SYNTHESIS AND ANTIHYPERTENSIVE ACTIVITY OF 4-(1,2-DIHYDRO-2-OXO-1-PYRIDYL)-2H-1-BENZOPYRANS AND RELATED-COMPOUNDS, NEW POTASSIUM CHANNEL ACTIVATORS
SYNTHESIS AND ANTIHYPERTENSIVE ACTIVITY OF 4-(1,2-DIHYDRO-2-OXO-1-PYRIDYL)-2H-1-BENZOPYRANS AND RELATED-COMPOUNDS, NEW POTASSIUM CHANNEL ACTIVATORS
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DOI：
10.1021/jm00164a005
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发表时间：
1990-02-01
影响因子：
7.3
通讯作者：
GERICKE, R
中科院分区：
文献类型：
--
作者：
BERGMANN, R;GERICKE, R
本文报道了4-（1，2-二氢-2-氧代-1-吡啶基）-2H-1-苯并吡喃-3-醇类化合物的合成及其抗高血压活性。未取代的吡啶酮加合物先导化合物7 e是高活性的，吡啶酮环上的取代基导致活性降低。在C-6位的强吸电子取代基是最佳活性所必需的。当2-吡啶酮环被其它杂环如4-吡啶二酮、嘧啶酮、哒嗪酮、吡嗪酮和1，4-丁磺内酰胺取代时，活性得以保持。3-羟基官能团的去除（→17 a）不会显著降低活性。从色原烷醇中除去水导致色烯的形成，色烯是已知的最有效的抗高血压药之一。在4-（2-氧代-1-吡咯烷基）苯并二氢吡喃-3-醇系列中研究了不同取代基，特别是杂环C-6取代基的影响。在3-羟基上与短链酸酯化的色满醇保持其活性。色烯双键的双氧化也产生活性化合物。环氧化物22的重排产生3-酮化合物23和烯醇衍生物25。酮23 a的还原产生顺式苯并二氢吡喃醇7ab沿着其反式异构体7 e。在自发性高血压大鼠中以1 mg/kg的剂量测试所有化合物的口服抗高血压活性;对于选定的化合物，测定ED 30值以及抗高血压作用的持续时间。4-（1，2-二氢-2-氧代-1-吡啶基）-2，2-二甲基-2H-1-苯并吡喃-6-甲腈（18 a）正在开发中，作为冠状血管扩张剂和治疗心绞痛的药物。
The synthesis and antihypertensive activity of 4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran-3-ols are described. The unsubstituted pyridone adduct lead compound 7e is highly active, with substituents on the the pyridone ring leading to a decrease in activity. Strongly electron-withdrawing substituents at the C-6 position are required for optimal activity. When the 2-pyridone ring is replaced by other heterocycles such as 4-pyridione, pyrimidone, pyridazinone, pyrazinone, and 1,4-butanesultam, the activity is maintained. The removal of the 3-hydroxy function (.fwdarw. 17a) does not significantly reduce the activity. The elimination of water from the chromanols leads to the formation of the chromenes, which are among the most potent antihypertensives known. The influence of diverse substituents, in particular heterocyclic C-6 substitutents, was investigated in the 4-(2-oxo-1-pyrrolidinyl)chroman-3-ol series. Chromanols esterified at the 3-hydroxy group with short-chain acids, maintain their activity. The expoxidation of the chromene double bond also produces active compounds. The rearrangement of the expoxides 22 produces the 3-keto compounds 23 and the enol derivatives 25. The reduction of the ketone 23a produces cis-chromanol 7ab along with its trans isomer 7e. All compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats with a dose of 1 mg/kg; for selected compounds ED30 values as well as the duration of the antihypertensive effect were determined 4-(1,2-Dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (18a) is under development as a coronary vasodilator and a drug for treating angina pectoris.