唑吡坦 | 82626-48-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 唑吡坦
• 中文别名: 左吡登；N,N,6-三甲基-2-(4-甲基苯基)咪唑并[1,2-Α]吡啶-3-乙酰胺；N,N,6-三甲基-2-(4-甲基苯基)咪唑并[1,2-A]吡啶-3-乙酰胺；N,N,6-三甲基-2-(4-甲基苯基)咪唑并[1,2-a]吡啶-3-乙酰胺
• 英文名称: N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide
• 英文别名: Zolpidem；cedrol；N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide
• CAS: 82626-48-0
• 化学式: C₁₉H₂₁N₃O
• 分子量: 307.395
• InChiKey: ZAFYATHCZYHLPB-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：
  L-(+)-半酒石酸唑吡坦(Zolpidem Hemitartrate)，化学式为(C19H21N3O)₂·C4H6O6，编号为[99294-93-6]。它是一种无色结晶体，无气味。在20℃的水中溶解度约为23毫克/毫升。

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  37.6
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

唑吡坦被肝脏中的细胞色素P450（CYP）同工酶，主要是CYP3A4，还有CYP1A2和CYP2C9代谢为三种药理上不活跃的代谢物。尽管唑吡坦被大量代谢，但这三种代谢物都是无活性的。人类主要的代谢途径是氧化苯环上的甲基团或咪唑吡啶部分上的甲基团，产生羧酸（代谢物I和II），以及羟基化咪唑吡啶基团中的一个（产生代谢物X）。另一种较少见的途径是通过取代酰胺上的甲基团的氧化。

Zolpidem is metabolized to three pharmacologically by various hepatic cytochrome P450 (CYP) isoenzymes, mainly CYP3A4, but also CYP1A2 and CYP2C9,. Although zolpidem is heavily metabolized, all three metabolites are inactive. The major metabolic routes in humans are oxidation of the methyl group on the phenyl ring or the methyl group on the imidazopyridine moiety, to produce carboxylic acids (metabolites I and II), and hydroxylation of one of the imidazopyridine groups (to produce metabolite X). Another less common pathway is by the oxidation of the methyl groups on the substituted amide.

来源:DrugBank

代谢

唑吡坦已知的人类代谢物包括甲氧唑吡坦。

Zolpidem has known human metabolites that include methoxyzolpidem.

来源:NORMAN Suspect List Exchange

代谢

唑吡坦在肝脏中被转化为无活性的代谢物。 消除途径：唑吡坦酒石酸片被转化为无活性的代谢物，主要通过肾脏排泄消除。 半衰期：2.6小时

Zolpidem is converted to inactive metabolites in the liver. Route of Elimination: Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated primarily by renal excretion. Half Life: 2.6 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

Zolpidem调节GABA_A受体氯离子通道大分子复合物中的α-亚单位，也称为苯二氮卓受体。与苯二氮卓类药物不同，后者非选择性作用于所有三种α-受体亚型，Zolpidem优先结合α-1受体。

Zolpidem modulates the alpha-subunit, known as the benzodiazepine receptor, within the GABA_A receptor chloride channel macromolecular complex. Unlike the benzodiazepines, which non-selectively interact with all three alpha-receptor subtypes, Zolpidem preferentially binds to the alpha-1 receptor.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在多个上市前的随机对照试验中，唑吡坦与安慰剂治疗相比，并未与血清酶升高率增加有关。已报告一例临床明显的肝损伤病例。损伤发生是在单次服用唑吡坦后2天，伴随腹痛，但没有黄疸。肝酶升高的模式是肝细胞型，异常是自限性的，尽管在重新暴露时似乎会复发。唑吡坦在肝脏中通过细胞色素P450系统（主要是CYP 3A4）代谢，可能会引起药物-药物相互作用，尽管这种相互作用很少见。因此，唑吡坦并未与黄疸的肝损伤病例有关联，但偶尔可能会引起短暂的、轻到中度的血清酶升高，伴有或不伴有症状。 可能性评分：E（不太可能是临床明显肝损伤的原因）。 药物类别：镇静剂和催眠药 同类其他药物，苯二氮卓受体激动剂：艾司唑仑，扎来普隆

In multiple premarketing randomized controlled trials, zolpidem was not associated with an increased rate of serum enzyme elevations in comparison to placebo therapy. A single instance of clinically apparent liver injury has been reported. The onset of injury was 2 days after a single dose of zolpidem and was accompanied by abdominal pain, but no jaundice. The pattern of liver enzyme elevations was hepatocellular and the abnormalities were self-limited, although they seemed to recur on reexposure. Zolpidem is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4) and can cause drug-drug interactions, although such interactions are rare. Thus, zolpidem has not been linked to cases of liver injury with jaundice, but rarely may cause transient, mild-to-moderate serum enzyme elevations with or without symptoms. Likelihood score: E (unlikely cause of clinically apparent liver injury). Drug Class: Sedatives and Hypnotics Other Drugs in the Subclass, Benzodiazepine Receptor Agonists: Eszopiclone, Zaleplon

来源:LiverTox

毒理性

• 药物性肝损伤

唑吡坦

Compound:zolpidem

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：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

严重等级：7

Severity Grade:7

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

唑吡坦从胃肠道迅速吸收。在一项45名健康受试者进行的单次交叉研究中，给予5毫克和10毫克唑吡坦酒石酸片，平均峰唑吡坦浓度（Cmax）分别为59和121纳克/毫升，两种剂量均在大约1.6小时（Tmax）出现。

Zolpidem is rapidly absorbed from the gastrointestinal tract. In a single-dose crossover study in 45 healthy subjects given 5 and 10 mg zolpidem tartrate tablets, the average peak zolpidem concentrations (Cmax) were 59 and 121 ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both doses.

来源:DrugBank

吸收、分配和排泄

• 消除途径

扎来普隆片剂转化为无活性的代谢物，主要通过肾脏排泄消除。

Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated mainly by renal excretion.

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.54至0.68升/公斤（人体）。在尚未进行血液透析的长期肾功能不全患者中，发现分布容积显著增加，药时曲线下面积（AUC）增加了60%，半衰期几乎增加了一倍。

0.54 to 0.68 L/kg (in humans). In patients with long term renal insufficiency who were not yet on hemodialysis, the volume of distribution was found to increase significantly, AUC increased by 60%, and half-life nearly doubled.

来源:DrugBank

吸收、分配和排泄

• 清除

在临床试验中，服用20毫克剂量后，唑吡坦的总清除率为0.24至0.27毫升/分钟/千克。

In a clinical trial, after a 20mg dose, total clearance of zolpidem 0.24 to 0.27 ml/min/kg.

来源:DrugBank

制备方法与用途

制备方法： 化合物(I)与草酰氯和二甲胺反应，可以得到唑吡坦。

合成制备方法： 化合物(I)与草酰氯及二甲胺作用，同样可得唑吡坦。

反应信息

• 作为反应物：
  描述：

  唑吡坦 在 盐酸 作用下， 以 水 为溶剂， 反应 18.0h， 以94%的产率得到6-甲基-2-(4-甲基苯基)咪唑并[1,2-a]吡啶-3-乙酸
  参考文献：
  名称：

  [EN] IMIDAZO[1,2-A]PYRIDINE ANXIOLYTICS
  [FR] ANXIOLYTIQUES D'IMIDAZO[1,2-A]PYRIDINE

  摘要：

  公开号：

  WO2005044818A3
• 作为产物：
  描述：

  α-hydroxy-zolpidem-O-propionate 在 5% Pd-BaSO4 硫酸 、 氢气 、 溶剂黄146 、 sodium bromide 作用下， 以 水 为溶剂， 反应 12.5h， 以97%的产率得到唑吡坦
  参考文献：
  名称：

  Synthesis Of Heteroaryl Acetamides From Reaction Mixtures Having Reduced Water Content

  摘要：

  提供了一种改进的方法，用于从杂环α-羟基乙酰胺制备杂环醋酰胺。该方法包括在强酸、卤化物和催化剂的存在下直接加氢杂环α-羟基乙酰胺，其中在氢解反应开始时，起始杂环α-羟基乙酰胺与水的摩尔比至少为2:1。在一个实施例中，杂环醋酰胺是唑吡坦，而杂环α-羟基乙酰胺是α-羟基唑吡坦。

  公开号：

  US20070213537A1
• 作为试剂：
  描述：

  二氯甲烷 、 Carbonyldiimidazole 、 6-甲基-2-(4-甲基苯基)咪唑并[1,2-a]吡啶-3-乙酸 、 在 二甲胺 、 二氯甲烷 、 水 、 唑吡坦 、 碳 、 丙酮 作用下， 以 丙酮 为溶剂， 2.0~85.0 ℃ 、12.26 MPa 条件下， 反应 22.67h， 以a vacuum of 650 mm Hg for 4 hours to get a crude title compound的产率得到唑吡坦
  参考文献：
  名称：

  PROCESS FOR PREPARING ZOLPIDEM

  摘要：

  一种制备唑来蒙的工艺。

  公开号：

  US20070027180A1

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。
• [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。
• 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。

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