Potential anticonvulsants: Some derivatives and analogues of 2-propylpentanoic acid

Abstract

Reaction of 2-(ethoxycarbonylamino)ethanol with 2-propylpentanoyl chloride gave the ester III. N-(4-Piperidinyl)-2-propylpentanamide (V) was prepared via the 1-benzyl-4-piperidinyl derivative IV and was acylated with ethanesulfonyl chloride and 2-propylpentanoyl chloride to give the amides VI and VII. Malonic ester syntheses afforded diethyl 2-ethyl- and 2-propyl-2-(2-(methylthio)ethyl)malonate VIII and XIII which were hydrolyzed and decarboxylated to the acids X and XV which, in turn, were transformed to the amides XII and XVII. 3-Thiapentanenitrile was alkylated with propyl bromide to the nitrile XIX which was hydrolyzed to the acid XX and the amide XXI. The acids X, XV, and XX, and the amides XII, XVII, and XXI are analogues of the anticonvulsant agents valproic acid (I) and valpromide (II). Compounds XX (V⁄FB-14 721) and XXI (V⁄FB-14 722) potentiate, in doses in which they ìper seî are ineffective as anticonvulsants in mice, significantly the anticonvulsant effect of diazepam.