Synthesis Of N-substituted Benzyl Haloperidol Chlorides And Their Hydrides, Biological Activities And Structure-Activity Relationship Of The Title Compounds

Haloperidol (Hal) is a typical antipsychotic drug as butyrophenones. Previous research showed that Hal cause coronary artery dilation. But the side effects on the extrapyramidal system limited further clinic application. For that, Zheng et al utilized the piperidino in Hal to synthesize a series of N-alkyl quaternary ammonium salt derivatives of Hal and N-benzyl haloperidol chloride. Preliminary pharmacological studies showed that -all ammonium salt derivatives of haloperidol could not cause the adverse effect of extrapyramidal system, compound F₂ (N-butyl haloperidol iodide) and F₃ (N-benzyl haloperidol chloride) showed ideal vasodilative activity. Due to the vasodilative activity of F3 is higher than F₂, F₃ was selected as the lead compound. N-substituted benzyl haloperidol chlorides and their hydrides were synthesized; Using the bioassay tested the effects of target compounds on isolated thoracic aorta, coronary artery spiral strips; Using the hemodynamics studied the effects of target compounds in rats.1. Synthesis of N-substituted benzyl haloperidol chlorides and their hydrides.Haloperidol or hydrohaloperidol which was the product of haloperidol reduced by sodium borohydride reacted with different substituted benzyl chlorides in reflux condition to synthesize the corresponding quaternary ammonium salt derivatives. Their chemical structures were determined by IR,¹HNMR, MS and Elemental Analysis.Results: 6 N-substituted benzyl haloperidol chlorides and 5 hydrides were synthesized. The target compounds were white crystal, melting point were about 220-230 °C. Data of elementalanalysis and spectroscopy were coincident with character of chemical structure. Conclusions: All target compounds haven't reported before in literature.2. Effects of N-substituted benzyl haloperidol chlorides and their hydrides on contraction of isolated thoracic aorta, coronary artery spiral strips.The vasodilative effects of the target compounds were tested in vitro in rat, rabbit and porcine aortic strips. Using the bioassay to observe the effects of compounds (20 jumol/L) on dose-response curve of contraction induced by KC1(2O mmol/L) in isolated rat and rabbit thoracic aorta; The action of compounds(20 //mol/L) on the contraction induced by KC1 (40 mmol/L) in isolated porcine coronary artery spiral strips respectively.Results: F9, Fn, FBn demonstrated superior dilation activities to the lead compound on isolated thoracic aorta strips. Inhibition(%): 46.35%, 52.49%, 53.53% (rat); 28.10%, 30.01%, 29.64% (rabbit). F13, FBn demonstrated superior dilation activities to the lead compound on isolated porcine coronary artery spiral strips: 38.54%, 32.73%.Conclusion: N-substituted benzyl haloperidol chlorides and their hydrides displayed superior dilatation activities to the lead compound F3. The target compounds showed regioselectivity: Fg, Fn act on peripheral smooth muscle mostly; FBn dilate smooth muscle blood vessel on peripheral vessel and coronary artery; F13 prefer to dilating coronary artery. In addition, rat sample was more sensitive to the target compounds than rabbit sample..3. Effects of N-substituted benzyl haloperidol chlorides and their hydrides on hemodynamicsSD rats were anesthetized with i.p. injection of urethane. One catheter was inserted into the right femoral artery for measurement of arterial blood pressure. And another catheter was inserted into the left ventricle through right common carotid artery for hemodynamic measurements. Sodium chloride, Solvent polyethylene glycol-400(PEG-400), target compounds (5 mg/kg) were injected into the sublingual vein respectively. The effects of the target compounds were evaluated by the changes of blood pressure and cardiac function.Result: After injection, Fo, Fn, F9 showed stronger dilating activities and reduced the blood pressure (P<0.01), AAP(%): 40.04%, 37.67%, 32.44%; F13 and F9 cause a significant decrease in SP^ DP^ AP^ LVSP and +dp/dtmax, but there is no difference in LVSP and +dp/dtmax of Fn, F10.