替马西泮 | 846-50-4

• 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: 替马西泮
• 中文别名: 甲羟安定
• 英文名称: temazepam
• 英文别名: 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one；7-chloro-3-hydroxy-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one；7-chloro-3-hydroxy-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one；(+/-)-lormetazepam；3-hydroxydiazepam
• CAS: 846-50-4
• 化学式: C₁₆H₁₃ClN₂O₂
• 分子量: 300.744
• InChiKey: SEQDDYPDSLOBDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  52.9
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

地西泮的一级代谢大约占给药剂量的5-8%。尽管如此，地西泮主要在肝脏代谢，其中大部分未改变的药物直接与葡萄糖醛酸结合并从尿液中排出。特别是，血液中的主要代谢物是地西泮的O-结合物。不到5%的药物被去甲基化为氧氮杂草，然后作为葡萄糖醛酸苷排出。尽管如此，地西泮的葡萄糖醛酸苷没有显示出中枢神经系统活性，并且普遍认为没有形成活性代谢物。由于地西泮主要经历第二阶段结合反应，因此建议它不涉及CYP450相互作用。

First-pass metabolism of temazepam is minimal at approximately 5-8% of an administered dose. Nevertheless, temazepam is principally metabolized in the liver where most of the unchanged drug is directly conjugated to glucuronide and excreted in the urine. In particular, the primary metabolite present in the blood is the O-conjugate of temazepam. Less than 5% of the drug is demethylated to oxazepam and subsequently eliminated as the glucuronide. Regardless, the glucuronides of temazepam have no demonstrable CNS activity and it is believed that no active metabolites are formed in general. Since temazepam mainly undergoes Phase II conjugation reactions, it is proposed that it is devoid of CYP450 interactions.

来源:DrugBank

代谢

Temazepam是已知的diazepam（安定）在人体内的代谢产物。

Temazepam is a known human metabolite of diazepam.

来源:NORMAN Suspect List Exchange

代谢

肝脏。在排泄之前，替马西泮会通过结合作用被完全代谢。主要代谢物是替马西泮的O-结合物（90%）。 消除途径：在排泄之前，替马西泮会通过结合作用被完全代谢；剂量的80%到90%出现在尿液中。 半衰期：10-20小时

Hepatic. Temazepam is completely metabolized through conjugation prior to excretion. The major metabolite is the O-conjugate of temazepam (90%). Route of Elimination: Temazepam was completely metabolized through conjugation prior to excretion; 80% to 90% of the dose appeared in the urine. Half Life: 10-20 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

Temazepam（替马西泮），像其他苯二氮䓬类药物一样，很少与血清ALT（谷丙转氨酶）升高有关，而且临床上明显的由替马西泮引起的肝损伤极为罕见，如果真的发生的话。目前还没有关于替马西泮引起的有症状的急性肝损伤的病例报告。其他苯二氮䓬类药物，包括阿普唑仑、氯氮䓬、氯硝西泮、地西泮、氟硝西泮、劳拉西泮和三唑仑，有报道出现孤立的单个临床明显肝损伤病例。苯二氮䓬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，停药后迅速缓解。发热和皮疹是不常见的，自身抗体的形成也不常见。

Temazepam, like other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from temazepam is extremely rare, if it occurs at all. There have been no case reports of symptomatic, acute liver injury from temazepam. 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 rapid resolution with discontinuation. Fever and rash are uncommon as is autoantibody formation.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：替马西泮

Compound:temazepam

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物诱导性肝损伤标注：模糊的药物诱导性肝损伤关注

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

研究表明，口服给药的替马西泮剂量有90至100%被吸收，使得该药物吸收非常好。口服15至45毫克替马西泮后，药物迅速吸收，30分钟内达到显著血药浓度，2至3小时达到峰值。特别是，直接研究口服30毫克替马西泮后显示，服药后10至20分钟可测得血浆浓度，峰值血浆浓度在666-982 ng/mL之间（平均为865 ng/mL），大约在服药后1.2-1.6小时（平均为1.5小时）出现。最后，在15至30毫克剂量范围内，建立了血浆浓度/时间曲线下面积的剂量-比例关系。

Studies demonstrate that between 90 to 100% of an orally administered temazepam dose is absorbed, making the medication very well absorbed. The oral administration of 15 to 45 mg temazepam resulted in rapid absorption with significant blood levels achieved in 30 minutes and peak levels at 2-3 hours. In particular, direct studies following the oral ingestion of 30 mg of temazepam revealed measurable plasma concentrations were obtained 10-20 minutes after dosing with peak plasma levels ranging between 666-982 ng/mL (with a mean of 865 ng/mL) presenting approximately 1.2-1.6 hours (with a mean of 1.5 hours) after the dosing. Finally, a dose-proportional relationship was established for the area under the plasma concentration/time curve over the 15 to 30 mg dose range.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在服用单剂量后，剂量的80-90%出现在尿液中，主要是O-结合代谢物，而剂量的3-13%出现在粪便中。不到2%的剂量以未改变的形式或作为N-脱甲基安定在尿液中排出。

Following a single dose, 80-90% of the dose appears in the urine, predominantly as the O-conjugate metabolite, and 3-13% of the dose appears in the faeces. Less than 2% of the dose is excreted unchanged or as N-desmethyltemazepam in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

替马西泮的分布容积记录为1.3-1.5 L/kg体重，特别是对于未结合部分，为43-68 L/kg。

The volume of distribution documented for temazepam is 1.3-1.5 L/kg body weight - and in particular, 43-68 L/kg for the unbound fraction.

来源:DrugBank

吸收、分配和排泄

• 清除

关于替马西泮的清除率研究记录了总替马西泮清除率为1.03毫升/分钟/千克，游离替马西泮清除率为31毫升/分钟/千克。

Studies regarding the clearance of temazepam have recorded the values of 1.03 ml/min/kg and 31 ml/min/kg for the clearance of total temazepam and the clearance of unbound temazepam, respectively.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  替马西泮 在 氯化亚砜 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 3,7-二氯-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮
  参考文献：
  名称：

  新型 TSPO PET 成像配体 [18F]氟乙基替马西泮的全自动合成

  摘要：

  简介：苯二氮卓类药物，包括替马西泮，被描述为 TSPO 拮抗剂。事实上，TSPO 最初被描述为具有地西泮次要结合位点的外周苯二氮卓受体 (PBR)。 TSPO 是神经炎症的潜在成像靶点，因为该受体的表达会放大。目的：在此，我们开发了一种新型氟化苯二氮卓配体，[ 18 F]氟乙基替马西泮（[ 18 F]F-FETEM），用于易位蛋白（18 kDa）的正电子发射断层扫描（PET）成像。方法：使用自动合成仪通过一锅法对[ 18 F]F-FETEM 进行放射性标记。我们对甲苯磺酰化前体进行了 [ 18 F]F-脂肪族亲核取代，然后在 C18 和 Alumina N SPE 小柱上进行纯化。还进行了质量控制测试。结果：在大约 33 分钟的整个合成时间内，我们获得了 2.0–3.0% 未衰变校正的放射化学活性产率（3.7% 衰变校正）。通过TLC分析，[ 18 F]F-FETEM的放射化学纯度超过90

  DOI：

  10.3390/molecules26082372
• 作为产物：
  描述：

  地西泮 在 human CYP₃A₄ expressed in Escherichia coli 、 NADPH-regenerating system 作用下， 以 phosphate buffer 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.25h， 生成 替马西泮
  参考文献：
  名称：

  Comparative study of the metabolism of drug substrates by human cytochrome P450 3A4 expressed in bacterial, yeast and human lymphoblastoid cells

  摘要：

  1. The aim was to compare the metabolic activity of human CYP3A4 expressed in bacteria (E. coli), yeast (S. cerevisiae) and human lymphoblastoid cells (hBl), with the native CYP3A4 activity observed in a panel of human livers.2. Three CYP3A4 substrates were selected for study: dextromethorphan (DEM), midazolam (MDZ) and diazepam (DZ). The substrate metabolism in each of the four systems was characterized by deriving the kinetic parameters K-m or S-50, V-max and intrinsic clearance (CLint) or maximum clearance (CLmax) from the kinetic profiles; the latter differing by 100-fold across the three substrates.3. The K-m or S-50 for the formation of metabolites 3-methoxymorphinan (MEM), 1'-hydroxymidazolam (1'-OH MDZ) and 3-hydroxydiazepam (3HDZ) compared well in all systems. For CYP3A4-mediated metabolism of DEM, MDZ and DZ, the V-max for hBl microsomes were generally 2-9-fold higher than the respective yeast and human liver microsomes and E. coli membrane preparations, resulting in greater CLint or CLmax. In the case of 3HDZ formation, non-linear kinetics were observed for E. coli, hBl microsomes and human liver microsomes, whereas the kinetics observed for S. cerevisiae were linear.4. The use of native human liver microsomes for drug metabolic studies will always be preferable. However, owing to the limited availability of human tissues, we find it is reasonable to use any of the recombinant systems described herein, since all three recombinant systems gave good predictions of the native human liver enzyme activities.

  DOI：

  10.1080/00498250210163289

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] PHENOTHIAZINE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE PHÉNOTHIAZINE ET LEURS UTILISATIONS
  申请人：CAMP4 THERAPEUTICS CORP

  公开号：WO2019195789A1

  公开（公告）日：2019-10-10

  The present invention provides phenothiazine compounds, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment of various diseases or conditions, for example ribosomal disorders and ribosomopathies, e.g. Diamond Blackfan anemia (DBA).

  本发明提供了吩噻嗪化合物，其制备方法，包含该化合物的药物组合物，以及在治疗各种疾病或症状中使用该化合物或组合物，例如核糖体紊乱和核糖体病，例如钻石-布莱克范贫血（DBA）。
• [EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2021234004A1

  公开（公告）日：2021-11-25

  The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.

  本发明涉及适用于质谱的化合物，以及利用该化合物进行分析物分子的质谱测定方法。
• [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。

表征谱图