奥美沙坦 | 144689-24-7

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 奥美沙坦
• 中文别名: 4-(1-羟基-1-甲基乙基)-2-丙基-1-[2'-(四唑-5-基)苯基]苯基]甲基咪唑-5-羧酸；奥美沙坦侧链；奥美沙坦酸；4-(1-羟基-1-甲基乙基)-2-丙基-1-[2"-(四唑-5-基)苯基]苯基]甲基咪唑-5-羧酸
• 英文名称: olmesartan
• 英文别名: 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid；4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid；5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid
• CAS: 144689-24-7
• 化学式: C₂₄H₂₆N₆O₃
• mdl: MFCD00914967
• 分子量: 446.509
• InChiKey: VTRAEEWXHOVJFV-UHFFFAOYSA-N

物化性质

• 熔点：
  186-188°C
• 沸点：
  738.3±70.0 °C(Predicted)
• 密度：
  1.33
• 溶解度：
  可溶于DMSO（轻微）、甲醇（轻微、加热）
• 物理描述：
  Solid
• 蒸汽压力：
  1.7X10-21 mm Hg at 25 °C (est)
• 解离常数：
  pKa1 = 0.91 (carboxyl); pKa2 = 4.96 (amine); pKa3 = 5.57 (amine); pKa4 = 13.93 (tertiary alcohol) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.291
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

代谢

Olmesartan medoxomil在从胃肠道吸收过程中通过酯水解迅速且完全地生物激活为奥美沙坦。这种快速的首过代谢通过血浆或排泄物中无法测量到奥美沙坦 medoxomil的量得到了证实。这种首过代谢不是由细胞色素酶驱动的，因此预计不会通过这种机制与其他药物发生相互作用。药理上活性的部分似乎不会进一步代谢。

Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. This rapid first-pass metabolism was confirmed by the lack of measurable amounts of olmesartan medoxomil in plasma or excreta. This first-pass metabolism is not driven by cytochrome enzymes and hence it is not expected to interact with other drugs via this mechanism. The pharmacologically active moiety does not appear to undergo further metabolism.

来源:DrugBank

代谢

紧随奥美沙坦酯在吸收过程中迅速且完全转化为奥美沙坦之后，奥美沙坦几乎没有进一步代谢。

Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：奥美沙坦是一种白色至浅黄色粉末或结晶性粉末，可制成口服片剂。奥美沙坦是血管紧张素II型1（AT1）受体的拮抗剂。它单独使用或与其他类别的抗高血压药物（例如，噻嗪类利尿剂）联合使用，用于治疗高血压。人类暴露和毒性：关于人类药物过量的数据有限。奥美沙坦过量的最可能表现包括低血压和心动过速；如果出现副交感（迷走神经）刺激，可能会遇到心动过缓。虽然奥美沙坦可用于高血压儿童，但不适用于1岁以下儿童。直接作用于肾素-血管紧张素系统（RAS）的药物可能对未成熟肾脏的发育产生影响。奥美沙坦在妊娠期间的使用也是禁忌的。尽管在第一季度使用并不表明有主要畸形的危险，但在第二和第三季度使用可能会导致胎儿畸形和严重的胎儿和新生儿毒性。胎儿毒性效应可能包括无尿、羊水过少、胎儿头骨软化、宫内生长受限、早产和动脉导管未闭。与无尿相关的羊水过少/羊水过少可能会产生胎儿肢体挛缩、颅面变形和肺发育不良。在子宫内暴露于奥美沙坦后，新生儿可能会出现严重的无尿和低血压，对升压药和容量扩张均无反应。动物研究：在长达2年的大鼠饮食给药中，奥美沙坦并未表现出致癌性。此外，雄性和雌性大鼠的生育能力也未受到奥美沙坦的影响。当药物以高达1000 mg/kg/日的口服剂量给予怀孕大鼠或以高达1 mg/kg/日的口服剂量给予怀孕家兔时，并未观察到致畸作用。然而，在大鼠中观察到了幼崽出生体重和体重增加的显著下降。此外，在大鼠中还观察到了发育里程碑（耳廓分离、下切牙萌出、腹部毛发出现、睾丸下降和眼睑分离）的延迟以及肾盂扩张发生率的剂量依赖性增加。奥美沙坦在体外叙利亚仓鼠胚胎细胞转化试验中呈阴性，并在 Ames（细菌突变性）试验中未显示出遗传毒性。然而，该药物在体外培养细胞（中国仓鼠肺）中诱导了染色体畸变，并在体外小鼠淋巴瘤试验中呈阳性反应。奥美沙坦在体内对MutaMouse肠和肾突变以及小鼠骨髓（微核试验）的致突变性进行了测试，在口服剂量高达2000 mg/kg时呈阴性。

IDENTIFICATION AND USE: Olmesartan is a white to light yellowish-powder or crystalline powder that is formulated into oral tablets. Olmesartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension. HUMAN EXPOSURE AND TOXICITY: Limited data are available related to drug overdose in humans. The most likely manifestations of olmesartan overdose include hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. While olmesartan can be used in hypertensive children, it is not approved for use in children less one 1 year of age. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys. The use of olmesartan in pregnancy is also contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated anhydramnios/oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to olmesartan. ANIMAL STUDIES: Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. Also, the fertility of male and female rats was unaffected by administration of olmesartan. No teratogenic effects were observed when drug was administered to pregnant rats at oral doses up to 1000 mg/kg/day or pregnant rabbits at oral doses up to 1 mg/kg/day. However, significant decreases in pup birth weight and weight gain were observed in rats. In addition, delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed in rats. Olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, the drug was shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

Olmesartan 已与低比率的血清转氨酶升高有关。

Olmesartan has been associated with a low rate of serum aminotransferase elevations (

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：奥美沙坦

Compound:olmesartan

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：模糊的药物性肝损伤关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：4

Severity Grade:4

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药时，前药奥美沙坦酯在胃肠系统中迅速吸收并代谢为奥美沙坦。通过medoxomil的酯化作用，旨在将奥美沙坦的生物利用度从4.5%提高到28.6%。口服10-160毫克奥美沙坦可以在1-3小时内达到0.22-2.1毫克/升的峰值血浆浓度，药时曲线下面积（AUC）为1.6-19.9毫克·小时/升。奥美沙坦的药代动力学特征在治疗剂量范围内几乎呈线性且剂量依赖性。每天一次给药，3到5天后可以达到奥美沙坦的稳态水平。

When taken orally, the prodrug olmesartan medoxomil is rapidly absorbed in the gastrointestinal tract and metabolized to olmesartan. The esterification with medoxomil was created with the intention of increasing olmesartan bioavailability from 4.5% to 28.6%. Oral administration of 10-160 mg of olmesartan has been shown to reach peak plasma concentration of 0.22-2.1 mg/L after 1-3 hours with an AUC of 1.6-19.9mgh/L. The pharmacokinetic profile of olmesartan has been observed to be nearly linear and dose-dependent under the therapeutic range. The steady-state level of olmesartan is achieved after once a day dosing during 3 to 5 days.

来源:DrugBank

吸收、分配和排泄

• 消除途径

奥美沙坦的主要排泄途径是以未改变的形式通过粪便排出。从系统生物利用度剂量中，大约有10-16%通过尿液排出。

The main elimination route of olmesartan is in the unchanged form through the feces. From the systemically bioavailable dose, about 10-16% is eliminated in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

17升

17 L

来源:DrugBank

吸收、分配和排泄

• 清除

总体血浆清除率是1.3升/小时，肾脏清除率是0.6升/小时。

Total plasma clearance is 1.3 L/h and the renal clearance is 0.6 L/h.

来源:DrugBank

吸收、分配和排泄

在大鼠中，奥美沙坦几乎不通过，甚至可能完全不能通过血脑屏障。奥美沙坦能够通过大鼠的胎盘屏障，并分布到胎儿中。

In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• RTECS号：
  NI4014100
• 海关编码：
  2921590090
• 包装等级：
  II
• 危险类别：
  4.1
• 危险性防范说明：
  P240,P210,P241,P264,P280,P302+P352,P370+P378,P337+P313,P305+P351+P338,P362+P364,P332+P313
• 危险品运输编号：
  1325
• 危险性描述：
  H228,H315,H319
• 储存条件：
  -20°C 冰箱

制备方法与用途

概述

奥美沙坦是奥美沙坦酯EP杂质A。奥美沙坦酯是一种新的血管紧张素Ⅰ（AT1R）受体拮抗剂，于2002年5月首次获得美国FDA批准上市，用于治疗高血压。

生物活性

Olmesartan（RNH-6270）是血管紧张素II受体（AT1R）拮抗剂，常用于高血压的相关研究。体外研究表明，奥美沙坦在0.7至5 mM浓度范围内对HeLa细胞的生长具有抑制作用，并且这种抑制作用呈时间和浓度依赖性。

细胞活性测定

• 细胞系：人宫颈癌细胞系（HeLa）
• 浓度：0.7-5 mM
• 孵育时间：24、48和72小时
• 结果：48小时和72小时的半数抑制浓度（IC50）分别为4.685 mM和1.651 mM

体内研究

重复给予奥美沙坦（1 mg/kg，2 mg/kg经口给药）可以剂量依赖性地降低 SHR 的平均动脉血压（MAP），且在10周内对体重和食物摄入没有显著影响。奥美沙坦（5 mg/kg/日，经口给药）与氢氯噻嗪治疗均能有效降低小鼠的收缩压。此外，奥美沙坦治疗还抑制了心脏肥大，这通过超声心动图、心脏重量、心肌细胞横截面积以及基因表达得到评估。在肾转录小鼠模型中，奥美沙坦治疗逆转了ACE2和Mas受体的下调，并抑制了NADPH氧化酶（Nox）4的过表达及其产生的活性氧。

用途

高血压是临床上常见的疾病，在治疗高血压病的各种药物中，血管紧张素Ⅱ受体拮抗剂（ARBs）因具有良好的有效性和安全性（妊娠妇女除外），成为应用比例上升最快的药物之一。

反应信息

• 作为反应物：
  描述：

  奥美沙坦 50.0 ℃ 、80.0 Pa 条件下， 反应 72.0h， 以1205 mg的产率得到奥美沙坦二聚酯杂质
  参考文献：
  名称：

  一种奥美沙坦酯二聚体杂质的制备分离方法

  摘要：

  本发明提供了一种奥美沙坦酯二聚体杂质的制备分离方法，其包括以下步骤：步骤S1，将奥美沙坦放于40～60℃下的真空环境下进行自身聚合反应，得到含有奥美沙坦酯二聚体杂质的粗品；步骤S2，采用超临界流体色谱对步骤S1所得的粗品中的奥美沙坦酯USP杂质C与其他成分进行洗脱分离，收集奥美沙坦酯二聚体杂质峰流分，把收集到的奥美沙坦酯二聚体杂质流分蒸干，便可得到奥美沙坦酯二聚体杂质。本发明的技术方案通过一步法反应生成奥美沙坦酯二聚体杂质，反应效率高、步骤简便、高效，后处理简单、成本低，污染小。

  公开号：

  CN111004223A
• 作为产物：
  描述：

  奥美沙坦酯 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 20.0h， 以90%的产率得到奥美沙坦
  参考文献：
  名称：

  抗高血压药奥美沙坦酯相关物质的合成

  摘要：

  奥美沙坦酯 1 是 FDA 批准用于治疗高血压的最新血管紧张素受体拮抗剂。在奥美沙坦酯的工艺开发过程中，观察到四种相关物质（杂质）以及最终的 API。这些杂质被鉴定为奥美沙坦酸、4-乙酰奥美沙坦、5-乙酰奥美沙坦和脱氢奥美沙坦。目前的工作描述了所有这四种杂质的合成和表征。

  DOI：

  10.3998/ark.5550190.0011.224

文献信息

• A process for the preparation or purification of olmesartan medoxomil
  申请人：LEK Pharmaceuticals d.d.

  公开号：EP2022790A1

  公开（公告）日：2009-02-11

  The present invention relates to a process for the preparation and purification of olmesartan medoxomil. The invention also relates to products obtainable by the process of the invention, to pharmaceutical compositions comprising the products and to their use in medicine, particularly to treat hypertension.

  本发明涉及一种用于制备和纯化奥美沙坦酯酯的方法。该发明还涉及通过该方法获得的产品，包括含有这些产品的药物组合物以及它们在医学上的应用，特别是用于治疗高血压。
• Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their
  申请人：Sankyo Company, Limited

  公开号：US05616599A1

  公开（公告）日：1997-04-01

  Compounds of the following formula (I) or the formula (I).sub.p : ##STR1## wherein R.sup.1 is alkyl or alkenyl; R.sup.2 and R.sup.3 are hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, aryl, or aryl fused to cycloalkyl; R.sup.4 is hydrogen, alkyl, alkanoyl, alkenoyl, arylcarbonyl, alkoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, tetrahydrofuryl, a group of formula --SiR.sup.a R.sup.b R.sup.c, in which R.sup.a, R.sup.b and R.sup.c are alkyl or aryl, alkoxymethyl, (alkoxyalkoxy)methyl, haloalkoxymethyl, aralkyl, aryl or alkanoyloxymethoxycarbonyl; R.sup.5 is carboxy or --CONR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 hydrogens or alkyl, or R.sup.8 and R.sup.9 together form alkylene; R.sup.6 is hydrogen, alkyl, alkoxy or halogen; R.sup.7 is carboxy or tetrazol-5-yl; R.sub.p.sup.1 is hydrogen, alkyl, cycloalkyl or alkanoyl; R.sub.p.sup.2 is a single bond, alkylene or alkylidene; R.sub.p.sup.3 and R.sub.p.sup.4 are each hydrogen or alkyl; R.sub.p.sup.6 is carboxy or tetrazol-5-yl; and X.sub.p is oxygen or sulfur; and pharmaceutically acceptable salts and esters thereof. The compounds are AII receptor antagonists and thus have hypotensive activity and can be used for the treatment and prophylaxis of hypertension. The compounds may be prepared by reacting a biphenylmethyl compound with an imidazole compound.

  以下式(I)或式(I).sub.p的化合物：其中R.sup.1是烷基或烯基；R.sup.2和R.sup.3是氢、烷基、烯基、环烷基、芳基烷基、芳基或与环烷基融合的芳基；R.sup.4是氢、烷基、烷酰基、烯酰基、芳基羰基、烷氧羰基、四氢吡喃基、四氢硫代吡喃基、四氢噻吩基、四氢呋喃基，具有式--SiR.sup.a R.sup.b R.sup.c的基团，其中R.sup.a、R.sup.b和R.sup.c是烷基或芳基、烷氧甲基、(烷氧基烷氧基)甲基、卤代烷氧甲基、芳基烷基、芳基或烷酰氧甲氧羰基；R.sup.5是羧基或--CONR.sup.8 R.sup.9，其中R.sup.8和R.sup.9是氢或烷基，或R.sup.8和R.sup.9一起形成亚烷基；R.sup.6是氢、烷基、烷氧基或卤素；R.sup.7是羧基或四唑-5-基；R.sub.p.sup.1是氢、烷基、环烷基或烷酰基；R.sub.p.sup.2是单键、烷基或烷基亚甲基；R.sub.p.sup.3和R.sub.p.sup.4分别是氢或烷基；R.sub.p.sup.6是羧基或四唑-5-基；X.sub.p是氧或硫；以及其药学上可接受的盐和酯。这些化合物是AII受体拮抗剂，因此具有降压活性，可用于治疗和预防高血压。这些化合物可以通过将联苯甲基化合物与咪唑化合物反应制备而成。
• [EN] PROCESS FOR OLMESARTAN MEDOXOMIL<br/>[FR] PROCÉDÉ DE PRÉPARATION D'OLMÉSARTAN MÉDOXOMIL
  申请人：HETERO RESEARCH FOUNDATION

  公开号：WO2012001694A1

  公开（公告）日：2012-01-05

  The present invention provides a process for the preparation of substantially pure trityl olmesartan medoxomil. The present invention also provides a process for purification of trityl olmesartan medoxomil. The present invention further provides a process for purification of olmesartan medoxomil.

  本发明提供了一种用于制备基本纯的三苯甲基奥美沙坦酯的方法。本发明还提供了一种用于纯化三苯甲基奥美沙坦酯的方法。本发明还提供了一种用于纯化奥美沙坦酯的方法。
• Understanding and Controlling the Formation of an <i>N</i>-Alkyl Impurity in Olmesartan Medoxomil: A Derivative via Michael-Type Addition between Tetrazole and Mesityl Oxide In Situ Generated from Acetone
  作者：Jianwu Lu、Yinfei Shi、Xiao Li、Xiaomin Liang、Yinquan Wang、Shun Yuan、Taizhi Wu

  DOI：10.1021/acs.oprd.0c00506

  日期：2021.5.21

  2-yl-protected olmesartan medoxomil by NMR and mass spectrometry (MS). The formation mechanism of this impurity was investigated. In summary, the tetrazole of the final product was condensed with the potential genotoxic compound mesityl oxide generated from acetone self-condensation in acidic conditions to form the N-Alkyl impurity. Further quality control of the reaction was investigated using statistical

  在奥美沙坦medoxomil活性药物成分（API）中检测到未知杂质，通过NMR和质谱（MS）确定该杂质为2-甲基-4-氧戊丹-2-基保护的奥美沙坦medoxomil。研究了该杂质的形成机理。总而言之，将最终产物的四唑与在酸性条件下由丙酮自缩合生成的潜在的遗传毒性化合物异氰酸酯缩合，以形成N-烷基杂质。通过确定的筛选设计，使用统计方法（实验设计，DoE）对反应的进一步质量控制进行了研究。确定反应的关键因素以控制工艺参数。三批验证实验表明，N的生成-烷基杂质被抑制（＜0.1％），并且未检测到残留的均三甲苯氧化物（＜2.5ppm）。
• PROCESS FOR OLMESARTAN MEDOXOMIL
  申请人：Parthasaradhi Reddy Bandi

  公开号：US20130190506A1

  公开（公告）日：2013-07-25

  The present invention provides a process for the preparation of substantially pure trityl olmesartan medoxomil. The present invention also provides a process for purification of trityl olmesartan medoxomil. The present invention further provides a process for purification of olmesartan medoxomil.

  本发明提供了一种制备基本纯的三苯基奥美沙坦酯醇酸酯的方法。本发明还提供了一种三苯基奥美沙坦酯醇酸酯的纯化方法。本发明还提供了一种奥美沙坦酯醇酸酯的纯化方法。