Synthesis of 2-piperidinecarboxylic acid derivatives as potential anticonvulsants

Article abstract of DOI:10.1016/S0223-5234(99)80072-5

A variety of 2-piperidinecarboxamides were synthesized and evaluated for anticonvulsant activity using the MES and sc PTZ tests in mice and rats. Neurotoxicity was determined by the rotorod test. Several N-(benzyl)-2- piperidinecarboxamides exhibited potent MES activity in mice [2-CF³ 14, ED₅₀ = 29 mg/kg; 3-F 16, ED₅₀ = 31 mg/kg; and 3-CF₃ 17, ED₅₀ = 24 mg/kg]. The most active compounds in the MES test in mice were the 2,6- dimethylanilides [(R,S)-34, ED₅₀ = 5.8 mg/kg; (R)-35, ED₅₀ = 5.7 mg/kg; and (S)-36, ED₅₀ = 14.8 mg/kg]. The enantiomer (S)-36 was about two-fold less potent in the MES test than (R)-35 and also was less neurotoxic. Acylation of the piperidine ring nitrogen of 12 anal 34 led to a decrease in the MES activity. In the N-(α-methylbenzyl)-2-piperidine-carboxamides, the stereochemistry at either the 2-position of the piperidine ring or at the α- position of the N-(α-methylbenzyl) group does not significantly affect MES activity.