扎莱普隆 | 151319-34-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 扎莱普隆
• 中文别名: N-乙基-N-3-[7-(3-氰基吡唑并[1,5a]嘧啶基)苯基]乙酰胺；扎来普隆N-乙基-N-3-[7-(3-氰基吡唑并[1,5a]嘧啶基)苯基]乙酰胺；扎来普隆；扎雷普隆；N-[3-(3-氰基吡唑并[1,5-Α]嘧啶-7-基)苯基]-N-乙基乙
• 英文名称: zaleplon
• 英文别名: N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethyl-acetamide；N-(3-(3-cyanopyrazolo-[1,5-a]pyrimidin-7-yl)phenyl)-N-ethylacetamide；N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethyl acetamide；N-(3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-N-ethylacetamide；zaleplone；N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide
• CAS: 151319-34-5
• 化学式: C₁₇H₁₅N₅O
• 分子量: 305.339
• InChiKey: HUNXMJYCHXQEGX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.176
• 拓扑面积：
  74.3
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

扎来普隆主要通过醛氧化酶代谢。

Zaleplon is primarily metabolized by aldehyde oxidase.

来源:DrugBank

代谢

扎来普隆已知的人类代谢物包括去甲基扎来普隆。

Zaleplon has known human metabolites that include Dementhylazed-zaleplon.

来源:NORMAN Suspect List Exchange

代谢

扎来普隆主要通过醛氧化酶代谢。扎来普隆在口服给药后迅速且几乎完全被吸收。口服给药后，扎来普隆被广泛代谢，不到1%的剂量以原形通过尿液排出。扎来普隆主要通过醛氧化酶代谢形成5-氧代-扎来普隆。扎来普隆也在较小程度上通过细胞色素P450（CYP）3A4代谢形成去乙基扎来普隆，后者很快被醛氧化酶假定转化为5-氧代-去乙基扎来普隆。这些氧化代谢物随后转化为葡萄糖苷酸并随尿液排出。扎来普隆的所有代谢物在药理上都是不活跃的（RxList, A308）。 消除途径：扎来普隆主要在肝脏代谢，并经历显著的系统前代谢。口服给药后，扎来普隆被广泛代谢，不到1%的剂量以原形通过尿液排出。未改变的扎来普隆的肾排泄量占给药剂量的不到1%。 半衰期：大约1小时

Zaleplon is primarily metabolized by aldehyde oxidase. Zaleplon is rapidly and almost completely absorbed following oral administration. After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Zaleplon is primarily metabolized by aldehyde oxidase to form 5-oxo-zaleplon. Zaleplon is metabolized to a lesser extent by cytochrome P450 (CYP) 3A4 to form desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon. These oxidative metabolites are then converted to glucuronides and eliminated in urine. All of zaleplon's metabolites are pharmacologically inactive (RxList, A308). Route of Elimination: Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose. Half Life: Approximately 1 hour

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

扎来普隆通过调节GABA_BZ受体氯离子通道大分子复合物的亚单位来发挥其作用。扎来普隆还选择性地与位于GABA-A/氯离子通道受体复合物alpha亚单位上的大脑omega-1受体结合，并增强t-丁基双环磷硫酯（TBPS）的结合。有机腈在体内和体外都会分解成氰离子。因此，有机腈的主要毒性机制是它们产生有毒的氰离子或氢氰酸。氰化物是电子传递链第四复合物（存在于真核细胞线粒体膜中）中的细胞色素c氧化酶的抑制剂。它与这种酶中的三价铁原子形成复合物。氰化物与这种细胞色素的结合阻止了电子从细胞色素c氧化酶传递到氧气。结果，电子传递链被破坏，细胞无法再通过有氧呼吸产生ATP能量。主要依赖有氧呼吸的组织，如中枢神经系统和心脏，受到特别影响。氰化物还通过结合过氧化氢酶、谷胱甘肽过氧化物酶、变性血红蛋白、羟钴胺素、磷酸酶、酪氨酸酶、抗坏血酸氧化酶、黄嘌呤氧化酶、琥珀酸脱氢酶和Cu/Zn超氧化物歧化酶来产生一些毒性作用。氰化物与变性血红蛋白中的三价铁离子结合形成无活性的氰化变性血红蛋白。

Zaleplon exerts its action through subunit modulation of the GABA_BZ receptor chloride channel macromolecular complex. Zaleplon also binds selectively to the brain omega-1 receptor located on the alpha subunit of the GABA-A/chloride ion channel receptor complex and potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)

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，唑吡坦与安慰剂治疗相比，并未与血清酶水平升高率增加有关，并且没有报告出现临床上明显的肝损伤的情况。自从获得批准并广泛使用以来，唑吡坦并未被证明会导致临床上明显的肝病。尽管如此，唑吡坦在肝脏中通过细胞色素P450系统（主要是CYP 3A4）代谢，并可能引起药物-药物相互作用，尽管这种相互作用似乎很少见。因此，如果唑吡坦引起的肝损伤真的发生，那也一定是罕见的。 可能性评分：E（不太可能是导致临床上明显肝损伤的原因）。 药物类别：镇静剂和催眠药 同类其他药物，苯二氮䓬受体激动剂：艾司唑仑，唑吡坦

In multiple premarketing randomized controlled trials, zaleplon 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, zaleplon has not been implicated in causing clinically apparent liver disease. Nevertheless, zaleplon is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4) and can cause drug-drug interactions, although such interactions appear to be rare. Thus, zaleplon 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: Eszopiclone, Zolpidem

来源:LiverTox

毒理性

• 药物性肝损伤

扎来普隆

Compound:zaleplon

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：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

吸收 佐匹克隆口服给药后迅速且几乎完全吸收。

Absorption Zaleplon is rapidly and almost completely absorbed following oral administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

扎来普隆主要通过肝脏代谢，并经历显著的系统前代谢。口服给药后，扎来普隆被广泛代谢，不足1%的剂量以原形从尿液中排出。未经改变的扎来普隆通过肾脏排出的量占给药剂量的不到1%。

Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose.

来源:DrugBank

吸收、分配和排泄

• 分布容积

1.4升/千克

1.4 L/kg

来源:DrugBank

吸收、分配和排泄

• 清除

1 升每小时每千克

1 L/h/kg

来源:DrugBank

制备方法与用途

根据提供的合成路线描述，以下是扎来普隆的主要合成步骤：

1. 以间氨基苯乙酮为原料：

   • 将间氨基苯乙酮、碳酸钾溶于二氯甲烷
   • 滴加醋酐，回流反应

2. 反应产物与二甲基甲酰胺二甲缩醛反应，过滤后水洗干燥，得到N-[3-(3-二甲基氨基-1-氧代-2-丙烯基)苯基]乙酰胺。

3. 用二甲基甲酰胺溶解上述产物，并加入氢化钠

   • 冷却后滴加溴乙烷，继续反应

4. 将反应混合物放入冰水，搅拌、静置、过滤、水洗干燥，再进行甲醇重结晶：

   • 得到3-二甲基氨基1-[(3-N-乙基-N-乙酰氨基)苯基]-2-丙烯-1-酮。

5. 将上述产物与3-氨基-4-氰基吡唑混合于冰醋酸中加热反应。

6. 冷却、过滤、滤饼用乙酸-水洗涤，干燥后进行乙酸乙酯重结晶：

   • 最终获得扎来普隆淡黄色固体，收率82%，熔点185~187°C。

整个合成过程涉及多个步骤及原料处理方法，并且需要严格控制反应条件以确保产品纯度。

反应信息

• 作为反应物：
  描述：

  扎莱普隆 在 硫酸 作用下， 以 二氯甲烷 为溶剂， 以78%的产率得到N-[3-(3-氰基吡唑并[1,5-a]嘧啶-7-基)苯基]-N-乙基乙酰胺硫酸盐
  参考文献：
  名称：

  Salts And Co-Crystals of Pyrazolopyrimidine Compounds, Compositions Thereof And Methods For Their Production And Use

  摘要：

  这项发明提供了吡唑基嘧啶化合物的药用可接受盐和共晶体，例如扎来普隆、印地普隆和奥西那普隆，以及它们的制备方法、包含这些盐和共晶体的组合物，以及利用这些盐和共晶体治疗各种疾病和症状的方法。

  公开号：

  US20080045547A1
• 作为产物：
  描述：

  3-乙酰胺基苯乙酮 在 sodium hydride 、 溶剂黄146 作用下， 以 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 13.0h， 生成 扎莱普隆
  参考文献：
  名称：

  一种合成扎莱普隆的新方法

  摘要：

  本发明提供了一种合成扎莱普隆的新方法。具体地，本发明方法以苯乙酮为原料，制得N-乙基-N-[3-(3-二甲基胺-1-氧代-2-丙烯基)苯基]乙酰胺，再与3-氨基-4-氰基吡唑反应，形成N-[3-(3-氰基吡唑并[1,5-α]嘧啶-7-基)苯基]-N-乙基乙酰胺。本发明的合成路线步骤少，后处理简单，成本低廉，适宜于产业化生产。

  公开号：

  CN105622615A
• 作为试剂：
  描述：

  N-乙基-N-3-((3-二甲氨基-1-氧代-2-丙烯基)苯基)乙酰胺 、 3-氨基-4-氰基吡唑 在 mixture 、 扎莱普隆 、 乙酸乙酯 作用下， 以 水 、 盐酸 为溶剂， 反应 8.0h， 以to give 100 mg of the mixture of the above two compounds的产率得到N-(3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl)-N-ethylacetamide
  参考文献：
  名称：

  Process for the production of N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (zaleplon)

  摘要：

  本发明提供了一种生产N-[3-(3-氰基吡唑并[1,5-a]嘧啶-7-基)苯基]-N-乙酰乙酸乙酯（扎来普隆）的方法，该活性成分已获批用于治疗失眠。该方法涉及在含水和水溶性有机化合物混合物的反应介质中，在酸性条件下将N-[3-[3-(二甲氨基)-1-氧代-2-丙烯基]苯基]-N-乙酰乙酰胺或其盐与3-氨基-4-氰基吡唑或其盐反应。

  公开号：

  US20050187225A1

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。