Synthesis, anticonvulsant properties, and SAR analysis of differently substituted pyrrolidine-2,5-diones and piperidine-2,6-diones.

Twenty-two differently substituted 1H-isoindole-1,3(2H)-diones (30-39), 8-azaspiro[4.5]decane-7,9-diones (40-45), and 3-azaspiro[5.5]undecane-2,4-diones (46-51) were synthesized and tested for anticonvulsant activity. These molecules were designed as analogs of previously obtained azaspirosuccinimides (1-24). Initial anticonvulsant screening was performed in mice using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined applying the minimal motor impairment rotorod test. The preliminary pharmacological results showed that 15 new compounds were effective in at least one animal model of epilepsy, from which nine molecules showed protection against both MES and scPTZ seizures. The structure-activity relationship analysis revealed that anticonvulsant activity was connected closely with the structure of the imide fragment; the most favorable one was the hexahydro-1H-isoindole-1,3(2H)-dione core. 2-(2-Chlorophenyl)hexahydro-1H-isoindole-1,3(2H)-dione (31) showed activity in the 6-Hz psychomotor seizure model, which identifies substances effective in partial and therapy-resistant epilepsy. 3-[(4-Chlorophenyl)amino]-3-azaspiro[5.5]undecane-2,4-dione (47) was active in the in vitro hippocampal slice culture neuroprotection assay.