Novel Phenoxyalkylamine Derivatives. IV Synthesis, Ca²⁺-Antagonistic Activity and Quantitative Structure Activity Analysis of α-Isopropyl-α-[3-[3-(3-methoxyphenoxy) propylamino] propyl]-α-phenylacetonitrile Derivatives

Abstract

α-Isopropyl-α-[3-[3-(3-methoxyphenoxy) propylamino] propyl] -α-phenylacetonitrile derivatives containing various substituents on the benzene ring (A ring) at the phenylacetonitrile moiety were prepared, and their Ca²⁺-antagonistic activity was evaluated. Among these compounds, the N-Me derivatives with m-OMe, p-F, p-Cl, 3, 4-(OMe) ₂ and 3, 5-(OMe) ₂ substituents on the A ring were found to show higher Ca²⁺-antagonistic activity than verapamil. The effect of substituents on the A ring was examined quantitatively using physicochemical substituent parameters and regression analysis. The analysis showed that substituents with a π value close to zero are favorable to the activity and that optimum steric conditions exist for m-and p-substituents, corresponding to those of m-OMe and p-F or p-Cl. The analysis for the whole series of analogs where substituents on the A ring, the benzene ring (B ring) at the phenoxy moiety and the quaternary carbon atom are simultaneously varied suggested that there is an optimum molecular hydrophobicity, perhaps participating in the transport process to the site of action, besides position-specific steric and hydrophobic effects.