阿折地平的合成

目的：合成阿折地平。方法：以二苯基甲胺为原料,经加成、酯化、酸化、氨化、缩合等反应合成阿折地平。结果：经元素分析、Ms,IR,NMR等测试确定了化学结构,总收率21％。结论：本方法原料易得,便于工业化生产。     

阿折地平

类别：化学药三类 剂型：片剂 作用与用途：抗高血压、治疗心绞痛     

阿折地平的合成

目的考察阿折地平的合成工艺。方法1-二苯甲基丫丁啶-3-醇经一步酯化反应、两步缩合反应合成阿折地平。结果及结论此合成路线原料易得,工艺可行。     

阿折地平的合成工艺改进

目的 改进抗高血压药物阿折地平的合成工艺。方法 以二苯甲胺和环氧氯丙烷为起始原料,经取代,酯化, 酸化,缩合等反应制得抗高血压药物阿折地平。结果与结论 目标化合物的结构经¹H-NMR、质谱确证。总收率为30.88%,比文献收率提高了10.62%。改进后的方法操作简便,有利于工业化生产。     

阿折地平的合成

二苯甲胺和环氧氯丙烷经亲核取代、闭环、酯化、氮解等反应制得3，3-二氨基丙烯酸1-二苯甲基-3-氮杂环丁酯乙酸盐（6）。另由间硝基苯甲醛和乙酰乙酸异丙酯在浓硫酸催化下反应制得2-（3-硝基苯亚甲基）乙酰乙酸异丙酯（7）。6和7再经Michael加成、闭环制得抗高血压药阿折地平，总收率约36％（以二苯甲胺计）。     

抗高血压药 阿折地平（azelnidipine）

简介 本品由日本三共制药研发，2003年5月首次在日本上市。 商品名=calblock 专利号=Gp266926，专利优先权为1986年10月。     

阿折地平（Azelnidipine）

化学药三类 剂型：片剂 抗高血压、治疗心绞痛；每片含主药8mg、每日一次，每次一片。化学名：2-氨基-6-甲基-4-(3-硝基苯基)-1，4-二氧-3，5-吡啶二羧酸-3-[1-(二苯甲基)-3-氮杂环丁基]-5-异丙基酯     

盐酸马尼地平的合成

以哌嗪为起始原料,经环氧乙烷加成、二苯甲基溴缩合、用双乙烯酮乙酰化得乙酰乙酸2-(4-二苯甲基-1-哌嗪基)乙酯,最后与间硝基苯甲醛和β-氨基巴豆酸甲酯环合制得盐酸马尼地平,总收率28.9%.     

阿折地平:一种新型二氢吡啶类钙拮抗药

阿折地平是日本Sankyo公司与Ube公司联合开发的一种新型二氢吡啶类钙拮抗药,选择性作用于L-型钙通道,在日本已被批准用于治疗高血压,其降压疗效与肾上腺素β受体阻断剂和血管紧张肽转换酶抑制药相当。本文对该药的药效学、药动学和临床应用等研究作一综述。     

Azelnidipine

Azelnidipine is a new dihydropyridine calcium channel antagonist with selectivity for L-type calcium channels that has recently been approved in Japan for the treatment of patients with hypertension. Results from clinical trials showed that, in 95 patients with mild-to-moderate hypertension, long-term treatment with azelnidipine effectively controls blood pressure (BP). The mean reduction from baseline in sitting systolic/diastolic BP after 1 year of treatment was 27.8/16.6 mm Hg. Among 172 patients with uncontrolled hypertension receiving non-calcium channel antagonist antihypertensive agents, the addition of azelnidipine therapy significantly reduced mean BP in a noncomparative, 1-year study (a reduction from 165.7/95.4 mm Hg at baseline to 138.2/79.9 mm Hg at study end). The antihypertensive efficacy of azelnidipine in patients with mild-to-moderate hypertension was shown to be similar to that of amlodipine or nitrendipine in randomised, double-blind studies. Azelnidipine and amlodipine controlled 24-hour BP to a similar extent. Azelnidipine is generally well tolerated; vasodilator adverse events such as as headache and hot facial flushes account for most of the adverse events. Its use is not associated with reflex tachycardia.     

阿折地平片工艺验证

目的通过本试验来验证阿折地平片中试工艺的可行性、可靠性。方法采用同步验证法,包括多种测试手段,对阿折地平片中试工艺各步骤进行验证。结果验证批次的阿折地平片各项指标符合质量标准要求。结论阿折地平片中试工艺生产可行,工艺流程及工艺参数能够保证产品质量;工艺可靠、稳定。     

Azelnidipine (Sankyov KK)

Azelnidipine (CS-905) is a long-acting, once-daily, orally-administered calcium channel antagonist which is being jointly developed by Sankyo and UBE. An NDA for the treatment of hypertension was filed in Japan in July 1997 [314648,271372,312610]. In a clinical trial presented at the European Meeting on Hypertension in 1995, azelnidipine decreased systolic and diastolic blood pressures at rest and during exercise. There were no significant changes in resting heart rate and cardiac output and the exercise-induced increase of these parameters was also unaffected [179222]. In February 1999, Lehman Brothers predicted a 90% probability that azelnidipine would reach the Japanese market and launch by 1999. Expected Japanese sales are predicted to be US dollar 16 million in 2000, rising to dollar 32 million in 2002. Peak annual sales of US dollar 100 million are predicted for 2008 [319225].     

阿折地平胶囊溶出度方法研究

目的建立一种合适的阿折地平胶囊溶出度的测定方法。方法以0.1 mol.L-1盐酸溶液(含0.3%十二烷基硫酸钠)1 000 mL为溶出介质,转速为100 r.min-1,紫外检测波长269 nm。结果在4.0~24.0μg.mL-1范围内阿折地平浓度与吸光度呈良好线性关系,r=0.999 6;平均回收率98.16%,RSD=0.62%(n=9)。结论该方法准确可靠,重复性好,可作为阿折地平胶囊溶出度检验和质量控制的方法。     

HPLC法测定阿折地平片含量

目的建立高效液相色谱法测定阿折地平片的含量.方法采用Diamonsil C18柱(250mm×4.6mm,5μm),以磷酸盐缓冲液(磷酸二氢钠0.005mol·L-1,磷酸氢二钠0.004mol L-1)-乙腈(30∶70)为流动相,流速1.0mL· min-1;检测波长256nm;柱温30℃.结果阿折地平在2.50~40.0μg·mL-1范围内线性关系良好,r=0.9995,高、中、低3种不同浓度的平均回收率分别为99.8%、100.2%、100.5%,RSD为0.49%、0.57%、0.64%.结论所用方法简便、准确,可用于阿折地平片剂的质量控制.     

Inhibitory Effects of Azelnidipine Tablets on Morning Hypertension

Background

Morning hypertension is a risk factor for cardiovascular and cerebrovascular events. Furthermore, it is a useful measure for definitive diagnosis of hypertension, and patients who self-assess their own blood pressure (BP) in the morning tend to exhibit better compliance with antihypertensive medication than those who do not.

Objective

The objective of this analysis was to determine the BP- and pulse rate-lowering effects of azelnidipine, a long-acting dihydropyridine calcium antagonist administered once daily in the morning.

Methods

We conducted the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study by surveying patients who were taking azelnidipine. According to the study protocol, high systolic BP (SBP) was defined as ≥135 mmHg when measured at home in the morning and ≥140 mmHg when measured at the clinic during the day. A total of 5,433 hypertensive patients, who were registered at 1,011 medical institutions across Japan, were enrolled in the study. Data obtained from 4,852 of these patients (mean age, 64.8 years; female, 52.9 %; previous medication with other antihypertensive agents used concomitantly with the present study agent, 45.5 %) were used for efficacy analysis.

Results

At baseline, the subjects’ mean [± standard deviation] SBP/diastolic BP values at home in the morning, at the clinic during the day, and at home in the evening were 156.9 ± 16.4/89.7 ± 12.0, 157.5 ± 18.7/89.1 ± 13.3, and 150.2 ± 17.6/85.6 ± 12.2 mmHg, respectively. The mean pulse rates were 72.7 ± 10.7, 74.9 ± 11.2, and 72.5 ± 9.6 beats/min, respectively. Patients whose BP was defined as high accounted for 83.4 % of the study population, whereas 9.9 % had ‘masked’ hypertension, defined as SBP of ≥135 mmHg at home in the morning and <140 mmHg at the clinic. However, from 4 weeks after initiation of azelnidipine treatment till the end of the study at week 16, all three daily BP determinations were significantly (p < 0.0001) lowered, and pulse rates at home in the morning, at the clinic, and at home in the evening were similarly and significantly reduced (by −3.7 ± 8.0, −3.5 ± 9.5, and −3.5 ± 7.3 beats/min, respectively). Whereas achievement of home SBP of <135 mmHg in the morning was noted in only 6.6 % of patients before the start of azelnidipine treatment, this was noted in 43.3 % after 16 weeks. Meanwhile, achievement of clinic SBP of <140 mmHg was increased from 12.9 % of patients to 56.1 % of patients at the same timepoints. After azelnidipine treatment, 32.2 % of patients had well-controlled hypertension in both the home and clinic settings. Adverse drug reactions occurred in 2.92 % of patients (154/5,265). All adverse drug reactions were as expected for the calcium antagonist class of agents.

Conclusion

These data suggest that azelnidipine controlled morning hypertension well. Furthermore, azelnidipine reduced pulse rates significantly.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-013-0006-8) contains supplementary material, which is available to authorized users.     

阿折地平片在健康人体内的药动学研究

目的:建立测定人血浆中阿折地平浓度的方法,并进行人体药动学研究。方法:20名健康受试者随机分成2组,分别单剂量口服阿折地平片8mg和16mg,8mg剂量组同时参与完成多剂量给药试验。采用液-质联用法测定人血浆中阿折地平浓度,并计算单剂量及多剂量给药后的药动学参数。结果:单剂量口服阿折地平片8mg和16mg后,阿折地平的药动学参数分别为:cmax(1.66±0.45)、(4.25±1.38)μg·L-1,tma(x3.50±1.08)、(4.00±1.16)h,t1/(221.3±8.1)、(19.5±4.0)h,AUC0～7(217.9±6.0)、(49.9±17.5)μg·h·L-1。多剂量口服阿折地平片8mg后,阿折地平的药动学参数为:cma(x2.63±1.41)μg·L-1,tma(x3.50±1.08)h,t1/(232.5±9.2)h,AUC0～7(243.8±26.4)μg·h·L-1,ca(v1.19±0.671)μg·L-1,AUCs(s28.4±16.1)μg·h·L-1,波动度(DF)为(1.78±0.49),稳态蓄积比(Rs)为(1.56±0.95)。结论:本试验建立的测定方法灵敏、准确、简便。阿折地平片单剂量给药的药动学参数cmax和AUC0～72随剂量的增加而增加,多剂量给药后阿折地平在体内有一定的蓄积。