Chiral 2-(3'-(5'-p-chlorophenyl)isoxazolidinyl)ethanolamines as conformationally restrained analogs of methyloxyiminomethyl (MOIM) beta-adrenergic antagonists: Synthesis, configuration and beta-adrenergic properties

The chiral N-isopropyl- and N-t-butyl-substituted 2-(3'-(5'-p-chlorophenyl)isoxazolidinyl) ethanolamines 2, 3, which can be viewed as conformationally restrained analogs of the corresponding methyloxyiminomethyl (MOIM) beta-adrenergic antagonists 1, were synthesized from optically active precursors with a known absolute configuration. The structure and configuration of the intermediate and final products 2, 3 were assigned on the basis of a comparison of the H-1-NMR spectral data of all compounds, crystallographic analysis of one of the intermediates [(2R,5'S)-7] and knowledge of the configuration of the chiral starting compounds 4. The new isoxazoline derivatives 2, 3 were tested for their affinity towards beta(1)- and beta(2)-adrenoceptors by radioligand binding experiments; compounds showing affinity indices lower than 10 mu M on beta(1)-adrenoceptors were also assayed for their P-adrenergic activity by functional tests on isolated preparations. The results showed that the cyclic derivatives 2, 3 possess a capacity to interact with beta-receptors which is clearly lower than that of the corresponding MOIM analogs 1.