Synthesis of aminomethyl-substituted cyclic imide derivatives for evaluation as anticonvulsants

A series of aminomethyl-substituted cyclic imides (II) based on the 2,5-pyrrolidinedione (X = CH2, succinimide) and 2,4-imidazolidinedione (X = NH, hydantoin) ring systems have been prepared. The compounds were designed on the basis of a potential interaction in the gamma-aminobutyric acid (GABA) neurotransmitter system and evaluated for anticonvulsant activity. The 3-(aminomethyl)-2,5-pyrrolidinediones were prepared by a dehydration procedure beginning with N-benzyl-2-(aminomethyl)succinic acid, whereas the 3-(aminomethyl)-3-methyl-2,3-pyrrolidinediones were best obtained by fusion of the amine salts of 2-(aminomethyl)-2-methylsuccinic acid. The hydantoin derivative, 5-(aminomethyl)-5-methyl-2,4-imidazolidinedione, was obtained by standard procedures. Although none of the compounds tested showed significant activity against convulsions induced by pentylenetetrazole (PTZ), some showed significant activity against maximal electroshock seizures in mice. Possible reasons for the lack of anti-PTZ activity and directions for further testing are discussed.