Synthesis, pharmacological activity, and chromatographic enantioseparation of new heterocyclic compounds of the aryloxyaminopropanol type derived from 4-hydroxyphenylalkanones

In the paper, a series of six pharmacologically active compounds (beta-adrenolytics) derived from 4-hydroxyphenylethanone and 4-hydroxyphenylpropan-1-one are reported. The compounds incorporate pyrrolidin-1-yl and 4-methylpiperazin-1-yl substituents in the hydrophilic part of the molecule and ethoxymethyl and methoxyethoxymethyl side chains on the aromatic ring in the lipophilic moiety. They were prepared by a four-step synthesis from 4-hydroxyalkanones via chloromethyl, alkoxymethyl, and oxirane intermediates. The purity of the target compounds was checked by TLC and their structures were confirmed by the interpretation of the IR, UV, H-1 NMR, and C-13 NMR spectra. The pharmacological evaluation of the obtained compounds confirmed their vasodilatory and specific antiisoprenaline activities. All evaluated compounds at conc. 10(-6) mol dm(-3) inhibited vasoconstrictory effect of phenylephrine (8.22-33.7%) on isolated rat aorta. The ability to inhibit positive chronotropic effect of isoprenaline was observed on isolated spontaneously beating rat's atria after pre-treatment with the evaluated compounds at conc. 10(-7) and 10(-6) mol dm(-3). The calculated pA(2) values of specific antagonistic effect against isoprenaline, related to their apparent beta-adrenolytic activity, ranged between 6.54 and 7.57. The value for the standard compound carvedilol was 8.15 +/- 0.22. The majority of the evaluated compounds at conc. 10(-6)-10(-7) mol dm(-3) also showed negative chronotropic effect on the basic heart rate of atria. Enantioseparation of the prepared compounds was performed by chiral HPLC on an amylose tris(3,5-dimethylphenylcarbamate) column (Chiralpak AD) and a native teicoplanin column (Chirobiotic T). The chromatographic characteristics as retention, separation, and resolution factors were reported. [GRAPHICS] .