Synthesis, physicochemical and anticonvulsant properties of N-benzyl and N-aminophenyl derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione. Part I

Article abstract of DOI:10.1016/j.farmac.2005.05.006

To continue our systematic SAR studies, two series of N-benzyl- (X = CH₂) and N-aminophenyl- (X = NH) derivatives of 2-azaspiro[4.4]nonane (1a-1j) and 2-azaspiro[4.5]decane-1,3-dione (2a-2j) were synthesized, and evaluated in maximum electroshock seizure (MES), subcutaneous pentylenetetrazole (sc.MET) and rotorod (TOX) tests for their anticonvulsant activity. Among those derivatives, the most potent N-aminophenyl-2-azaspiro[4.4]nonane-1,3-dione 1j had ED₅₀ = 76.27 mg kg^-1. X-ray structures for two pairs of derivatives with a different linker were solved. Then 3-D data for the active 1j versus less active 2j, both having an imine linker (X = NH), and the respective parent of compounds with a methylene linker (X = CH₂) (1a and 2a) were discussed.