Conformationally restrained β-blocking oxime ethers. 2. Synthesis and β-adrenergic properties of diastereoisomeric anti and syn 2-(5′-(3′-aryl-substituted)isoxazolidinyl)-N-alkylethanolamines

Abstract The diastereoisomeric 2-(5′-(3′-aryl)isoxazolidinyl)ethanolamines 1c-h-4c-h were synthesized as analogs of the corresponding β-blocking isoxazolines unsubstituted on the aromatic ring 1a-4a , with the aim of checking the effects on the adrenergic properties of the insertion of a methoxy group or a chlorine atom in the ortho, meta or para position of the phenyl ring of 1a-4a . The relative configurations of 1c-h-4c-h were assigned on the basis of their 1 H-NMR spectral characteristics. The new isoxazolines 1c-h-4c-h were tested for their affinity towards β 1 - and β 2 -adrenoceptors by radioligand binding experiments; compounds showing the highest affinity were also assayed for their β-adrenergic activity by functional tests on isolated preparations. The results showed that most of the new compounds ( 1c-h-4c-h ) possess a slightly better capacity to interact with the β-receptors, compared with the corresponding analogs unsubstituted on the phenyl ring ( 1a-4a ), and that the substitution that leads to compounds with the best properties is the one with the chlorine atom. Quantum mechanical calculations carried out in order to look for possible correlations between the β-adrenergic properties and the conformational and electronic characteristics induced by the presence of the substituents on the phenyl ring of compounds of types 1–4 do not suggest any reasonable explanation for the trend of the affinity data.