乙替唑仑 | 40054-69-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻烯杂卓类
• 中文名称: 乙替唑仑
• 中文别名: 依替唑仑
• 英文名称: etizolam
• 英文别名: ZINC00001402；Depas；4-(2-chloro-phenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine；etinozolam；7-(2-chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene
• CAS: 40054-69-1
• 化学式: C₁₇H₁₅ClN₄S
• 分子量: 342.852
• InChiKey: VMZUTJCNQWMAGF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.235
• 拓扑面积：
  71.3
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

乙替唑仑的生物转化是广泛的，涉及羟基化和结合。通过1'-羟基化形成的主要代谢物是α-羟基乙替唑仑，它保留了与母药相当的药理活性，表明代谢物的作用可能有助于乙替唑仑的临床效果。预测CYP3A4是介导乙替唑仑代谢的主要CYP酶。CYP2C18和CYP2C19也参与代谢途径。

Biotransformation of etizolam is extensive and involves hydroxylation and conjugation. The main metabolite formed via 1'-hydroxylation is α-hydroxyetizolam which retains pharmacological activity comparable to that of the parent drug, indicating that the action of metabolites may contribute to the clinical effects of etizolam. CYP3A4 is predicted to be the main CYP enzyme responsible for mediating etizolam metabolism. CYP2C18 and CYP2C19 are also involved in the metabolic pathways.

来源:DrugBank

代谢

7-(2-氯苯基)-4-乙基-13-甲基-3-噻嗪-1,8,11,12-四氮杂三环[8.3.0.02,6]十三碳-2(6),4,7,10,12-五烯-9-醇和alpha-羟基艾替唑仑。

Etizolam has known human metabolites that include 7-(2-chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-ol and alpha-Hydroxyetizolam.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

苯二氮卓类药物非特异性地与苯二氮卓受体BNZ1结合，后者介导睡眠，以及与BNZ2结合，影响肌肉松弛、抗惊厥活性、运动协调和记忆。由于认为苯二氮卓受体与γ-氨基丁酸-A (GABAA) 受体相耦合，这通过增加GABA对GABA受体的亲和力来增强GABA的效果。抑制性神经递质GABA结合到该位点时，会打开氯离子通道，导致细胞膜超极化，阻止细胞进一步兴奋。

Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构IARC清单）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概要：依替唑仑没有获得美国食品药品监督管理局在美国市场的批准。关于依替唑仑进入母乳的信息非常有限。在哺乳新生儿或早产儿时，应优先选择其他药物。如果使用依替唑仑，需监测婴儿是否出现镇静、进食不良和体重增长不良的情况。 ◉ 对哺乳婴儿的影响：一名妇女在产后3个月内每日一次服用1毫克的依替唑仑和50毫克的曲唑酮。她的婴儿超过50%的时间接受母乳喂养，在1个月和3个月的检查中没有表现出不良反应。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Etizolam is not approved for marketing in the United States by the U.S. Food and Drug Administration. Very little information is available on the passage of etizolam into milk. An alternate drug is preferred, especially while nursing a newborn or preterm infant. If etizolam is used, monitor the infant for sedation, poor feeding and poor weight gain. ◉ Effects in Breastfed Infants:A woman took etizolam 1 mg and trazodone 50 mg once daily for 3 months postpartum. Her infant was over 50% breastfed and demonstrated no adverse reactions at the 1- and 3-month checkups. ◉ 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

• 暴露处理

一般支持性措施应予以实施，包括静脉输液，并保持气道通畅。低血压可以通过使用去甲肾上腺素或美芬丁胺来对抗。透析的价值有限。氟马西尼（安易醒）是一种竞争性的苯二氮卓受体拮抗剂，可以用作苯二氮卓过量的解毒剂。特别是，氟马西尼在逆转与苯二氮卓相关的中枢神经系统抑制方面非常有效，但在逆转呼吸抑制方面效果较差。然而，其使用存在争议，因为它有许多禁忌症。长期服用苯二氮卓的患者、服用降低癫痫发作阈值的物质的患者，或心动过速或有癫痫病史的患者禁用。一般来说，医疗观察和支持性护理是治疗苯二氮卓过量的主要方法。尽管苯二氮卓可以通过活性炭吸收，但在纯苯二氮卓过量中，使用活性炭进行胃部净化并无益处，因为不良反应的风险往往超过该程序可能带来的任何潜在益处。只有在苯二氮卓与其他可能从净化中受益的药物一起服用时，才建议使用。胃灌洗（胃抽吸）或全肠灌洗也不推荐。

General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained. Hypotension may be combated by the use of norepinephrine or metaraminol. Dialysis is of limited value. Flumazenil (Anexate) is a competitive benzodiazepine receptor antagonist that can be used as an antidote for benzodiazepine overdose. In particular, flumazenil is very effective at reversing the CNS depression associated with benzodiazepines but is less effective at reversing respiratory depression. Its use, however, is controversial as it has numerous contraindications. It is contraindicated in patients who are on long-term benzodiazepines, those who have ingested a substance that lowers the seizure threshold, or in patients who have tachycardia or a history of seizures. As a general rule, medical observation and supportive care are the mainstay of treatment of benzodiazepine overdose. Although benzodiazepines are absorbed by activated charcoal, gastric decontamination with activated charcoal is not beneficial in pure benzodiazepine overdose as the risk of adverse effects often outweigh any potential benefit from the procedure. It is recommended only if benzodiazepines have been taken in combination with other drugs that may benefit from decontamination. Gastric lavage (stomach pumping) or whole bowel irrigation are also not recommended.

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

Etizolam从肠道吸收良好，口服给药的生物利用度为93%。单次口服0.5毫克Etizolam后，大约需要0.9小时达到峰值血浆浓度8.3 ng/mL。

Etizolam is well absorbed from the intestines with a biological bioavailability of 93% following oral administration. After a single oral dosing of 0.5mg etizolam, it takes approximately 0.9 hours to reach the peak plasma concentration of 8.3 ng/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在大鼠研究中，排泄的乙替唑仑有30%通过尿液，70%通过粪便；而在小鼠研究中，尿液中的排泄量为40%，粪便中的排泄量为60%。

In a rat study, the amounts of etizolam excreted was 30% in urine was 70% in feces, while the values in a mouse study were 40% in urine and 60% in feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

表观分布容积在一次口服0.5毫克艾司唑仑后为0.9 ± 0.2 L/kg。

Apparent distribution volume was 0.9 ± 0.2 L/kg following a single oral doing of 0.5mg etizolam.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  乙替唑仑 在 air 作用下， 以 甲醇 为溶剂， 反应 7.0h， 生成 1-[4-(2-chloro-phenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-ethanone
  参考文献：
  名称：

  Tahara; Araki; Shiroki, Arzneimittel-Forschung/Drug Research, 1978, vol. 28, # 7, p. 1153 - 1158

  摘要：

  DOI：
• 作为产物：
  描述：

  4-(2-chloro-phenyl)-2-ethyl-9-methyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 在 potassium permanganate 作用下， 以 丙酮 为溶剂， 生成 乙替唑仑
  参考文献：
  名称：

  Weber,K.-H. et al., Justus Liebigs Annalen der Chemie, 1978, p. 1257 - 1265

  摘要：

  DOI：

文献信息

• Substituted 1,3-thiazole compounds, their production and use
  申请人：——

  公开号：US20040053973A1

  公开（公告）日：2004-03-18

  (1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.

  (1) 一种1,3-噻唑化合物，其5位被取代为含有一个取代基的4-吡啶基团，该取代基不包括芳香基，或者(2) 一种1,3-噻唑化合物，其5位被取代为一个吡啶基团，该吡啶基团的氮原子邻近位置有一个取代基，该取代基不包括芳香基，具有出色的p38 MAP激酶抑制活性。
• [EN] TREATMENT OF AUTISM SPECTRUM DISORDERS, OBSESSIVE-COMPULSIVE DISORDER AND ANXIETY DISORDERS<br/>[FR] TRAITEMENT DE TROUBLES DU SPECTRE AUTISTIQUE, DE TROUBLES OBSESSIVO-COMPULSIFS ET DE TROUBLES DE L'ANXIÉTÉ
  申请人：RUGEN HOLDINGS CAYMAN LTD

  公开号：WO2018098128A1

  公开（公告）日：2018-05-31

  Disclosed are methods for treating NMDA receptor-mediated disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. NMDA receptor-mediated disorders include autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders.

  揭示了通过给予特定NR2B亚单位选择性NMDA（N-甲基-D-天冬氨酸）拮抗剂来治疗NMDA受体介导的疾病的方法。NMDA受体介导的疾病包括自闭症谱系障碍、强迫症和焦虑症。
• [EN] TREATMENT OF ANXIETY DISORDERS AND AUTISM SPECTRUM DISORDERS<br/>[FR] TRAITEMENT DES TROUBLES DE L'ANXIÉTÉ ET DES TROUBLES DU SPECTRE AUTISTIQUE
  申请人：RUGEN HOLDINGS CAYMAN LTD

  公开号：WO2016049048A1

  公开（公告）日：2016-03-31

  Disclosed are methods for treating autism spectrum disorders and/or anxiety disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. Anxiety disorders include agoraphobia (with or without panic disorder), generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD).

  本文披露了通过给予特定NR2B亚单位选择性NMDA（N-甲基-D-天冬氨酸）拮抗剂来治疗自闭症谱系障碍和/或焦虑障碍的方法。焦虑障碍包括广场恐惧症（伴有或不伴有惊恐障碍）、广泛性焦虑障碍（GAD）、社交焦虑障碍（SAD）、惊恐障碍（PD）、创伤后应激障碍（PTSD）和强迫症（OCD）。
• BENZAZEPINE DERIVATIVE, PROCESS FOR PRODUCING THE SAME, AND USE
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP1422228A1

  公开（公告）日：2004-05-26

  The present invention provides a novel benzazepine derivative represented by formula : wherein, R1 is a 5- or 6-membered aromatic ring, R2 is lower alkyl group, etc., Y is an optionally substituted imino group, ring A and ring B are independently an optionally substituted aromatic ring, W is formula -W1-X2-W2- (W1 and W2 are independently S(O)m1 (m1 is 0, 1 or 2), etc., and X2 is an optionally substituted alkylene groupetc. ), a preparation method and use thereof.

  本发明提供了一种新型的苯并氮杂环衍生物，其由以下公式表示： 其中，R1是一个5-或6-成员的芳香环，R2是低级烷基团等，Y是可选地取代的亚氨基，环A和环B是独立地选自一个可选地取代的芳香环，W是公式-W1-X2-W2-（W1和W2是独立地为S(O)m1（m1是0、1或2）等，X2是一个可选地取代的亚烷基团等），其制备方法及其用途。
• [EN] HETEROCYCLIC COMPOUNDS AND THEIR USE AS RETINOID-RELATED ORPHAN RECEPTOR (ROR) GAMMA-T INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES ET LEUR UTILISATION EN TANT QU'INHIBITEURS GAMMA-T DU RÉCEPTEUR ORPHELIN APPARENTÉ AUX RÉCEPTEURS DES RÉTINOÏDES (ROR) )
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2016002968A1

  公开（公告）日：2016-01-07

  Provided are heterocyclic compounds having a RORγt inhibitory action represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.

  提供的是具有RORγt抑制作用的杂环化合物，其由公式(I)表示：其中每个符号如说明书中定义，或其盐。