劳拉西泮 | 846-49-1

• 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: 劳拉西泮
• 中文别名: 氯羟安定；罗拉；乙腈(分析7-氯-5-(2-氯苯基)-3-羟基-1,3-二氢-2H-1,4-苯二氮卓-2-酮；7-氯-5-(2-氯苯基)-3-羟基-1,3-二氢-2H-1,4-苯二氮卓-2-酮；氯拉西泮
• 英文名称: lorazepam
• 英文别名: 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one
• CAS: 846-49-1
• 化学式: C₁₅H₁₀Cl₂N₂O₂
• 分子量: 321.163
• InChiKey: DIWRORZWFLOCLC-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：
  常温常压下稳定，应避免接触氧化剂。

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  61.7
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

劳拉西泮通过CYP450同工酶在肝脏中代谢，并广泛与3-0-酚基葡萄糖醛酸结合。这是一种无活性的代谢物，主要通过肾脏排出。

Lorazepam is hepatically metabolized by CYP450 isoenzymes and extensively conjugated to the 3-0-phenolic glucuronide. This is an inactive metabolite and is eliminated mainly by the kidneys.

来源:DrugBank

代谢

劳拉西泮有人类已知的代谢物，包括劳拉西泮葡萄糖苷酸。

Lorazepam has known human metabolites that include Lorazepam glucuronide.

来源:NORMAN Suspect List Exchange

代谢

劳拉西泮在肝脏中代谢，并广泛与3-0-酚基葡萄糖苷酸结合。这是一种无活性的代谢物，主要通过肾脏排出。 消除途径：当给健康受试者单次口服2毫克剂量时，88±4%的给药剂量在尿液中回收，7±2%在粪便中回收。以劳拉西泮葡萄糖苷酸形式在尿液中回收的给药剂量百分比为74±4%。只有0.3%的剂量以未改变的劳拉西泮形式回收，其余的放射性活性代表次要代谢物。 半衰期：静脉注射 = 14±5小时；口服给药 = 2小时。

Lorazepam is hepatically metabolized and is extensively conjugated to the 3-0-phenolic glucuronide. This is an inactive metabolite and is eliminated mainly by the kidneys. Route of Elimination: When a single 2 mg oral dose is give to healthy subjects, 88±4% of the administered dose was recovered in urine and 7±2% was recovered in feces. The percent of administered dose recovered in urine as lorazepam glucuronide was 74±4%. Only 0.3% of the dose was recovered as unchanged lorazepam, and the remainder of the radioactivity represented minor metabolites. Half Life: Parenteral administration = 14±5 hours; Oral administration = 2 hours.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

劳拉西泮结合到GABA-A受体的一个变构位点上，GABA-A受体是中枢神经系统中的五聚体离子通道受体。结合增强了抑制性神经递质GABA的效果，GABA结合后打开受体中的氯离子通道，允许氯离子流入，导致神经元超极化。

Lorazepam binds to an allosteric site on GABA-A receptors, which are pentameric ionotropic receptors in the CNS. Binding potentiates the effects of the inhibitory neurotransmitter GABA, which upon binding opens the chloride channel in the receptor, allowing chloride influx and causing hyperpolerization of the neuron.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

劳拉西泮与其他苯二氮卓类药物一样，在治疗期间很少与血清ALT或碱性磷酸酶升高有关，考虑到它的广泛使用，由劳拉西泮引起的临床上明显的肝损伤极为罕见。只有一例报告了由劳拉西泮引起的有症状的急性肝损伤。发病潜伏期为9个月，临床模式为自限性胆汁淤积性肝炎，在停药后2个月内缓解。其他苯二氮卓类药物，包括阿普唑仑、氯氮卓、氯硝西泮、地西泮、氟拉西泮和三唑仑，也有类似的孤立单一的临床明显肝炎病例报告。苯二氮卓类药物引起的急性肝损伤的临床模式通常是胆汁淤积性的，严重程度为轻到中度，潜伏期为1到6个月。发热和皮疹并不常见，也不会形成自身抗体。

Lorazepam, as with other benzodiazepines, is rarely associated with serum ALT or alkaline phosphatase elevations during therapy, and considering its widescale use, clinically apparent liver injury from lorazepam is extremely rare. There has been only a single case report of symptomatic, acute liver injury from lorazepam. The latency to onset was 9 months and the clinical pattern that of a self-limited cholestatic hepatitis that resolved within 2 months of stopping. Similar isolated single cases of clinically apparent hepatitis have been reported with other benzodiazepines including alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam and triazolam. The clinical pattern of acute liver injury from benzodiazepines is typically cholestatic and mild-to-moderate in severity with a latency of 1 to 6 months. Fever and rash are not common nor is autoantibody formation.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：劳拉西泮

Compound:lorazepam

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：模糊的 DILI 关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

易于吸收，口服给药的生物利用度为90%。当以4毫克剂量肌肉注射时，劳拉西泮会被完全且迅速吸收，并在15-30分钟内达到最大血清浓度48纳克/毫升。口服给药时，达到最大浓度的时间观察到为2小时。

Readily absorbed with an absolute bioavailability of 90% when given orally. When intramuscularly administered a dose of 4 mg, lorazepam is completely and rapidly absorbed and achieves a maximal serum concentration of 48 ng/ml in 15-30 minutes. When administered orally, the time to attained maximum concentration is observed to be of 2 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

当给健康受试者单次口服2毫克剂量时，给药剂量的88%在尿液中回收，7%在粪便中回收。从尿液中排出的剂量中，主要形式是葡萄糖苷酸版本，占74%，而仅有0.3%的剂量以未改变的劳拉西泮形式回收。

When a single 2 mg oral dose is given to healthy subjects, 88% of the administered dose is recovered in urine and 7% was recovered in feces. From the excreted dose in urine, the major form is the glucuronide version that represents 74% while only 0.3% of the dose is recovered as unchanged lorazepam.

来源:DrugBank

吸收、分配和排泄

• 分布容积

据报道，劳拉西泮的分布体积为1.3 L/kg。值得注意的是，由于劳拉西泮的亲脂性，它在大脑中的重新分布速度并不快。

The reported volume of distribution of lorazepam is 1.3 L/kg. It is important to mention that due to the lipophilicity of lorazepam, it does not redistribute as fast in the brain.

来源:DrugBank

吸收、分配和排泄

• 清除

体内研究表明，劳拉西泮的清除率为5.8毫升/分钟/千克。

_In vivo_ studies with lorazepam have shown a clearance rate of 5.8 ml.min/kg.

来源:DrugBank

制备方法与用途

制备方法

2-氨基2',5-二氯二苯甲酮依次与羟胺、氯乙酰氯、甲胺反应，然后与乙酐反应制得3-醋酸基-7-氯-5-(邻氯苯)-1,3-二氢-2H-1,4-苯并二氮-2-酮，再用氢氧化钠溶液处理，得到白色固体沉淀，过滤，水洗，用乙醇结晶，即得氯羟安定。

合成制备方法

2'-氨基2',5-二氯二苯甲酮依次与羟胺、氯乙酰氯、甲胺反应，然后与乙酐反应制得3-醋酸基-7-氯-5-(邻氯苯)-1,3-二氢-2H-1,4-苯并二氮-2-酮。再用氢氧化钠溶液处理，得到白色固体沉淀，过滤，水洗，用乙醇结晶，即得氯羟安定。

用途简介

该品具有镇静、肌肉松弛和抗惊厥作用。催眠作用较强，可持续8小时。

用途

该品具有镇静、肌肉松弛和抗惊厥作用。催眠作用较强，可持续8小时。

反应信息

• 作为反应物：
  描述：

  劳拉西泮 在 hydroxypropyl-α-cyclodextrin 作用下， 以 水 为溶剂， 生成 4-(2'-Chlorphenyl)-6-chlor-chinazolinon
  参考文献：
  名称：

  Study of the lorazepam: cyclodextrin inclusion complexes using electrospray ionization mass spectrometry

  摘要：

  As an example of drug-cyclodextrin interactions in aqueous media, the cyclodextrin complexation of lorazepam was studied by electrospray ionization mass spectroscopy (ES-MS). It was concluded that highly concentrated aqueous hydroxypropylcyclodextrins are more suited for the drug complexation and that the inclusion complex includes one molecule of the drug with two and three cyclodextrin molecules as well as two molecules of the drug with three molecules of hydroxypropylcyclodextrins. It was postulated that in the hydroxycyclodextrin cavity the drug molecule decomposes via the elimination of one molecule of formaldehyde. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4039(01)01181-9
• 作为产物：
  描述：

  2-氨基-2',5-二氯二苯酮 在 dipotassium peroxodisulfate 、 乌洛托品 、 ammonium acetate 、 水 、 碘 、 溶剂黄146 、 methyloxirane 、 sodium hydroxide 作用下， 以 乙醇 、 乙酸乙酯 、 甲苯 为溶剂， 反应 10.0h， 生成 劳拉西泮
  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
• 作为试剂：
  描述：

  Lorazepam ethanol 在 劳拉西泮 、 乙酸乙酯 作用下， 以 乙酸乙酯 为溶剂， 15.0~60.0 ℃ 、1.16 MPa 条件下， 反应 3.0h， 以to give crystalline lorazepam (3.8 kg, 80%)的产率得到劳拉西泮
  参考文献：
  名称：

  Process for preparing pure crystalline lorazepam

  摘要：

  本发明提供了一种制备结晶性劳拉西泮的方法，从劳拉西泮醇溶剂合物或水合物中，通过将劳拉西泮溶剂合物悬浮在乙酸乙酯、环己烷、二氯甲烷、甲苯和它们的混合物中的有机介质中，实现几乎无束缚溶剂的结晶劳拉西泮。该方法有助于提高抗焦虑和镇静剂劳拉西泮的产量。本发明还揭示了将劳拉西泮低级醇溶剂合物转化为劳拉西泮水合物的方法。

  公开号：

  US06350870B2

文献信息

• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
  申请人：Xu Feng

  公开号：US20100120727A1

  公开（公告）日：2010-05-13

  In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.

  在一个方面，本发明提供了一种氟硝西汀类似物与抗炎药物的共价结合物的组合物。在另一个方面，本发明提供了一种氟硝西汀前药的组合物。在另一个方面，本发明提供了一种氟硝西汀或其衍生物水杨酸盐的组合物。在另一个方面，本发明提供了使用氟硝西汀类似物或氟硝西汀前药的共轭物或盐来治疗或预防癌症的方法。
• [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。
• New Drug Delivery System for Crossing the Blood Brain Barrier
  申请人：Lipshutz H. Bruce

  公开号：US20070203080A1

  公开（公告）日：2007-08-30

  New ubiquinol analogs are disclosed, as well as methods of using these compounds to deliver drug moieties to the body.

  新的泛醌类似物被披露，以及利用这些化合物将药物基团输送到人体的方法。
• [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。

表征谱图