艾司唑仑 | 29975-16-4

• 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: 艾司唑仑
• 中文别名: 6-苯基-8-氯-4H-[1,2,4]三氮唑并[4,3-a][1,4]苯并二氮杂卓；6-苯-8-氯-4H-[1,2,4]三氮唑-[4,3α][1,4]苯并二氮杂卓；8-氯-6-苯基-4H-[1,2,4]三氮唑-[4,3α][1,4]苯并二氮杂卓；艾思唑仑；舒乐安定;；舒乐安定
• 英文名称: estazolam
• 英文别名: 8-Chloro-6-phenyl-4H-s-triazolo<4,3-a><1,4>benzodiazepin；ProSom；8-Chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine；8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
• CAS: 29975-16-4
• 化学式: C₁₆H₁₁ClN₄
• 分子量: 294.743
• InChiKey: CDCHDCWJMGXXRH-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：
  常温常压下稳定。

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.062
• 拓扑面积：
  43.1
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

广泛在肝脏代谢。用人肝脏微粒体的体外研究表明，艾司唑仑转化为主要循环代谢物4-羟基-艾司唑仑的过程是由细胞色素P450 3A（CYP3A）介导的。

Extensively metabolized in the liver. In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by cytochrome P450 3A (CYP3A).

来源:DrugBank

代谢

艾司唑仑已知的人类代谢物包括4-羟基艾司唑仑。

Estazolam has known human metabolites that include 4-hydroxyestazolam.

来源:NORMAN Suspect List Exchange

代谢

广泛在肝脏代谢。用人肝微粒体的体外研究表明，艾司唑仑转化为主要循环代谢物4-羟基-艾司唑仑是由细胞色素P450 3A（CYP3A）介导的。 消除途径：艾司唑仑广泛代谢。母药的消除通过肝脏代谢艾司唑仑为羟基化和其他代谢物，这些代谢物大部分以自由态和结合态在尿液中排出。2毫克剂量的艾司唑仑有不到5%以原形在尿液中排出，仅有4%的剂量出现在粪便中。放射性质量平衡研究表明，主要的排泄途径是通过肾脏。5天后，87%的给药放射性在人类尿液中排出。不到4%的剂量以原形排出。 半衰期：艾司唑仑的平均消除半衰期的估计范围从10到24小时。

Extensively metabolized in the liver. In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by cytochrome P450 3A (CYP3A). Route of Elimination: Estazolam is extensively metabolized. The elimination of the parent drug takes place via hepatic metabolism of estazolam to hydroxylated and other metabolites that are eliminated largely in the urine both free and conjugated. Less than 5% of a 2 mg dose of estazolam was excreted unchanged in the urine, with only 4% of the dose appearing in the feces. Radiolabel mass balance studies indicate that the main route of excretion is via the kidneys. After 5 days, 87% of the administered radioactivity was excreted in human urine. Less than 4% of the dose was excreted unchanged. Half Life: The range of estimates for the mean elimination half-life of estazolam varies from 10 to 24 hours.

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结合，这影响肌肉放松、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（GABA_A）受体相偶联，这增强了GABA的效果，通过增加GABA对GABA受体的亲和力。抑制性神经递质GABA与该位点的结合打开了氯离子通道，导致细胞膜超极化，阻止细胞的进一步兴奋。

Benzodiazepines bind nonspecifically to benzodiazepine receptors, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA_A) receptors, this enhances the effects 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

• 肝毒性

艾司唑仑与其他苯二氮䓬类药物一样，很少与血清ALT（肝酶）升高有关，临床上明显的艾司唑仑引起的肝损伤极为罕见，如果真的发生的话。目前还没有公开发表的关于艾司唑仑引起的有症状的急性肝损伤的案例报告。其他苯二氮䓬类药物，包括阿普唑仑、氯氮卓、氯硝西泮、地西泮、氟硝西泮、劳拉西泮和三唑仑，有过个别报告出现临床上明显的肝炎病例。苯二氮䓬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，严重程度从中度到轻度，潜伏期为1到6个月，在1到2个月内完全恢复。发热和皮疹尚未有描述，也未形成自身抗体。

Estazolam, as with other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from estazolam is extremely rare, if it occurs at all. There have been no published case reports of symptomatic, acute liver injury from estazolam. Isolated cases of clinically apparent hepatitis have been reported with other benzodiazepines including alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam, 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 and full recovery within 1 to 2 months. Fever and rash have not been described nor has autoantibody formation.

来源:LiverTox

毒理性

• 药物性肝损伤

艾司唑仑

Compound:estazolam

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

片剂在吸收方面已被发现与奥拉西坦口服溶液等效。在接受了高达推荐剂量三倍的健康受试者中，服用剂量后两小时内出现峰值奥拉西坦血浆浓度（范围0.5至6.0小时），并且与给药剂量成比例，这表明在测试的剂量范围内药物动力学呈线性。

Tablets have been found to be equivalent in absorption to an orally administered solution of estazolam. In healthy subjects who received up to three times the recommended dose, peak estazolam plasma concentrations occurred within two hours after dosing (range 0.5 to 6.0 hours) and were proportional to the administered dose, suggesting linear pharmacokinetics over the dosage range tested.

来源:DrugBank

吸收、分配和排泄

• 消除途径

艾司唑仑被广泛代谢。母药的消除通过肝脏代谢艾司唑仑为羟基化和其他代谢物，这些代谢物大部分以自由态和结合态在尿液中排出。小于2毫克剂量的5%的艾司唑仑以原形在尿液中排出，仅有4%的剂量出现在粪便中。放射性质量平衡研究表明，主要排泄途径是通过肾脏。5天后，87%的给药放射性在人类尿液中排出。小于4%的剂量以原形排出。

Estazolam is extensively metabolized. The elimination of the parent drug takes place via hepatic metabolism of estazolam to hydroxylated and other metabolites that are eliminated largely in the urine both free and conjugated. Less than 5% of a 2 mg dose of estazolam was excreted unchanged in the urine, with only 4% of the dose appearing in the feces. Radiolabel mass balance studies indicate that the main route of excretion is via the kidneys. After 5 days, 87% of the administered radioactivity was excreted in human urine. Less than 4% of the dose was excreted unchanged.

来源:DrugBank

制备方法与用途

制备方法

由对硝基氯苯与氰苄环合，经开环、还原后用氯乙酰氯酰化，再与乌洛托品环合，P2S2硫化，用水合肼肼化，最后与原甲酸乙酯环合制得该品。

合成制备方法

1. 由对硝基氯苯与氰苄环合，经开环、还原后用氯乙酰氯酰化，再与乌洛托品环合，P2S2硫化，用水合肼肼化，最后与原甲酸乙酯环合制得该品。

用途简介

具有较强的镇静、安眠、抗惊厥、抗焦虑作用，及较弱的中枢性骨骼肌松弛作用。适用于失眠、惊厥、焦虑、紧张、恐惧和癫痫发作等症。小鼠口服LD50为740-830mg/kg，大鼠为2500-3200mg/kg。

用途

具有较强的镇静、安眠、抗惊厥、抗焦虑作用，及较弱的中枢性骨骼肌松弛作用。适用于失眠、惊厥、焦虑、紧张、恐惧和癫痫发作等症。小鼠口服LD50为740-830mg/kg，大鼠为2500-3200mg/kg。

反应信息

• 作为反应物：
  描述：

  艾司唑仑 在 氘代氯仿 、 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 1.0h， 以97.5%的产率得到deuterated estazolam
  参考文献：
  名称：

  氘代艾司唑仑及其制备方法

  摘要：

  本发明公开氘代艾司唑仑及其制备方法，氘代艾司唑仑的制备方法，包括如下步骤：（1）将6‑苯基‑8‑氯‑4H‑[1,2,4]三氮唑并[4,3‑a][1,4]苯并二氮杂卓和二甲基亚砜或N,N‑二甲基甲酰胺中混合，搅拌；（2）加入催化剂碳酸铯或碳酸钾，并加入氘代氯仿，搅拌并加热至40摄氏度以上；（3）分离得氘代艾司唑仑。本发明制备方法简短，操作简便，成本低廉，易纯化。通过本发明，在较短的时间内，即可用少量氘代试剂作氘源，将市售非氘代艾司唑仑在非氘代溶剂氛围内转化为氘代艾司唑仑，且通过用柱层析方法进行简单纯化就可获得纯品。依据本发明制备的氘代艾司唑仑标准品纯度高，化学性质稳定，可方便用于分析用标准品的配制。本发明制备方法可用于生产分析检测艾司唑仑时使用的氘代内标物。

  公开号：

  CN103864798B
• 作为产物：
  描述：

  在 乌洛托品 、 ammonium acetate 作用下， 以 乙醇 为溶剂， 以80%的产率得到艾司唑仑
  参考文献：
  名称：

  5-氯-2-(3-氯甲基-S-三氮唑基)二苯甲酮的氯乙酸盐及其晶型和制备方法

  摘要：

  本发明公开了一种5‑氯‑2‑(3‑氯甲基‑S‑三氮唑基)二苯甲酮的氯乙酸盐及其晶型和制备方法。本发明将5‑氯‑2‑((N‑氯乙酰基‑N‑氯乙酰基肼甲基)氨基)苯甲酮溶解在溶剂中，加入氯乙酸，搅拌升温进行重排反应，反应结束后冷却结晶，固液分离，干燥得到5‑氯‑2‑(3‑氯甲基‑S‑三氮唑基)二苯甲酮的氯乙酸盐晶型，即化合物A晶型。本发明所述的5‑氯‑2‑(3‑氯甲基‑S‑三氮唑基)二苯甲酮的氯乙酸盐，既能满足后续合成艾司唑仑的需要，且在制备过程中用氯乙酸进行重排和成盐，避免了复杂的溶剂转换后处理操作。

  公开号：

  CN111689913B

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] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
  申请人：UNIV EMORY

  公开号：WO2013181135A1

  公开（公告）日：2013-12-05

  The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.

  该披露涉及喹唑啉衍生物、组合物以及相关方法。在某些实施例中，该披露涉及NADPH-氧化酶（Nox酶）和/或髓过氧化物酶的抑制剂。

表征谱图