Synthesis of 2-piperidinecarboxylic acid derivatives as potential anticonvulsants

Abstract

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-CF 3 14, ED 50 = 29 mg/kg; 3-F 16, ED 50 = 31 mg/kg; and 3-CF 3 17, ED 50 = 24 mg/kg]. The most active compounds in the MES test in mice were the 2,6-dimethylanilides [ (R,S)- 34, ED 50 = 5.8 mg/kg; (R)- 35, ED 50 = 5.7 mg/kg; and (S)- 36, ED 50 = 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 and 34 led to a decrease in the MES activity. In the N-(α-methylbenzyl)-2-piperidinecarboxamides, 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