苯乙肼 | 51-71-8

• 物质功能分类: 原料药 - 神经系统用药 - 抗抑郁、躁狂药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 苯乙肼
• 中文别名: 2-苯乙基肼
• 英文名称: Phenelzine
• 英文别名: Phenelzin；2-phenylethylhydrazine
• CAS: 51-71-8
• 化学式: C₈H₁₂N₂
• 分子量: 136.197
• InChiKey: RMUCZJUITONUFY-UHFFFAOYSA-N

物化性质

• 熔点：
  25°C
• 沸点：
  bp0.1 74°
• 密度：
  1.0348 (rough estimate)
• 物理描述：
  Solid
• 颜色/状态：
  Liquid
• 溶解度：
  In water, 2.91X10+4 mg/L at 25 °C (est)
• 蒸汽压力：
  4.85X10-2 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition material emits toxic fumes of /sulfur oxides and nitrogen oxides/.
• 折光率：
  Index of refraction: 1.5494 at 20 °C/D
• 保留指数：
  1340;1328;1329;1330;1335

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  10
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  38
• 氢给体数：
  2
• 氢受体数：
  2

ADMET

代谢

对于代谢研究，假设苯乙肼会被乙酰化。苯乙肼的一些代谢物包括苯乙酸、2-苯乙胺和4-羟基苯乙酸作为主要代谢物，以及N-乙酰苯乙肼作为次要代谢物。

For the metabolic studies, it is assumed that phenelzine is acetylated. Some of the metabolites of phenelzine are phenylacetic acid, 2-phenylethylamine and 4-hydroxyphenylacetic acid as major metabolites and N-acetyl-phenelzine as a minor metabolite.

来源:DrugBank

代谢

Nardil 在体内被广泛代谢，主要通过单胺氧化酶途径进行氧化。在口服给予 (13)C6-苯乙肼后，96小时内，给药剂量的73%以苯乙酸和对羟基苯乙酸的形式在尿液中回收。乙酰化形成N2-乙酰苯乙肼是一个次要的代谢途径。

Nardil is extensively metabolized, primarily by oxidation via monoamine oxidase. After oral administration of (13)C6-phenelzine, 73% of the administered dose was recovered in urine as phenylacetic acid and parahydroxyphenylacetic acid within 96 hours. Acetylation to N2-acetylphenelzine is a minor pathway.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给大鼠注射2.5 mg/kg体重的phenelzine-1-(14)C硫酸盐后，24小时内62%的剂量在尿液中回收。主要排泄产物是苯乙酸，这也是小鼠中phenelzine的代谢物。参与这一消除过程的第一种酶是单胺氧化酶。

Following ip injection of 2.5 mg/kg bw phenelzine-1-(14)C sulfate to rats, 62% of the dose was recovered in the urine within 24 hours. The major excretion product was phenylacetic acid, which is also a metabolite of phenelzine in mice. The first enzyme involved in this elimination process is monoamine oxidase.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏。苯乙肼的乙酰化似乎是一个次要的代谢途径。β-苯乙胺是苯乙肼的代谢产物，并有间接证据表明苯乙肼也可能被环羟基化和N-甲基化。 消除途径：NARDIL®（一种药物）被广泛代谢，主要是通过单胺氧化酶的氧化作用。 半衰期：单次给药后为1.2-11.6小时。多次给药的药代动力学尚未研究。

Hepatic. Acetylation of phenelzine appears to be a minor metabolic pathway. Beta-phenylethylamine is a metabolite of phenelzine, and there is indirect evidence that phenelzine may also be ring-hydroxylated and N-methylated. Route of Elimination: NARDIL® is extensively metabolized, primarily by oxidation via monoamine oxidase. Half Life: 1.2-11.6 hours following single dose administration. Multiple-dose pharmacokinetics have not been studied.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

尽管尚未确定确切的作用机制，但看起来苯乙肼通过不可逆地、非选择性地抑制MAO，通过增加神经元中5-羟色胺、去甲肾上腺素和多巴胺的水平来缓解抑郁症状。

Although the exact mechanism of action has not been determined, it appears that the irreversible, nonselective inhibition of MAO by phenelzine relieves depressive symptoms by causing an increase in the levels of serotonin, norepinephrine, and dopamine in the neuron.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

苯乙肼，像大多数单胺氧化酶抑制剂一样，可能会在部分患者中引起短暂的血清转氨酶升高。这些升高通常是轻微的、无症状的，并且是自限性的，不需要调整剂量。苯乙肼还与急性、临床上明显的肝损伤病例有关。与MAO抑制剂相关的肝损伤通常在开始治疗后的1到3个月内出现，表现为血清酶升高的肝细胞模式。急性肝炎样综合征可能是严重的，甚至可能是致命的。苯乙肼引起的胆汁淤积性肝损伤也已有描述（案例1）。免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）不常见，自身抗体的形成也不常见。尽管公开发表的苯乙肼肝损伤案例较少，但美国食品药品监督管理局（FDA）和药品赞助商已经报告了由于肝损伤导致的严重黄疸和死亡病例。

Phenelzine, like most monoamine oxidase inhibitors, can cause transient serum aminotransferase elevations in a proportion of patients. These elevations are usually mild, asymptomatic and self-limited and do not require dose modification. Phenelzine has also been associated with cases of acute, clinically apparent liver injury. The liver injury associated with MAO inhibitors typically arises 1 to 3 months after starting therapy and presents with a hepatocellular pattern of serum enzyme elevations. The acute hepatitis-like syndrome can be severe and even fatal. Cholestatic liver injury due to phenelzine has also been described (Case 1). Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. While few cases of phenelzine liver injury have been published, instances of severe jaundice and fatalities due to liver injury have been reported to the FDA and the sponsor.

来源:LiverTox

毒理性

• 药物性肝损伤

复合物：苯乙肼

Compound:phenelzine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

苯乙肼从胃肠道迅速吸收。药物作用的衰减不依赖于药代动力学参数，而是依赖于蛋白质合成速率，该速率恢复单胺氧化酶的功能水平。平均Cmax为19.8 ng/ml，在给药后43分钟出现。

Phenelzine is rapidly absorbed from the gastrointestinal tract. The decay of the drug action is not dependent on the pharmacokinetic parameters but on the rate of protein synthesis which restores the functional levels of monoamine oxidase. The mean Cmax is 19.8 ng/ml and it occurs after 43 minutes of dose administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

给药剂量的消除主要是由苯乙肼代谢物组成，包括苯乙酸和对羟基苯乙酸，它们在头96小时内尿液中发现的剂量占79%。

The elimination of the administered dose is mainly composed of the phenelzine metabolites, phenylacetic acid and parahydroxyphenylacetic acid that constitute 79% of the dose found in the urine in the first 96 hours.

来源:DrugBank

吸收、分配和排泄

• 分布容积

苯乙肼的分布容积难以确定，因为这类药物非常容易渗透到中枢神经系统，进入期望其发挥作用的组织。

The volume of distribution of phenelzine is hard to determine as drugs from this kind penetrate the CNS very well into the tissue where their activity is desired.

来源:DrugBank

吸收、分配和排泄

在给大鼠注射2.5毫克/千克体重的phenelzine-1-(14)C硫酸盐后，24小时内尿液中回收了62%的剂量。

Following ip injection of 2.5 mg/kg bw phenelzine-1-(14)C sulfate to rats, 62% of the dose was recovered in the urine within 24 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在单次服用30毫克Nardil（2片，每片15毫克）后，平均血浆峰浓度（Cmax）为19.8 ng/mL，在给药后43分钟达到峰值。

Following a single 30 mg dose of Nardil (2 X 15 mg tablets), a mean peak plasma concentration (Cmax) of 19.8 ng/mL occurred at a time (Tmax) of 43 minutes post dose.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xi
• 海关编码：
  2928000090
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P260,P264,P270,P271,P280,P301+P310,P302+P352,P304+P340,P311,P312,P314,P321,P322,P330,P361,P363,P403+P233,P405,P501
• 危险品运输编号：
  2810
• 危险性描述：
  H311,H301,H331,H372
• 储存条件：
  2-8℃

制备方法与用途

抗抑郁症药——苯乙肼

苯乙肼是一种抗抑郁躁狂药，属单胺氧化酶抑制剂。其抗抑郁作用与尼亚酰胺相似，通过减少脑内儿茶酚胺（去甲肾上腺素、多巴胺、5-羟色胺）的降解，增加这些物质在体内的含量，从而发挥抗抑郁效果。对于内源性抑郁症较为有效，而对外源性和反应性抑郁症疗效不佳。

在治疗重型抑郁症、心境恶劣性障碍和非典型抑郁症方面，硫酸苯乙肼表现出良好的疗效，并且对惊恐性障碍和恐怖性障碍也有积极作用。对于某些难以通过三环类药物控制的患者，尤其是那些患有非典型抑郁症或严重焦虑症的个体，苯乙肼或许能带来有效治疗。

值得注意的是，苯乙肼在某些贪食症患者中可以改善饮食习惯，但其确切作用仍需临床对照试验验证。由于其毒性较大，在临床上已较少使用。

作用与用途

苯乙肼作为单胺氧化酶抑制剂（MAOI），通过减少脑内儿茶酚胺的降解增加这些物质在体内的含量，从而发挥抗抑郁作用。对于内源性抑郁症效果显著，但对其他类型的抑郁症疗效较弱。

产品特性

反苯环丙胺和苯乙肼是常用的处方药，用于治疗抑郁症及焦虑症。与反苯环丙胺相比，苯乙肼的刺激性较小，适用于那些对反苯环丙胺有强烈不适感的患者。同时，它引发体重增加的程度低于反苯环丙胺，并且可能具有类似氟西汀等SSRI类药物减少食欲的效果。

一般而言，若服用苯乙肼，则需在摄取的食物中至少含有10毫克酪胺才能引发高血压反应；而反苯环丙胺则只需5毫克的酪胺即可产生相同效果。

研究发现

研究表明，苯乙肼具有抗肿瘤活性，并与PD-1抗体表现出协同抗肿瘤效应。常见的单胺氧化酶-A（MAO-A）抑制剂还包括溴法罗明、托洛沙酮及司立吉兰等。

不良反应与注意事项 一般不良反应

常见的不良反应包括直立性低血压和自主神经功能紊乱，如口干、水肿、便秘、失眠、恶心以及震颤、共济失调、反射亢进等症状。过量使用可导致昏厥、多汗、心跳加速及呼吸表浅等问题，此时可用氯丙嗪进行肌内注射对抗。

肝脏毒性

苯乙肼具有肝脏毒性，长期用药需定期检查肝功能，并且禁用于肝功能不全的患者。

其他注意事项

• 肾功能不全、高血压和癫痫患者应慎用。
• 不可突然停药。在使用三环类抗抑郁药物（如盐酸丙咪嗪、盐酸阿米替林等）期间或前后均不可同时或交替使用苯乙肼，以免产生毒性反应。
• 禁止与抗胆碱药、抗组胺药、降糖药、降压药、巴比妥类及麻醉药合用。

反应信息

• 作为反应物：
  描述：

  苯乙肼 在 盐酸 、 sodium hydride 作用下， 以 1,4-二氧六环 为溶剂， 生成 N²-propargylphenelzine hydrochloride
  参考文献：
  名称：

  Synthesis of N-propargylphenelzine and analogues as neuroprotective agents

  摘要：

  A series of N-1- and N-2-propargylphenelzine derivatives and analogues (1-7) was synthesized. In addition to their activity as monoamine oxidase inhibitors, two of the compounds, N-1- and N-2-propargylphenelzines. (3 and 6), were found to be potent at preventing DSP-4-induced noradrenaline (NA) depletion in mouse hippocampus, suggesting that they have neuroprotective properties. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(01)00549-2
• 作为产物：
  描述：

  乙基溴苯 在 一水合肼 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以97%的产率得到苯乙肼
  参考文献：
  名称：

  一种吡唑并嘧啶并三唑环类化合物的制备方法

  摘要：

  本发明属于有机化合物合成技术领域，具体涉及一种吡唑并嘧啶并三唑环类化合物的制备方法。本发明提供了一种吡唑并嘧啶并三唑环类化合物的制备方法，包括以下步骤：将2‑氨基‑4,6‑二氯嘧啶‑5‑甲醛、与肼化合物混合进行缩合反应，得到嘧啶并吡唑；将所述嘧啶并吡唑、酰基肼混合进行取代反应，得到4‑酰肼基嘧啶并吡唑；将所述4‑酰肼基嘧啶并吡唑和缩合剂混合进行缩合重排反应，得到吡唑并嘧啶并三唑环类化合物。本发明提供的制备方法合成路径短，易于操作，适合工业化生产。

  公开号：

  CN113773327B
• 作为试剂：
  描述：

  (2S,4R)-4-Cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic Acid Methyl Ester 、 苯乙肼 在 苯乙肼 作用下， 反应 192.0h， 以51-71-8) to give the title compound as brown solid的产率得到(2S,4R)-4-Cyclopropylmethanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic Acid Methyl Ester
  参考文献：
  名称：

  Proline derivatives

  摘要：

  本发明涉及一种式为(I)的化合物，其中A，R1-R6在说明书和权利要求书中定义。式(I)化合物可用作药物。

  公开号：

  US08163793B2

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] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
  申请人：MERCK SHARP & DOHME

  公开号：WO2013169567A1

  公开（公告）日：2013-11-14

  The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及螺内酰胺类似物，其为CGRP受体拮抗剂，可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。

表征谱图