CHIRAL 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-chloroph enyl)isoxazolidinyl) ethanolamines 2, 3, which can be viewed as confor mationally restrained analogs of the corresponding methyloxyiminomethy l (MOIM) beta-adrenergic antagonists 1, were synthesized from opticall y active precursors with a known absolute configuration. The structure and configuration of the intermediate and final products 2, 3 were as signed on the basis of a comparison of the H-1-NMR spectral data of al l compounds, crystallographic analysis of one of the intermediates [(2 R,5'S)-7] and knowledge of the configuration of the chiral starting co mpounds 4. The new isoxazoline derivatives 2, 3 were tested for their affinity towards beta(1)- and beta(2)-adrenoceptors by radioligand bin ding experiments; compounds showing affinity indices lower than 10 mu M on beta(1)-adrenoceptors were also assayed for their P-adrenergic ac tivity by functional tests on isolated preparations. The results showe d 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.