右佐匹克隆 | 138729-47-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡嗪类
• 中文名称: 右佐匹克隆
• 中文别名: 4-甲基-1-哌嗪甲酸6-(5-氯-2-吡啶基)-6,7-二氢-7-氧代-5H-吡咯并[3,4-b]吡嗪-5-基酯；艾司佐匹克隆；4-甲基-1-哌嗪甲酸 6-(5-氯-2-吡啶基)-6,7-二氢-7-氧代-5H-吡咯并[3,4-b]吡嗪-5-基酯
• 英文名称: eszopiclone
• 英文别名: (S)-zopiclone；(+)-Zopiclone；(S)-6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methyl-1-piperazinecarboxylate；LUNESTA；[(7S)-6-(5-chloropyridin-2-yl)-5-oxo-7H-pyrrolo[3,4-b]pyrazin-7-yl] 4-methylpiperazine-1-carboxylate
• CAS: 138729-47-2
• 化学式: C₁₇H₁₇ClN₆O₃
• 分子量: 388.813
• InChiKey: GBBSUAFBMRNDJC-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  91.8
• 氢给体数：
  0
• 氢受体数：
  7

ADMET

代谢

口服给药后，eszopiclone广泛生物转化为其主要代谢物S-去甲基唑吡克隆和唑吡克隆-N-氧化物，这些代谢物大部分活性较低。参与eszopiclone代谢的酶主要是CYP3A（主要代谢酶）、CYP2C8和CYP2E1。N-氧化物衍生物在动物中显示出较弱的药理活性。N-去甲基代谢物具有药理活性。

Following oral administration, eszopiclone is extensively biotransformed and the major metabolites are S-desmethylzopiclone and zopiclone-N-oxide, which are largely inactive.. The enzymes involved in the metabolism of eszopiclone are CYP3A (the primary metabolizing enzyme), CYP2C8, and CYP2E1. The N-oxide derivative shows weak pharmacological activity in animals. The N-desmethyl metabolite is pharmacologically active.

来源:DrugBank

代谢

广泛通过CYP3A4和CYP2E1的氧化和去甲基化代谢。两种主要代谢物是(S)-佐匹克隆-N-氧化物（无活性）和(S)-N-去甲基佐匹克隆，它们与GABA受体的结合能力低于艾司佐匹克隆。

Extensively metabolized by CYP3A4 and CYP2E1 via oxidation and demethylation. The two primary metabolites are (S)-zopiclone-N-oxide (inactive) and (S)-N-demethylzopiclone which binds to GABA receptors with lower potency then eszopiclone.

来源:Hazardous Substances Data Bank (HSDB)

代谢

eszopiclone 已知的人体代谢物包括 N-氧化唑吡克隆和 N-去甲基唑吡克隆。

Eszopiclone has known human metabolites that include N-oxide-zopiclone and N-desmethyl-zopiclone.

来源:NORMAN Suspect List Exchange

代谢

口服给药后，eszopiclone通过氧化和去甲基化广泛代谢。 消除途径：口服剂量的扎盼隆对映体（racemic zopiclone）的75%以上以代谢物形式通过尿液排出。 半衰期：6小时

Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. Route of Elimination: Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. Half Life: 6 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

唑吡坦的作用机制尚未完全了解。人们认为唑吡坦作为激动剂作用于苯二氮卓受体，并与GABA受体复合物相互作用。

The mechanism of action of Eszopiclone is not completely understood. It is thought that Eszopiclone acts on the benzodiazepine receptors as an agonist and interacts with GABA-receptor complexes.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在多个上市前随机对照试验中，eszopiclone与安慰剂治疗相比，并未发现血清酶升高率有所增加，并且没有报告出现临床上明显的肝损伤的实例。自从eszopiclone获得批准并广泛使用以来，没有发现它会导致临床上明显的肝病，尽管肝炎和肝损伤在产品标签中被列为罕见的不良反应。Eszopiclone主要通过肝细胞色素P450系统（主要是CYP 3A4和2E1）代谢。然而，药物相互作用似乎并不常见。因此，如果eszopiclone确实引起肝损伤，那么这种情况也一定非常罕见。 可能性评分：E（不太可能是临床上明显肝损伤的原因）。 药物类别：镇静剂和催眠药 该亚类药物中的其他药物，苯二氮卓类受体激动剂：扎来普隆，唑吡坦。

In multiple premarketing randomized controlled trials, eszopiclone was not associated with an increased rate of serum enzyme elevations in comparison to placebo therapy, and no instance of clinically apparent liver injury was reported. Since its approval and widescale use, eszopiclone has not been implicated in causing clinically apparent liver disease, although hepatitis and liver injury are listed as a rare adverse reactions in the product label. Eszopiclone is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4 and 2E1). Nevertheless, drug-drug interactions appear to be uncommon. Thus, eszopiclone induced liver injury must be rare, if it occurs at all. Likelihood score: E (unlikely cause of clinically apparent liver injury). Drug Class: Sedatives and Hypnotics Other Drugs in the Subclass, Benzodiazepine Receptor Agonists: Zaleplon, Zolpidem

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：eszopiclone

Compound:eszopiclone

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

艾司佐匹克隆口服给药后迅速吸收，大约在1小时后达到峰值浓度。服用3毫克艾司佐匹克隆后的平均药时曲线下面积（AUC）为278 ng/mL × h。研究表明，高脂肪饮食会减慢吸收速度。艾司佐匹克隆的稳态浓度在24-48小时内达到。

Eszopiclone is rapidly absorbed and the peak concentration is reached within about 1 hour after oral administration. The mean AUC after a 3 mg dose of eszopiclone was 278 ng/mL × h. The consumption of a high-fat has been shown to slow absorption. Steady-state concentrations of eszopiclone are reached within 24-48 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约只有10%的右佐匹克隆剂量以原药形式在尿液中排出。而口服给药的消旋佐匹克隆剂量的多达75%以代谢物形式在尿液中排出。右佐匹克隆是消旋佐匹克隆的S型异构体，很可能显示出相同的排泄模式。

Only about 10% of an eszopiclone dose is found excreted in the urine as the parent drug. As much as 75% of an orally administered dose of racemic zopiclone as is found to be excreted in the urine in the form of metabolites. Eszopiclone, the S-isomer of racemic zopiclone, would likely show the same excretion pattern.

来源:DrugBank

吸收、分配和排泄

• 分布容积

eszopiclone的分布体积估计为89.9升

The volume of distribution of eszopiclone is estimated at 89.9L

来源:DrugBank

吸收、分配和排泄

• 清除

在一项药代动力学研究中，埃索佐匹克隆在年轻健康志愿者体内的平均清除率为184毫升/分钟。

The mean clearance of eszopiclone in young, healthy volunteers was 184 mL/min in one pharmacokinetic study.

来源:DrugBank

吸收、分配和排泄

eszopiclone口服给药后可以迅速吸收。口服给药后约1小时达到最高血浆浓度。eszopiclone与血浆蛋白的结合力弱（52-59%）。大量游离部分表明，eszopiclone的处置不应受到由蛋白结合引起的药物-药物相互作用的 影响。eszopiclone的血液-血浆比例小于1，这表明eszopiclone对红细胞没有选择性摄取。

Eszopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Eszopiclone is weakly bound to plasma protein (52-59%). The large free fraction suggests that eszopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for eszopiclone is less than one, indicating no selective uptake by red blood cells.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  右佐匹克隆 在 硫酸 作用下， 以 乙酸乙酯 为溶剂， 反应 2.0h， 以96%的产率得到(S)-zopiclone sulfate
  参考文献：
  名称：

  [EN] SALTS OF 6-(5-CHLORO-2-PYRIDYL)-5-[(4-METHYL-1-PIPERAZINYL)CARBONYLOXY]-7-OXO-6,7- DIHYDRO-5H-PYRROLO[3,4-B]PYRAZINE
  [FR] SELS DE 6-(5-CHLORO-2-PYRIDYL)-5-[(4-MÉTHYL-1-PIPÉRAZINYL)CARBONYLOXY]-7-OXO-6,7-DIHYDRO-5H-PYRROLO[3,4-B] PYRAZINE

  摘要：

  提供了（6-(5-氯-2-吡啶基)-5-[(4-甲基-1-哌嗪基)羰氧基]-7-氧代-6,7-二氢-5H-吡咯并[3,4-b]吡嗪）的新美索那铵盐、(R)-苹果酸盐、琥珀酸盐、柠檬酸盐、富马酸盐、D-苹果酸盐、D-酒石酸盐、硫酸盐和L-酒石酸盐。

  公开号：

  WO2009085988A1
• 作为产物：
  描述：

  佐匹克隆 以36的产率得到右佐匹克隆
  参考文献：
  名称：

  Methods of making and using N-desmethylzopiclone

  摘要：

  本发明涉及包含及使用外消旋N-去甲基唑吡克隆、光学纯(+)-N-去甲基唑吡克隆和光学纯(−)-N-去甲基唑吡克隆的组合物在哺乳动物的疾病和状况的治疗和预防方面的方法。本发明还涉及制备N-去甲基唑吡克隆、光学纯(+)-N-去甲基唑吡克隆和光学纯(−)-N-去甲基唑吡克隆的新方法。

  公开号：

  US06339086B1

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。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• [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。