雷诺嗪的合成

2,6-二甲苯胺加氯乙酰氯制得酰胺后与哌嗪反应得N-(2,6-二甲苯基)-2-(1-哌嗪基)乙酰胺,其与由邻甲氧基苯酚和环氧氯丙烷反应得到的2-(2-甲氧苯氧基甲基)环氧乙烷反应制得抗心绞痛药雷诺嗪,总收率51%(以2,6-二甲苯胺计).     

雷诺嗪的合成

To synthesize Ranolazine, anew drug for the treatment of antianginal. METHODRanolazine was prepared from 2,6-dimethylaniline by chloacetylation, condensation with piperazine,at last treated with 1-(2-methoxyphenoxy)-2,3-epoxypropane(2) to get Ranolazine.R     

雷诺嗪（ranolazine）

雷诺嗪[ranolazine，CVT-303，KEG,-1295，RS-43285（diHCl）]是2006年1月由美国食品药品管理局（FDA）批准的治疗慢性心绞痛新药，由CV Therapeutics公司开发研制，商品名为Ranexa，该药为口服缓释片。     

FDA批准雷诺嗪缓释片

美国FDA批准CV Therapeutics公司的雷诺嗪（ranolazine）500mg薄膜包衣缓释片（Ranexa）上市，用于治疗慢性心绞痛。本品可延长心电图QT间隔，建议保留用于对其它抗心绞痛药物治疗无效者。本品必需与氨氯地平、β受体阻断剂或硝酸酯类药物联用。女性心绞痛患者接受本品治疗的疗效及治疗后运动耐量的改善，均低于男性患者。     

雷诺嗪的合成工艺改进

目的:合成抗心绞痛药雷诺嗪并进行工艺改进。方法:以邻甲氧基苯酚、2,6-二甲基苯胺为原料经过酰化、烃化、缩合、加成四步反应合成雷诺嗪。结果:所得产物化学结构经核磁共振氢谱及质谱确证,总收率为49.1%。结论:改进的合成工艺简便、合理且可行。     

手性药物雷诺嗪的研究进展

慢性心绞痛是缺血性心脏病的常见临床表现,严重影响人们的生活质量。随着人们生活水平的提高和生活方式的改变,以及人口趋于老龄化,心绞痛的发病率及死亡率呈逐年上升,心绞痛的治疗与新药的开发越来越受到关注。慢性稳定性心绞痛的重要病理生理机制是暂时性缺血、缺氧,是由血和氧的供需间平衡失调所致,     

盐酸雷诺嗪原料及片

国外研制情况及知识产权状况.本品由瑞士Roche公司开发，目前处在临床研究阶段。本品品种专利为：EP126449、JP56／219271（A2）、US4567264，未申请中国专利。     

雷诺嗪的合成工艺研究

目的合成雷诺嗪并进行工艺改进。方法以2,6-二甲基苯胺、愈创木酚为原料,经酰化、烃化等4步反应制得雷诺嗪。结果总收率36．8％,产物结构经熔点、红外光谱和核磁共振确证。结论此合成路线操作简单可行、适合工业化生产。     

雷诺嗪在心血管疾病中的应用进展

雷诺嗪于2006年作为抗心绞痛药物被美国食品和药物管理局(FDA)批准。随着多项临床试验的开展,雷诺嗪也被证实在房性和室性心律失常的预防和治疗上有效,并对于肺动脉高压的治疗有一些探索性的研究。本文就雷诺嗪的药理学特点及其近年来在心血管疾病方面的临床应用进展做一综述。     

抗心绞痛药雷诺嗪的研究进展

雷诺嗪(ranolazine)于2006年1月美国FDA批准上市,用于治疗慢性心绞痛.它是一种脂肪酸部分氧化抑制剂,通过改变葡萄糖和脂肪酸的代谢而发挥作用.临床研究表明,雷诺嗪单独使用或者与其他药物联合应用,可以安全有效地治疗慢性心绞痛.雷诺嗪常见的不良反应是眩晕、头痛、便秘、恶心.文中对雷诺嗪的药理作用、药动学、临床研究、药物相互作用、安全性评价等进行综述.     

Clinical pharmacokinetics of ranolazine

Ranolazine is a compound that is approved by the US FDA for the treatment of chronic angina pectoris in combination with amlodipine, beta-adrenoceptor antagonists or nitrates, in patients who have not achieved an adequate response with other anti-anginals. The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure. It acts through different pharmacological mechanisms where inhibition of the late inward sodium current (reducing calcium overload and thereby left ventricular diastolic tension) is one plausible mechanism of reduced oxygen consumption. Initial studies used an oral solution or an immediate-release (IR) capsule, but subsequently an extended-release (ER) formulation was developed to allow for twice-daily administration with maintained efficacy. Following administration of an oral solution or IR capsule, peak plasma concentrations (C(max)) are observed within 1 hour. After administration of radiolabelled ranolazine, 73% of the dose was excreted in urine, and unchanged ranolazine accounted for <5% of radioactivity in both urine and faeces. The absolute bioavailability ranges from 35% to 50%. Food has no effect on rate or extent of absorption from the ER formulation. Ranolazine protein binding is about 61-64% over the therapeutic concentration range. Volume of distribution at steady state ranges from 85 to 180 L. Ranolazine is extensively metabolised by cytochrome P450 (CYP) 3A enzymes and, to a lesser extent, by CYP2D6, with approximately 5% excreted renally unchanged. Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine. Oral plasma clearance diminishes with dose from, on average, 45 L/h at 500 mg twice daily to 33 L/h at 1000 mg twice daily. The departure from dose proportionality for this dose range is modest, with increases in steady-state C(max) and area under plasma concentration-time curve (AUC) from 0 to 12 hours of 2.5- and 2.7-fold, respectively. Ranolazine pharmacokinetics are unaffected by sex, congestive heart failure and diabetes mellitus. AUC increases up to 2-fold with advancing degree of renal impairment. Ranolazine is a weak inhibitor of CYP3A, and increases AUC and C(max) for simvastatin, its metabolites and HMG-CoA reductase inhibitor activity <2-fold. Digoxin AUC is increased 40-60% by ranolazine through P-glycoprotein inhibition. Ranolazine AUC is increased by CYP3A inhibitors ranging from 1.5-fold for diltiazem 180 mg once daily to 3.9-fold for ketoconazole 200 mg twice daily. Verapamil increases ranolazine exposure approximately 2-fold. CYP2D6 inhibition has a negligible effect on ranolazine exposure.     

Effects of ranolazine on cardiovascular system

Chronic stable angina affects 6-7 million Americans and contributes to a significant reduction in quality of life and life expectancy. Current pharmacotherapy for reducing episodes of exertional angina includes β-blockers, calcium channel blockers and long-acting nitrates. Patients may have contraindications to the use of one or more of these agents or be unable to tolerate initial or larger therapeutic doses. As a result of the inability of current management strategies to optimally control episodes of chronic angina, new therapies have been investigated that do not have some of the limitations of current therapies. New therapies for chronic stable angina are based on a mechanism involving membrane current such as the funny current and the late Na current. Ranolazine (Ran) is an antianginal drug acting on I(Na). After its current indication in the chronic stable angina, the role of this molecule is still being studied for prophylaxis of certain arrhythmias and treatment of heart failure. Moreover, have been recently developed new interesting patents of novel pharmaceutical effects and derivates of Ran.     

雷诺嗪对大鼠的长期毒性试验*

目的:考察反复给予雷诺嗪{N-(2,6二甲基苯基)-2-4-[2-羟基-3-(2-甲氧苯氧基)丙基]-1-哌嗪乙酰胺}对大鼠产生的毒性反应。方法:SD大鼠随机分为雷诺嗪高、中、低剂量(400,150和50 mg.kg-1.d-1)组和溶媒对照(0.5%羧甲基纤维素钠)组,每组32只大鼠,雌雄各半。各组均灌胃给予等体积的药物或溶媒(20 mL.kg-1),每周给药7 d,连续给药4周。停药后每组留12只动物(雌雄各半)再饲喂2周进行恢复性观察。观察动物一般状况、体重、进食量、饮水量、血液学、血液生化学、脏器重量系数及组织病理学改变。结果:雷诺嗪400 mg.kg-1组大鼠给药初期出现活动减少、呆滞和抽搐,体重增加值低于对照组,饮水量、丙氨酸氨基转换酶(ALT)、尿素氮(BUN)、总胆固醇(T-Cho)及肝、肾系数高于对照组。雷诺嗪50和150 mg.kg-1组各项指标与对照组比较均无统计学差异。恢复期各剂量的各项指标与对照组比较均无统计学差异。结论:雷诺嗪150 mg.kg-1为安全剂量,400 mg.kg-1有短时神经系统毒性并对动物生长,肝、肾功能和脂代谢产生可逆性影响。     

雷诺嗪在健康人体的药代动力学

目的 评价中国健康人单剂量口服雷诺嗪缓释片后体内的药代动力学.方法 随机双盲单中心Ⅰ期临床研究,2名受试者口服安慰剂,8名受试者单次口服雷诺嗪缓释片1500 mg后,用LC-MS-MS法测定血浆中雷诺嗪浓度,用WinNonlin@6.3软件对血药浓度数据进行处理,计算药代动力学参数.结果 血浆中雷诺嗪浓度线性范围为5～4000 ng·mL-1,定量下限为5 ng· mL-1,日内、日间精密度均小于15％.主要的药代动力学参数:Cmax为(1.27 ±0.50) mg·mL-,tmax为(3.13 ±1.55) h,t1/2为(5.02±1.47) h,V为(0.74 ±0.35) L,CL为(0.10±0.05) L· h-1,AUCo-48为(17.50±8.31) mg·h·mL-1.结论 本方法操作简便、快捷、灵敏度高,可用于雷诺嗪缓释片在中国健康受试者体内药代动力学的研究.     

新型抗心绞痛药雷诺嗪的合成研究

目的 合成新型抗心绞痛药雷诺嗪。方法 以邻甲氧基苯酚、环氧氯丙烷、2，6-二甲基苯胺、哌嗪为原料，采用常规的化学合成法。结果 通过优化条件以较高的收率合成雷诺嗪二盐酸盐。结论 用元素分析、质谱、氢谱、碳谱等鉴定了目标物的结构。优化了反应条件，简化了后处理过程，为进一步工业生产和临床应用打下基础。     

雷诺嗪缓释片体外释放度的测定

目的建立雷诺嗪缓释片的体外释放度测定方法。方法以0.9%的盐酸水溶液为溶出介质,溶出方法为转篮法(100 r.min-1)。结果采用紫外分光光度法在272 nm测定雷诺嗪的浓度,其检测线性范围为10～200 mg.L-1(r=0.999 9),平均回收率为98.04%(RSD=1.26%);3批样品在2、6、12 h的释放量分别为标示量的30%、60%、70%以上。结论该方法准确、可靠,可用于该制剂的释放度测定。     

新型抗心绞痛药物雷诺嗪的合成工艺改进

目的:对抗心绞痛药雷诺嗪现有合成工艺进行改进.方法:以2,6-二甲基苯胺为起始原料,经过酰化、缩合、环加成、成盐等4步反应合成产品雷诺嗪.结果:产品总收率为51.9%,其化学结构经1H NMR、MS、IR确证,HPLC法检测纯度达到99.2%.结论:该工艺反应条件温和,收率较高,操作简便,易于工业化生产.