Delta2-1,2,3-triazoline anticonvulsants and their active metabolite analogues, the aminoalkylpyridines, are excitatory amino acid antagonists and antiischemic agents, useful in the treatment of cerebral ischemia resulting from stroke

Abstract

Pharmaceutical compositions comprise as the active ingredient, nonneurotixic antiischemic compounds that are highly effective by the intraperitoneal route, and that are excitatory amino acid and NMDA/sigma receptor antagonists and are selected from the group consisting of those of the formulae, wherein R 2 is 4-pyridyl, 3-pyridyl, or 2-oxo- 1 -pyrrolidino and R 1 is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p-methyl, p-methoxy, or hydrogen, and those of the formulae, wherein R 2 is 4-pyridyl or 3-pyridyl, R 3 is hydrogen, methyl or ethyl and R 1 is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p-methyl, p-methoxy or hydrogen.

What is claimed is:  
     
         1 . A potent non-neurotoxic antiischemic composition, highly effective by the intraperitoneal route of administration, in the treatment of both global and focal ischemia, and comprising as the active ingredient, an effective amount of an antiischemic Δ 2 -1,2,3-triazoline compound, selected from the group consisting of those of the formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 2  is 4-pyridyl, 3-pyridyl, or 2-pyridyl and R 1  is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen, and a pharmaceutical carrier.  
     
     
         2 . A composition according to  claim 1  wherein R is 4-pyridyl and R 1  is hydrogen.  
     
     
         3 . A composition according to  claim 1  wherein R 2  is 4-pyridyl and R 1  is p-chloro.  
     
     
         4 . A composition according to  claim 1  wherein R 2  is 4-pyridyl and R 1  is 3,4-dichloro.  
     
     
         5 . A composition according to  claim 1  wherein R 2  is 4-pyridyl and R 1  is p-fluoro.  
     
     
         6 . A composition according to  claim 1  wherein R 2  is 4-pyridyl and R 1  is p-trifluoromethyl.  
     
     
         7 . A composition according to  claim 1  wherein R 2  is 4-pyridyl and R 1  is m-chloro.  
     
     
         8 . A composition according to  claim 1  wherein R is 4-pyridyl and R 1  is p-bromo.  
     
     
         9 . A composition according to  claim 1  wherein R 2  is 4-pyridyl and R 1  is 3,5-dichloro.  
     
     
         10 . A composition according to  claim 1  wherein R 2  is 3-pyridyl and R 1  is m-chloro.  
     
     
         11 . A composition according to  claim 1  wherein R 2  is 3-pyridyl and R 1  is p-chloro.  
     
     
         12 . A composition according to  claim 1  wherein R 2  is 3-pyridyl and R 1  is hydrogen.  
     
     
         13 . A composition according to  claim 1  wherein R 2  is 2-pyridyl and R 1  is p-bromo.  
     
     
         14 . A composition according to  claim 1  wherein R is 2-pyridyl and R 1  is p-chloro.  
     
     
         15 . A non-neurotoxic antiischemic composition, effective by the intraperitoneal route of administration in the treatment of both global and focal ischemia, and comprising as the active ingredient an effective amount of an antiischemic triazoline compound, selected from the 2-oxo-1-pyrrolidino-Δ 2 -1,2,3-triazoline group consisting of those of the formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen and a pharmaceutical carrier.  
     
     
         16 . A composition according to  claim 15  wherein R 1  is p-chloro, p-bromo or p-fluoro.  
     
     
         17 . A composition according to  claim 15  wherein R 1  is p-trifluoromethyl or m-trifluoromethyl.  
     
     
         18 . A composition according to  claim 15  wherein R 1  is 3,4-dichloro or 3,5-dichloro.  
     
     
         19 . A composition according to  claim 15  wherein R 1  is hydrogen.  
     
     
         20 . A 2-oxo-1-pyrrolidino-Δ 2 -1,2,3-triazoline compound of the following formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.  
     
     
         21 . A 2-oxo-1-pyrrolidino-Δ 2 -1,2,3-triazoline compound according to  claim 20  wherein R 1  is p-bromo or p-fluoro.  
     
     
         22 . A 2-oxo-1-pyrrolidino-Δ 2 1,2,3-triazoline compound according to  claim 20  wherein R 1  is m-chloro or 3,5-dichloro.  
     
     
         23 . A 4-pyridyl methylamine compound of the following formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is p- or m-chloro, 3,4- or 3,5-dichloro, p- or m-bromo, p- or m-fluoro, p -methyl or methoxyl.  
     
     
         24 . A 1-(4-pyridyl)-1-ethylamine compound of the following formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is 3,4- or 3,5-dichloro, 3,4- or 3,5-difluoro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.  
     
     
         25 . A 1-(4-pyridyl)-1-ethylamine compound according to  claim 24  wherein R 1  is 3,5-dichloro.  
     
     
         26 . A 1-(4-pyridyl)-1-ethylamine compound according to  claim 24  wherein R 1  is m-bromo, m-fluoro, m-trifluoromethyl, or 3,4-difluoro.  
     
     
         27 . A 1-(3-pyridyl)-1-ethylamine compound of the following formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.  
     
     
         28 . A 1-(3-pyridyl)-1-ethylamine compound according to  claim 27  wherein R 1  is p-chloro, p-bromo or 3,4-dichloro.  
     
     
         29 . A 1-(4-pyridyl)-1-propylamine compound of the following formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is 3,4- or 3,5-dichloro, 3,4- or 3,5-difluoro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.  
     
     
         30 . A 1-(3-pyridyl)-1-propylamine compound of the following formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is 3,4- or 3,5-dichloro, 3,4- or 3,5-difluoro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.  
     
     
         31 . A α-phenyl-α-(4-pyridyl)methylamine compound of the following formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, m-trifluoromethyl, p-dimethylamino, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.  
     
     
         32 . A α-phenyl-α-(3-pyridyl)methylamine compound of the following formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is 3,4- or 3,5-dichloro, p- or m-chloro, p-bromo, m-trifluoromethyl, p-methyl, p-methoxy or hydrogen.  
     
     
         33 . A α,α-bis-(2-pyridyl)methylamine compound of the following formula,  
       
         
           
           
               
               
           
         
       
     
     
         34 . A non-neurotoxic antiischemic composition, effective by the intrapentoneal route of administration in the treatment of global ischemia and comprising as the active ingredient, an effective amount of an antiischemic compound selected from the group consisting of those of the formulae,  
       
         
           
           
               
               
           
         
       
       wherein R 2  is 4-pyridyl or 3-pyridyl, R 3  is hydrogen, methyl or ethyl, and R 1  is 3, 4- or 3,5-dichloro, 3,4- or 3,5-difluoro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen, and a pharmaceutical carrier.  
     
     
         35 . A composition according to  claim 34  wherein R 2  is 4-pyridyl, R 3  is hydrogen, methyl or ethyl, and R 1  is 3,4- or 3,5-dichloro.  
     
     
         36 . A composition according to  claim 34  wherein R 2  is 3-pyridyl, R 3  is hydrogen, methyl or ethyl, and R 1  is p-chloro, p-bromo, or 3,4-dichloro.  
     
     
         37 . A composition consisting of an effective amount of an excitatory amino acid inhibitor (glutamate inhibitor) compound according to  claim 1 ,  claim 15  and  claim 34  to yield an antiischemic composition effective against global and focal ischeria.  
     
     
         38 . A composition according to  claim 1 ,  claim 15 ,  claim 34  and  claim 37 , wherein a sufficient amount of the triazoline in claims  1 ,  15  and  20  or aminoalkylpyridine in claims  23 ,  24 ,  27 ,  29 ,  30 ,  31 ,  32  and  33  is contained in said composition to provide a dosage amount ranging from about 25 mg/kg to 200 mg/kg.  
     
     
         39 . A method for the treatment of cerebral ischemia resulting from stroke in mammals, including man, which comprises administration thereto of an effective dosage amount of a triazoline or aminoalkylpyridine antiischemic composition of  claim 1 ,  claim 15 ,  claim 34  and  claim 37 .  
     
     
         40 . A composition according to  claim 34  wherein R 2  is 3-pyridyl, R 3  is hydrogen, methyl or ethyl, and R 1  is p-chloro, p-bromo, or 3,4-dichloro.  
     
     
         41 . A composition consisting of an effective amount of an excitatory amino acid inhibitor (glutamate inhibitor) compound according to  claim 1 ,  claim 15  and  claim 34  to yield an antiischemic composition effective against global and focal ischemia.  
     
     
         42 . A composition according to  claim 1 ,  claim 15 ,  claim 34  and  claim 37 , wherein a sufficient amount of the triazoline in claims  1 ,  15  and  20  or aminoalkylpyridine in claims  23 ,  24 ,  27 ,  29 ,  30 ,  31 ,  32  and  33  is contained in said composition to provide a dosage amount ranging from about 25 mg/kg to 200 mg/kg.  
     
     
         43 . A method for the treatment of cerebral ischemia resulting from stroke in mammals, including man, which comprises administration thereto of an effective dosage amount of a triazoline or aminoalkylpyridine antiischemic composition of  claim 1 ,  claim 15 ,  claim 34  and  claim 37.