盐酸艾司洛尔 | 81161-17-3

• 物质功能分类: 原料药 - 循环系统用药 - 抗心律失常药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 盐酸艾司洛尔
• 中文别名: 4-{[3-(1-甲基乙基氨基)-2-羟基]丙氧基}苯丙酸甲酯盐酸盐；半水盐酸阿扑吗啡；艾司洛尔盐酸盐
• 英文名称: esmolol hydrochloride
• 英文别名: Brevibloc；methyl 3-[4-[2-Hydroxy-3-(isopropylamino)propoxy]phenyl]propionate Hydrochloride；Hydron;methyl 3-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]propanoate;chloride
• CAS: 81161-17-3
• 化学式: C₁₆H₂₅NO₄*ClH
• 分子量: 331.84
• InChiKey: GEKNCWBANDDJJL-UHFFFAOYSA-N

物化性质

• 熔点：
  48-50°C
• 密度：
  1.026
• 溶解度：
  H2O：可溶12mg/mL
• 颜色/状态：
  White or off-white crystalline powder
• 稳定性/保质期：
  Esmolol hydrochloride concentrate for injection should be stored at 15-30 °C, and exposure to temperatures of 40 °C or warmer should be avoided; freezing does not adversely affect the concentrate for injection. When stored at 15-30 °C, unopened ampules of the drug have an expiration date of 3 years following the date of manufacture.
• 解离常数：
  In alcohol, 350 mg/l at room temperature

计算性质

• 辛醇/水分配系数(LogP)：
  1.95
• 重原子数：
  22
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  67.8
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

艾司洛尔通过酯酶（可能是芳酯酶）迅速且广泛地在红细胞胞浆中代谢。药物代谢也可能会发生在含有酯酶的高血流组织（如肝脏、肾脏）。甲基酯部分的水解导致去酯化（游离酸）代谢物4-(2-羟基-3-((1-甲基乙基)氨基)丙氧基)苯丙酸（ASL 8123）和甲醇的形成。艾司洛尔似乎不容易通过血清胆碱酯酶（假性胆碱酯酶）、乙酰胆碱酯酶或碳酸酐酶发生水解。估计大约83%的艾司洛尔剂量会代谢为ASL 8123。ASL 8123对β-肾上腺素受体的亲和力较低，在动物中仅表现出最小的β-阻断活性（比艾司洛尔低大约1,000到1,500倍），在人类中没有明显的阻断作用。与艾司洛尔不同，ASL 8123主要通过肾脏消除，代谢物的消除半衰期在肾功能损害的患者中可能增加多达十倍；然而，由于ASL 8123只有最小的β-阻断活性，因此这种积累被认为临床上并不重要。在药物水解过程中形成的甲醇量似乎临床上并不重要。在静脉输注艾司洛尔盐酸剂量为300ug/kg/分钟，最长16小时，或150ug/kg/分钟，持续24小时后，血液甲醇浓度分别为2.8-5.9或2.9-13.2ug/ml，分别低于与甲醇毒性相关的浓度的2%。

Esmolol is rapidly and extensively metabolized via esterases (probably arylesterase), principally in the cytosol of erythrocytes. Metabolism of the drug also may occur in highly perfused tissues that contain esterases (eg, liver, kidneys). Hydrolysis of the methyl ester moiety results in formation of the de-esterified (free acid) metabolite, 4-(2-hydroxy-3-((1-methylethyl)amino) propoxy)benzenepropanoic acid (ASL 8123), and methanol. Esmolol does not appear to be susceptible to hydrolysis via serum cholinesterase (pseudocholinesterase), acetylcholinesterase, or carbonic anhydrase. It is estimated that about 83% of an esmolol dose is metabolized to ASL 8123. ASL 8123 has a low affinity for beta-adrenergic receptors, exhibiting only minimal (about 1,000- to 1,500-fold less potent than esmolol) beta-blocking activity in animals and no appreciable blockade in humans. Unlike esmolol, ASL 8123 is eliminated principally by the kidneys, and the elimination half-life of the metabolite may be increased up to tenfold in patients with renal impairment; however, such accumulation is not thought to be clinically important since ASL 8123 has only minimal beta-blocking activity. The amount of methanol formed during hydrolysis of the drug does not appear to be clinically important. Following IV infusion of esmolol hydrochloride doses of 300 ug/kg per minute for up to l6 hours of 150 ug/kg per minute for 24 hours, blood methanol concentrations ranged from 2.8-5.9 or 2.9-13.2 ug/ml, respectively, being less than 2% of those usually associated with methanol toxicity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当同时给予艾司洛尔和耗竭儿茶酚胺类药物（例如，利血平）时，药物的效果可能是累加的。

When esmolol and a catecholamine-depleting drug (eg, reserpine) are administered concomitantly, the effects of the drugs may be additive.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在健康成年人中，同时给予艾司洛尔和吗啡，使艾司洛尔的稳态血药浓度大约增加了50%，尽管吗啡的药代动力学没有受到影响。

Concomitant administration of esmolol and morphine in healthy adults resulted in about a 50% increase in steady-state blood esmolol concentrations, although the pharmacokinetics of morphine were not affected.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

艾司洛尔可能会延长琥珀酰胆碱的效果，尽管神经肌肉阻滞的发作不受影响。在一些患者中，艾司洛尔给药的同时，琥珀酰胆碱引起的神经肌肉阻滞延长了大约60% ... 另外，在其他患者中，神经肌肉阻滞的持续时间并未因联合治疗而延长。

Esmolol may prolong the effects of succinylcholine, although the onset of neuromuscular blockade is not affected. Succinylcholine-induced neuromuscular blockade has been prolonged by about 60% during concomitant esmolol administration in some patients. ... In addition, the duration of neuromuscular blockade was not prolonged in other patients during concomitant therapy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在同时使用华法林治疗期间，血液中的艾司洛尔浓度可能会略有增加。

Blood esmolol concentration may be increased slightly during concomitant warfarin therapy ... .

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支持性措施。1. 保持呼吸道通畅，必要时协助通气。2. 如出现昏迷、惊厥、低血压、高血钾和低血糖，则予以治疗。3. 用阿托品治疗心动过缓，... 静脉注射；异丙肾上腺素...；或心脏起搏。4. 用雾化支气管扩张剂治疗支气管痉挛。5. 摄入后至少连续监测生命体征和心电图6小时。/艾司洛尔，β-肾上腺素能受体阻滞剂/

Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, hyperkalemia, and hypoglycemia if they occur. 3. Treat bradycardia with atropine, ... IV; isoproterenol ... ; or cardiac pacing. 4. Treat bronchospasm with nebulized bronchodilators. 5. Continuously monitor the vital signs and ECG for at least 6 hours after ingestion. /Esmolol, Beta-adrenergic blockers/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚未知悉esmolol和/或ASL 8123是否会在人类中跨越胎盘，但该药物已在动物中被证实能够跨越胎盘。在动物中，胎儿动脉中的esmolol浓度在输注完成时约为母体浓度的10%。同样也不知道esmolol和/或ASL 8123是否会分布进入乳汁。

It is not known whether esmolol and/or ASL 8123 cross the placenta in humans, but the drug has been shown to cross the placenta in animals. In animals, fetal artery esmolol concentrations were about 10% of maternal concentrations at the completion of infusion. It also is not known whether esmolol and/or ASL 8123 are distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉给药后，艾司洛尔迅速且广泛分布。在健康成年人中，艾司洛尔及其脱酯代谢物（ASL 8123）的表观分布容积分别约为3.4和0.41升/公斤。在健康成年人中，艾司洛尔在中心室和稳态时的分布容积分别约为0.87和1.2升/公斤。表观分布容积在冠状动脉旁路手术的患者中似乎降低，而在进行腹膜透析的肾功能障碍患者和肝硬化的患者中增加。

Following IV administration, esmolol is rapidly and widely distributed. The apparent volumes of distribution of esmolol and its de-esterifed metabolite (ASL 8123) in healthy adults are approximately 3.4 and 0.41 l/kg, respectively, following iv administration. In healthy adults, the volumes of distribution of esmolol in the central compartment and at steady state are approximately 0.87 and 1.2 l/kg, respectively, following IV administration. The apparent volume of distribution appears to be decreased in patients undergoing coronary artery bypass surgery and increased in patients with renal impairment undergoing peritoneal dialysis and in patients with liver cirrhosis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射给药后，在大鼠体内，艾司洛尔主要分布到肝脏和肾脏，但在脑脊液、脾脏或睾丸中的分布非常少。

Following IV administration in rats, esmolol is ditributed into liver and kidneys, but only minimally into CSF, spleen, or testes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

体外实验中，艾司洛尔大约有55%与血浆蛋白结合，主要是白蛋白和α-1-酸性糖蛋白。艾司洛尔与α-1-酸性糖蛋白的结合似乎在艾司洛尔浓度为3-110微克/毫升时不依赖于浓度。体外实验中，ASL 8123大约有10%与血浆蛋白结合。

In vitro, esmolol is approximately 55% bound to plasma proteins, mainly albumin and alpha-1-acid glycoprotein. Protein binding of esmolol to alpha-1-acid glycoprotein does not appear to be concentration dependent at esmolol concentrations of 3-110 ug/ml. In vitro, ASL 8123 is approximately 10% bound to plasma proteins.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S61
• 危险类别码：
  R52/53
• 海关编码：
  2922199090
• 危险品运输编号：
  NONH for all modes of transport
• 危险标志：
  GHS07
• 危险性描述：
  H319
• 危险性防范说明：
  P305 + P351 + P338
• 储存条件：
  -20°C

制备方法与用途

概述

盐酸艾司洛尔是一种心脏选择性β受体阻滞剂，主要用于控制心跳急或异常心率节律。

应用

主要用于室上性心律失常和急性心肌局部缺血症的治疗，对急性心肌梗塞、不稳型心绞痛、术后高血压等症有明显的疗效。相关概述、制备方法、应用及不良反应由Chemicalbook的丁红编辑整理（2016-01-22）。

不良反应

最重要的不良反应是低血压，其次是外周缺血、神志不清、头痛、易激惹、乏力、呕吐等。

生物活性

Esmolol（ASL8052）是一种心脏选择性β受体阻滞剂，具有迅速起效和失活的功能。主要活性部位是窦房结和房室结传导系统。

靶点

Target	Value
beta-adrenergic receptor

体外研究

Esmolol含有一个不对称中心且以一对对映体的形式存在，(-)- 对映体是有活性的，(+)- 对映异构体是无活性的。这与其他具有一个oxypropranolamine细胞核的P-抑制剂类似。

体内研究

1. Esmolol (20 mg/kg)注射用于败血症大鼠可提高心肌氧利用率和保护心肌功能。 2. Esmolol (5 mg/kg, i.v.)作用于兔产生剂量依赖性的心率（HR）降低和平均动脉压（MAP）降低，最大百分比分别为13％和38.2％。 3. Esmolol (300 mg/kg)作用于犬类显著降低心脏速率、心率收缩压乘积、左室收缩、心输出量、右心室相对不应期，并提高右心室不应期的效率和左心室的前负荷。同时，Esmolol 还能显著降低异丙基肾上腺素诱导的心率增加和心室收缩。

化学性质

盐酸艾司洛尔为白色固体。

反应信息

• 作为反应物：
  描述：

  盐酸艾司洛尔 在 盐酸 、 三丁基氧化锡 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 48.25h， 生成 艾司洛尔酸钠
  参考文献：
  名称：

  Hitting a Soft Drug with a Hard Nucleophile: Preparation of Esmolol's Metabolite by Treatment with Bis(tributyltin) Oxide

  摘要：

  A facile method for the production of esmolol's metabolite in high purity is described. Bis(tributyltin) oxide is used to disrupt esmolol's ester linkage, and hydrolysis is completed by addition of water, which also allows the inorganic side products to be conveniently extracted into ether. Evaporation of the aqueous phase and trituration with ethyl acetate provides the carboxylic acid-amine internal salt as a white, free-flowing powder.

  DOI：

  10.1080/00397911.2010.530375
• 作为产物：
  描述：

  对羟基苯丙酸甲酯 在 盐酸 、 potassium carbonate 、 间氯过氧苯甲酸 、 potassium iodide 作用下， 以 甲醇 、 二氯甲烷 、 甲基叔丁基醚 、 水 、 丙酮 为溶剂， 反应 26.0h， 生成 盐酸艾司洛尔
  参考文献：
  名称：

  一种盐酸艾司洛尔及其制剂的制备

  摘要：

  本发明设计了新型的艾司洛尔盐酸盐合成路线，并制备出具有纳米线结构的甲基3‑[4‑(烯丙氧基)苯基]丙酸酯中间体，该结构使中间体更加稳定，有利于提高目标产物产率。本发明选取对溴苯酚为原料，首先是在醋酸钯的催化下与丙烯酸甲酯通过Heck反应合成对羟基肉桂酸甲酯，选用钯碳催化氢化对羟基肉桂酸甲酯得到中间体对羟基苯丙酸甲酯，同时，利用烯丙基溴与羟基的协同作用进行醚化得到中间体甲基3‑[4‑(烯丙氧基)苯基]丙酸酯，经过间氯过氧苯甲酸、异丙胺开环氧化物氧化，与氯化氢成盐得到终产品艾司洛尔盐酸盐。本发明克服传统合成路线缺点，在合成工艺上实施了进一步优化，具有原料易得，操作简捷，反应条件温和的优点。

  公开号：

  CN117304043A

文献信息

• [EN] TARGETED DRUG DELIVERY THROUGH AFFINITY BASED LINKERS<br/>[FR] ADMINISTRATION CIBLÉE D'UN MÉDICAMENT FAISANT APPEL À DES COUPLEURS FONDÉS SUR L'AFFINITÉ
  申请人：INVICTUS ONCOLOGY PVT LTD

  公开号：WO2015148126A1

  公开（公告）日：2015-10-01

  The current invention discloses targeted drug delivery conjugates comprising a targeting moiety linked to a drug via a molecule having an affinity for the targeting moiety. Typically, the conjugate comprises a targeting ligand and a molecule of interest, e.g., a therapeutic agent. The targeting ligand and the molecule of interest are linked to each other via an affinity ligand. The affinity ligand is further covalently or non-covalently linked to a drug or therapeutic agent. The drug can be modified to make it more soluble and so that it cleaves from the linking molecule at the target site.

  当前的发明揭示了包括通过具有与靶向基团亲和力的分子连接到药物的靶向药物传递共轭物。通常，该共轭物包括一个靶向配体和一个感兴趣的分子，例如，一个治疗剂。靶向配体和感兴趣的分子通过一个亲和配体相互连接。该亲和配体进一步以共价或非共价方式连接到药物或治疗剂。药物可以被修改以使其更溶解，并使其在靶点处从连接分子中解离。
• Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions
  申请人：Graziano P. Michael

  公开号：US20050096307A1

  公开（公告）日：2005-05-05

  The present invention provides compositions, therapeutic combinations and methods including: (a) at least one lipid modulating agent; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity and lowering plasma levels of sterols or 5α-stanols.

  本发明提供了包括以下内容的组合物、治疗组合和方法：(a)至少一种脂质调节剂；和(b)至少一种取代的噁唑烷酮或取代的β-内酰胺甾醇吸收抑制剂，可用于治疗血管疾病、糖尿病、肥胖以及降低血浆中甾醇或5α-甾烷醇的水平。
• Combinations of substituted azetidinones and CB1 antagonists
  申请人：Veltri P. Enrico

  公开号：US20060069080A1

  公开（公告）日：2006-03-30

  The present invention provides compositions, therapeutic combinations and methods including: (a) at least one selective CB 1 antagonist; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity, metabolic syndrome and lowering plasma levels of sterols or 5α-stanols.

  本发明提供了包括以下内容的组合物、治疗组合和方法：(a)至少一种选择性CB1拮抗剂；和(b)至少一种取代的氮杂环丁烷或取代的β-内酰胺甾醇吸收抑制剂，可用于治疗血管疾病、糖尿病、肥胖、代谢综合征以及降低血浆中的甾醇或5α-甾烷醇水平。
• [EN] DIPHENYLAZETIDINONE DERIVATES PROCESSING CHOLESTEROL ABSORPTION INHIBITORY ACTIVITY<br/>[FR] DERIVES DIPHENYLAZETIDINONE PRESENTANT UNE ACTIVITE D'INHIBITION D'ABSORPTION DU CHOLESTEROL
  申请人：ASTRAZENECA AB

  公开号：WO2005061451A1

  公开（公告）日：2005-07-07

  Compounds of formula (XV): [Chemical formula should be inserted here. Please see paper copy] (XV) (wherein variable groups are as defined within) pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia are described. Processes for their manufacture and pharmaceutical compositions containing them are also described.

  公式（XV）的化合物：[应在此处插入化学公式。请参见纸质副本]（XV）（其中变量组如内部定义）药物可接受的盐、溶剂化物、这些盐的溶剂化物和前药及其用作治疗高脂血症的胆固醇吸收抑制剂。还描述了它们的制造过程和含有它们的药物组合物。
• [EN] SUBSTITUTED PIPERAZINES AS CB1 ANTAGONISTS<br/>[FR] PIPÉRAZINES SUBSTITUÉES EN TANT QU'ANTAGONISTES DE CB1
  申请人：SCHERING CORP

  公开号：WO2009005645A1

  公开（公告）日：2009-01-08

  Compounds of Formula (I) or pharmaceutically acceptable salts, solvates, or esters thereof, are useful in treating diseases or conditions mediated by CB1 receptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive disorders and psychosis, addiction (e.g., smoking cessation), gastrointestinal disorders, and cardiovascular conditions.

  化合物式(I)或其药用可接受的盐、溶剂合物或酯，可用于治疗由CB1受体介导的疾病或症状，如代谢综合征和肥胖症、神经炎症性疾病、认知障碍和精神病、成瘾（例如戒烟）、胃肠道疾病和心血管疾病。