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.