苯海索 | 144-11-6

• 物质功能分类: 原料药 - 神经系统用药 - 抗震颤麻痹药
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 苯海索
• 中文别名: 安坦；1-环己基-1-苯基-3-哌啶基-1-丙醇
• 英文名称: trihexyphenidyl
• 英文别名: 1-cyclohexyl-1-phenyl-3-piperidin-1-ylpropan-1-ol
• CAS: 144-11-6
• 化学式: C₂₀H₃₁NO
• 分子量: 301.472
• InChiKey: HWHLPVGTWGOCJO-UHFFFAOYSA-N

物化性质

• 熔点：
  258.5°C
• 沸点：
  442.59°C (rough estimate)
• 密度：
  0.9941 (rough estimate)
• 物理描述：
  Solid
• 溶解度：
  In water, 18 mg/L at 25 °C (est)
• 蒸汽压力：
  5.61X10-10 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 9.86 (est)
• 碰撞截面：
  175.1 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated]
• 保留指数：
  2236;2226;2226;2240;2260;2240.6;2254.2;2226;2230;2233;2236;2236;2236;2211;2250;2275;2275;2280

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

关于三己苯哌啶的代谢数据不容易获得。然而，它可能不会被大量代谢。

Data regarding the metabolism of trihexyphenidyl are not readily available. However, it is likely not heavily metabolized.

来源:DrugBank

代谢

苯海索及其三种代谢物在人尿中通过气相色谱-质谱法进行了研究。三种同分异构体的羟基代谢物被鉴定为1-(羟基环己基)-1-苯基-3-哌啶丙醇。在两名健康成人单次口服剂量后，对苯海索及其已鉴定代谢物的量进行了半定量测定。大约56%的剂量以羟基代谢物的形式被排出。苯海索排出的水平太低，无法用所使用的技术进行测量。

Benzhexol and three of its metabolites excreted in urine in man have been investigated by glc.--mass spectrometry. Three isomeric hydroxylated metabolites were identified as the 1-(hydroxycyclohexyl)-1-phenyl-3-piperidinopropan-1-ols. 3. The amounts of benzhexol and its identified metabolites have been semiquantitatively determined after a single oral dose in two healthy adults. Approx. 56% of the dose was excreted as the hydroxylated metabolites. The levels of benzhexol excreted were too low to be measured by the techniques used.

来源:Hazardous Substances Data Bank (HSDB)

代谢

半衰期：3.3-4.1小时

Half Life: 3.3-4.1 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

三己苯哌啶是一种选择性M1毒蕈碱型乙酰胆碱受体拮抗剂。它能够区分M1（皮质或神经型）和周围毒蕈碱亚型（心脏和腺体）。三己苯哌啶部分阻断中枢神经系统中的胆碱能活动，这种活动与帕金森病的症状有关。它还被认为能够增加多巴胺的可用性，多巴胺是一种对自主肌肉运动的发起和顺畅控制至关重要的大脑化学物质。

Trihexyphenidyl is a selective M1 muscarinic acetylcholine receptor antagonist. It is able to discriminate between the M1 (cortical or neuronal) and the peripheral muscarinic subtypes (cardiac and glandular). Trihexyphenidyl partially blocks cholinergic activity in the CNS, which is responsible for the symptoms of Parkinson's disease. It is also thought to increase the availability of dopamine, a brain chemical that is critical in the initiation and smooth control of voluntary muscle movement.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

三己芬尼定尚未有报告称会导致血清转氨酶升高，但尚未以前瞻性的方式评估其对血清酶水平的影响。在日本文献中，三己芬尼定被引用为两例急性肝损伤导致死亡的病因，但给出的细节很少，而且在随后的40年里文献中没有其他此类损伤的报告。因此，如果三己芬尼定确实会导致肝损伤，那么它一定是一个非常罕见的原因。

Trihexyphenidyl has not been reported to cause serum aminotransferase elevations, but it has not been evaluated for effects on serum enzyme levels in a prospective manner. Trihexyphenidyl was cited as the cause of two cases of acute liver injury resulting in death in the Japanese literature, but few details were given and there have been no other reports of such injury in the literature in the subsequent 40 years. Thus, trihexyphenidyl must be a very rare cause of liver injury, if it occurs at all.

来源:LiverTox

毒理性

• 药物性肝损伤

药物名称：三己苯多巴

Compound:trihexyphenidyl

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：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

三己苯哌啶从胃肠道被吸收。三己苯哌啶达到7.2 ng/mL的Cmax，Tmax为1.3小时，AUC为201 ng·h/mL。

Trihexyphenidyl is absorbed from the gastrointestinal tract. Trihexyphenidyl reaches a Cmax of 7.2 ng/mL, with a Tmax of 1.3 hours, and an AUC of 201 ng\*h/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

关于三己苯哌啶的消除途径的数据并不容易获得。然而，它很可能是主要通过尿液排出的。

Data regarding the route of elimination of trihexyphenidyl are not readily available. However, it is likely eliminated predominantly in the urine.

来源:DrugBank

吸收、分配和排泄

使用对抗胆碱能药物敏感的放射受体分析，对三己酚酰胺进行了人体血清中的测定，并研究了短期和长期给药后患者的药代动力学。未经治疗的患者血清浓度-时间对数图呈双相，包括最初的快速分布相和后来的缓慢消除相。长期治疗的患者只表现出缓慢的消除相。消除遵循一级动力学，且速度较快，半衰期为3.7 ± 0.4（SEM）小时。半衰期与峰血清水平、年龄、治疗持续时间、 dystonia 的病因或严重程度之间没有关系。尽管急性抗胆碱能副作用与血清抗胆碱能水平的升高和降低平行，但 dystonia 的反应并没有改变。

Using a sensitive radioreceptor assay for anticholinergic drugs, trihexyphenidyl /was assayed/ in human serum and ... its pharmacokinetics following short-term and long-term administration to patients with dystonia /was studied/. Previously untreated patients had a biphasic semilogarithmic plot of serum concentration-time consisting of an initial rapid distribution phase and a later slower elimination phase. Patients on long-term treatment showed only the slower elimination phase. Elimination followed first-order kinetics and was rapid, with a half-life of 3.7 + or - 0.4 (SEM) hours. There was no relationship between half-life and peak serum level, age, duration of therapy, or etiology or severity of dystonia. Although acute anticholinergic side effects paralleled the rise and fall of serum anticholinergic levels, the response of dystonia did not.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

丙环定（Trihexyphenidyl）从胃肠道迅速吸收。口服丙环定 hydrochloride片剂后，药效在1小时内开始，高峰效果持续2-3小时，作用持续时间6-12小时。丙环定的代谢命运尚未确定；药物以原形药物的形式在尿液中排出。/丙环定 hydrochloride/

Trihexyphenidyl is rapidly absorbed from the GI tract. Following oral administration of trihexyphenidyl hydrochloride tablets, the onset of action occurs within 1 hour, peak effects last 2-3 hours, and the duration of action is 6-12 hours. The metabolic fate of trihexyphenidyl has not been determined; the drug is excreted in the urine, probably as unchanged drug. /Trihexylphenidyl hydrochloride/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予大鼠高剂量（3.2 mg/kg）静脉注射后，研究了比哌立登（BP）、三己酚酰胺（TP）和（-）-奎尼克林基苄酯（QNB）在大脑、心脏和肺部的亚细胞分布。临床上使用的BP或TP的亚细胞分布与QNB相似，QNB是一种典型的强效中枢毒蕈碱拮抗剂。这些药物在大脑亚细胞组分中的浓度-时间过程有两种类型，它们缓慢下降并与血浆浓度平行。在大脑和心脏中的亚细胞分布取决于每个组分的蛋白质含量。与心脏相比，肺部的核后组分（P2）占总浓度的百分比特征性地大约高出3-5倍。阐明肺部分布与大脑和心脏不同，具有高亲和力，这种亲和力不依赖于含有溶酶体的P2组分的蛋白质含量。另一方面，在低剂量（650 ng/kg）的3H-QNB下，与高剂量相比，大脑中每个组分占总浓度的百分比在突触膜和突触囊泡中增加，在细胞核和细胞质中减少。这些结果表明，尽管抗胆碱药物的组织浓度-时间过程似乎简单地与血浆浓度平行下降，但亚细胞分布在不同组织中表现出多种模式。

The subcellular distribution of biperiden (BP), trihexyphenidyl (TP) and (-)-quinuclidinyl benzylate (QNB) in brain, heart and lung following high dose (3.2 mg/kg) iv administration was investigated in rats. The subcellular distribution of BP or TP used clinically conformed with that of QNB, a typical potent central muscarinic antagonist. The concentration-time courses of the brain subcellular fractions for these drugs were of two types which decreased slowly and in parallel to the plasma concentration. The subcellular distribution in the brain and heart was dependent on the protein amount of each fraction. The percent post-nuclear fraction (P2) of the total concentration in the lung was characteristically about 3-5 times larger than that in the heart. It was elucidated that the distribution in the lung differs from that in the brain and heart, with high affinity which is not dependent on the protein amount in the P2 fraction containing lysosomes. On the other hand, at a low dose (650 ng/kg) of 3H-QNB, each fraction as a percentage of the total concentration in the brain increased in synaptic membrane and synaptic vesicles and decreased in nuclei and cytosol as compared with the high dose. These results show that although the tissue concentration-time courses of anticholinergic drugs appear to decrease simply in parallel to plasma concentration, the subcellular distribution exhibits a variety of patterns among various tissues.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933399090
• 储存条件：
  存于室温、密闭且干燥的环境中。

制备方法与用途

苯海索简介

苯海索作为抗帕金森病药物，在20世纪50年代国外就开始上市，60年代逐步在国内推广。它是一种中枢抗胆碱药，主要用于治疗老年震颤麻痹病症。该药物通过选择性阻断纹状体的胆碱能神经通路，对外周作用较小，从而有助于恢复帕金森病患者脑内多巴胺和乙酰胆碱的平衡，并改善患者的症状。

临床应用

临床上苯海索主要用于治疗震颤麻痹、脑炎后或动脉硬化引起的震颤麻痹。它能够有效缓解流涎症状，但对僵直及运动迟缓的疗效较差，但在减少震颤方面表现显著。总体而言，苯海索的效果不如左旋多巴和金刚烷胺。对于轻症患者或不能耐受左旋多巴的患者，常与左旋多巴联合使用。此外，苯海索还可用于肝豆状核变性、畸形性肌张力障碍、癫痫、慢性精神分裂症及抗精神病药物引起的静坐不能，并能帮助缓解由药物引起的锥体外系疾患。

反应信息

• 作为反应物：
  描述：

  苯海索 在 磷化氢 、 氢碘酸 、 溶剂黄146 作用下， 生成 1-(3-cyclohex-1-enyl-3-phenyl-propyl)-piperidine
  参考文献：
  名称：

  Antispasmodics. N-(3-Phenylpropyl)-amines and 3-Amino-1-phenyl-1-propanols¹

  摘要：

  DOI：

  10.1021/ja01158a018
• 作为产物：
  描述：

  哌啶 在 苯 作用下， 生成 苯海索
  参考文献：
  名称：

  [合成具有解痉活性的化合物。二。氨基叔醇的制备新方法]

  摘要：

  DOI：

  10.1002/ardp.19582910107

文献信息

• [EN] 3,5-DIAMINO-6-CHLORO-N-(N-(4-PHENYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2- CARBOXAMIDE COMPOUNDS<br/>[FR] COMPOSÉS 3,5-DIAMINO -6-CHLORO-N-(N- (4-PHÉNYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2-CARBOXAMIDE
  申请人：PARION SCIENCES INC

  公开号：WO2014099673A1

  公开（公告）日：2014-06-26

  The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.

  本发明涉及以下化合物的公式：或其药学上可接受的盐，用作钠通道阻滞剂，以及含有这些化合物的组合物，制备这些化合物的方法，以及在促进粘膜表面水合和治疗包括囊性纤维化、慢性阻塞性肺病、哮喘、支气管扩张、急性和慢性支气管炎、肺气肿和肺炎等疾病的治疗方法。
• CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
  申请人：Parion Sciences, Inc.

  公开号：US20140171447A1

  公开（公告）日：2014-06-19

  This invention provides compounds of the formula I: and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.

  这项发明提供了式I的化合物及其药用盐，可用作钠通道阻滞剂，包含这些化合物的组合物，以及用于这些化合物的治疗方法和用途，以及制备这些化合物的方法。
• [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。
• CYCLOPROPYLAMINES AS LSD1 INHIBITORS
  申请人：Incyte Corporation

  公开号：US20150225379A1

  公开（公告）日：2015-08-13

  The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

  本发明涉及环丙胺衍生物，这些衍生物是LSD1抑制剂，可用于治疗癌症等疾病。

表征谱图