Synthesis and anticonvulsant properties of new Mannich bases derived from 3-aryl-pyrrolidine-2,5-diones. Part 1.

A series of new Mannich bases of N-[(4-arylpiperazin-1-yl)-methyl]-3-(chlorophenyl)-pyrrolidine-2,5-diones 10-23 have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Their neurotoxicity was determined using a rotorod screen. Several molecules showed a promising anticonvulsant profile especially in the MES-test. In this model of seizures, the most active were N-[{4-(4-chlorophenyl)-piperazin-1-yl}-methyl]-3-(3-chlorophenyl)-pyrrolidine-2,5-dione 16 and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-(3-chlorophenyl)-pyrrolidine-2,5-dione 17 with ED(50) values of 21.4 mg/kg and 28.83 mg/kg, respectively. Selected derivatives 10, 14, and 16 were tested in the psychomotor seizure 6-Hz test from which N-[{4-(2-chlorophenyl)-piperazin-1-yl}-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione 10 revealed the highest protection with an ED(50) of 78 mg/kg. Compounds 10, 12, and 17 were also tested in the pilocarpine-induced status PIPS test. Furthermore, 17 was examined in the hippocampal kindling screen after i. p. administration to rats.