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 . 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 nucleophilic and 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.   
     
     
         2 . The compound according to  claim 1  wherein the lipophilic cationic moiety is a substituted or an unsubstituted triphenylphosphonium cation. 
     
     
         3 . The compound of  claim 1  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. 
       
     
     
         4 . The compound of  claim 1  wherein the pharmaceutically acceptable anion is an alkyl sulfonate. 
     
     
         5 . The compound of  claim 1  wherein the pharmaceutically acceptable anion is selected from the group consisting of methanesulfonate, p-toluenesulfonate, ethanesulfonate, benzenesulfonate and 2-naphthalenesulfonate. 
     
     
         6 . The compound of  claim 1  wherein the pharmaceutically acceptable anion is methanesulfonate. 
     
     
         7 . The compound according to  claim 1  wherein the antioxidant moiety is a quinone or a quinol. 
     
     
         8 . The compound of  claim 3  wherein Z is selected from the group consisting of an alkyl sulfonate and an aryl sulfonate. 
     
     
         9 . The compound of  claim 3  wherein C of (C) n  is saturated. 
     
     
         10 . The compound of  claim 3  which is a compound of formula (II): 
       
         
           
           
               
               
           
         
         or its quinol form, wherein Z is the anionic complement. 
       
     
     
         11 . The compound of  claim 3  which is a compound of formula (III): 
       
         
           
           
               
               
           
         
         or its quinol form. 
       
     
     
         12 . A pharmaceutical composition, comprising:
 the chemically stable antioxidant compound of  claim 1 ; and a carrier or excipient.   
     
     
         13 . The pharmaceutical composition of  claim 12  wherein at least one of:
 (a) the lipophilic cationic moiety is a substituted or an unsubstituted triphenylphosphonium cation; 
 (b) the pharmaceutically acceptable anion is an alkyl sulfonate; 
 (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 is a compound of formula (II): 
 
       
         
           
           
               
               
           
         
         or its quinol form, wherein Z is the anionic complement; and 
         (g) the compound is a compound of formula (III): 
       
       
         
           
           
               
               
           
         
       
     
     
         14 . The pharmaceutical composition according to  claim 12  in which the carrier comprises cyclodextrin. 
     
     
         15 . The pharmaceutical composition of  claim 14  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. 
     
     
         16 . The pharmaceutical composition according to  claim 14  wherein the cyclodextrin is β-cyclodextrin. 
     
     
         17 . The pharmaceutical composition according to  claim 12  that is selected from the group consisting of a pharmaceutical composition that is formulated for oral administration to a subject and comprises an enteric coating agent, and a pharmaceutical composition that is formulated for parenteral administration to a subject and comprises an isotonicity agent so that the pharmaceutical composition formulated for parenteral administration is substantially isotonic with blood of the subject. 
     
     
         18 . The pharmaceutical composition according to  claim 12  in which the antioxidant compound is a compound of formula (III): 
       
         
           
           
               
               
           
         
         and in which the carrier or excipient comprises cyclodextrin, wherein the pharmaceutical composition is selected from a pharmaceutical composition that is formulated for oral administration and a pharmaceutical composition that is formulated for parenteral administration. 
       
     
     
         19 . A method of reducing oxidative stress in a cell, comprising: contacting a cell that comprises mitochondria with the chemically stable antioxidant compound of  claim 1  under conditions and for a time sufficient for accumulation of the antioxidant compound in the mitochondria, and thereby reducing oxidative stress in the cell. 
     
     
         20 . The method of  claim 19  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. 
       
     
     
         21 . 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 12 . 
     
     
         22 . 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 3 . 
     
     
         23 . The method of  claim 22  wherein the compound is a compound of formula (III): 
       
         
           
           
               
               
           
         
         or its quinol form.