佐匹克隆 | 43200-80-2

• 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: 佐匹克隆
• 中文别名: (5RS)-6-(5-氯吡啶-2-基)-7-[(4-甲基哌嗪-1-基)羰氧基]-5,6-二氢吡咯并[3,4-b]吡嗪-5-酮；6-(5-氯吡啶-2-基)-5-(4-甲基哌嗪-1-基)羰酰氧基-7-氧-6,7-二氢-5H-吡咯并[3,4-B]吡嗪；吡嗪哌酯
• 英文名称: zopiclon
• 英文别名: Zopiclone；[6-(5-chloropyridin-2-yl)-5-oxo-7H-pyrrolo[3,4-b]pyrazin-7-yl] 4-methylpiperazine-1-carboxylate
• CAS: 43200-80-2
• 化学式: C₁₇H₁₇ClN₆O₃
• mdl: MFCD00133931
• 分子量: 388.813
• InChiKey: GBBSUAFBMRNDJC-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：
  常规情况下不会分解，也没有危险反应。

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

广泛在肝脏通过脱羧（主要途径）、脱甲基和侧链氧化代谢。代谢物包括一个N-氧化物衍生物（弱活性；约占总剂量的12%）和一个N-去甲基代谢物（无活性；约占总剂量的16%）。大约50%的剂量通过脱羧转化为其他无活性的代谢物。肝脏微粒体酶似乎不参与佐匹克隆的清除。

Extensively metabolized in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance.

来源:DrugBank

代谢

在肝脏中通过脱羧（主要途径）、脱甲基和侧链氧化广泛代谢。代谢物包括一个N-氧化物衍生物（弱活性；约占总剂量的12%）和一个N-去甲基代谢物（无活性；约占总剂量的16%）。大约50%的剂量通过脱羧转化为其他无活性的代谢物。肝脏微粒体酶似乎不参与佐匹克隆的清除。 半衰期：消除半衰期大约为5小时（范围3.8至6.5小时），在肝功能不全的患者中延长至11.9小时。

Extensively metabolized in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance. Half Life: Elimination half life is approximately 5 hours (range 3.8 to 6.5 hours) and is prolonged to 11.9 hours in patients with hepatic insufficiency.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

佐匹克隆通过结合苯二氮卓受体复合物并调节GABA_BZ受体氯通道大分子复合物来发挥其作用。佐匹克隆和苯二氮卓类药物在含有alpha1、alpha2、alpha3和alpha5的GABAA受体上的苯二氮卓结合位点作为完全激动剂，无差别地发挥作用，导致增强GABA的抑制性作用，从而产生佐匹克隆的治疗效果（催眠和抗焦虑）以及不良反应。

Zopiclone exerts its action by binding on the benzodiazepine receptor complex and modulation of the GABA_BZ receptor chloride channel macromolecular complex. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on alpha1, alpha2, alpha3 and alpha5 GABAA containing receptors as full agonists causing an enhancement of the inhibitory actions of GABA to produce the therapeutic (hypnotic and anxiolytic) and adverse effects of zopiclone.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

它们会导致说话含糊不清、迷失方向和“醉酒”行为。它们在身体和心理上都具有成瘾性。

They cause slurred speech, disorientation and "drunken" behavior. They are physically and psychologically addictive.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：目前没有关于哺乳期间使用eszopiclone的数据。来自其对映体zopiclone的数据表明，在哺乳较大婴儿时偶尔使用对婴儿的风险很小。一个安全评分系统发现zopiclone在哺乳期间可以使用，但应监测婴儿是否出现镇静、进食不良和体重增长不良。可能更倾向于使用另一种催眠药，特别是在哺乳新生儿或早产儿时。 对哺乳婴儿的影响：在12位分娩后2至6天且服用7.5毫克zopiclone的母亲中，婴儿哺乳被中断了8至10小时后恢复。婴儿中没有发现不寻常的影响。 一对30周的早产双胞胎出生于一位在怀孕期间为紧张性头痛每天四次服用zopiclone 3.75毫克的母亲。他们在出生后的第一周出现了戒断症状。从2周大开始，他们大约有三分之二的时间由继续服用同样剂量的药物的他们的母亲哺乳。这些婴儿没有临床异常，并在出生后6周出院。 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No data are available on the use of eszopiclone during breastfeeding. Data from the racemate, zopiclone, indicate that occasional use while breastfeeding an older infant should pose little risk to the infant. A safety scoring system finds zopiclone possible to use during breastfeeding, but the infant should be monitored for sedation, poor feeding and poor weight gain. An alternate hypnotic may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:In 12 mothers who were 2 to 6 days postpartum and took 7.5 mg of zopiclone, infant breastfeeding was interrupted for 8 to 10 hours before resuming. No unusual effect were noted in the infants. Thirty-week preterm twins were born to a mother who took zopiclone 3.75 mg 4 times daily for tension headache during pregnancy. They developed withdrawal symptoms during the first week of life. Beginning at 2 weeks of age, they were about two-thirds breastfed by their mother who continued the drug at the same dose. The infants had no clinical abnormalities and were discharged from the hospital 6 weeks after birth. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 暴露途径

口服给药后迅速吸收。

Rapidly absorbed following oral administration.

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

口服给药后迅速吸收。

Rapidly absorbed following oral administration.

来源:DrugBank

制备方法与用途

制备方法

吡嗪-2,3-二酸酐和2-氨基-5-氯吡啶溶于乙腈，回流后冷却，抽滤，洗涤，干燥。得到的固体悬浮于水中，并用1mol/L盐酸酸化至pH值1。搅拌后抽滤，水洗，干燥，得化合物(Ⅰ)，收率92%。接着将化合物(Ⅰ)与乙酐一起回流，冷却后抽滤、洗涤、干燥，得到化合物(Ⅱ)，收率82%。化合物(Ⅱ)溶于二氧六环∶水（19:1）溶液，在13℃下并剧烈搅拌的情况下，缓慢加入硼氢化钾。将混合物倾入水中，并缓慢加入冰乙酸后抽滤、水洗、干燥，再悬浮于氯仿中进行室温搅拌。最终抽滤、洗涤、干燥得到化合物(Ⅲ)，收率63%。化合物(Ⅲ)溶于无水吡啶，在-10℃下并持续搅拌的条件下加入4-甲基-1-哌嗪甲酰氯盐酸盐，反应结束后升温至20℃，倾入冰水中静置后抽滤、洗涤、干燥得到粗品，并经精制最终获得白色粉末状佐匹克隆，收率65%，熔点为174~177°C。

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  右佐匹克隆 在 四甲基胍 作用下， 以 二甲基亚砜 为溶剂， 反应 5.0h， 以89%的产率得到佐匹克隆
  参考文献：
  名称：

  一种左旋佐匹克隆的消旋方法

  摘要：

  本发明涉及一种左旋佐匹克隆的消旋方法，使用廉价易得的四甲基胍作为消旋剂，操作简便，安全稳定，收率高，产品质量好，适合工业化生产。

  公开号：

  CN102690268B

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] 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。
• [EN] IMIDAZOPYRIDINE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS IMIDAZOPYRIDINE ET LEURS UTILISATIONS
  申请人：NEOMED INST

  公开号：WO2014117274A1

  公开（公告）日：2014-08-07

  This invention generally relates to substituted imidazopyridine compounds, particularly substituted 4-(imidazo[1,2-a]pyridin-2-yl)benzamide compounds and salts thereof. This invention also relates to pharmaceutical compositions and kits comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), processes for making such a compound, and intermediates used in such processes.

  这项发明通常涉及取代咪唑吡啶化合物，特别是取代的4-(咪唑[1,2-a]吡啶-2-基)苯甲酰胺化合物及其盐。这项发明还涉及包含这种化合物的药物组合物和试剂盒，以及这种化合物的用途（包括治疗方法和药物制剂等），制备这种化合物的方法，以及用于这些方法的中间体。

表征谱图