Synthesis and Anxiolytic Activity of N-Substituted Cyclic Imides (1R^*, 2S^*, 3R^*, 4S^*)-N-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-2, 3-bicyclo[2.2.1]heptanedicarboximide (Tandospirone) and Related Compounds

Abstract

A series of cyclic imides bearing a ω-(4-aryl and 4-heteroaryl-1-piperazinyl)alkyl moieties was synthesized and tested in vivo for anxiolytic activity. The in vitro binding affinities of these compounds were also examined for 5-HT_1A receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, (1R^*, 2S^*, 3R^*, 4S^*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2, 3-bicyclo[2.2.1]heptanedicarboximide (1 : tandospirone), was found to be equipotent with buspirone in its anxiolytic activity and more anxio-selective than buspirone and diazepam. Tandospirone (1) is currently undergoing clinical evaluation as a selective anxiolytic agent.