Design, Synthesis Of Anti-Angina Drug Ranolazine And Its No-Donating Derivatives

Ranolazine is a partial fatty acid oxidation inhibitor, which can reduce the heart oxygen requirement through the enzyme control action, improve the imbalance between oxygen supply and demand, and relieve the symptoms of partial myocardial ischemia. In addition, Ranolazine could also increase cardiac oxygen utilization ratio through regulating the body's metabolism, enhancing the glucose oxidation while reducing oxidation of free fatty acids. The difference of Ranolazine and other medicine lies in its anti-angina effect without affecting the heart rate or the blood pressure. Ranolazine became the first authorized medicine for chronic angina pectoris in 20 years when it was obtained the FDA's authorization on January 27, 2006. Ranolazine is likely to become the adjuvant therapeutic drug for treatment of chronic stable angina pectoris, which is recommended by American Heart Association and the American Heart Association (AHA-ACC).Clinical trials showed that the NO production decreased obviously in coronary artery of angina pectoris patient. Supplementing NO may become a choice for treating ischemic heart disease. Administering the exogenetic NO with physiological dosage to blood stream or local tissue and damaged cell spot, which may help to maintain normal NO demand, and keep the stability of the environment within the blood vessels. The main exogenous originates of NO is NO donor. Among NO-donating cardiovascular drugs, 3, 4-bisphenylsulfonyl-1, 2, 5-oxadiazole-2-oxides is an important Furoxan category NO donor. Recent results have shown that Furoxan derivatives are able to activate the soluble guanylate cyclase by releasing nitric oxide under the action of thiol cofactors, so it shows a variety of biological activities, such as vasodilation and the inhibition of platelet aggregation. Thus, the furoxan system is useful in designing NO-releasing drugs by incorporating with many drugs and active molecules.Based on the research described above, through the structure characteristics of Ranolazine and the structure-activity relationship study, the pharmacophore of Ranolazine was coupled with NO-donor group Furoxan and nitrate ester moiety according to chemical principles, synthesized 8 kinds of nitric oxide-donating compounds in all, the structure of all the compounds were confirmed by 1H-NMR, their NO-releasing abilities were determined by Griess regents in vitro.Objective: In order to search for the lead compounds which are more effective and with low toxical anti-angina, 8 NO-donating Ranolazine derivatives were synthesized,and their ability of the NO-release were assessed in vitro.Methods: (1) Ranolazine was synthesized from 2, 6-dimethylaniline and 2-chloroacetylchloride by amidation and subsequent condensation with piperazine to give N-(2, 6-dimethylphenl)-2-(1-piperazinyl) acetamide, which subjected to condensation with 2-(2-methoxyphenoxy) oxirane prepared by condensation of 2-methoxyphenol and epichlorohydrin. (2) 3, 4-bisphenylsulfonylfuroxan was prepared by etherification, oxidation and cyclization from thiophenol, seven different glycol was respectively joined by an ether linkage to 3, 4-bisphenylsulfonylfuroxan. Thus, seven intermediates were obtained. Conjugating intermediate (C) to different intermediates with esterification by using DCC as condensing agent, seven target compoundsⅠ1-Ⅰ7 were obtained. The sodium salt of (C) reacts with 2-nitre oxygen chloroethane can get nitrate ester compoundⅡ.(3) A solution (2.5×10-4mol/L)of the appropriate compound was prepared at 37℃,using phosphate buffer (pH7.4) in presence of excess L-cysteine. The reaction mixture was taken at diferent time and determined by Griess reagent.Absorbance was detected at 540nm.Results: (1) The synthesis of Ranolazine has been improved and its reaction conditions have been optimized as well. (2) 7 new Furazan nitrogen oxides and 1 nitrate NO-donating compound were successfully synthesized. The structure of eight compounds has been confirmed by 1H- NMR. (3) The results of NO-release in vitro experiment indicated that seven compounds obviously released NO at the initial 2h. At a later time, the release was stable. The maximum concentrations (Cmax) of NO-release in vitro were 0.742,0.624,0.854,0.751,0.515,0.973 and 0.776㎎/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:Ⅰ6>Ⅰ3>Ⅰ7>Ⅰ4>Ⅰ1>Ⅰ2>Ⅰ5.