1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) is a potent α₁-adrenoceptor antagonist that is currently under Phase II clinic trials. However, the fast metabolism has restricted its further use. In this paper, 11 DDPH analogs were designed according to the probable metabolism pathways of DDPH, and featured the structures of halogen, methyl, and cyano groups at the 3-, or 4-position of aromatic ring A to block the hydroxylation, and one hydroxyl group at the 3-, or 4-position of aromatic ring B to extend the duration time. These compounds were synthesized in moderate to good yields from the reductive amination of substituted phenoxyacetones with substituted phenylethylamines, and fully characterized with ¹H NMR, IR, and HRMS. Biological evaluation indicated that most of the compounds exhibited strong blocking and moderate to good antihypertensive activities. It is clear that the compounds having 4-OH/3-OMe on group B exhibited higher blocking activities and longer duration time than their corresponding analogs having 4-OMe/3-OMe (and also 3-OH/4-OMe). Among them, compound 13 having bromo group at the 4-position of ring A and 4-OH/3-OMe on group B, exhibited the highest blocking activity, whereas compound 17 that had a methyl group at the 4-position of ring A and a hydroxyl group at the 4-position of ring B, was more active than potent DDPH in terms of both blocking and antihypertensive activities. In addition, the possible correlations between the blocking and antihypertensive activities are also briefly discussed.

1-（2,6-二甲基苯氧基）-2-（3,4- dimethoxyphenylethylamino）丙烷盐酸盐（DDPH）是一种强效α ₁ -肾上腺素能受体拮抗剂，它是目前在II期临床试验。但是，快速代谢限制了它的进一步使用。本文根据DDPH可能的代谢途径设计了11种DDPH类似物，并以芳香环A的3或4位上的卤素，甲基和氰基的结构为特征，以阻止羟基化。芳香环B的3或4位的羟基延长了反应时间。这些化合物由取代的苯氧基丙酮与取代的苯乙胺还原胺化而以中等至良好的产率合成，并用^1进行了全面表征1 H NMR，IR和HRMS。生物学评估表明，大多数化合物表现出较强的阻断作用，并具有中等至良好的降压活性。显然，与它们相应的具有4-OMe / 3-OMe（以及3-OH / 4-OMe）的类似物相比，在B组上具有4-OH / 3-OMe的化合物表现出更高的阻断活性和更长的持续时间。其中，在环A的4-位具有溴基且在基团B上具有4-OH / 3-OMe的化合物13表现出最高的阻断活性，而化合物17在封闭和降压活性方面，在环A的4位具有甲基而在环B的4位具有羟基的维生素D9的活性比有效的DDPH高。此外，还简要讨论了阻断和降压活动之间的可能相关性。