Ashwood V A, Cassidy F, Evans J M, Gagliardi S, Stemp G
SmithKline Beecham Pharmaceuticals, Harlow, Essex, England.
J Med Chem. 1991 Nov;34(11):3261-7. doi: 10.1021/jm00115a015.
The synthesis and oral antihypertensive activity in conscious spontaneously hypertensive rats of two new series of compounds related to the prototype potassium channel activator cromakalim (1) are described. In the first series, replacement of the benzopyran oxygen atom by nitrogen or methylene led to the 1,2,3,4-tetrahydroquinoline 12 and 1,2,3,4-tetrahydronaphthalene 13, which were both less active than 1. However, in contrast to the equivalent activity found previously for 1 and its dehydrated analogue 28, the dihydronaphthalene 27 was found to be more active than 13. In the second series, replacement of the C(4) amide nitrogen atom in acyclic amides related to cromakalim by methylene gave ketone 16 that was less active than the corresponding amide 15. However, replacement of the 4-acetonyl substituent in 16 by N,N-dimethylacetamido as in compound 22 resulted in a marked enhancement in activity. The compounds described in this paper thus illustrate the importance of the benzopyran oxygen and C(4) substituent on antihypertensive activity in the cromakalim series of potassium channel activators.
本文描述了与原型钾通道激活剂色满卡林（1）相关的两个新系列化合物在清醒自发性高血压大鼠中的合成及其口服抗高血压活性。在第一个系列中，用氮原子或亚甲基取代苯并吡喃的氧原子得到了1,2,3,4 - 四氢喹啉12和1,2,3,4 - 四氢萘13，二者活性均低于1。然而，与之前发现的1及其脱水类似物28的等效活性不同，二氢萘27的活性比13更高。在第二个系列中，用亚甲基取代与色满卡林相关的无环酰胺中的C(4)酰胺氮原子得到酮16，其活性低于相应的酰胺15。然而，如化合物22那样用N,N - 二甲基乙酰胺基取代16中的4 - 丙酮基会导致活性显著增强。因此，本文所述化合物表明了苯并吡喃氧原子和C(4)取代基对色满卡林系列钾通道激活剂抗高血压活性的重要性。
