| Calcium-channel blocker is a kind of widely used antihypertensive agents, it can inhibit transmembrane inward calcium fluxes and intracellular calcium release selectively, reduce the intracellular free calcium concentration and its utilization rate, depress the ATPase activity, lower the cardiaccontractility, relax the smooth muscle cells and dilate the vascular ,then bring down the peripheral ascular resistance ,thus lower blood pressure effectively. Dihydropyridine calcium channel blocker is widely accepted as a drug of first choice for patients with hypertension, and is particularly appropriate for the one who is accompanied with angina pectoris due to coronary heart disease. As for remarkable curative effect and few side-effects, it has drawn a great deal of attention.In recent years, Nitric Oxide (NO)-donating antihypertensive drugs have attracted widely attention, because of its important role in maintaining angiotasis, regulating blood pressure and hemodynamics. Supplementing NO may become a choice for treating hypertension disease. The main exogenous originates of NO are NO donors, among these there are two major kinds which are mostly studied, furoxan and nitrate ester, they have good NO-releasing ability and participate in regulation of multiple physiological functions.Based on the research described above, through the C-3 carboxyl, furoxan or nitrate ester moieties were coupled to 5-(methoxy-carbonyl)-2,6-dimethyl-4-(3-nitro- -phenyl)-1,4-dihydropyridine-3-carboxylic acid(M). Synthesized eight kinds of nitric oxide donating compounds in all, the structure of all the compounds were confirmed by 1H-NMR. Their NO-releasing ability were determined by Griess Regents in vitro.Objective:In order to search for the lead compounds which are most effective and with low toxical antihypertensive agents, eight NO-donating dihydropyridine derivatives were synthesized, and their NO-releasing ability were assessed in vitro.Methods:(1) 3,5-dimethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine(N) was synthesized from m-nitrobenzaldehyde, methyl acetoacetate and ammonium bicarbonate. Hydrolyzed N with sodium hydroxide, then got5-(methoxy- carbonyl)- 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyr--idine-3-carboxylic acid(M)(2) 3,4-bisphenylsulfonylfuroxan was prepared by etherification, oxidation and cyclization from thiophenol, six different glycol was respectively joined by an ether linkage to 3,4-bisphenylsulfonylfuroxan.Thus,six intermediates were obtained. Conjugating intermediate(M) to different intermediates with esterification by using DCC as condensing agent, six target compoundsⅠa~Ⅰf were obtained. Conjugate intermediate(M) to 1,4-dibromobutane and react with silver nitrate afterwards, then get nitrate ester compoundⅡa. The sodium salt of (M) reacts with 2-nitre oxygen chloroethane can get nitrate ester compoundⅡb.(3) A soution (0.025 mmol/L) of appropriate compound was prepared at 37℃,using phosphate buffer (pH 7.4) in presence of excess L-cysteine.The reaction mixture was taken at different time and determined by Griss reagent. Absorbance was detected at 540 nm.Results:(1) Six new Furoxan nitrogen oxides and one nitrate NO-donating compound were successfully synthesized. The structure of all the compounds were confirmed by 1H-NMR.(2) The results of NO-release in vitro experiment indicated that six compounds obviously released NO at the initial 1.5h.At a later time, the release was stable. The maximum concentrations (Cmax) of NO-release in vitro were 0.843,0.756,0.724, 0.788,0.761, 0.957mg/L respectively.Conclusion: Target compounds synthesized are novel compounds, and all of them could release NO in vitro effectively. The ability of NO-release followed below order:Ⅰf>Ⅰa>Ⅰd>Ⅰe>Ⅰb>Ⅰc.
|
PDF Full Text Request