安乃近酸 | 50567-35-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 安乃近酸
• 中文别名: 2-{3-[4-(4-氯苯基)哌嗪-1-基]丙基}-4-乙基-5-(1-羟基乙基)-2,4-二氢-3H-1,2,4-三唑-3-酮；[(2,3-二氢-1,5-二甲基-3-氧代-2-苯基-1H-吡唑-4-基)甲基氨基]甲烷磺酸
• 英文名称: Metamizol
• 英文别名: Metamizole；[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)-methylamino]methanesulfonic acid
• CAS: 50567-35-6
• 化学式: C₁₃H₁₇N₃O₄S
• 分子量: 311.362
• InChiKey: LVWZTYCIRDMTEY-UHFFFAOYSA-N

物化性质

• 密度：
  1.46±0.1 g/cm3(Predicted)
• 熔点：
  131-132 °C (decomp)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  89.5
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

美他佐辛（Metamizole）会迅速水解为活性成分4-甲基氨基安替比林（MAA）。MAA随后通过c-氧化代谢转化为4-甲酰氨基安替比林（FAA），以及通过N-去甲基化代谢转化为4-氨基安替比林（AA）。MAA的N-去甲基化主要是由CYP3A4介导，尽管CYP2B6、CYP2C8和CYP2C9也可能参与其中。FAA是终末代谢产物，而AA则通过N-乙酰转移酶乙酰化形成4-乙酰氨基安替比林（AAA）。在静脉注射美他佐辛后，未改变的药物可能存在于血浆中；然而，在口服给药后，无法在血浆或尿液中检测到。

Metamizole undergoes rapid hydrolysis to the active moiety 4-methyl-amino-antipyrine (MAA). MAA is then metabolized to 4-formyl-amino-antipyrine (FAA) via c-oxidation and 4-amino-antipyrine (AA) via N-demethylation. The N-demethylation of MAA is mainly mediated by CYP3A4, although CYP2B6, CYP2C8 and CYP2C9 may also be involved. FAA is an end metabolite, while AA is acetylated by N-acetyl-transferase to form 4-acetyl-amino-antipyrine (AAA). The unchanged drug may be present in plasma following the intravenous administration of metamizole; however, following oral administration, it cannot be detected in plasma or urine.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概述：母亲摄入后，安乃近及其代谢物以相当大的量出现在母乳中。在母乳喂养婴儿的血液和尿液中可以发现，并可能在母乳喂养婴儿中产生药理效应。一例母乳喂养婴儿出现青紫发作，归因于母乳中的安乃近。在服用剂量后48小时内，药物及其代谢物从母乳中消除。 安乃近未在美国获得食品药品监督管理局的市场批准，也未在加拿大和许多欧洲国家获得批准，因为其不良反应，包括粒细胞缺乏症。然而，在其他国家在分娩和哺乳期间广泛使用。欧洲药品管理局建议不要在哺乳期母亲中使用安乃近；然而，以色列的几个药物咨询中心不同意。一家制造商建议在服用剂量后48小时内暂停哺乳。在哺乳期间有更安全的镇痛替代品可用。 ◉ 对母乳喂养婴儿的影响：一名42天大的母乳喂养婴儿在母亲口服安乃近500毫克3剂，分别在第一次发作前18、7和2小时，30分钟内出现了2次青紫发作。第三次发作发生在入院后24小时。在最后一剂服用后24小时，在母亲的母乳中和婴儿的血清和尿液中检测到了安乃近。除了安乃近之外，无法找到青紫发作的解释，在暂停母亲的安乃近摄入后，婴儿在3岁之前没有再发生进一步的发作。这种反应被认为是可能由母乳中的安乃近引起的。 在一项双盲研究中，至少分娩后3天的母亲因产后子宫疼痛请求镇痛，被给予1克安乃近或安慰剂。在药物给药后14小时内，接受安乃近的母亲所生的婴儿哭泣次数较少，持续时间较短，比接受安慰剂的母亲所生的婴儿更明显。这种效果在按需喂养的婴儿中比在固定时间喂养的婴儿中更为明显。尽管这项研究似乎表明了母乳中的安乃近在婴儿身上的药理效应，但婴儿行为改变的原因尚无明确解释。 在巴西的一项多中心病例对照研究中，比较了在2岁前发展成白血病的231名儿童与411名患有各种其他非恶性疾病的儿童。对母亲进行了访谈，以确定她们在怀孕和哺乳期间使用镇痛药的情况。在分娩后三个月内服用安乃近的哺乳期母亲，其孩子患急性淋巴细胞白血病的风险增加了2倍，在一岁以下婴儿中MLL基因重排的风险增加了3.87倍。 ◉ 对哺乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:After ingestion by the mother, dipyrone and its metabolites appear in breastmilk in rather large amounts. It is found in the blood and urine of breastfed infants and can cause pharmacological effects in the breastfed infant. One case of cyanotic episodes in a breastfed infant was attributed to dipyrone in breastmilk. The drug and metabolites are eliminated from the breastmilk by 48 hours after a dose. Dipyrone is not approved for marketing in the United States by the U.S. Food and Drug Administration nor in Canada and many European countries because of its adverse reactions, including agranulocytosis. However, it is widely used in other countries during labor and breastfeeding. The European Medicines Agency recommends that dipyrone not be used in nursing mothers; however, several drug consultation centers in Israel disagree. One manufacturer recommends to withhold breastfeeding for 48 hours after a dose. Safer alternatives are available for analgesia during breastfeeding. ◉ Effects in Breastfed Infants:A 42-day-old breastfed infant had 2 cyanotic episodes within 30 minutes after his mother took 3 doses of dipyrone 500 mg orally, 18, 7 and 2 hours before the first episode. A third episode occurred 24 hours after admission to the hospital. Dipyrone was detected in the mother's breastmilk 24 hours after the last dose and in the infant's serum and urine. No explanation could be found for the cyanotic episodes other than dipyrone and after suspending maternal dipyrone intake, no further episodes occurred in the infant up to age 3 years. The reaction is rated as possibly caused by dipyrone in breastmilk. In a blinded study, mothers who were at least 3 days postpartum and requesting analgesia for postpartum uterine pain were given either 1 gram of dipyrone or placebo. The infants of mothers who received dipyrone cried fewer times and for shorter durations in the 14 hours after drug administration than the infants of mothers who received placebo. This effect was more apparent in infants who demand fed than in those who fed on a fixed schedule. Although this study appears to demonstrate a pharmacologic effect in the infants from dipyrone in milk, there is no clear explanation for the change in infant behavior. A multicenter case-control study in Brazil compared 231 children who developed leukemia before 2 years of age with 411 children with various other nonmalignant diseases. Mothers were interviewed to ascertain their analgesic use during pregnancy and lactation. Nursing mothers who took dipyrone during the three months after delivery had a 2-fold risk of having a child with acute lymphocytic leukemia and a 3.87-fold risk in having rearrangement of the MLL gene in infants under one year of age. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

美洛昔康及其代谢物的蛋白质结合率较低，其中代谢物4-甲基氨基安替比林、4-甲酰氨基安替比林、4-氨基安替比林和4-乙酰氨基安替比林的平均结合率为60%。

The protein binding of metamizole and its metabolites is low, with an average of 60% for the metabolites 4-methyl-amino-antipyrine, 4-formyl-amino-antipyrine, 4-amino-antipyrine and 4-acetyl-amino-antipyrine.

来源:DrugBank

吸收、分配和排泄

• 吸收

美他佐辛在胃液中水解为4-甲基氨基安替比林（MAA），并主要以这种形式被吸收。MAA的生物利用度因给药途径而异。给予美他佐辛片的患者，MAA的生物利用度为85%，给予滴剂的患者为89%，给予栓剂的患者为54%，给予肌肉注射的患者为87%。美他佐辛口服剂量与MAA Cmax之间存在线性关系。在口服剂量在0.75至3克之间时，tmax在1.4-2.0小时达到。

Metamizole is hydrolyzed to 4-methyl-amino-antipyrine (MAA) in gastric juice and is mostly absorbed in this form. MAA bioavailability differs based on the administration route. In patients given metamizole tablets, the bioavailability of MAA is 85%, in patients given drops, 89%, in patients given suppositories, 54%, and in patients given an intramuscular injection, 87%. There is a linear relationship between metamizole oral dose and MAA Cmax. After oral doses ranging between 0.75 and 3 g, the tmax is reached at 1.4-2.0 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

静脉或口服给药后，90%的安乃近在尿液中回收，而10%在粪便中回收。大约60%的四种安乃近代谢物（4-甲基氨基安替比林、4-甲酰氨基安替比林、4-氨基安替比林和4-乙酰氨基安替比林）通过尿液排出。

After intravenous or oral administration, 90% of metamizole is recovered in urine, while 10% is recovered in feces. Approximately 60% of four metamizole metabolites (4-methyl-amino-antipyrine, 4-formyl-amino-antipyrine, 4-amino-antipyrine and 4-acetyl-amino-antipyrine) are excreted through urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

美他佐辛（Metamizole）迅速代谢为4-甲基氨基安替比林（MAA），其活性代谢物。MAA的分布体积为1.15 L/kg。

Metamizole is quickly metabolized into 4-methyl-amino-antipyrine (MAA), its active metabolite. MAA has a volume of distribution of 1.15 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

4-甲基氨基安替比林（MAA），美沙拉嗪的活性代谢物，在口服给药后的清除率范围为110 mL/min至180 mL/min。

The clearance of 4-methyl-amino-antipyrine (MAA), the active metabolite of metamizole, ranges from 110 mL/min to 180 mL/min after oral administration.

来源:DrugBank

制备方法与用途

甲氨咪唑是一种用于治疗甲状腺疾病的抗甲状腺药物，能够抑制甲状腺激素的生成。安乃近则可能引发肝脏损伤。

反应信息

• 作为反应物：
  描述：

  安乃近酸 在 双氧水 、 horseradish peroxidase 作用下， 以 水 为溶剂， 反应 24.0h， 以35%的产率得到Oxalsaeure-mono(2-acetyl-2-methyl-1-phenyl)hydrazid
  参考文献：
  名称：

  Characterization of oxalic acid derivatives as new metabolites of metamizol (dipyrone) in incubated hen's egg and human

  摘要：

  Metamizol (dipyrone, 1), a widely used drug with effective analgesic and antispasmodic properties, shows severe side effects like agranulocytosis and anaphylactic shock reactions, the reasons of which are not known until today. After oral administration 1 is completely metabolized. All hitherto known metabolites have an intact pyrazolinone ring structure like the parent compound and are completely extractable from urine with polar organic solvents. However, only a fractional amount of the applied dosage can be recovered by this procedure. To clarify the reason of this deficit of unknown metabolites we followed the hypothesis of oxidative rupture of the heterocyclic ring during metabolism of 1. on the basis of former in vitro results we now were able to identify in quality three oxalic acid derivatives and one acetic acid phenylhydrazide as new metabolites of metamizol in the allantoic fluid (AF) of incubated hen's eggs as well as in human urine by means of GC-MS analysis and comparison with unequivocally synthesized authentic reference compounds. Whereas the oxamazide 7, the phenylhydrazide 8 and N-methyloxamic acid 9 are only present in trace concentrations and therefore cannot account for the deficit in the balance of metabolites, the oxalic acid monohydrazide 11 seems to be excreted in higher amount. But quantitative determination of this new metabolite would be required to answer the open questions concerning the biotransformation of metamizol and thereby to detect new facts about mode of action and side effects of this drug. (c) 2005 Elsevier B.V.All rights reserved.

  DOI：

  10.1016/j.ejps.2005.11.010
• 作为产物：
  描述：

  metamizol 在 盐酸 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以93.3%的产率得到安乃近酸
  参考文献：
  名称：

  1-苯基-2,3-二甲基-4-甲氨基吡唑啉-5-酮-N-甲基磺酸镁六水合物的制备

  摘要：

  本申请公开了一种1‑苯基‑2,3‑二甲基‑4‑甲氨基吡唑啉‑5‑酮‑N‑甲基磺酸镁六水合物的制备方法。所述方法包括以安乃近酸为原料，在反应介质中与镁盐反应得到所述1‑苯基‑2,3‑二甲基‑4‑甲氨基吡唑啉‑5‑酮‑N‑甲基磺酸镁六水合物。本发明工艺简单，制备出的安乃近镁的收率较高、质量高且工艺稳定，适宜于工业化大规模生产。

  公开号：

  CN109897002B

文献信息

• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。
• CYCLODEXTRIN-BASED POLYMERS FOR THERAPEUTIC DELIVERY
  申请人：Cerulean Pharma Inc.

  公开号：US20130196906A1

  公开（公告）日：2013-08-01

  Provided are methods relating to the use of CDP-therapeutic agent conjugates for the treatment of a disease or disorder, e.g., autoimmune disease, inflammatory disease, central nervous system disorder, cardiovascular disease, or metabolic disorder. Also provided are CDP-therapeutic agent conjugates, particles comprising CDP-therapeutic agent conjugates, and compositions comprising CDP-therapeutic agent conjugates.

  提供了关于使用CDP-治疗剂偶联物治疗疾病或紊乱的方法，例如自身免疫疾病、炎症性疾病、中枢神经系统紊乱、心血管疾病或代谢紊乱。还提供了CDP-治疗剂偶联物、包含CDP-治疗剂偶联物的颗粒以及包含CDP-治疗剂偶联物的组合物。
• [EN] PEPTIDE-BASED MULTIPLE-DRUG DELIVERY VEHICLE<br/>[FR] VÉHICULE D'ADMINISTRATION DE MÉDICAMENTS MULTIPLES À BASE DE PEPTIDES
  申请人：ARIEL-UNIVERSITY RES AND DEV COMPANY LTD

  公开号：WO2017068577A1

  公开（公告）日：2017-04-27

  A molecular structure comprising a targeting moiety, a multi-functional peptide platform and a plurality of controllably released bioactive agents attached thereto is provided herein.

  本文提供了一种包括靶向基团、多功能肽平台和附着在其上的多种可控释放的生物活性剂的分子结构。
• DIAZENIUMDIOLATED NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, COMPOSITIONS THEREOF, AND RELATED METHODS
  申请人：Velázquez Carlos A.

  公开号：US20090186859A1

  公开（公告）日：2009-07-23

  Disclosed are compounds that release nitric oxide, e.g., a compound of Formula (I) wherein R 1-10 , X, and n are as described herein, which are NSAID derivatives comprising a diazeniumdiolate moiety N 2 O 2 − . The compounds are chemopreventive agents with gastric-sparing, analgesic, cardioprotective, and/or anti-inflammatory properties. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed is a method of preventing or treating cancer or treating inflammation or an inflammation-related condition in a mammal comprising administering an effective amount of a compound of the invention to the mammal.

  披露了释放一氧化氮的化合物，例如，式(I)的化合物，其中R1-10、X和n如本文所述，这些化合物是非甾体抗炎药（NSAID）衍生物，包含亚硝基二醇基团N2O2−。这些化合物是具有胃保护、镇痛、心脏保护和/或抗炎特性的化学预防剂。还披露了一种药物组合物，包括本发明的化合物和药用载体。还披露了一种预防或治疗癌症或治疗炎症或炎症相关状况的方法，包括向哺乳动物施用本发明的化合物的有效量。
• 2,5-DIALKYL-4-H/HALO/ETHER-PHENOL COMPOUNDS
  申请人：Tansna Therapeutics Inc.

  公开号：US20150148430A1

  公开（公告）日：2015-05-28

  The present disclosure provides phenolic compounds useful in the treatment of neurological conditions such as convulsions and tremors, having the structure of Formula (I): wherein R 2 , R 4 , & R 5 , are as defined in the detailed description; pharmaceutical compositions comprising at least one of the compounds; and methods for treating neurological conditions.

  本公开提供用于治疗诸如惊厥和震颤等神经学状况的酚类化合物，其具有公式（I）的结构： 其中R2、R4和R5如详细描述中定义；包含至少一种该化合物的药物组合物；以及用于治疗神经学状况的方法。