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Design, Synthesis of Anti-Angina Drug Ranolazine and Its No-Donating Derivatives

Author: ZhengJinE
Tutor: LuoZhi；XiangGuangYa
School: Huazhong University of Science and Technology
Course: Medicinal Chemistry
Keywords: Antianginal drugs Ranolazine Nitric Oxide Donor Synthesis NO release in vitro
CLC: R914
Type: Master's thesis
Year: 2008
Downloads: 110
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Abstract

Ranolazine is a partial fatty acid oxidation inhibitors, and adjustable by an enzyme reduces cardiac oxygen demand, improve the imbalance between oxygen supply and demand, and to alleviate the symptoms of local myocardial ischemia. In addition, ranolazine also by regulating the body's metabolism, strengthened at the same time to reduce the free fatty acid oxidation glucose oxidation, thereby increasing cardiac oxygen utilization. Ranolazine and other therapeutic drugs is different in that it play the role of the anti-anginal and does not affect the heart rate or blood pressure. The ranolazine received FDA approval on January 27, 2006 Over the past decade, the first approved chronic angina therapy. And adjuvant therapy drugs is expected to be recommended by the American College of Cardiology and the American Heart Association (ACC-AHA) with chronic stable angina treatment programs. Clinical trials have found that patients with angina coronary NO production significantly reduced supplementary NO may be one of the means for the treatment of ischemic heart disease, derived physiological dose of NO in the bloodstream or local tissue and cell damage parts to maintain NO normal requirements, the to maintain intravascular environmental stability. Exogenous sources of NO NO donor, the current study confirmed that it has a smooth muscle relaxant effect, given a certain amount of exogenous NO treatment of the disease will be of great significance. NO donors Body cardiovascular drugs, 3,4 - diphenyl-1 ,2,5 - oxadiazol-2 - oxide is an important furazan class NO donor, studies show that 3,4 - Diphenyl the the sulfonyl Furoxan in thiol cofactor effect release of NO, NO can activate the water soluble guanylyl cyclase, resulting in vasodilation and anti-platelet aggregation activity. It can be coupled with a variety of known drugs or active compounds, with a wide range of applications in drug research. Based on the above background, through the structural characteristics and the investigation of the structure-activity relationship of ranolazine, according to the chemical fight and principle Furoxan coupled and nitrates to their pharmacophore were synthesized eight kinds of nitric oxide donating compounds, the structure of all compounds was confirmed by 1H-NMR. Simultaneous Determination of NO release in vitro ability of the target compound, the results show that furosemide Zan ring compounds in vitro can be effectively released NO. Objective: To find, efficacy and toxic side effects of nitric oxide donating antianginal drugs, synthetic the eight NO Body Type ranolazine derivatives, the study compounds in vitro release of NO, continue to synthesize new compounds lead compound. Methods: (1) 2,6 - dimethylaniline, chloroacetyl chloride system obtain an amide to react with piperazine obtained N-(2,6 - xylyl) -2 - (1 - piperazin-yl) acetamide, with guaiacol and epichlorohydrin obtained 3 - (2 - methoxyphenoxy yloxy) -1,2 - epoxy-propane obtained by the reaction antianginal drugs ranolazine, and to change the side chain of the ranolazine the structure to give the intermediate 2 - (4 - (2 - hydroxy-3 - (2 - methoxyphenoxy oxy) - propyl) - 1-piperazinyl) acetic acid (C). (2) thiophenol as raw material with chloroacetic acid etherification, hydrogen peroxide, followed by and fuming nitric cyclization get donor Furoxan NO 3,4 - diphenyl sulfonyl-1 2,5 - oxadiazol-2 - oxide. The 3,4 - diphenyl sulfonyl Furoxan were in series glycol ethers to give the intermediate 7. Dicyclohexylcarbodi imide (DCC) as a condensing agent, of the intermediate with (C) an ester-forming the 7 target compound (I-1 - Ⅰ 7), the sodium salt of (C) with 2 - denitrification group chloroacetamide The alkoxy obtained by reacting the nitrate type compounds II. (3) using the phosphate buffer solution (pH7.4, containing L-cysteine-3.4mmol / L), respectively paired compound Ie 1 - I 7, and II (2.5 x 10-4mol / L)-containing solution, the solution was set in a 37 ° C environment, the reaction solution was taken at different time points, mixed with a certain amount of Griess reagent (Griess), allowed to stand for 10min at room temperature, and absorbance values ??were measured at 540nm wavelength. Results: (1) the synthesis process of ranolazine improved, optimized reaction conditions. (2) Synthesis of a 7 furosemide of Zan nitrogen oxides and a nitrates NO donating compounds. The structure of the eight compounds were confirmed by NMR spectra. (3) of NO in vitro release test determination shows that, seven target compounds Ⅰ 1 - Ⅰ 7 in 2h release NO obvious, 2h after the release of leveling off, Ⅰ 6 release of NO amount up to, the rest turn to Ⅰ 3, Ⅰ 7, Ⅰ 4, Ⅰ 1, Ⅰ 2 , Ⅰ 5, in vitro release of NO Cmax were 0.742,0.624,0.854,0.751,0.515,0.973 and 0.776 mg / L. Conclusion: 7 Furoxan class and a nitrates NO donating compounds were no reported new compounds. Target compounds Ⅰ 1 - Ⅰ 7 in cysteine ??existence, pH 7.4, environment able to release out of NO, seven compounds NO release order Ⅰ 6 gt; Ⅰ 3 gt; Ⅰ 7 gt; I 4 gt; Ⅰ 1 gt; Ⅰ 2 gt; Ⅰ 5.

Design, Synthesis of Anti-Angina Drug Ranolazine and Its No-Donating Derivatives

Abstract

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