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 2 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.

1 - 22 . (canceled)  
   
   
       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 intraperitoneal 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 34  to yield and antiischemic composition effective against global and focal ischemia.  
   
   
       38 . (canceled)  
   
   
       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 aminoalkylpyridine antiischemic composition of  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 34  to yield an antiischemic composition effective against global and focal ischemia.  
   
   
       42 . A composition according to  claim 37 , wherein a sufficient amount of the aminoalkylpyridine in claim 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 which comprises administration thereto of an effective dosage amount of a triazoline or aminoalkylpyridine antiischemic composition of  claim 34 .  
   
   
       44 . 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 34.