Multifunctional nitroxide derivatives and uses thereof

Abstract

Multifunctional nitroxide derivatives contain a potassium channel opener and a reactive oxygen species (ROS) degradation catalyst that can act as an anti-oxidant. Pharmaceutical compositions can include the derivatives. The multifunctional compounds and pharmaceutical compositions are useful for treatment of diseases, disorders or conditions associated with oxidative stress or endothelial dysfunction.

What is claimed is: 
     
         1 . A compound of the formula I: 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, racemate, or a pharmaceutically acceptable salt or solvate thereof, 
         wherein 
         A is a moiety of the formula II linked through its terminal —NH group to any carbon atom of the phenyl ring: 
       
       
         
           
           
               
               
           
         
         X is absent or —(CR 2 R 2 ) n —; 
         R 1  is absent or 1 to 5 substituents each independently selected from the group consisting of halogen, —CN, —OH, —NO 2 , —N(R 6 ) 2 , —OCF 3 , —CF 3 , —OR 6 , —COR 6 , —COOR 6 , —CON(R 6 ) 2 , —OCOOR 6 , —OCON(R 6 ) 2 , —(C 1 -C 8 )alkyl, —(C 1 -C 8 )alkylene-COOR 6 , —SR 6 , —SO 2 R 6 , —SO 2 N(R 6 ) 2 , and —S(═O)R 6 , wherein said —(C 1 -C 8 )alkyl and —(C 1 -C 8 )alkylene-COOR 6  may optionally be substituted with —OH, —OR 3 , —OCF 3 , —CF 3 , —COR 3 , —COOR 3 , —OCOOR 3 , —OCON(R 3 ) 2 , —(C 1 -C 8 )alkylene-COOR 3 , —CN, —NH 2 , —NO 2 , —SH, —SR 3 , —(C 1 -C 8 )alkyl, —O—(C 1 -C 8 )alkyl, —N(R 3 ) 2 , —CON(R 3 ) 2 , —SO 2 R 3 , or —S(═O)R 3 , or two adjacent R 1  groups and the carbon atoms to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic ring, (C 6 -C 10 )aryl, or 6- to 10-membered heteroaryl; 
         R 2  each independently is selected from the group consisting of H, halogen, —OCF 3 , —CF 3 , —OR 7 , —COR 3 , —COOR 3 , —OCOOR 7 , —OCON(R 7 ) 2 , —(C 1 -C 8 )alkylene-COOR 7 , —CN, —NO 2 , —SH, —SR 7 , —(C 1 -C 8 )alkyl, —N(R 7 ) 2 , —CON(R 7 ) 2 , —SO 2 R 7 , SO 2 N(R 7 ) 2 , and —S(═O)R 7 ; 
         R 3  each independently is selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, and (C 2 -C 8 )alkynyl; 
         R 4  is selected from the group consisting of H, —COOR 3 , —(C 1 -C 8 )alkylene-COOR 7 , —CN, —(C 1 -C 8 )alkyl, and —CON(R 7 ) 2 ; 
         R 5  is selected from the group consisting of H, —OH, —O—(C 1 -C 8 )alkyl, —CO 4 C 1 -C 8 )alkyl, —COO—(C 1 -C 8 )alkyl, —CN, and —NH 2 ; 
         R 6  each independently is selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, 4-12-membered heterocyclyl, (C 6 -C 14 )aryl, and (C 1 -C 8 )alkylene-NH 2 ; 
         R 7  each independently is selected from the group consisting of H, (C 1 -C 8 )alkyl, —(C 1 -C 8 )alkylene-NH 2 , (C 3 -C 10 )cycloalkyl, 4-12-membered heterocyclyl, and (C 6 -C 14 )aryl, each of which other than H may optionally be substituted with —OR 6 , —COR 6 , —COOR 6 , —OCOOR 6 , —OCON(R 6 ) 2 , (C 1 -C 8 )alkylene-COOR 6 , —CN, —NO 2 , —SR 6 , —(C 1 -C 8 )alkyl, —N(R 6 ) 2 , —CON(R 6 ) 2 , —SO 2 R 6 , or —S(═O)R 6 ; and 
         n is an integer of 1 or 2. 
       
     
     
         2 . The compound of  claim 1 , wherein
 (i) R 1  is absent, or 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , —N(R 6 ) 2 , —OR 6 , —OCF 3 , —CF 3 , —COR 6 , —COOR 6 , —CON(R 6 ) 2 , —OCOOR 6 , —OCON(R 6 ) 2 , (C 1 -C 8 )alkyl, —(C 1 -C 8 )alkylene-COOR 6 , —SR 6 , —SO 2 R 6 , —SO 2 N(R 6 ) 2 , and —S(═O)R 6 , wherein R 6  each independently is H, (C 1 -C 8 )alkyl, or —(C 1 -C 8 )alkylene-NH 2 ; or   (ii) two adjacent R 1  groups and the carbon atoms to which they are attached form a 5- or 6-membered carbocyclic or heterocyclic ring, (C 6 -C 10 )aryl, or 6- to 10-membered heteroaryl.   
     
     
         3 . The compound of  claim 1 , wherein (i) R 2  is H; or (ii) R 3  each independently is (C 1 -C 4 )alkyl; or (iii) R 4  is H; or (iv) R 5  is —CN. 
     
     
         4 . The compound of  claim 3 , wherein R 3  are identical. 
     
     
         5 . The compound of  claim 1 , wherein A is linked to any position of the phenyl ring; R 1  is absent or 1 to 5 substituents each independently is halogen; X is absent or —(CR 2 R 2 ) n —, wherein n is 1 or 2; R 2  is H; R 3  each independently is (C 1 -C 4 )alkyl; R 4  is H; and R 5  is —CN. 
     
     
         6 . The compound of  claim 5 , wherein:
 (i) X is absent; R 1  is absent; R 2  is H; and R 3  is methyl, herein identified compound 22;   (ii) X is absent; R 3  is methyl; and R 1  is F, Cl or Br, linked to the phenyl ring at position ortho, meta or para with respect to A, herein identified compounds 23 a-c -25 a-c , respectively;   (iii) X is absent; R 3  is methyl; and R 1  represents 2 substituents each independently is F, Cl or Br, linked to the phenyl ring at position ortho, meta or para with respect to A;   (iv) X is —(CR 2 R 2 ) n — wherein n is 1; R 1  is absent; R 2  is H; and R 3  is methyl, herein identified compound 32;   (v) X is —(CR 2 R 2 ) n — wherein n is 1; R 3  is methyl; and R 1  is F, Cl or Br, linked to the phenyl ring at position ortho, meta or para with respect to A, herein identified compounds 33 a-c -35 a-c , respectively;   (vi) X is —(CR 2 R 2 ) n — wherein n is 1; R 3  is methyl; and R 1  represents 2 substituents each independently is F, Cl or Br, linked to the phenyl ring at position ortho, meta or para with respect to A;   (vii) X is —(CR 2 R 2 ) n — wherein n is 2; R 1  is absent; R 2  is H; and R 3  is methyl, herein identified compound 36;   (viii) X is —(CR 2 R 2 ) n — wherein n is 2; R 3  is methyl; and R 1  is F, Cl or Br, linked to the phenyl ring at position ortho, meta or para with respect to A, herein identified compounds 37 a-c -39 a-c , respectively; or   (ix) X is —(CR 2 R 2 ) n — wherein n is 2; R 3  is methyl; and R 1  represents 2 substituents each independently is F, Cl or Br, linked to the phenyl ring at position ortho, meta or para with respect to A.   
     
     
         7 . The compound of  claim 6 , wherein X is absent; R 3  is methyl; and R 1  represents 2 substituents each is Cl, linked to the phenyl ring at positions ortho and ortho, ortho and meta, ortho and para, meta and meta, or meta and para with respect to A, herein identified compounds 26-31, respectively. 
     
     
         8 . A pharmaceutical composition comprising a compound of  claim 1 , or an enantiomer, diastereomer, racemate, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         9 . The pharmaceutical composition of  claim 8 , for intravenous, intramuscular, subcutaneous, transdermal, oral, nasal, parenteral or topical administration, or for administration by inhalation. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the composition is for oral administration and formulated as a tablet, capsule, aqueous or oily solution, suspension or emulsion; or the composition is for topical administration and formulated as a cream, ointment, gel, aqueous or oil solution or suspension, salve, patch, plaster, lubricant or suppository. 
     
     
         11 . The pharmaceutical composition of  claim 8 , wherein said carrier comprises a biodegradable polymer. 
     
     
         12 . The pharmaceutical composition of  claim 11 , formulated for slow release of the compound. 
     
     
         13 . The pharmaceutical composition of  claim 8 , wherein X is absent; R 2  is H; R 3  is methyl; and A is linked to any position of the phenyl ring. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein said compound is selected from the group consisting of the oxy radical of 2-cyano-1-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)-3-phenylguanidine, 2-cyano-1-(2-fluoro phenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(2-chlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(2-bromophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl) guanidine, 2-cyano-1-(3-fluorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(3-chlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(3-bromo phenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(4-fluorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(4-chlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(4-bromophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(2,6-dichlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(2,5-dichlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(2,3-dichlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(2,4-dichlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, 2-cyano-1-(3,5-dichlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine, and 2-cyano-1-(3,4-dichlorophenyl)-3-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)guanidine. 
     
     
         15 . The pharmaceutical composition of  claim 8 , wherein X is —(CR 2 R 2 ) n — wherein n is 1; R 2  is H; R 3  is methyl; and A is linked to any position of the phenyl ring. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein said compound is selected from the group consisting of the oxy radical of 2-cyano-1-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)-3-phenyl guanidine, 2-cyano-1-(2-fluorophenyl)-3-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)guanidine, 2-cyano-1-(2-chlorophenyl)-3-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)guanidine, 2-cyano-1-(2-bromophenyl)-3-(1-hydroxy-2,2,6,6-tetramethyl piperidin-4-yl)guanidine, 2-cyano-1-(3-fluoro phenyl)-3-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)guanidine, 2-cyano-1-(3-chlorophenyl)-3-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)guanidine, 2-cyano-1-(3-bromophenyl)-3-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)guanidine, 2-cyano-1-(4-fluorophenyl)-3-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)guanidine, 2-cyano-1-(4-chlorophenyl)-3-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)guanidine, and 2-cyano-1-(4-bromo phenyl)-3-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)guanidine. 
     
     
         17 . The pharmaceutical composition of  claim 8 , wherein X is —(CR 2 R 2 ) n — wherein n is 2; R 2  is H; R 3  is methyl; and A is linked to any position of the phenyl ring. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein said compound is selected from the group consisting of the oxy radical of 2-cyano-1-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)-3-phenylguanidine, 2-cyano-1-(2-fluorophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine, 2-cyano-1-(2-chlorophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine, 2-cyano-1-(2-bromophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine, 2-cyano-1-(3-fluorophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine, 2-cyano-1-(3-chlorophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine, 2-cyano-1-(3-bromophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine, 2-cyano-1-(4-fluorophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine, 2-cyano-1-(4-chlorophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine, and 2-cyano-1-(4-bromophenyl)-3-(1-hydroxy-2,2,7,7-tetramethylazepan-4-yl)guanidine.