Novel Phenoxyalkylamine Derivatives. V. Synthesis, α-Blocking Activity and Quantitative Structure-Activity Analysis of α-[(Phenoxyethylamino) propyy]-α-phenyyacetonitrile Derivatives

Abstract

α-[(Phenoxyethylamino) propyy]-α-phenylacetonitrile derivatives possessing various substituents on the benzene ring (A ring) at the phenylacetonitrile moiety, on the quaternary carbon atom and on the benzene ring (B ring) at the phenoxy moiety, and exhibiting various degrees of ablocking activity, were prepared. The variations in the activity were analyzed qualitatively as well as quantitatively by using physicochemical substituent parameters and a regression technique. The effect of substituents on the A ring was rationalized in terms of a parabolic function of their hydrophobic parameter. As regards substituents on the quaternary carbon atom, alkyl groups were desirable for high activity. The effects of substituents on the B ring were such that an optimum hydrophobic condition exists and that an alkoxy substituent at the o-position as well as smaller substituents at the m-and p-positions are favorable for high activity. The analysis for the combined series of analogs where substituents on the A and B rings are varied showed the existence of an optimum hydrophobicity for the whole molecule for the transport process of the molecule, besides above-mentioned various position-specific structural effects.