双氯苯卓醇 | 848-75-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 中文名称: 双氯苯卓醇
• 中文别名: 氯甲西泮
• 英文名称: lormetazepam
• 英文别名: 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-1-methyl-2H-1,4-benzodiazepin-2-one；7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-1-methyl-2H-1,4-benzodiazepin-2-one；methyllorazepam；7-chloro-5-(2-chloro-phenyl)-3-hydroxy-1-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one；7-Chlor-1,3-dihydro-3-hydroxy-1-methyl-5-(o-chlor-phenyl)-2H-1,4-benzodiazepin-2-on；7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-3H-1,4-benzodiazepin-2-one
• CAS: 848-75-9
• 化学式: C₁₆H₁₂Cl₂N₂O₂
• 分子量: 335.189
• InChiKey: FJIKWRGCXUCUIG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  52.9
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

通过葡萄糖醛酸苷结合代谢成无活性代谢物

Metabolised to an inactive metabolite via glucuronide conjugation

来源:DrugBank

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

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

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：劳瑞安定（Lormetazepam）未获得美国食品药品监督管理局（U.S. Food and Drug Administration）在美国市场的批准。劳瑞安定在母乳中的含量较低，且相对于许多其他苯二氮卓类药物，其半衰期较短。有限的证据来自哺乳母亲，表明在常规的母亲剂量下，劳瑞安定不会对哺乳的婴儿造成任何不良反应。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：五名产后2到3天的妇女每天晚上8点服用2毫克的劳瑞安定，持续10天，并完全用母乳喂养她们的婴儿。研究作者指出，在研究期间，任何婴儿都没有出现药理学的或不良反应。

◉ Summary of Use during Lactation:Lormetazepam is not approved for marketing in the United States by the U.S. Food and Drug Administration. Lormetazepam has low levels in breastmilk and a short half-life relative to many other benzodiazepines. Limited evidence from nursing mothers indicates that lorazepam does not cause any adverse effects in breastfed infants with usual maternal dosages. Monitor the infant for sedation, poor feeding and poor weight gain. ◉ Effects in Breastfed Infants:Five women who were 2 to 3 days postpartum took 2 mg of lormetazepam daily at 8 pm for 10 days and fully breastfed their infants. The authors of the study noted no pharmacological or adverse effects in any of the infants during the study.

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类药物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。长期使用苯二氮卓类药物的患者、摄入降低癫痫发作阈值的物质的患者、或有心动过速或癫痫病史的患者禁用。通常情况下，医疗观察和支持性护理是治疗苯二氮卓过量的主要手段。尽管苯二氮卓类药物可以被活性炭吸收，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了该程序可能带来的任何潜在益处。只有在苯二氮卓类药物与其他可能从净化中受益的药物联合使用时，才建议使用。胃灌洗（胃抽吸）或全肠灌洗也不推荐使用。

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)

反应信息

• 作为反应物：
  描述：

  双氯苯卓醇 在 18-冠醚-6 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 3.5h， 生成 Succinic acid 7-chloro-5-(2-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 7-methoxy-2-oxo-2H-chromen-4-ylmethyl ester
  参考文献：
  名称：

  Janssen; Hulst; Kellogg, Pharmazie, 2000, vol. 55, # 1, p. 42 - 48

  摘要：

  DOI：
• 作为产物：
  描述：

  7-chloro-5-(2-chlorophenyl)-1-methyl-3-acetoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one 在 水 、 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以176.3 g的产率得到双氯苯卓醇
  参考文献：
  名称：

  氯甲西泮的晶型及其制备方法

  摘要：

  本发明涉及氯甲西泮，具体涉及一种氯甲西泮的晶型及其制备方法。所述的氯甲西泮的晶型X射线粉末衍射图的反射角2θ在12.20°、14.69°、14.77°、18.43°、18.55°、20.85°、21.19°、24.43°、28.32°处具有特征峰。其制备方法是将溶剂加入到氯甲西泮粗品中，升温至回流，待粗品全部溶解后，继续保温回流，回流完毕过滤，滤液经降温、保温析晶后，再进行过滤，滤饼经干燥至恒重，得到氯甲西泮的晶型。本发明的制备方法简单易行，易于实现。

  公开号：

  CN105601576A

文献信息

• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
• [EN] COMT INHIBITING METHODS AND COMPOSITIONS<br/>[FR] PROCÉDÉS D'INHIBITION DE LA COMT ET COMPOSITIONS ASSOCIÉES
  申请人：LIEBER INST FOR BRAIN DEV

  公开号：WO2016123576A1

  公开（公告）日：2016-08-04

  The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinson's disease and/or schizophrenia.

  这些发明包括一种抑制受试者中COMT酶的方法，以及式I的化合物或其药用可接受盐，这些化合物在治疗由COMT介导的各种疾病中有用，包括帕金森病和/或精神分裂症。

表征谱图