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DOI: 10.1055/s-0031-1297089
Synthesis, Evaluation of the Calcium Antagonistic Activity and Biotransformation of Hexahydroquinoline and Furoquinoline Derivatives
Publication History
Publication Date:
25 December 2011 (online)
Summary
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 biotransformation 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 by modified 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.
Zusammenfassung
Synthese, Evaluierung der Kalzium-antagonistischen Wirkung und Metabolismus von Hexahydrochinolinand Furochinolin-Derivaten
Es wurden neue 1,4-Dihydropyridin-Derivative synthesiert und auf Kalziumantagonistische Wirkung untersucht. Außerdem wurde die hepatische mikrosomale Biotransformation eines Hexahydrochinolin-Derivates an Ratten untersucht. Die 2,6,6-Trimethyl-3-carbmethoxy (carbethoxy)-4-aryl-5-oxo-1,4,5,6,7,8-hexahydrochinolin-Derivate wurden nach der modifizierten Hantzsch-Methode synthesiert und die 1,3,4,5,6,7,8,9-Obtahydro-7,7-dimethyl-9-arylfuro[3,4-b]chinolin-1,8-dion-Derivate durch Reaktion von Hexahydrochinolin-Derivaten mit Pyridiniumbromid-Perbromid. Die Kalzium-antagonistischen Eigenschaften der Verbindungen wurden am isolierten Kaninchenileum und an der Lammkarotis untersucht. Die hepatische Biotransformation wurde in vitro an Rattenmikrosomen evaluiert.
Der Verbindungen 3, 18 und 28 zeigten vielversprechende relaxierende Wirkung, obwohl sie weniger wirksam waren als Nicardipin (CAS 55985-32-5). An der Lammkarotis waren die Verbindungen 5 und 20 aktiver als Nicardipin. Diese Verbindungen besaßen im Vergleich zu Nicardipin hohe Gewebeselektivität. Die Verbindungen mit ortho-substituiertem Phenyl-Substituenten waren aktiver als die meta-Isomere. Die Hexahydrochinolin-Derivate zeigten größere Wirkung als die Lakton-Derivate.