夸西泮 | 36735-22-5

• 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: 夸西泮
• 中文别名: 氟硫安定；7-氯-5-(2-氟苯基)-1,3-二氢-1-(2,2,2-三氟乙基)-2H-1,4-苯并二氮杂卓-2-硫酮；7-氯-5-(2-氟苯基)-1-(2,2,2-三氟乙基)-3H-1,4-苯并二氮杂卓-2-硫酮
• 英文名称: quazepam
• 英文别名: Selepam；7-chloro-5-(2-fluoro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1,3-dihydro-benzo[e][1,4]diazepine-2-thione；7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine-2-thione
• CAS: 36735-22-5
• 化学式: C₁₇H₁₁ClF₄N₂S
• 分子量: 386.8
• InChiKey: IKMPWMZBZSAONZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  47.7
• 氢给体数：
  0
• 氢受体数：
  6

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

喹唑仑已知的人类代谢物包括2-氧喹唑仑。

Quazepam has known human metabolites that include 2-oxoquazepam.

来源:NORMAN Suspect List Exchange

代谢

肝的。 半衰期：39小时

Hepatic. Half Life: 39 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，这影响了肌肉放松、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）受体相关联，这通过增加GABA对GABA受体的亲和力来增强GABA的效果。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，阻止细胞进一步兴奋。

Benzodiazepines bind nonspecifically to benzodiazepine receptors, which 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 of 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

喹唑仑与其他苯二氮卓类药物一样，很少与血清ALT或碱性磷酸酶升高有关，临床上明显的喹唑仑引起的肝损伤极为罕见，如果有的话。目前还没有喹唑仑引起有症状的急性肝损伤的病例报告，但它的使用并不广泛。已经报道了其他苯二氮卓类药物引起的临床上明显的肝损伤的孤立个案，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。苯二氮卓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，严重程度从中度到中度，潜伏期为1到6个月，停药后1到2个月内恢复。发热和皮疹是不常见的，自身抗体的形成也不常见。

Quazepam, like other benzodiazepines, is rarely associated with serum ALT or alkaline phosphatase elevations, and clinically apparent liver injury from quazepam is extremely rare, if it occurs at all. There have been no case reports of symptomatic, acute liver injury from quazepam, but it has not had extensive use. Isolated single cases of clinically apparent liver injury 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 recovery within 1 to 2 months of stopping. Fever and rash are uncommon as is autoantibody formation.

来源:LiverTox

毒理性

• 药物性肝损伤

夸西泮

Compound:quazepam

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：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后的生物利用度为29-35%。

Bioavailability is 29-35% following oral administration.

来源:DrugBank

制备方法与用途

制备方法

7-氯-1-(2,2,2-三氟乙基)-2,3-二氢-5-(2-氟苯基)-1,4-苯并二氮杂卓(I) 用四氧化钌或三氧化铬氧化，得化合物(Ⅱ)。将1.8克（0.005摩尔）的化合物(I)溶于20毫升无水二氧六环中，加入1.1克（0.005摩尔）五硫化磷，沸腾回流4小时（装置上装有氯化钙干燥管，以防空气中的湿气侵入）。减压浓缩后，将剩余物溶解在二氯甲烷中，并通过含有200克硅胶的柱子过滤。滤液经浓缩后，使用二氯甲烷-己烷重结晶，最终得到1.2克夸西泮，熔点为137.5～139℃。

合成制备方法

同样地，7-氯-1-(2,2,2-三氟乙基)-2,3-二氢-5-(2-氟苯基)-1,4-苯并二氮杂卓(I) 用四氧化钌或三氧化铬氧化得化合物(Ⅱ)。1.8克（0.005摩尔）的化合物(I)溶于20毫升无水二氧六环中，加入1.1克（0.005摩尔）五硫化磷，沸腾回流4小时（装置上装有氯化钙干燥管，以防空气中的湿气侵入）。减压浓缩后，将剩余物溶解在二氯甲烷中，并通过含有200克硅胶的柱子过滤。滤液经浓缩后，使用二氯甲烷-己烷重结晶，最终得到1.2克夸西泮，熔点为137.5～139℃。

上下游信息

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  7-氯-5-(2-氟苯基)-1,3-二氢-1-(2,2,2-三氟乙基)-2H-1,4-苯并二氮杂卓-2-酮	[3H]-2-Oxoquazepam	49606-44-2	C17H11ClF4N2O	370.734

反应信息

• 作为反应物：
  描述：

  夸西泮 在 Hg(CH₃COO)2 作用下， 反应 0.25h， 以100%的产率得到7-氯-5-(2-氟苯基)-1,3-二氢-1-(2,2,2-三氟乙基)-2H-1,4-苯并二氮杂卓-2-酮
  参考文献：
  名称：

  使用极谱法进行药物分析，XXXII：quazepam [7-chloro-5- (2-fluorophenyl) -1,3-dihydro-1- (2,2,2-trifluoroethyl) -2H 电流-电压曲线异常的原因] -1,4- benzodiazepine-2-thione]

  摘要：

  Quazepam (1) 是第一个具有硫内酰胺结构的苯二氮卓类药物，在 i-E 曲线中显示出与其他苯二氮卓类药物的曲线明显不同的行为（图 1）。在酸性缓冲液中，在更负电位的正常还原步骤之后发生催化步骤，而在强碱性缓冲液中发生阳极步骤。1 中的硫原子负责这两个附加步骤。通过合成7-氯-5-(2-氟苯基)-1,3-二氢-1-(2,2,2-三氟乙基)-2H-1,4-苯并二氮杂-2-一(2)及其电分析与图 1 的极谱结果相比较可以证实该假设。此外，通过核磁共振光谱在碱性缓冲液中证明了 1 的烯硫醇的惊人形成，从而阐明了阳极阶段的起源。

  DOI：

  10.1002/ardp.19883210806

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。