1,4 substituted piperidinyl NMDA/NR2B antagonists

Abstract

Novel piperidinyl compounds substituted in the 1- and 4-positions are effective as NMDA NR2B antagonists useful for relieving pain.

What is claimed is:  
     
         1 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is i) 2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or 2-quinazoline, each optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy; or ii) phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy;  
 R 2  is a) 2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or 2-quinazoline, each optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy; or b) phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy;  
 When R 1  is i, then R 2  is b; when R 1  is ii, then R 2  is a;  
 When R 1  or R 2  is 2-benzimidazole, respective L 1  or L 2  is not C 1 -C 2 alkyl, except when R 1  or R 2  is hydroxy-substituted 2-benzimidazole, respective L 1  or L 2  includes C 1 -C 2 alkyl  
 L 1  and L 2  are independently C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkoxy, aminoC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, carbonyl, cycloC 3 -C 6 alkyl or aminocarbonyl; and  
 optionally substituted at any of the 2, 3, 5, or 6 positions independently with X, wherein X is hydroxy, amino, C 1 -C 4 alkylamino, di(C 1 -C 4 )alkylamino, C 1 -C 4 alkyl, ester, carbamate, carbonate, or ether.  
 
     
     
         2 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is 2-imidazopyridine, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy;  
 R 2  is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy;  
 L 1  and L 2  are independently C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkoxy, aminoC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, carbonyl, cycloC 3 -C 6 alkyl or aminocarbonyl; and  
 optionally substituted at any of the 2, 3, 5, or 6 positions independently with X, wherein X is hydroxy, amino, C 1 -C 4 alkylamino, di(C 1 -C 4 )alkylamino, C 1 -C 4 alkyl, ester, carbamate, carbonate, or ether.  
 
     
     
         3 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is purine, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy;  
 R 2  is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy;  
 L 1  and L 2  are independently C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkoxy, aminoC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, carbonyl, cycloC 3 -C 6 alkyl or aminocarbonyl; and  
 optionally substituted at any of the 2, 3, 5, or 6 positions independently with X, wherein X is hydroxy, amino, C 1 -C 4 alkylamino, di(C 1 -C 4 )alkylamino, C 1 -C 4 alkyl, ester, carbamate, carbonate, or ether.  
 
     
     
         4 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is 2-benzimidazole, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy;  
 R 2  is phenyl, optionally substituted with one to five substituents, each substituent independently being chloro, fluoro, bromo, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylsulfonamide, hydroxy, or carboxy;  
 L 1  is not C 1 -C 2 alkyl, except when R 1  is hydroxy-substituted 2-benzimidazole, L 1  includes C 1 -C 2 alkyl;  
 L 1  and L 2  are independently C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 1 -C 4 alkoxy, aminoC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, carbonyl, cycloC 3 -C 6 alkyl or aminocarbonyl; and  
 optionally substituted at any of the 2, 3, 5, or 6 positions independently with X, wherein X is hydroxy, amino, C 1 -C 4 alkylamino, di(C 1 -C 4 )alkylamino, C 1 -C 4 alkyl, ester, carbamate, carbonate, or ether.  
 
     
     
         5 . The compound according to  claim 1 , wherein said compound is 2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-b]pyridine; 8-(4-Benzyl-piperidin-1-ylmethyl)-purine; 2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-c]pyridine; 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-1H-benzimidazole; 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-imidazo[4,5-b]pyridine; 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H-benzimidazole; 2-{3-[4-(4-Chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole; 2-{3-[4-(4-Methyl-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole; 2-[3-(4-Benzyl-piperidin-1-yl)-1-methyl-propyl]-1H-benzimidazole; 2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole; 2-[3-(4-Benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole; or N-[2-(4-Benzyl-piperidin-1-ylmethyl)-3H-benzoimidazol-5-yl]-methanesulfonamide.  
     
     
         6 . The compound according to  claim 1 , wherein said compound is  
       
         
           
           
               
               
           
         
       
     
     
         7 . A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to  claim 1 .  
     
     
         8 . The pharmaceutical composition according to  claim 7  useful for the treatment of pain.  
     
     
         9 . The pharmaceutical composition according to  claim 7  useful for the treatment of migraine, depression, anxiety, schizophrenia, Parkinson's disease, or stroke.  
     
     
         10 . A method of treating pain comprising a step of administering to one in need of such treatment an effective amount of a compound according to  claim 1 .  
     
     
         11 . A method of treating migraine, depression, anxiety, schizophrenia, Parkinson's disease, or stroke comprising a step of administering to one in need of such treatment an effective amount of a compound according to  claim 1.