Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(alpha -meth ylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of ana logues were synthesised and evaluated for anticonvulsant activity in the ME S test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl- 2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the alpha -methyl group by either i-Pr or benzyl groups enh anced MES activity with no increase in neurotoxicity. Substitution on the p iperidine ring nitrogen led to a decrease in MES activity and neurotoxicity , while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the p iperidine ring decreased MES activity and neurotoxicity. Incorporation of t he piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, openi ng of the piperidine ring between the 1- and 6-positions gave the active no rleucine derivative 75 (ED50 = 5.8 mg kg(-1), TD50 = 36.4 mg kg(-1), PI = 6 .3). Replacement of the piperidine ring of I by cycloalkane (cyclohexane, c yclopentane, and cyclobutane) resulted in compounds with decreased MES acti vity and neurotoxicity, whereas replacement of the piperidine ring by a 4-p yridyl group led to a retention of MES activity with a comparable PI. Simpl ification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxa mide nucleus led to about a six-fold decrease in MES activity. The 2,6-dime thylanilides were the most potent compounds in the MES test in each group o f compounds evaluated, and compounds 50 and 75 should be useful leads in th e development of agents for the treatment of tonic-clonic and partial seizu res in man. (C) 2001 Editions scientifiques et medicales Elsevier SAS.