Structure-activity relationships in 1,4-benzodioxan-related compounds. 4. Effect of aryl and alkyl substituents at position 3 on alpha-adrenoreceptor blocking activity.

The observation that the insertion of a phenyl ring at position 3 of WB 4101 (1) afforded a potent and selective alpha 1-adrenoreceptor antagonist, phendioxan (2), prompted us to further investigate that position of the 2,3-dihydro-1,4-benzodioxin moiety. Thus the 3-phenyl of 2 was replaced by methyl, isopropyl, cyclohexyl, or para-substituted phenyl groups either in a cis or a trans relationships affording compounds 3-17 and 58. The structure of these new derivatives was assigned on the basis of the coupling constant of hydrogens at positions 2 and 3 and confirmed by a crystallographic study. The blocking activity and relative selectivity of 3-17 on alpha 1- and alpha 2-adrenoreceptors were evaluated in the isolated rat vas deferens. The results were compared with those obtained for 1 and 2. All the compounds, with the exception of isopropyl and cyclohexyl derivatives 5-8, were effective alpha 1-adrenoreceptor antagonists with a significant alpha 1/alpha 2-selectivity. The lipophilic and/or electronic character of para substituents of the 3-phenyl ring does not alter markedly the affinity toward alpha 1-adrenoreceptors. However, the 3-p-tolyl derivative 10 was slightly more potent and even more selective than 2.