甲麦角新碱 | 113-42-8

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 垂体激素类药
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 麦角林及其衍生物
• 中文名称: 甲麦角新碱
• 英文名称: methylergonovine
• 英文别名: methylergometrine；Methylergobrevin；(6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4-3-indolo[4,3-fg]quinoline-9-carboxamide；Methergine；6-methyl-9,10-didehydro-ergoline-8β-carboxylic acid-((S)-1-hydroxymethyl-propylamide)；(6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
• CAS: 113-42-8
• 化学式: C₂₀H₂₅N₃O₂
• 分子量: 339.437
• InChiKey: UNBRKDKAWYKMIV-QWQRMKEZSA-N

物化性质

• 熔点：
  172-173℃ (decomposition)
• 比旋光度：
  D20 -45° (c = 0.4 in pyridine)
• 沸点：
  475.4°C (rough estimate)
• 密度：
  1.1492 (rough estimate)
• 物理描述：
  Solid
• 颜色/状态：
  Prisms from methanol, acetone
• 溶解度：
  In water, 691 mg/L at 25 °C (est)
• 蒸汽压力：
  7.75X10-14 mm Hg at 25 °C (est)
• 稳定性/保质期：
  It must be protected from light and heat /Maleate/
• 旋光度：
  Specific optical rotation: -45 deg at 20 °C/D
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 解离常数：
  pKa = 9.11 (piperidine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  68.4
• 氢给体数：
  3
• 氢受体数：
  3

ADMET

代谢

肝脏的，具有广泛的首次通过代谢。

Hepatic, with extensive first-pass metabolism.

来源:DrugBank

代谢

麦角生物碱主要通过肝脏代谢和排泄消除，口服给药后生物利用度降低可能是由于肝脏的首过代谢作用。

Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏的，具有广泛的首次通过代谢。 消除途径：麦角生物碱主要通过肝脏代谢和排泄，口服给药后生物利用度降低可能是肝脏首次通过代谢的结果。 半衰期：3.39小时

Hepatic, with extensive first-pass metabolism. Route of Elimination: Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver. Half Life: 3.39 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

Ergoline alkaloids have been shown to have the significant affinity towards the 5-HT1 and 5-HT2 serotonin receptors, D1 and D2 dopamine receptors, and alpha-adrenergic receptors. This can result in a number of different effects, including vasoconstriction, convulsions, and hallucinations. (A2914, A2915, A2916) translating into Chinese Ergoline alkaloids have been shown to have the significant affinity towards the 5-HT1 and 5-HT2 serotonin receptors, D1 and D2 dopamine receptors, and alpha-adrenergic receptors. This can result in a number of different effects, including vasoconstriction, convulsions, and hallucinations. (A2914, A2915, A2916) Ergoline alkaloids have been shown to have the significant affinity towards the 5-HT1 and 5-HT2 serotonin receptors, D1 and D2 dopamine receptors, and alpha-adrenergic receptors. This can result in a number of different effects, including vasoconstriction, convulsions, and hallucinations. (A2914, A2915, A2916)

Ergoline alkaloids have been shown to have the significant affinity towards the 5-HT1 and 5-HT2 serotonin receptors, D1 and D2 dopamine receptors, and alpha-adrenergic receptors. This can result in a number of different effects, including vasoconstriction, convulsions, and hallucinations. (A2914, A2915, A2916)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：甲基麦角新碱

Compound:methylergonovine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服（60%生物利用度）和肌肉注射（78%生物利用度）后吸收迅速。

Absorption is rapid after oral (60% bioavailability) and intramuscular (78% bioavailability) administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

麦角生物碱主要通过肝脏代谢和排泄消除，口服给药后生物利用度降低可能是由于肝脏的首过代谢作用。

Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver.

来源:DrugBank

吸收、分配和排泄

• 分布容积

56.1 ± 0 L

56.1 ± 0 L

来源:DrugBank

吸收、分配和排泄

延迟的胃肠道吸收（达峰时间大约3小时）可能会在产后妇女使用缩宫素类似物甲麦角新碱片剂持续治疗期间观察到。

A delayed gastrointestinal absorption (Tmax about 3 hours) of methylergonovine tablets might be observed in postpartum women during continuous treatment with this oxytocic agent.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

药物动力学研究表明，静脉注射后，甲基麦角新碱在2-3分钟或更短时间内从血浆迅速分布到周围组织。口服给药的生物利用度报告约为60%，重复剂量后无累积。在分娩时，通过肌肉注射，生物利用度增加到78%。麦角生物碱主要通过肝脏代谢和排泄，口服给药后生物利用度下降可能是肝脏首过代谢的结果。

Pharmacokinetic studies following an iv injection have shown that methylergonovine is rapidly distributed from plasma to peripheral tissues within 2-3 minutes or less. The bioavailability after oral administration was reported to be about 60% with no accumulation after repeated doses. During delivery, with intramuscular injection, bioavailability increased to 78%. Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  甲麦角新碱 在 咪唑 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 N-溴代丁二酰亚胺(NBS) 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 9.83h， 生成 (6aR,9R)-N-[(2S)-1-[tert-butyl(diphenyl)silyl]oxybutan-2-yl]-5,7-dimethyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
  参考文献：
  名称：

  NOVEL METHYSERGIDE DERIVATIVES

  摘要：

  本发明提供了新颖的美西麦角衍生物及其组合物。在其他实施例中，本发明提供了治疗、预防或缓解各种医疗疾病或其症状的方法，例如使用本文披露的化合物和组合物治疗偏头痛和帕金森病。在其他实施例中，本发明提供了例如使用本文披露的化合物和组合物拮抗5-HT2B受体而不激动5-HT2B受体的方法。在其他实施例中，本发明提供了例如使用本文披露的化合物和组合物激动5-HT1A受体的方法。

  公开号：

  US20140179730A1
• 作为产物：
  描述：

  6-methyl-9,10-didehydro-5α-ergoline-8β-carboxylic acid-((S)-1-hydroxymethyl-propylamide) 在 氢氧化钾 、 苄胺 作用下， 生成 甲麦角新碱
  参考文献：
  名称：

  Semonsky; Cerny, Collection of Czechoslovak Chemical Communications, 1957, vol. 22, p. 1866,1868,1871

  摘要：

  DOI：

文献信息

• [EN] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
  申请人：MERCK SHARP & DOHME

  公开号：WO2013169567A1

  公开（公告）日：2013-11-14

  The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及螺内酰胺类似物，其为CGRP受体拮抗剂，可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。
• [EN] IMIDAZOLINONE DERIVATIVES AS CGRP RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS D'IMIDAZOLINONE EN TANT QU'ANTAGONISTES DE RÉCEPTEURS CGRP
  申请人：MERCK SHARP & DOHME

  公开号：WO2010077752A1

  公开（公告）日：2010-07-08

  The present invention is directed to imidazolinone derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及嘧啶啉酮衍生物，其为CGRP受体拮抗剂，可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。
• [EN] BUPRENORPHINE ANALOGS<br/>[FR] ANALOGUES DE BUPRÉNORPHINE
  申请人：PURDUE PHARMA LP

  公开号：WO2012038813A1

  公开（公告）日：2012-03-29

  The present invention is directed to Buprenorphine Analog compounds of the Formula (I), Formula (IA) or Formula (IB) shown below, wherein R1, R2, R8, R 3a, R 3b, G, X, Z and Y are as defined herein. Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors.

  本发明涉及如下所示的公式(I)、公式(IA)或公式(IB)的丁丙诺啡类似物化合物，其中R1、R2、R8、R 3a、R 3b、G、X、Z和Y的定义如本文所述。本发明的化合物可用于治疗疼痛、便秘以及通过阿片类和ORL-1受体的活性调节的其他状况。
• PYRIDINE AND PIPERIDINE DERIVATIVES AND USE THEREOF
  申请人：Purdue Pharma L.P.

  公开号：US20150141434A1

  公开（公告）日：2015-05-21

  The invention provides compounds that are useful as sodium channel blockers. In one aspect, the invention provides compounds of Formula I: or pharmaceutically acceptable salts, solvates, hydrates, or diastereomers thereof, wherein R 1 , R 4 , X, G, n, p, W 1 , W 2 , W 3 , W 4 , and the E ring are defined in the disclosure. In certain embodiments, the invention provides compounds of Formulae II-XIII as set forth supra. The invention also provides the use of compounds of any of the above discussed formulae to treat a disorder responsive to blockade of sodium channels. In one embodiment, Compounds of the Invention are useful for treating pain.

  本发明提供了一种用作钠通道阻断剂的化合物。在一方面，本发明提供了公式I的化合物： 或其药用可接受的盐、溶剂化物、水合物或对映异构体，其中R1、R4、X、G、n、p、W1、W2、W3、W4和E环在公开中定义。在某些实施例中，本发明提供了上述公式II-XIII的化合物。本发明还提供了使用上述任何讨论公式的化合物来治疗对钠通道阻断有反应的疾病。在一个实施例中，发明化合物用于治疗疼痛。
• [EN] BIOREVERSABLE PROMOIETIES FOR NITROGEN-CONTAINING AND HYDROXYL-CONTAINING DRUGS<br/>[FR] PRO-FRAGMENTS BIORÉVERSIBLES POUR MÉDICAMENTS CONTENANT DE L'AZOTE ET DE L'HYDROXYLE
  申请人：BAIKANG SUZHOU CO LTD

  公开号：WO2015081891A1

  公开（公告）日：2015-06-11

  Disclosed are promoieties of the following formula which can be used to form prodrugs of nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent: (I) and pharmaceutical compositions comprising the prodrugs.

  披露了以下公式的促销性质，它们可用于形成含有氮或羟基的药物或药物活性剂的的前药：(I)以及包含这些前药的药物组合物。