Mitochondria targeted cationic anti-oxidant compounds for prevention, therapy or treatment of hyper-proliferative disease, neoplasias and cancers

Abstract

The inventions disclosed include methods of treating cancers and related neoplasias, especially prostate cancer, with pharmaceutically acceptable salts comprising lipophilic cation moieties linked to nitroxide or linked to hydroxylamine anti-oxidant groups.

What is claimed is: 
     
         1 . A salt comprising a cation having the formula: 
       
         
           
           
               
               
           
         
         wherein 
         A is an antioxidant moiety selected from 
       
       
         
           
           
               
               
           
         
         E is a nitrogen or phosphorus atom; 
         R 1 ′, R 1 ″, and R 1 ′″ are each independently organic moieties comprising between 1 and 12 carbon atoms, and E, R 1 ′, R 1 ″, and R 1 ′″ together form a quaternary ammonium or phosphonium cation; 
         each R 2  is independently C 1 -C 4  alkyl; 
         Lg is —CH 2 —; 
         L comprises a polyalkylene chain having 1 to 21 carbon chain atoms, wherein any one or more of the hydrogens bonded to said carbon chain atoms can be optionally substituted with one or two independently selected hydroxyl, halogen, amino, methylamino, dimethylamino, or C 1 -C 4  organic moieties selected from alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, carboxy, or carboxyalkyl moieties; and 
         wherein the salt further comprises one or more anions X m−  wherein m is an integer from 1 to 4, to form the salt. 
       
     
     
         2 . The salt of  claim 1 , wherein X m−  is a halide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, carbonate, hydrogen carbonate, fumarate, maleate, maltolate, succinate, acetate, benzoate, oxalate, citrate, or tartrate anion. 
     
     
         3 . The salt of  claim 1 , wherein X m−  is a bromide anion. 
     
     
         4 . The salt of  claim 1 , wherein all R 2  are methyl. 
     
     
         5 . The salt of  claim 1 , wherein L is —(CH 2 )n-, wherein n is from 5 to 20. 
     
     
         6 . The salt of  claim 5 , wherein n is 10. 
     
     
         7 . The salt of  claim 1 , wherein L further comprises, in the polyalkylene, one to 10 groups independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, —NH—, —NCH 3 —, —C(O)—, or —CO 2 —. 
     
     
         8 . The salt of  claim 7 , wherein L is —(CH 2 CH 2 O)m-CH 2 CH 2 O—, wherein m is an integer from 0 to 3. 
     
     
         9 . The salt of  claim 1 , wherein R 1 ′, R 1 ″, and R 1 ′″ are independently C 4 -C 10  alkyl or phenyl moieties, each of which is optionally substituted with one or two independently selected hydroxyl, halogen, amino, cyano, methylamino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, carboxy, or carboxyalkyl moieties. 
     
     
         10 . The salt of  claim 9 , wherein R 1 ′, R 1 ″, and R 1 ′″ are each independently selected from the group consisting of n-C 4 H 9  moieties, phenyl moieties, and benzyl moieties. 
     
     
         11 . The salt of  claim 10 , wherein R 1 ′, R 1 ″, and R 1 ′″ are all phenyl. 
     
     
         12 . The salt of  claim 1 , wherein E is a phosphorus atom. 
     
     
         13 . The salt of  claim 12 , wherein E is a phosphorus atom and R 1 ′, R 1 ″, and R 1 ′″ are all phenyl or benzyl. 
     
     
         14 . The salt of  claim 1 , wherein A together with L g  is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The salt of  claim 1 , wherein A together with L g  is 
       
         
           
           
               
               
           
         
       
       L is —(CH 2 )n-, wherein n is from 5 to 24; and E is a phosphorus atom; and R 1 ′, R 1 ″, and R 1 ′″ are all phenyl. 
     
     
         16 . A pharmaceutical composition comprising one or more pharmaceutically acceptable salts of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . A method for treating or inhibiting the occurrence, recurrence, progression or metastasis, of a cancer or a neoplasia precursor thereof, consisting of administering to a mammal diagnosed as having a cancer or precursor neoplasia thereof, in an amount effective to treat the cancer or neoplasia precursor thereof or inhibit the occurrence, recurrence, progression, or metastasis of the cancer or precursor neoplasia thereof, a salt of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein the cancer is prostate cancer. 
     
     
         19 . A method for treating or inhibiting the occurrence, recurrence, or progression of a non-cancerous inflammation or hyperplasia, comprising administering to a mammal diagnosed as having a non-cancerous inflammation or hyperplasia, in an amount effective to treat the non-cancerous inflammation or hyperplasia or inhibit the occurrence, recurrence, or progression of the non-cancerous inflammation or hyperplasia, a salt of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein the non-cancerous hyperplasia is prostate hyperplasia. 
     
     
         21 . A salt comprising a cation having the formula: 
       
         
           
           
               
               
           
         
         wherein 
         A is an antioxidant moiety selected from 
       
       
         
           
           
               
               
           
         
         E is a nitrogen or phosphorus atom; 
         R 1 ′, R 1 ″, and R 1 ′″ are each independently organic moieties comprising between 1 and 12 carbon atoms, and E, R 1 ′, R 1 ″, and R 1 ′″ together form a quaternary ammonium or phosphonium cation; 
         L is an organic moiety comprising from 1 to 8 carbon atoms; and 
         wherein the salt further comprises one or more anions X m−  wherein m is an integer from 1 to 4, to form the salt. 
       
     
     
         22 . The salt of  claim 21  wherein E is a phosphorus atom. 
     
     
         23 . The salt of  claim 21 , wherein R 1 ′, R 1 ″, and R 1 ′″ are independently C 4 -C 10  alkyl or phenyl moieties, each of which is optionally substituted with one or two independently selected hydroxyl, halogen, amino, cyano, methylamino, dimethylamino, alkyl, hydroxyalkyl, alkoxy, alkoxylalkyl, carboxy, or carboxyalkyl moieties. 
     
     
         24 . The slat of  claim 23 , wherein R 1 ′, R 1 ″, and R 1 ′″ are each independently selected from the group consisting of n-C 4 H 9  moieties, phenyl moieties, and benzyl moieties. 
     
     
         25 . The salt of  claim 24 , wherein R 1 ′, R 1 ″, and R 1 ′″ are all phenyl 
     
     
         26 . The salt of  claim 21 , wherein L is —(CH 2 )n-, wherein n is 3, 4, 5, 6, 7, 8, or 9. 
     
     
         27 . The salt of  claim 21 , wherein L is —(CH 2 CH 2 O)m-CH 2 CH 2 O—, wherein m is an integer from 0 to 3. 
     
     
         28 . The salt of  claim 21 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         29 . The salt of  claim 21 , wherein the cation is of formula: 
       
         
           
           
               
               
           
         
         wherein 
         n is 3, 4, 5, 6, 7, 8, or 9; 
       
     
     
         30 . The salt of  claim 21 , wherein the salt is: 
       
         
           
           
               
               
           
         
       
     
     
         31 . A pharmaceutical composition comprising one or more pharmaceutically acceptable salts of  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         32 . A method for treating or inhibiting the occurrence, recurrence, progression or metastasis, of a cancer or a neoplasia precursor thereof, consisting of administering to a mammal diagnosed as having a cancer or precursor neoplasia thereof, in an amount effective to treat the cancer or neoplasia precursor thereof or inhibit the occurrence, recurrence, progression, or metastasis of the cancer or precursor neoplasia thereof, a salt of  claim 1 . 
     
     
         33 . The method of  claim 32 , wherein the cancer is prostate cancer. 
     
     
         34 . A method for treating or inhibiting the occurrence, recurrence, or progression of a non-cancerous inflammation or hyperplasia, comprising administering to a mammal diagnosed as having a non-cancerous inflammation or hyperplasia, in an amount effective to treat the non-cancerous inflammation or hyperplasia or inhibit the occurrence, recurrence, or progression of the non-cancerous inflammation or hyperplasia, a salt of  claim 1 . 
     
     
         35 . The method of  claim 34 , wherein the non-cancerous hyperplasia is prostate hyperplasia.