依米丁 | 483-18-1

• 物质功能分类: 原料药 - 抗寄生虫病药 - 抗阿米巴病及抗滴虫病药
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吐根碱生物碱
• 中文名称: 依米丁
• 英文名称: (+-)-Emetin
• 英文别名: (+/-)-emetine；(+/-)-Emetin；Emetin；d,l-Emetin；rac-Emetin；Emetine；(2S,3R,11bS)-2-[[(1R)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]-3-ethyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizine
• CAS: 483-18-1
• 化学式: C₂₉H₄₀N₂O₄
• 分子量: 480.648
• InChiKey: AUVVAXYIELKVAI-CKBKHPSWSA-N

物化性质

• 熔点：
  89-96°C
• 比旋光度：
  D20 -50° (c = 2 in CHCl3)
• 沸点：
  578.63°C (rough estimate)
• 密度：
  1.1174 (rough estimate)
• 溶解度：
  溶于水 (100 毫克/毫升)
• 颜色/状态：
  WHITE AMORPHOUS POWDER
• 味道：
  Very bitter taste
• 稳定性/保质期：

  TURNS YELLOW ON EXPOSURE TO LIGHT AND HEAT.

• 旋光度：
  SPECIFIC OPTICAL ROTATION: -50 DEG @ 20 °C/D (CHLOROFORM, 2%)
• 分解：
  When heated to decomposition it emits highly toxic fumes of /nitrogen oxides/.
• 解离常数：
  PK1 5.77; PK2 6.64
• 碰撞截面：
  219.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  52.2
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

emetine的氨基酰化

AMINOACYLATION OF EMETINE

来源:Hazardous Substances Data Bank (HSDB)

代谢

吐根碱在肝脏中代谢缓慢，尿液中可检测到代谢物持续40-60天。

Emetine undergoes slow hepatic metabolism, with urine metabolites detectable for 40-60 days ... .

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在大鼠孤立的胃底平滑肌中，用5-15微克吐根碱预处理10分钟可以拮抗前列腺素E2诱导的收缩增加。最大抑制作用在10和15微克吐根碱时获得。

IN ISOLATED RAT FUNDUS SMOOTH MUSCLE, PRETREATMENT FOR 10 MIN WITH 5-15 UG EMETINE ANTAGONIZED THE INCREASED CONTRACTIONS INDUCED BY PROSTAGLANDIN E2. MAX INHIBITION WAS OBTAINED WITH 10 AND 15 UG EMETINE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 医疗监测

SRP：应对接触吐根碱的工人进行身体检查，重点评估和监测心脏、肝脏和肾脏功能。

SRP: Physical exam of workers exposed to emetine should emphasize evaluation and monitoring of cardiac, liver and kidney function.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

心血管反应是最严重的，包括胸痛、呼吸困难、心动过速、低血压、奔马律、心脏扩张、充血性心力衰竭和死亡。吐根制剂。

CARDIOVASCULAR REACTIONS ARE THE MOST SERIOUS AND INCLUDE PRECORDIAL PAIN, DYSPNEA, TACHYCARDIA, HYPOTENSION, GALLOP RHYTHM, CARDIAC DILATATION, CONGESTIVE FAILURE AND DEATH. /EMETINE FORMULATIONS/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

副反应/在肌肉注射或皮下注射后/观察到50-75%使用吐根素治疗的人出现。/吐根素制剂/

ADVERSE REACTIONS /FOLLOWING SC OR IM INJECTION/ ARE OBSERVED IN 50-75% OF INDIVIDUALS TREATED WITH EMETINES. /EMETINE FORMULATIONS/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

心电图变化表现为传导延迟，可能持续较长时间（平均6周）。变化包括QRS复合波增宽，P-R和Q-T间期延长，S-T段改变以及T波的平坦或倒置。......心肌和其他器官可能会受到损伤。

ELECTROCARDIOGRAPHIC CHANGES ARE THOSE OF CODUCTION DELAY AND CAN BE OF LONG DURATION (AVG, 6 WEEKS). ALTERATIONS INCLUDE WIDENING OF QRS COMPLEX, PROLONGATION OF P-R AND Q-T INTERVALS, CHANGES IN S-T SEGMENT AND FLATTENING OR INVERSION OF T WAVE. ... INJURY TO MYOCARDIUM AND OTHER ORGANS MAY OCCUR.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

EMETINE从给药的 parenteral 站点被吸收并且被缓慢排泄...。

EMETINE IS ABSORBED FROM PARENTERAL SITES OF ADMINISTRATION & IS EXCRETED ... SLOWLY.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

药物在注射后20-40分钟出现在尿液中，但在治疗停止后40-60天仍能在尿液中检测到吐根碱。 ... 在肝脏中发现的生物碱浓度最高 ... 在肺、肾和脾脏中也能检测到相当数量的生物碱。

ALTHOUGH DRUG APPEARS IN URINE 20-40 MIN AFTER INJECTION, EMETINE CAN STILL BE FOUND THERE 40-60 DAYS AFTER TREATMENT HAS BEEN DISCONTINUED. ... HIGHEST CONCN OF ALKALOID IS FOUND IN LIVER ... APPRECIABLE AMT ARE ALSO FOUND IN LUNG, KIDNEY, & SPLEEN.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... 乙基吗啡显示出在肌肉器官中积累的偏好 ...

... EMETINE SHOWS A PREDILECTION FOR ACCUMULATING IN MUSCULAR ORGANS ... .

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险品运输编号：
  UN 1544

制备方法与用途

抗阿米巴病药物——依米丁（又称吐根碱），对阿米巴大滋养体有直接杀灭作用，但对肠腔内的小滋养体和包囊无效。适用于治疗急性阿米巴痢疾及肠外阿米巴病，能够迅速控制临床症状，但难以达到根治目的。

反应信息

• 作为反应物：
  描述：

  依米丁 在 氢溴酸 、 溶剂黄146 作用下， 反应 1.0h， 以100%的产率得到emethine dihydrobromide
  参考文献：
  名称：

  Cytotoxic Alangium alkaloids from Alangium longiflorum

  摘要：

  Seven alkaloids (1-7) were isolated from the stem bark of Alangium longiflorum. Compound 1, (-)-10-O-demethylisocephaeline, was isolated for the first time as a naturally occurring product from a plant source. All structures were elucidated by detailed spectroscopic analysis. Biological evaluation showed that 2, 10-O-demethylcephaeline, exhibited potent cytotoxic activity against human lung carcinoma (A549) and breast adenocarcinoma (MCF-7) with ED50 values of 0.013 and 0.062 mu M, respectively. The stereoisomer 1 was less potent than 2, and related compounds with different hydroxy/methoxy substitution patterns were also less potent or inactive. Thus, compound 2 merits attention as a cytotoxic lead for further study. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.phytochem.2006.01.009
• 作为产物：
  描述：

  (S)-tert-butyl 1-allyl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 palladium on activated charcoal 、 Cl[(1S,2S)-N-p-Ts-1,2-diphenylethanediamine](p-cymene)Ru(II) 甲酸 、 三氟甲磺酸三甲基硅酯 、 氢气 、 三甲基铝 、 苯基锂 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 49.1h， 生成 依米丁
  参考文献：
  名称：

  Formal Total Synthesis of (−)-Emetine Using Catalytic Asymmetric Allylation of Cyclic Imines as a Key Step

  摘要：

  Catalytic asymmetric allylation of 3,4-dihydro-6,7-dimethoxyisoquinoline was carried out using allyltrimethoxysilane in the presence of Cu(I) and tol-BINAP. The allyl adduct thus obtained was transformed to a chiral synthetic intermediate for (-)-emetine in good yield. The procedure was applied to the total synthesis of ent-emetine.

  DOI：

  10.1021/ol0530326

文献信息

• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。
• [EN] AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION<br/>[FR] DÉGRONIMÈRES DE C3-GLUTARIMIDE LIÉS À UNE AMINE POUR LA DÉGRADATION DE PROTÉINES CIBLES
  申请人：C4 THERAPEUTICS INC

  公开号：WO2017197051A1

  公开（公告）日：2017-11-16

  This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.

  这项发明提供了胺连接的C3-戊二酰亚胺Degronimers和Degrons，用于治疗应用，如本文进一步描述的，以及它们的使用方法、组合物以及它们的制备方法。
• [EN] TRICYCLIC TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY<br/>[FR] COMPOSÉS TRIAZOLES TRICYCLIQUES MODULANT L'ACTIVITÉ HSP90
  申请人：SYNTA PHARMACEUTICALS CORP

  公开号：WO2009139916A1

  公开（公告）日：2009-11-19

  The present invention relates to substituted tricyclic triazole compounds and compositions comprising substituted tricyclic triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

  本发明涉及替代三环三唑化合物和包含替代三环三唑化合物的组合物。该发明还涉及在需要的受体中抑制Hsp90活性的方法，以及预防或治疗高增殖性疾病（如癌症）的方法，其中包括向受体施用本发明的化合物或包含这种化合物的组合物。
• [EN] ISOTOPE ENHANCED AMBROXOL FOR LONG LASTING AUTOPHAGY INDUCTION<br/>[FR] AMBROXOL À ISOTOPE AMÉLIORÉ POUR INDUCTION D'AUTOPHAGIE DURABLE
  申请人：STC UNM

  公开号：WO2018148113A1

  公开（公告）日：2018-08-16

  The present invention is directed to 13C and/or 2H isotope enhanced ambroxol ("isotope enhanced ambroxol") and its use in the treatment of autophagy infections, especially mycobacterial and other infections, disease states and/or conditions of the lung, such as tuberculosis, especially including drug resistant and multiple drag resistant tuberculosis. Pharmaceutical compositions comprising isotope enhanced amhroxol, alone or in combination with an additional bioactive agent, especially rifamycin antibiotics, including an additional autophagy modulator (an agent which is active to promote or inhibit autophagy), thus being useful against, an autophagy mediated disease state and/or condition), especially an antophagy mediated disease state and/or condition which occurs in the lungs, for example, a Mycobacterium infection. Chronic Obstructive Pulmonary Disease (COPD), asthma, pulmonary fibrosis, cystic fibrosis, Sjogren's disease and lung cancer (small cell and non-small cell lung cancer, among other disease states and/or conditions, especially of the lung. Methods of treating autophagy disease states and/or conditions, especially including autophagy disease states or conditions which occur principally in the lungs of a patient represent a further embodiment of the present invention. An additional embodiment includes methods of synthesizing compounds according to the present invention as otherwise disclosed herein.

  本发明涉及13C和/或2H同位素增强的氨溴索（“同位素增强的氨溴索”）及其在治疗自噬感染，特别是结核分枝杆菌和其他感染、疾病状态和/或肺部疾病条件中的用途，如肺结核，特别是包括耐药和多重耐药结核病。包括同位素增强的氨溴索的药物组合物，单独或与额外的生物活性剂（特别是利福霉素类抗生素，包括额外的自噬调节剂（一种能够促进或抑制自噬的剂），因此对抗自噬介导的疾病状态和/或条件有用），特别是在肺部发生的自噬介导的疾病状态和/或条件，例如分枝杆菌感染。慢性阻塞性肺病（COPD）、哮喘、肺纤维化、囊性纤维化、干燥综合征和肺癌（小细胞和非小细胞肺癌等其他肺部疾病状态和/或条件，特别是肺部疾病状态和/或条件。治疗自噬疾病状态和/或条件的方法，特别包括治疗主要发生在患者肺部的自噬疾病状态或条件的方法，代表本发明的另一实施例。另一实施例包括根据本发明在此披露的其他方法合成化合物的方法。
• Complex drug delivery composition and method for treating cancer
  申请人：Minko Tamara

  公开号：US20050043215A1

  公开（公告）日：2005-02-24

  The present invention relates to compositions and methods for producing a complex drug delivery system which specifically targets cancer cells, has an increase in cellular uptake, is cytotoxic, and suppresses antiapoptotic cellular defenses.

  本发明涉及用于制备特异靶向癌细胞、具有细胞摄取增加、具有细胞毒性并抑制抗凋亡细胞防御的复杂药物输送系统的组合物和方法。