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

Abstract

In the paper, a series of six pharmacologically active compounds (β-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, 1H NMR, and 13C 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 pA2 values of specific antagonistic effect against isoprenaline, related to their apparent β-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.