溴替唑仑 | 57801-81-7

• 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: 溴替唑仑
• 中文别名: 2-溴-4-(2-氯苯基)-9-甲基-6H-噻嗯并[3,2-F][1,2,4]三唑并[4,3-Α][1,4]苯并二氮杂卓
• 英文名称: brotizolam
• 英文别名: 2-Brom-4-(2-chlorphenyl)-9-methyl-6H-thieno<3,2-f><1,2,4>triazolo<4,3-a><1,4>diazepin；2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine；Brotizolam (We 941)；Lendormin；2-bromo-4-(2-chloro-phenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine；4-bromo-7-(2-chlorophenyl)-13-methyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene
• CAS: 57801-81-7
• 化学式: C₁₅H₁₀BrClN₄S
• 分子量: 393.694
• InChiKey: UMSGKTJDUHERQW-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：
  从乙醇中可获得无色结晶，其熔点为212～214℃。急性毒性实验显示：小鼠和大鼠口服该物质的半数致死剂量（LD50）均大于10000毫克/千克；而腹腔注射时，小鼠的LD50约为920毫克/千克，大鼠为1000毫克/千克。

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.133
• 拓扑面积：
  71.3
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

有两种主要代谢物：1-甲基-羟基-和4-羟基-衍生物（Eberts等人，1981年；勃林格殷格翰，产品信息）。4-羟基代谢物的药理活性远低于母药，但1-甲基-羟基代谢物可能具有相当的活性（Gall等人，1978年；Jochemsen等人，1982年；Sethy和Harris，1982年；Jochemsen等人，未发表结果）。然而，在给年轻健康受试者单次服用溴替唑仑后，这些活性化合物在血浆中并未以可测量量存在（Jochemsen等人，1982年；Jochemsen等人，未发表结果）。

There are two primary metabolites: 1-methyl-hydroxy- and the 4-hydroxy-derivatives (Eberts et al., 1981; Boehringer Ingelheim, product information). The 4-hydroxymetabolites have a pharmacological activity which is far less than that of the parent drugs, but the 1-methyl-hydroxymetabolites probably have comparable activity (Gall et al., 1978; Jochemsen et al., 1982; Sethy & Harris, 1982; Jochemsen et al., unpublished results). These active compounds are, however, not present in plasma in measurable amounts following a single dose of brotizolam to young healthy subjects (Jochemsen et al., 1982; Jochemsen et al., unpublished results).

来源:DrugBank

代谢

Brotizolam 已知的人类代谢物包括 6-羟基-BRT 和 alpha-羟基-BRT。

Brotizolam has known human metabolites that include 6-hydroxy-BRT and alpha-hydroxy-BRT.

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，防止细胞进一步兴奋。

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

◉ 母乳喂养期间使用总结：布托唑仑在美国未获得食品药品监督管理局的市场批准。关于布托唑仑进入乳汁的信息非常有限，尽管乳汁中的量似乎非常低。在哺乳新生儿或早产儿时，可能会优先选择其他药物。如果使用布托唑仑，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：一名双相情感障碍的妇女在孕期和产后每天接受布托唑仑0.25毫克、阿普唑仑0.4毫克和曲唑酮50毫克的治疗。她还每天接受舍曲林25毫克的治疗，逐渐增加到每天两次100毫克。婴儿因新生儿戒断综合症被送往新生儿ICU，并于出生后第8天出院。母亲在每天服用布托唑仑0.25毫克、舍曲林50毫克两次、阿普唑仑0.4毫克和唑吡坦10毫克的情况下，纯母乳喂养了3个月的婴儿。在1个月、3个月和6个月的检查中没有发现与药物相关的不良反应。 ◉ 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:Brotizolam 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 brotizolam into milk, although amounts in milk appear to be very low. An alternate drug might be preferred, especially while nursing a newborn or preterm infant. If brotizolam is used, monitor the infant for sedation, poor feeding and poor weight gain. ◉ Effects in Breastfed Infants:A woman with bipolar disorder received brotizolam 0.25 mg, alprazolam 0.4 mg, and trazodone 50 mg daily during pregnancy and postpartum. She also received sertraline 25 mg daily, which was increased gradually to 100 mg twice daily. The infant was admitted to the neonatal ICU for neonatal abstinence syndrome and was discharged on day 8 of life. The mother exclusively breastfed her infant for 3 months while taking brotizolam 0.25 mg daily, sertraline 50 mg twice daily, alprazolam 0.4 mg daily and zolpidem 10 mg daily. No drug-related adverse effects were detected at the 1-, 3-, or 6-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，氟马西尼非常有效地逆转与苯二氮卓相关的中枢神经系统抑制，但对逆转呼吸抑制的效果较差。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不有益，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。只有当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)

毒理性

• 蛋白质结合

自由分数的平均值（%）：8.4 ± 0.7。

The mean value of the free fraction (%): 8.4 ± 0.7.

来源:DrugBank

吸收、分配和排泄

• 吸收

溴替唑仑的血浆浓度曲线可以用具有一级吸收的单室开放模型来描述。

The plasma concentration profile of brotizolam can be described as a one compartmental open model with first-order absorption.

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.63升/千克。

0.63 l/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

总清除率：109毫升/分钟。

Total clearance: 109 ml/min.

来源:DrugBank

制备方法与用途

制备方法： 11.5g 的7-溴-5-(2-氯苯基)-3H-噻嗯并[2，3-e][1，4]苯并二氮杂卓-2-酮(I)、100ml 无水吡啶和6.5g 五硫化磷，在55～60℃下搅拌4小时。冷却后，将其倾入100ml 的饱和冰盐水中。过滤收集析出的沉淀，用水洗涤。然后溶于100ml 二氯甲烷中，干燥，浓缩。剩余物加入少量三氯甲烷，过滤得6g 棕色的化合物(Ⅱ)结晶，熔点214℃（分解）。

6.0g 化合物(Ⅲ)悬浮在100ml 四氢呋喃中，加入1.2g 水合肼，在室温下搅拌20分钟。浓缩至10ml 后，加入20ml 乙醚。过滤收集结晶，得5.2g 化合物(Ⅲ)，熔点约300℃（分解）。

5.2g 化合物(Ⅲ)悬浮在50ml 原乙酸三乙酯中，在80℃下加热30分钟，得到澄清溶液。放置冷却后，过滤收集析出的结晶，并用乙醚洗涤，得5g 溴替唑仑，熔点211～213℃。

合成制备方法： 同上步骤。

用途简介和用途： 有苯并二氮杂卓类的抗激动、抗惊厥、肌肉松弛以及催眠等作用。主要用于入睡障碍和通眠障碍（午夜醒后不易再入睡）者。

反应信息

• 作为反应物：
  描述：

  溴替唑仑 在 manganese(IV) oxide 、 sodium tetrahydroborate 、 copper(l) iodide 、 palladium diacetate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (E)-4-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-1-oxo-2-propenyl}morpholine
  参考文献：
  名称：

  Thienotriazolodiazepines作为血小板活化因子拮抗剂。第2位取代基的空间限制。

  摘要：

  描述了在2-位带有取代的乙炔基的噻吩并氮杂二氮杂卓的制剂，以及相应的顺式烯烃和完全饱和的类似物。在体外和体外测试模型中，将这些化合物评估为血小板活化因子（PAF）的潜在拮抗剂。将新的噻吩并氮杂二氮杂卓与已知的相关化合物如WEB 2086（化合物6）和苯乙基衍生物27和28进行了比较。

  DOI：

  10.1021/jm00108a031
• 作为产物：
  描述：

  2-bromo-4-(2-chloro-phenyl)-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 溴替唑仑
  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

• [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