1, 5-Benzoxathiepin Derivatives. III. Optical Resolution of Methyl (±)-cis-3-Hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3, 4-dihydro-2H-1, 5-benzoxathiepin-4-carboxylate Hydrochloride ((±)-CV-5197) with Selective 5-Hydroxytryptamine₂(5-HT₂)-Antagonistic Activity

Abstract

The selective 5-HT₂-receptor antagonist, methyl (±)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3, 4-dihydro-2H-1, 5-benzoxathiepin-4-carboxylate hydrochloride ((±)-CV-5197) was resolved in high optical purity using (R)-(-)- and (S)-(+)-1, 1'- binaphthyl-2, 2'-diyl hydrogen phosphates ((R)-(-)- and (S)-(+)-BNP). The absolute configuration of (+)-CV-5197 was determined to be 3S, 4R by X-ray crystallographic analysis. In the binding assay, it was demonstrated that (+)-CV-5197 was a more active isomer (IC₅₀=23 nM±6.3) for 5-HT₂ receptor binding than the (-)-enantiomer (IC₅₀=1600 nM±82). (+)-CV-5197 completely inhibited the 5-HT-induced contraction of the isolated pig coronary artery at a concentration of 3×10^-7 M, whereas (-)-CV-5197 showed little antagonistic activity, even at 3×10^-4 M. Thus, the agreement between the results of the binding assays and the biological activities for the 3S, 4R enantiomer of CV-5197 suggeste that its physiological activiy is probaly exerted through 5-HT₂-receptor antagonism.