Synthesis and anticonvulsant activity of 2-benzylglutarimides

A series of 2-benzylglutarimides (4) and their N-methyl analogues (5) were prepared according to the Topliss scheme for the selection of benzyl substituents to maximize anticonvulsant activity. A total of 22 such compounds were subjected to initial (phase I) screening in mice against seizures induced by maximal electroshock (MES) and pentylenetetrazol (scMet) and in the rotorod assay for neurotoxicity. From this series of test compounds, 10 were advanced to quantitative (phase II) testing. Of these, 2-(4-chlorobenzyl)glutarimide (4b) emerged as the most promising anticonvulsant drug candidate by demonstrating both good anti-scMet and anti-MES activity combined with low neurotoxicity after intraperitoneal administration in mice. In drug differentiation tests, 4b was also effective in nontoxic doses against seizures induced by bicuculline, picrotoxin, and strychnine. When compared with the clinically useful drugs phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide, 4b exhibited an overall pharmacological profile most closely resembling that of valproate.