Clark R D, Caroon J M, Repke D B, Strosberg A M, Bitter S M, Okada M D, Michel A D, Whiting R L
J Med Chem. 1983 Jun;26(6):855-61. doi: 10.1021/jm00360a013.
Forty-one 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones were prepared for antihypertensive screening in the spontaneously hypertensive rat (SHR). For the 9-(2-indol-3-ylethyl) series, the parent compound, 9-(2-indol-3-ylethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (21), was the most potent antihypertensive agent. Substitution of lower alkyl groups on the spirolactam ring gave compounds close in activity to 21, while substitution with large alkyl or aryl groups led to a significant decrease in activity. Ring-opened analogues of 21 that contained the same functionality were markedly less active. Several 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones substituted at the 9 position with 1,4-benzodioxan-2-ylmethyl, 1,4-benzodioxan-2-ylhydroxyethyl, and 2-phenylethyl groups also demonstrated significant activity. Compound 21 was chosen for a detailed pharmacological evaluation. Its antihypertensive activity appears to be predominantly due to peripheral alpha 1-adrenoceptor blockade.
制备了41种9-取代的1-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮，用于在自发性高血压大鼠（SHR）中进行抗高血压筛选。对于9-(2-吲哚-3-基乙基)系列，母体化合物9-(2-吲哚-3-基乙基)-1-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮（21）是最有效的抗高血压药物。在螺内酰胺环上取代低级烷基得到的化合物活性与21相近，而用大烷基或芳基取代则导致活性显著降低。含有相同官能团的21的开环类似物活性明显较低。几种在9位被1,4-苯并二恶烷-2-基甲基、1,4-苯并二恶烷-2-基羟乙基和2-苯乙基取代的1-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮也表现出显著活性。选择化合物21进行详细的药理学评价。其抗高血压活性似乎主要归因于外周α1-肾上腺素能受体阻滞。
