Synthesis and anticonvulsant activities of 3,3-dialkyl- and 3-alkyl-3-benzyl-2-piperidinones (delta-valerolactams) and hexahydro-2H-azepin-2-ones (epsilon-caprolactams).

A series of 3-substituted 2-piperidinone (delta-valerolactam) and hexahydro-2H-azepin-2-one (epsilon-caprolactam) derivatives were prepared and evaluated as anticonvulsants in mice. In the 2-piperidinone series, 3,3-diethyl compound 7b is the most effective anticonvulsant against pentylenetetrazole-induced seizures (ED50, 37 mg/kg; PI (TD50/ED50), 4.46), and 3-benzyl compound 4c (ED50, 41 mg/kg; PI, 7.05) is the most effective anticonvulsant against seizures induced by maximal electroshock. By contrast, none of the epsilon-caprolactams tested had anticonvulsant effects below doses causing rotorod toxicity. log P values were correlated with neurotoxicity and [35S]TBPS displacement, but not with anticonvulsant activity. Electrophysiological evaluations of selected compounds from each series indicated that both the delta-valero-lactams and epsilon-caprolactams potentiated GABA-mediated chloride currents in rat hippocampal neurons.

3,3-Dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones: a new class of anticonvulsant agents.

A series of 3,3-dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones (lactams) have been prepared and evaluated for their anticonvulsant activities. In the pentylenetetrazole mouse seizure model, 3,3-diethyl lactam 7c and 3-benzyl-3-ethyl lactam 7j are the most effective anticonvulsants (ED50 = 46 and 42 mg/kg, respectively) and have protective index (PI = TD50/ED50) values of 5.65 and 3.00, respectively. These protective index values compare favorably to those of the clinically used antiepileptic drugs ethosuximide (ED50 = 161 mg/kg), phenobarbital (ED50 = 22 mg/kg), and valproic acid (ED50 = 133 mg/kg), which have PI values of 2.35, 4.00, and 2.12, respectively. The benzyl compounds [3-substituents are Bn, H (7h); Bn, Me (7i); and Bn, Et (7j)] are also very effective anticonvulsants against seizures induced by maximal electroshock (ED50 = 41, 55, and 74 mg/kg, respectively) and have PI values of 3.51, 3.04, and 1.70, respectively. The corresponding PI values for phenobarbital and valproic acid are 1.37 and 5.18, respectively. As a class of anticonvulsants, the 3,3-disubstituted 2-pyrrolidinones have a broad spectrum of action and may be useful for the treatment of human epilepsies.