7-氯-5-(2-氯苯基)-1,3-二氢-3H-1,4-苯并二氮杂卓-2-酮 | 2894-67-9

• 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: 7-氯-5-(2-氯苯基)-1,3-二氢-3H-1,4-苯并二氮杂卓-2-酮
• 中文别名: 地洛西泮；7-氯-5-(2-氯苯基)-1,3-二氢-2H-1,4-苯并二氮杂卓-2-酮；7-氯-5-(邻-氯苯基)-1,3-二氢-2H-1,4-苯并杂卓-2-酮
• 英文名称: delorazepam
• 英文别名: 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one；7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one
• CAS: 2894-67-9
• 化学式: C₁₅H₁₀Cl₂N₂O
• 分子量: 305.163
• InChiKey: CHIFCDOIPRCHCF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.066
• 拓扑面积：
  41.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

Delorazepam 在肝脏中的代谢速度相对较慢。主要代谢物（占母药的15-34%）是劳拉西泮。老年患者的 Delorazepam 代谢速度比年轻患者慢。

Delorazepam is metabolized at a relatively slow pace by the liver. The major metabolite (15-34% of the parent drug) is lorazepam. Older patients metabolize delorazepam slower than younger patients.

来源:DrugBank

代谢

Delorazepam 在肝脏中的代谢速度相对较慢。主要代谢物（占母药的15-34%）是劳拉西泮。老年患者的 Delorazepam 代谢速度比年轻患者慢。

Delorazepam is metabolized at a relatively slow pace by the liver. The major metabolite (15-34% of the parent drug) is lorazepam. Older patients metabolize delorazepam slower than younger patients.

来源:Toxin and Toxin Target Database (T3DB)

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，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

• 暴露途径

77-87% 口服生物利用度，吸收速率相对较慢。在给药后1-2小时内达到血浆峰值。食物可能会延缓吸收，然而其他药代动力学变量保持不变。多次给药后，去甲劳拉西泮会积累，但在年轻患者中积累较慢。

77-87% oral bioavailability, with a relatively slow absorption rate. Reaches peak plasma levels within 1-2 hours of administration. Food may slow absorption, however other pharmacokinetic variables remain unchanged. After multiple doses delorazepam accumulates, however accumulation is slower in younger patients.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

年长的患者代谢去甲劳拉西泮的速度比年轻的患者慢，因此遭受更多的副作用。

Older patients metabolize delorazepam slower than younger patients and thus suffer from more adverse effects.

来源:Toxin and Toxin Target Database (T3DB)

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norepinephrine（去甲肾上腺素）或metaraminol（甲氧胺）来对抗。透析的价值有限。Flumazenil（安克塞特）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，flumazenil非常有效地逆转与苯二氮卓类药物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，它的使用是有争议的，因为它有许多禁忌症。长期服用苯二氮卓类药物的患者、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不有益，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联合使用时，才建议使用。胃灌洗（胃抽吸）或全肠道灌洗也不推荐。

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

77-87% 口服生物利用度，吸收速率相对较慢。在给药后1-2小时内达到血浆峰值。食物可能会延缓吸收，然而其他药代动力学变量保持不变。多次给药后，去甲劳拉西泮会积累，尽管在年轻患者中积累速度较慢。

77-87% oral bioavailability, with a relatively slow absorption rate. Reaches peak plasma levels within 1-2 hours of administration. Food may slow absorption, however other pharmacokinetic variables remain unchanged. After multiple doses delorazepam accumulates, although accumulation is slower in younger patients.

来源:DrugBank

吸收、分配和排泄

• 消除途径

肾脏消除。

Renally eliminated.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在11名肾功能正常患者中，表观分布容积为140 L/kg；在11名肾功能衰竭并定期进行血液透析的患者中，表观分布容积为47 L/kg。在另一项研究中，8名肝脏疾病患者的表观分布容积为65 L/kg，而在12名健康对照者中为118.4 L/kg。

140 L/kg apparent volume of distribution in 11 patients with normal renal function; 47 L/kg in 11 patients with renal failure and on regular hemodialysis. In another study, apparent volume of distribution was 65 L/kg in 8 patients with liver disease and 118.4 L/kg in 12 healthy controls.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康患者中，给药后72小时仍可检测到。患有肝病的患者的清除率从0.13降低到0.25 ng/mLh。

Still detectable 72 hours after dosing in healthy patients. Patients with liver disease experienced a reduction in clearance from 0.13 to 0.25 ng/mLh.

来源:DrugBank

制备方法与用途

制备方法

用于劳拉西泮、三唑仑、氯马唑仑等原料药的合成。

用途简介

暂无相关信息。

反应信息

• 作为反应物：
  描述：

  7-氯-5-(2-氯苯基)-1,3-二氢-3H-1,4-苯并二氮杂卓-2-酮 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成 7-氯-2-氧代-5-(2-氯苯基)-1,4-苯并二氮杂卓-4-氧化物
  参考文献：
  名称：

  劳拉西泮连续流动合成的开发

  摘要：

  劳拉西泮是一种广泛使用的镇静剂，出现在世界卫生组织的基本药物清单中，经常出现短缺。使用涉及路线探索、高通量实验和杂质分析的工作流程来开发最佳序列，我们报告了一种用于流式合成劳拉西泮的新型 5 步路线。这五个步骤包括 N-酰化、二氮杂环闭合、亚胺 N-氧化、Polonovski 型重排和酯水解得到劳拉西泮。每个步骤都经过优化并转化为连续流动。对于 5 步序列，每个单独流动反应的平均停留时间总计为 72.5 分钟。我们还报告了对纯度和副产品概况的综合分析，以最大限度地提高每一步所需的产品纯度，从而产生超过 99% 的纯度劳拉西泮。

  DOI：

  10.1021/acs.oprd.2c00184
• 作为产物：
  描述：

  2-氯乙酰氨基-2',5-二氯二苯甲酮 在 ammonium hydroxide 作用下， 以 乙醇 为溶剂， 反应 2.5h， 生成 7-氯-5-(2-氯苯基)-1,3-二氢-3H-1,4-苯并二氮杂卓-2-酮
  参考文献：
  名称：

  咪唑啉丁-4-酮的合成及其转化为1,4-苯并二氮杂-2-酮

  摘要：

  α-卤代乙酰苯胺Ia-e与乙醇中的六胺反应，生成双咪唑啉丁-4-酮衍生物IIa-e，该衍生物在酸性介质中水解成相应的单咪唑啉丁-4-酮Ⅲa-e。在不同条件下，在多种试剂的存在下，化合物IIa-d被转化为1,4-苯并二氮杂-2-酮。产率在50％至100％之间。

  DOI：

  10.1002/jhet.5570180523

文献信息

• [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）。
• [EN] 5-HT2C RECEPTOR AGONISTS AND COMPOSITIONS AND METHODS OF USE<br/>[FR] AGONISTES DE RÉCEPTEUR 5-HT2C ET COMPOSITIONS ET PROCÉDÉS D'UTILISATION
  申请人：ARENA PHARM INC

  公开号：WO2017023679A1

  公开（公告）日：2017-02-09

  Provided in some embodiments are compounds of Formula A, as defined herein, that modulate the activity of 5-HT2C receptor. Also provided in some embodiments are methods, such as, for weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction, pathological gambling, reward deficiency syndrome, and sex addiction), obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders (including insomnia, fragmented sleep architecture, and disturbances of slow-wave sleep), urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea.

  在某些实施例中提供了一些符合本文所定义的A式化合物，其调节5-HT2C受体的活性。在某些实施例中还提供了一些方法，例如用于体重管理、诱导饱腹感、减少食物摄入，以及预防和治疗肥胖、抗精神病药物引起的体重增加、2型糖尿病、普拉德-威利综合征、烟草/尼古丁依赖、药物成瘾、酒精成瘾、病理性赌博、奖赏缺乏综合征和性成瘾，强迫症谱系障碍和冲动控制障碍（包括咬指甲和咬甲症），睡眠障碍（包括失眠、睡眠结构碎裂和慢波睡眠紊乱），尿失禁，精神障碍（包括精神分裂症、厌食症和暴食症），阿尔茨海默病，性功能障碍，勃起功能障碍，癫痫，运动障碍（包括帕金森病和抗精神病药物引起的运动障碍），高血压，血脂异常，非酒精性脂肪肝病，肥胖相关肾脏疾病和睡眠呼吸暂停症。
• [EN] 5-HT2C RECEPTOR AGONISTS AND COMPOSITIONS AND METHODS OF USE<br/>[FR] AGONISTES DU RÉCEPTEUR 5-HT2C ET COMPOSITIONS ET PROCÉDÉS D'UTILISATION
  申请人：ARENA PHARM INC

  公开号：WO2015066344A1

  公开（公告）日：2015-05-07

  Provided are 5-HT2C receptor agonists. Also provided are methods for weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction, pathological gambling, reward deficiency syndrome, and sex addiction), obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders (including insomnia, fragmented sleep architecture, and disturbances of slow-wave sleep), urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea. Also provided are compositions comprising a selective 5-HT2C receptor agonist, optionally in combination with a supplemental agent, and methods for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product; aiding in smoking cessation and preventing associated weight gain; controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising administering a selective 5-HT2C receptor agonist, optionally in combination with a supplemental agent.

  提供了5-HT2C受体激动剂。还提供了用于体重管理、诱导饱腹感、减少食物摄入量、预防和治疗肥胖、抗精神病药物引起的体重增加、2型糖尿病、普拉德-威利综合征、烟草/尼古丁依赖、药物成瘾、酒精成瘾、病态赌博、奖赏缺乏综合征和性成瘾）、强迫症谱系障碍和冲动控制障碍（包括咬指甲和咬甲）、睡眠障碍（包括失眠、睡眠结构碎裂和慢波睡眠紊乱）、尿失禁、精神障碍（包括精神分裂症、厌食症和暴食症）、阿尔茨海默病、性功能障碍、勃起功能障碍、癫痫、运动障碍（包括帕金森病和抗精神病药物引起的运动障碍）、高血压、血脂异常、非酒精性脂肪肝病、肥胖相关肾脏疾病和睡眠呼吸暂停。还提供了包含选择性5-HT2C受体激动剂的组合物，可选地与辅助剂结合，以及用于减少个体尝试减少吸烟频率的吸烟频率；帮助个体戒除或减少使用烟草制品的个体戒除或减少使用烟草制品；帮助戒烟并预防相关体重增加；通过个体尝试戒烟来控制与戒烟相关的体重增加；通过个体尝试戒烟来减少与戒烟相关的体重增加；治疗尼古丁依赖、成瘾和/或戒断的个体尝试治疗尼古丁依赖、成瘾和/或戒断；或减少个体尝试戒除尼古丁使用的复发可能性，包括给予选择性5-HT2C受体激动剂，可选地与辅助剂结合。
• 3-(Substituted
  申请人：The Upjohn Company

  公开号：US03933816A1

  公开（公告）日：1976-01-20

  A compound of the formula: ##SPC1## Wherein R, R.sub.0, and R.sub.3 are hydrogen or alkyl of 1 to 3 carbon atoms, inclusive; wherein R.sub.1 and R.sub.2 are alkyl of 1 to 3 carbon atoms, or the group ##EQU1## together is pyrrolidino, piperidino, morpholino and N-methylpiperazino; wherein R.sub.7 is 2-pyridyl or a phenyl radical of the formula ##SPC2## Wherein R.sub.4 is hydrogen, fluoro, or chloro; wherein R.sub.5 is hydrogen or fluoro, with the proviso that R.sub.5 is not fluoro, when R.sub.4 is chloro; and wherein R.sub.6 is hydrogen, chloro, fluoro, bromo, trifluoromethyl, or nitro. The new compounds of formula II have tranquilizing and antianxiety activity and are thus useful to treat mammals and birds.

  一个化学式为：##SPC1##的化合物。其中R、R.sub.0和R.sub.3是氢或1至3个碳原子的烷基；其中R.sub.1和R.sub.2是1至3个碳原子的烷基，或者组##EQU1##一起是吡咯啉、哌啶、吗啉和N-甲基哌嗪；其中R.sub.7是2-吡啶基或化学式##SPC2##的苯基。其中R.sub.4是氢、氟或氯；其中R.sub.5是氢或氟，但R.sub.5不是氟，当R.sub.4是氯时；其中R.sub.6是氢、氯、氟、溴、三氟甲基或硝基。公式II的新化合物具有镇静和抗焦虑活性，因此对于治疗哺乳动物和鸟类是有用的。

表征谱图