Novel Phenoxyalkylamine Derivatives. IV. : Synthesis, Ca^<2+>-Antagonistic Activity and Quantitative Structure-Activity Analysis of α-Isopropyl-α-[3[3-(3-methoxyphenoxy)propylamino]propyl]-α-phenylacetonitrile Derivatives

概要

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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 Ca^<2+>-antagobistic activity was evaluated. Among these compounds, the N-Mederivatives 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 Ca^<2+>-antagonistic activity than varapamil. 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.
社団法人日本薬学会の論文
1988-10-25