Conformationally restrained β -blocking oxime ethers: synthesis and β -adrenergic properties of diastereoisomeric anti and syn 2-(5-isoxazolidinyl)ethanolamines

The diastereoisomeric N-isopropyl- and N-t-butyl-substituted 2-(5'-(3'-phenyl)- and 2-(5'-(3'-isopropyl)-isoxazolidinyl)ethanolamines (5-8), which can be viewed as conformationally restrained analogs of the corresponding β-blocking oxime ethers 10 and 11, were synthesized. The relative configurations of 5-8 were assigned by 1H-NMR studies and by the determination of the solid-state structure of one of the new compounds (6a). The new isoxazoline derivatives (5-8) were tested both by radioligand binding assays and by functional tests on isolated preparations. Compounds 5a-8a were found to retain, albeit to a lower extent, the β-blocking properties of the corresponding oxime ethers 10a and 11a, thus indicating that these last compounds may prove to be still capable of interacting with the β-receptors, even if their C = NOCH 2 portion is constrained in a conformationally semi-rigid isoxazoline structure. Possible rationalizations of the results were sought by comparing the conformations and the molecular reactivity of model compounds of the isoxazolines 5-8 and of the oxime ethers 10 and 11.