Porphyrin Catalysts and Methods of Use Thereof

Abstract

This invention provides a novel class of substituted macrocyclic porphyrin compounds. The compounds are useful as peroxynitrite decomposition catalysts. Pharmaceutical compositions, and methods of making and using the compounds, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof are also described.

1 . A method of lowering peroxynitrite levels in a cell or tissue, the method comprising contacting said cell or tissue with a compound of Formula I in an amount sufficient to lower peroxynitrite levels in said cell or tissue: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, or stereoisomer, or mixtures thereof, wherein
 at least one of R 1 , R 2 , R 3 , and R 4  is independently selected from the group consisting of CH 2 C(O)NR 5 R 6  and (CH 2 CH 2 O) t CH 3 , wherein t is 1, 2, 4, 5, 6, 7, 8, 9, or 10, and the remaining R 1 , R 2 , R 3 , and R 4  are hydrogen; 
 R 5  and R 6  are selected from the group consisting of 
 H, 
 CH 2 CH 2 OCH 3 , 
 CH 2 CH 2 OCH 2 CH 2 OCH 3 , 
 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 , 
 CH 2 COO − , 
 (CH 2 ) n —X, 
 (CH 2 ) n —Y, 
 (CH 2 ) n R 9 —X, 
 (CH 2 ) n R 9 —Y, 
 CH 2 CO 2 CH 2 CH 3 , 
 (OCH 2 CH 2 ) m —X, 
 (OCH 2 CH 2 ) m —Y, 
 Y 2 —X, 
 Y 2 C(Z 1 ) 3 ,
 further wherein: Z 1  is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y; 
 
 (CH 2 ) n C(O)Y 2 C(Z 2 ) 3 ,
 wherein: Z 2  is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3  and Z 4  is CH 2 OCH 2 CH 2 X; 
 
 (CH 2 ) n C(O)—Y 2 —C(Z 5 ) 3 ,
 wherein: Z 5  is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 6 ) 3  and Z 6  is 
 CH 2 OCH 2 CH 2 C(O)O(CH 2 CH 2 O) m CH 2 CH 2 O; 
 
 (CH 2 ) n OCH 2 C(CH 2 OH) 3 , 
 (CH 2 ) n OCH 2 CH(CH 2 OH) 2 , 
 (CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 ), 
 (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 , 
 (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] m CH 2 CH 2 OX) 3 ] 3 , 
 CH 2 CONH—Y, 
 CH 2 CO—Y, 
 CH 2 CO(CH 2 ) p —Y; 
 alkyl, 
 cycloalkyl, and 
 aralkyl; 
 
         wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; m is an integer from 1 to 200, and p is 1 or 2; 
         X is COOH, COOR′, CONH 2 , CONHR′, CONR′ 2 , CO(CH 2 ) p R′, OPO 3 H 2 , PO 3 H 2 , SO 3 H, NH 2 , NR′ 2 , or NR′ 3   + , a steroid, an amino acid, an oligosaccharide, a peptide, or a polycarboxylic acid, further wherein R′ is alkyl, CH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 3 , (CH 2 ) n —X, (CH 2 ) n —Y, (CH 2 ) n Ar—X, (CH 2 ) n Ar—Y, CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 , CH 2 CO 2 CH 2 CH 3 , (OCH 2 CH 2 ) m —X, (OCH 2 CH 2 ) m —Y, Y 2 —X, Y 2 C(Z 1 ) 3 , further wherein: Z 1  is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y; (CH 2 ) n C(O)Y 2 C(Z 2 ) 3 , wherein: Z 2  is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3  and Z 4  is CH 2 OCH 2 CH 2 X; (CH 2 ) n C(O)—Y 2 —C(Z 5 ) 3 , wherein: Z 5  is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 6 ) 3  and Z 6  is CH 2 OCH 2 CH 2 C(O)O(CH 2 CH 2 O) n CH 2 CH 2 O; (CH 2 ) n OCH 2 C(CH 2 OH) 3 , (CH 2 ) n OCH 2 CH(CH 2 OH) 2 , (CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 ), (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 , (CH 2 ) m OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] m CH 2 CH 2 OX) 3 ] 3 , CH 2 CONH—Y, CH 2 CO—Y, and CH 2 CO(CH 2 ) p —Y; 
         Y is OH or (OCH 2 CH 2 ) m —W 1  or (CH 2 CH 2 ) m —W 2 ; where W 1  is OH, or (OCH 2 CH 2 ) m OH and W 2  is OR″, further wherein R″ is an alkyl group; 
         Y 2  is selected from the group consisting of (CH 2 ) n O, (CH 2 ) n NH, and (CH 2 ) n S, CH 2 CONH, CH 2 COO, or CH 2 CO(CH 2 ) p ; 
         R 9  is substituted phenyl, unsubstituted phenyl, substituted napthyl, or unsubstituted naphthyl; 
         L 1  and L 2  are, independently, absent, halide, oxo, OH 2 , hydroxo, CN, OPO 3 H or alcohol; 
         and M is absent, Mn or Fe; 
         provided that R 5  and R 6  are not both alkyl. 
       
     
     
         2 . The method of  claim 1 , wherein R 1 , R 2 , R 3 , and R 4  are each CH 2 C(O)NR 5 R 6 . 
     
     
         3 . The method of  claim 1 , wherein one of R 5  or R 6  is H. 
     
     
         4 . The method of  claim 1 , wherein one of R 5  or R 6  is selected from aralkyl, alkyl, cycloalkyl, substituted cycloalkyl, and CH 2 CH 2 OCH 3 . 
     
     
         5 . The method of  claim 4 , wherein aralkyl is (CR 7 R 8 ) s —R 9 , wherein R 7  and R 8  are, independently, selected from H, alkyl, OH, and halogen, and s is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 
     
     
         6 . The method of  claim 5 , wherein aralkyl is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 4 , wherein one of R 5  or R 6  is selected from alkyl, cycloalkyl, and substituted cycloalkyl. 
     
     
         8 . The method of  claim 7 , wherein cycloalkyl or substituted cycloalkyl is a bicyclic ring system. 
     
     
         9 . The method of  claim 8 , wherein the bicyclic ring system is bicycle[2.2.1]heptane. 
     
     
         10 . The method of  claim 8 , wherein the bicyclic ring system is 1,7,7-trimethylbicyclo[2.2.1]heptane. 
     
     
         11 . The method of  claim 4 , wherein one of R 5  or R 6  is CH 2 CH 2 OCH 3 . 
     
     
         12 . The method of  claim 1 , wherein R 1 , R 2 , R 3 , and R 4  are (CH 2 CH 2 O) t CH 3 . 
     
     
         13 . The method of  claim 1 , wherein t=1. 
     
     
         14 . The method of  claim 1 , wherein the compound is an ααββ atropisomer. 
     
     
         15 . The method of  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein L 1  and L 2  are, independently, absent, halide, oxo, OH 2 , hydroxo, CN, OPO 3 H or alcohol; and M is absent, Mn or Fe. 
       
     
     
         16 . A method of treating or inhibiting the development of a pathology associated with peroxynitrite damage in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, or stereoisomer, or mixtures thereof, wherein
 at least one of R 1 , R 2 , R 3 , and R 4  is independently selected from the group consisting of CH 2 C(O)NR 5 R 6  and (CH 2 CH 2 O) t CH 3 , wherein t is 1, 2, 4, 5, 6, 7, 8, 9, or 10, and the remaining R 1 , R 2 , R 3 , and R 4  are hydrogen; 
 R 5  and R 6  are selected from the group consisting of 
 H, 
 CH 2 CH 2 OCH 3 , 
 CH 2 CH 2 OCH 2 CH 2 OCH 3 , 
 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 , 
 CH 2 COO − , 
 (CH 2 ) n —X, 
 (CH 2 ) n —Y, 
 (CH 2 ) n R 9 —X, 
 (CH 2 ) n R 9 —Y, 
 CH 2 CO 2 CH 2 CH 3 , 
 (OCH 2 CH 2 ) n , —X, 
 (OCH 2 CH 2 ) m —Y, 
 Y 2 —X, 
 Y 2 C(Z 1 ) 3 ,
 further wherein: Z 1  is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y; 
 
 (CH 2 ) n C(O)Y 2 C(Z 2 ) 3 ,
 wherein: Z 2  is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3  and Z 4  is CH 2 OCH 2 CH 2 X; 
 
 (CH 2 ) n C(O)—Y 2 —C(Z 5 ) 3 ,
 wherein: Z 5  is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 6 ) 3  and Z 6  is CH 2 OCH 2 CH 2 C(O)O(CH 2 CH 2 O) m CH 2 CH 2 O − ; 
 
 (CH 2 ) n OCH 2 C(CH 2 OH) 3 , 
 (CH 2 ) n OCH 2 CH(CH 2 OH) 2 , 
 (CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 ), 
 (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 , 
 (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] m CH 2 CH 2 OX) 3 ] 3 , 
 CH 2 CONH—Y, 
 CH 2 CO—Y, 
 CH 2 CO(CH 2 ) p —Y; 
 alkyl, 
 cycloalkyl, and 
 aralkyl; 
 
         wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; m is an integer from 1 to 200, and p is 1 or 2;
 X is COOH, COOR′, CONH 2 , CONHR′, CONR′ 2 , CO(CH 2 ) p R′, OPO 3 H 2 , PO 3 H 2 , SO 3 H, NH 2 , NR′ 2 , or NR′ 3   + , a steroid, an amino acid, an oligosaccharide, a peptide, or a polycarboxylic acid, further wherein R′ is alkyl, CH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 3 , (CH 2 ) n —X, (CH 2 ) n —Y, (CH 2 ) n Ar—X, (CH 2 ) n Ar—Y, CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 , CH 2 CO 2 CH 2 CH 3 , (OCH 2 CH 2 ) m —X, (OCH 2 CH 2 ) m —Y, Y 2 —X, Y 2 C(Z 1 ) 3 , further wherein: Z 1  is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y; (CH 2 ) n C(O)Y 2 C(Z 2 ) 3 , wherein: Z 2  is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3  and Z 4  is CH 2 OCH 2 CH 2 X; (CH 2 ) n C(O)—Y 2 —C(Z 5 ) 3 , wherein: Z 5  is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 6 ) 3  and Z 6  is CH 2 OCH 2 CH 2 C(O)O(CH 2 CH 2 O) m CH 2 CH 2 O − ; (CH 2 ) n OCH 2 C(CH 2 OH) 3 , (CH 2 ) n OCH 2 CH(CH 2 OH) 2 , (CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 ), (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 , (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] n CH 2 CH 2 OX) 3 ] 3 , CH 2 CONH—Y, CH 2 CO—Y, and CH 2 CO(CH 2 ) p —Y; 
 Y is OH or (OCH 2 CH 2 ) m —W 1  or (CH 2 CH 2 ) m —W 2 ; where W 1  is OH, or (OCH 2 CH 2 ) m OH and W 2  is OR″, further wherein R″ is an alkyl group; 
 Y 2  is selected from the group consisting of (CH 2 ) n O, (CH 2 ) n NH, and (CH 2 ) n S, CH 2 CONH, CH 2 COO, or CH 2 CO(CH 2 ) p ; 
 R 9  is substituted phenyl, unsubstituted phenyl, substituted napthyl, or unsubstituted naphthyl; 
 L 1  and L 2  are, independently, absent, halide, oxo, OH 2 , hydroxo, CN, OPO 3 H or alcohol; 
 
         and M is absent, Mn or Fe;
 provided that R 5  and R 6  are not both alkyl. 
 
       
     
     
         17 . The method of  claim 16 , wherein said pathology is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, stroke, AIDS dementia, Huntington's disease, atherosclerosis, inflammation, arthritis, neurodegeneration, sepsis, autoimmune diseases, cancer, ischemia-reperfusion injury, septic shock, diabetes, diabetic vascular complications, diabetic cardiomyopathy, diabetic neuropathy, hyperglycemia, pathophysiological conditions of the heart, acute myocardial infarction, chronic ischemic heart failure, doxorubicin-induced cardiac dysfunction, oxidative stress, obliterative bronchiolitis, colitis, vascular dysfunction, myocardial dysfunction, myocardial necrosis, and chronic graft rejection.