Hexahydrochinolinone mit calciummodulatorischem Effekt ‐ Synthese und pharmakologische Wirkung

Abstract

The hexahydroquinolinones 4a-I were prepared by Knoevenagel-reaction of cyclohexandione (1) and the aromatic aldehydes 2a-I and subsequent cyclising Michael-addition with methyl beta-aminocrotonate 3. The new compounds are characterized by IR-, 1H-NMR-and mass spectroscopy. At the electrically stimulated left guinea pig-atrium structures of type 4 show marked positive inotropic effects, whereas BaCl2-induced contractions of the guinea pig-ileum are supressed dose-dependently with activity rates comparable to those of nifedipine. Furthermore, relaxation of KCl-stimulated aorta-musculature is observed.

Fused 1,4-Dihydropyridines as Potential Calcium Modulatory Compounds

“…Various 4-arylhexahydroquinoline derivatives showed positive inotropic effects in stimulated left guinea pig atrium, whereas barium chloride induced contractions are suppressed in a dose dependently manner in guinea pig ileum [67]. Similar results were obtained in 5-oxo-1,4-indenopyridine (I) and furoquinoline (II) derivatives [66,79].…”

“…Active derivatives can be obtained by replacing ester groups with other electron drawing substituents such as acyl, amide, nitrile, nitro, and sulfonyl [45,46,49,53,[64][65][66][67]. Many studies defined the structure-activity relationships of 1,4-DHPs.…”

Electrospray ionisation and ion‐trap fragmentation of substituted 3,4‐dihydro‐2(1H)‐pyridin‐2‐ones

“…3 On the other hand, it has been previously determined that cyclohexanone and lactone rings fused to the 1,4-DHP moiety result in a striking effect on the entry of calcium ions into the intracellular space (calcium agonist effect). 4 We have recently conducted a structural study based on X-ray analysis and semiempirical (AM1) calculations of 4-aryl-substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones and hexahydrofuro[3,4-b]-2(1H)-pyridones. 5 These compounds fulfil, from the structural point of view, all the requirements needed for exhibiting pharmacological effects as calcium channel modulators.…”

“…After crystallisation from ethanol, compounds 1a±i and 2a±i were obtained as crystalline solids in 76±88% yield. 2,3,4,5,-2(1H)-pyridones (3a±c) were obtained by refluxing for 12 h equimolecular amounts of the corresponding 2(1H)-pyridone 1 with N-bromosuccinimide in anhydrous chloroform. The reaction mixture was cooled and the solid precipitated was further purified by recrystallisation from ethanol.…”

2,6‐Diaryl‐4,4‐disubstituted 1,4‐dihydropyridines: Source for spiro heterocycles

“…Indeed dihydropyridine and its derivatives were used in the treatment of cardiovascular diseases such as angina, hypertension, or arrhythmia [2]. On the other hand 1,4-dihydropyridine fused to a carbocyclic ring exhibited calcium modulatory properties [3,4]. On the basis of this, it was thought to develop spiro heterocycles from 1,4-dihydropyridines.…”