms and comprises a straight alkylene chain, a substituted carbon chain or a branched carbon chain,   wherein the antioxidant moiety is selected from the group consisting of (i) a quinone or a quinol, (ii) vitamin E or a vitamin E derivative, (iii) a chain breaking antioxidant, (iv) a derivatized fullerene, (v) a spin trap, (vi) butylated hydroxyanisole, (vii) butylated hydroxytoluene, (viii) 5,5-dimethylpyrroline-N-oxide, (ix) tert-butylnitrosobenzene, (x) tert-nitrosobenzene and (xi) α-phenyl-tert-butylnitrone,   wherein the anionic complement is a pharmaceutically acceptable anion that is not a halogen ion or a nitrate anion and is selected from the group consisting of an alkyl sulfonate, an aryl sulfonate, tetrafluoroborate, trifluoromethanesulfonate, hexafluoroantimonate, hexafluoroarsenate, hexafluorophosphate, tetraphenylborate, and tetra(perfluorophenyl)borate, and   wherein said anionic complement does not exhibit reactivity against the antioxidant moiety, the cationic moiety or the linking moiety.   
     
     
         121 . The compound according to  claim 120  wherein the lipophilic cationic moiety is a substituted or an unsubstituted triphenylphosphonium cation. 
     
     
         122 . The compound of  claim 120  having the general formula I: 
       
         
           
           
               
               
           
         
       
       or its quinol form, wherein R 1 , R 2 , and R 3  are the same or different and are selected from C 1  to C 5  alkyl, substituted C 1  to C 5  alkyl and H, wherein R 4  and R 5  are independently selected from the group consisting of H, hydroxyl, carboxyl, amide, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl and unsubstituted or substituted alkynyl, and wherein n is an integer from 2 to 20, and wherein Z is the anionic complement. 
     
     
         123 . The compound of  claim 120  wherein the pharmaceutically acceptable anion is not nucleophilic. 
     
     
         124 . The compound of  claim 120  wherein the pharmaceutically acceptable anion is an alkyl sulfonate. 
     
     
         125 . The compound of  claim 120  wherein the pharmaceutically acceptable anion is selected from the group consisting of methanesulfonate, p-toluenesulfonate, ethanesulfonate, benzenesulfonate and 2-naphthalenesulfonate. 
     
     
         126 . The compound of  claim 120  wherein the pharmaceutically acceptable anion is methanesulfonate. 
     
     
         127 . The compound according to  claim 120  wherein the antioxidant moiety is a quinone or a quinol. 
     
     
         128 . The compound of  claim 122  wherein Z is selected from the group consisting of an alkyl sulfonate and an aryl sulfonate. 
     
     
         129 . The compound of  claim 122  wherein C of (C) n  is saturated. 
     
     
         130 . The compound of  claim 122  having the formula: 
       
         
           
           
               
               
           
         
       
       or its quinol form, wherein Z is the anionic complement. 
     
     
         131 . The compound of  claim 122  having the formula: 
       
         
           
           
               
               
           
         
       
       or its quinol form. 
     
     
         132 . A pharmaceutical composition, comprising:
 the chemically stable antioxidant compound of  claim 120 ; and a carrier or excipient.   
     
     
         133 . The pharmaceutical composition of  claim 132  wherein at least one of:
 (a) the lipophilic cationic moiety is a substituted or an unsubstituted triphenylphosphonium cation; 
 (b) the pharmaceutically acceptable anion is selected from the group consisting of (i) an alkyl sulfonate, (ii) a pharmaceutically acceptable anion that is not a halogen ion, and (iii) a pharmaceutically acceptable anion that is not nucleophilic; 
 (c) the pharmaceutically acceptable anion is selected from the group consisting of methanesulfonate, p-toluenesulfonate, ethanesulfonate, benzenesulfonate and 2-naphthalenesulfonate; 
 (d) the pharmaceutically acceptable anion is methanesulfonate; 
 (e) the antioxidant moiety is selected from the group consisting of (i) a quinone or a quinol, (ii) vitamin E or a vitamin E derivative, (iii) a chain breaking antioxidant, (iv) a derivatized fullerene, and (v) a spin trap; 
 (f) the compound has the formula: 
 
       
         
           
           
               
               
           
         
       
       or its quinol form, wherein Z is the anionic complement; and
 (g) the compound has the formula: 
 
       
         
           
           
               
               
           
         
       
     
     
         134 . The pharmaceutical composition according to  claim 132  which comprises cyclodextrin. 
     
     
         135 . The pharmaceutical composition of  claim 134  wherein the compound and cyclodextrin are present at a compound-to-cyclodextrin molar ratio that is selected from the group consisting of (i) from about 10:1 to about 1:10, (ii) from about 5:1 to about 1:5, (iii) from about 4:1 to about 1:4, (iv) from about 2:1 to about 1:2, (v) about 1:1 and (vi) about 1:2. 
     
     
         136 . The pharmaceutical composition according to  claim 134  wherein the cyclodextrin is β-cyclodextrin. 
     
     
         137 . The pharmaceutical composition according to  claim 132  that is selected from the group consisting of a pharmaceutical composition that is formulated for oral administration and a pharmaceutical composition that is formulated for parenteral administration. 
     
     
         138 . The pharmaceutical composition according to  claim 133 (g) which comprises cyclodextrin, and that is selected from the group consisting of a pharmaceutical composition that is formulated for oral administration and a pharmaceutical composition that is formulated for parenteral administration. 
     
     
         139 . A method of reducing oxidative stress in a cell, comprising:
 contacting a cell that comprises mitochondria with the chemically stable antioxidant compound of  claim 120  under conditions and for a time sufficient for accumulation of the antioxidant compound in the mitochondria, and thereby reducing oxidative stress in the cell.   
     
     
         140 . The method of  claim 139  wherein the chemically stable antioxidant compound has the general formula I: 
       
         
           
           
               
               
           
         
       
       or its quinol form, wherein R 1 , R 2 , and R 3  are the same or different and are selected from C 1  to C 5  alkyl, substituted C 1  to C 5  alkyl and H, wherein R 4  and R 5  are independently selected from the group consisting of H, hydroxyl, carboxyl, amide, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl and unsubstituted or substituted alkynyl, and wherein n is an integer from 2 to 20, and wherein Z is the anionic complement. 
     
     
         141 . A method of therapy or prophylaxis of a patient who would benefit from reduced oxidative stress, comprising administering to said patient a therapeutically efficacious dose of the pharmaceutical composition of  claim 132 . 
     
     
         142 . A method of preparing an antioxidant compound that is capable of reducing oxidative stress in a cell, comprising admixing cyclodextrin or a cyclodextrin derivative that is selected from β-cyclodextrin, sulfobutylcyclodextrin, maltosylcyclodextrin, and hydroxypropylcyclodextrin, with the compound of  claim 122 . 
     
     
         143 . The method of  claim 142  wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or its quinol form.