3,4-DIHYDRO-3-AMINO-2H-1-BENZOPYRAN DERIVATIVES AS 5-HT1A RECEPTOR LIGANDS AND POTENTIAL ANXIOLYTIC AGENTS .1. SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP STUDIES

A series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives were prepa red in order to determine the necessary structural requirements for go od affinity for 5-HT1A receptors and high selectivity versus other rec eptors. Modifications of the extracyclic amino substituents, the lengt h of the alkyl side chains, and their substituents were explored. The best compounds (9g, 9k, 15b, 15d) possess imido or sulfonamido functio nal groups with, a preferential length of four methylenes for the side chain. After resolution, the dextrorotatory enantiomers showed better affinity and selectivity for 5-HT1A receptors. These compounds have b een proven to be full agonists. 9g and its enantiomers showed anxiolyt ic activity in vivo in various comportemental models. The compound (+) -9g is currently under clinical investigation.