Simşek Rahime, Safak Cihat, Erol Kevser, Ataman Sule, Ulgen Mert, Linden Anthony
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
Arzneimittelforschung. 2003;53(3):159-66.
The objective of this study was to synthesise new condensed 1,4-dihydropyridine derivatives and investigate their calcium channel blocking activity. In addition, the in vitro hepatic microsomal bio-transformation of one hexahydroquinoline derivative was studied, 2,6,6-Trimethyl-3-carbmethoxy (carbethoxy)-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives were synthesised bymodified Hantzsch synthesis. 1,3,4,5,6,7,8,9-octahydro-7,7-dimethyl-9-arylfuro [3,4-b]quinoline-1,8-dione derivatives were synthesised the reaction of hexahydroquinoline derivatives with pyridinium bromide perbromide. The calcium antagonistic activities of the compounds were determined by tests performed on isolated rat ileum and lamb carotid artery. In vitro hepatic biotransformation of one compound was studied in rat microsomes. Although compounds 3, 18 and 28 showed promising relaxant activity, they were less active than nicardipine (CAS 55985-32-5) in isolated rat ileum. In all studied concentrations, compounds 5 and 20 were more active than nicardipine in lamb carotid artery. These compounds showed high tissue selectivity compared with nicardipine. In addition, in vitro hepatic microsomal biotransformation of compound 2 produced its lactone derivative (compound 34). This metabolite was verified by HPLC. In the hexahydroquinoline series, the compounds having ortho substituted phenyl substituent were more active than the meta isomers. Lactone derivatives were found less active than hexahydroquinoline derivatives in respect to calcium antagonistic activity.
本研究的目的是合成新的稠合1,4 - 二氢吡啶衍生物，并研究其钙通道阻断活性。此外，还研究了一种六氢喹啉衍生物的体外肝微粒体生物转化，通过改良的汉茨希合成法合成了2,6,6 - 三甲基 - 3 - 甲氧羰基（乙氧羰基）- 4 - 芳基 - 5 - 氧代 - 1,4,5,6,7,8 - 六氢喹啉衍生物。通过六氢喹啉衍生物与过溴化吡啶鎓的反应合成了1,3,4,5,6,7,8,9 - 八氢 - 7,7 - 二甲基 - 9 - 芳基呋喃并[3,4 - b]喹啉 - 1,8 - 二酮衍生物。通过对离体大鼠回肠和羊颈动脉进行测试来测定化合物的钙拮抗活性。在大鼠微粒体中研究了一种化合物的体外肝生物转化。尽管化合物3、18和28显示出有前景的舒张活性，但在离体大鼠回肠中它们的活性低于尼卡地平（CAS 55985 - 32 - 5）。在所有研究浓度下，化合物5和20在羊颈动脉中的活性高于尼卡地平。与尼卡地平相比，这些化合物表现出高组织选择性。此外，化合物2的体外肝微粒体生物转化产生了其内酯衍生物（化合物34）。该代谢产物通过高效液相色谱法得到验证。在六氢喹啉系列中，具有邻位取代苯基取代基的化合物比间位异构体更具活性。就钙拮抗活性而言，发现内酯衍生物的活性低于六氢喹啉衍生物。
