Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists

A method for treating a disease of the nervous system in which the pathophysiology of the disorder involves excessive excitation of nerve cells by agonists of NMDA receptors, comprising the administration to a mammal exhibiting symptoms of such disorders or is susceptible to such disorders an effective amount of a N,N,N',N'-tetrasubstituted guanidine of the formula:

• ##STR5## wherein R, R', R" and R"' are independently a C.sub.1 -C.sub.8 alkyl group, a C.sub.2 -C.sub.6 alkenyl group, C.sub.2 -C.sub.6 alkynyl group, cycloalkyl group, cycloalkyl group substituted with one or more substituents, cycloalkenyl group, cycloalkenyl group substituted with one or more substituents, carbocyclic aryl group, carbocyclic aryl group substituted with one or more substituents, alkaryl group, alkaryl group substituted with one or more substituents, aralkyl group, aralkyl group substituted with one or more substituents, heterocyclic group, heterocyclic group substituted with one or more substituents, heteroaryl group, or a heteroaryl group substituted with one or more substituents;
• or a physiologically acceptable salt thereof;
• wherein said substituent is chloro, fluoro, bromo, iodo, C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, cyano, C.sub.3 -C.sub.15 dialkylaminoalkyl, carboxy, carboxamido, C.sub.1 -C.sub.8 alkylthio, allyl, aralkyl, C.sub.3 -C.sub.6 cycloalkyl, aroyl, aralkoxy, C.sub.2 -C.sub.8 acyl, aryl, heteroaryl, an aryl fused to a benzene ring, a heteroaryl fused to a benzene ring, C.sub.3 -C.sub.6 heterocycloalkyl, a C.sub.3 -C.sub.6 heterocycloalkyl ring fused to a benzene ring, C.sub.1 -C.sub.8 alkylsulfonyl, arylthio, amino, C.sub.1 -C.sub.8 alkylamino, C.sub.2 -C.sub.15 dialkylamino, hydroxy, hydroxyalkyl, carbamoyl, C.sub.1 -C.sub.8 N-alkylcarbamoyl, C.sub.2 -C.sub.15 N,N-dialkylcarbamoyl, nitro, azido or C.sub.2 -C.sub.15 dialkylsulfamoyl;
• and
• wherein said guanidine exhibits high binding to the receptor.

A method of treating a disease selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome, Korsakoff's disease or epilepsy, comprising administering to a mammal suffering from said disease an effective amount of a compound of the formula:

• ##STR6## wherein R, R' and R" are independently a C.sub.1 -C.sub.8 alkyl group, a C.sub.2 -C.sub.6 alkenyl group, a C.sub.2 -C.sub.6 alkynyl group, a cycloalkyl group, cycloalkyl group substituted by one or more substituents, a cycloalkenyl group, cycloalkenyl group substituted by one or more substituents, carbocyclic aryl group, carbocyclic aryl group substituted by one or more substituents, alkaryl group, alkaryl group substituted by one or more substituents, aralkyl group, aralkyl group substituted with one or more substituents, heterocyclic group, heterocyclic group substituted by one or more substituents, heteroaryl groups, or a heteroaryl group substituted by one or more substituents;
• or a physiologically acceptable salt thereof;
• wherein said substituent is chloro, fluoro, bromo, iodo, C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, cyano, C.sub.3 -C.sub.15 dialkylaminoalkyl, carboxy, carboxamido, C.sub.1 -C.sub.8 alkylthio, allyl, aralkyl, alkaryl, C.sub.3 -C.sub.6 cycloalkyl, aroyl, aralkoxy, C.sub.2 -C.sub.8 acyl, aryl, heteroaryl, an aryl fused to a benzene ring, a heteroaryl fused to benzene ring, C.sub.3 -C.sub.6 heterocycloalkyl, a C.sub.3 -C.sub.6 heterocycloalkyl ring fused to a benzene ring, C.sub.1 -C.sub.8 alkylsulfonyl, arylthio, amino, C.sub.1 -C.sub.8 alkylamino, C.sub.2 -C.sub.15 dialkylamino, hydroxy, hydroxyalkyl, carbamoyl, C.sub.1 -C.sub.6 N-alkylcarbamoyl, C.sub.2 -C.sub.15 N,N-dialkylcarbamoyl, nitro, azido or C.sub.2 -C.sub.15 dialkylsulfamoyl.

A method of treating or preventing a disease selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome, Korsakoff's disease or epilepsy, comprising administering to a mammal suffering from or susceptible to said disease an effective amount of a compound of the formula:

• ##STR7## wherein R, R', R" and R"' are independently a C.sub.1 -C.sub.8 alkyl group, C.sub.2 -C.sub.6 alkenyl group, C.sub.2 -C.sub.6 alkynyl group, cycloalkyl group, cycloalkyl group substituted by one or more substituents, cycloalkenyl group, cycloalkenyl group substituted with one or more substituents, carbocyclic aryl group, carbocyclic aryl group substituted by one or more substituents, alkaryl group, alkaryl group substituted by one or more substituents, aralkyl group, aralkyl group substituted with one or more substituents, heterocyclic group, heterocyclic group substituted by one or more substituents, heteroaryl group or a heteroaryl group substituted by one or more substituents;
• or a physiologically acceptable salt thereof;
• wherein said substituent is chloro, fluoro, bromo, iodo, C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 alkoxy, cyano, C.sub.3 -C.sub.15 dialkylaminoalkyl, carboxy, carboxamido, C.sub.1 -C.sub.8 alkylthio, allyl, aralkyl, alkaryl, C.sub.3 -C.sub.8 cycloalkyl, aroyl, aralkoxy, C.sub.2 -C.sub.8 acyl, aryl, heteroaryl, an aryl fused to a benzene ring, a heteroaryl fused to a benzene ring, C.sub.3 -C.sub.6 heterocycloalkyl, a C.sub.3 -C.sub.6 heterocycloalkyl ring fused to a benzene ring, C.sub.1 -C.sub.8 alkylsulfonyl, arylthio, amino, C.sub.1 -C.sub.8 alkylamino, C.sub.2 -C.sub.15 dialkylamino, hydroxy, hydroxyalkyl, carbamoyl, C.sub.1 -C.sub.8 N-alkylcarbamoyl, C.sub.2 -C.sub.15 N,N'-dialkylcarbamoyl, nitro, azido or C.sub.2 -C.sub.15 dialkylsulfamoyl.