Synthesis and In Vitro Pharmacological Evaluation of 5-(Alkoxymethyl)-2-(3-alkylamino-2-hydroxypropoxy)phenylethanones Related to Acebutolol and Celiprolol.

The structure-activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2-hydroxyphenylethanone as potential ß-blockers are described. The synthesized compounds possess an isopropyl or a tert-butyl group in the hydrophilic part of the molecule and an alkoxymethyl substitution in the lipophilic moiety. The target compounds were prepared by an established four-step method and their structures were confirmed by interpretation of their UV, IR, (1) H NMR and (13) C NMR spectra, and by elemental analysis. The ß-adrenolytic efficacy of the prepared racemic compounds was determined on isolated guinea pig atria (ß1 ) and trachea (ß2 ) and expressed as pA2 values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as ß1 /ß2 ratio and the values of compounds with an alkoxy group (CH3 O, iC3 H5 O, C5 H11 O, CH2 CHCH2 O, CH3 OCH2 CH2 O) in the lipophilic part and with tert-butyl in the hydrophilic part of the molecule were found to be comparable or higher than those of the standards acebutolol and celiprolol. All evaluated substances at a concentration of 10(-7) mol/dm(3) showed also negative chronotropic effects.

Synthesis and pharmacological evaluation of the antifibrillatory effect of fluorinated derivatives of carazolol and celiprolol: comparison with propranolol.

1. The effects of carazolol, celiprolol and their respective fluorinated derivatives (FD) on electrical stimulation threshold (EST) and ventricular fibrillation threshold (VFT) were compared with those of propranolol and propranolol-FD in Langendorff-perfused rabbit hearts. 2. Carazolol, carazolol-FD, propranolol and propranolol-FD produced significant dose-dependent elevation of both EST and VFT at all tested concentration levels. In contrast, celiprolol and celiprolol-FD did not produce a significant change in either threshold. 3. On a dosage basis, the order of antifibrillatory potency of these compounds is: carazolol-FD > propranolol-FD > carazolol > propranolol > celiprolol-FD > celiprolol. 4. The results of this study seem to indicate the importance of membrane stabilizing effect for a potent antifibrillatory action of beta-adrenoceptor blocking agents. Furthermore, fluorination is demonstrated to produce more potent antifibrillatory activity than that of the parent drugs.