比哌立登 | 514-65-8

• 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: 比哌立登
• 中文别名: 碧卜利旦；1-(5-双环[2.2.1]庚-2-烯基)-1-苯基-3-(1-哌啶基)丙-1-醇；3-哌啶基-1-苯基-双环庚烯基-1-丙醇；安克痉；双环哌丙醇
• 英文名称: biperiden
• 英文别名: akineton；1-norborn-5-en-2-yl-1-phenyl-3-piperidin-1-yl-propan-1-ol；1-norborn-5-en-2-yl-1-phenyl-3-piperidino-propan-1-ol；1-(5-bicyclo[2.2.1]hept-2-enyl)-1-phenyl-3-(1-piperidyl)propan-1-ol；1-(2-bicyclo[2.2.1]hept-5-enyl)-1-phenyl-3-piperidin-1-ylpropan-1-ol
• CAS: 514-65-8
• 化学式: C₂₁H₂₉NO
• 分子量: 311.467
• InChiKey: YSXKPIUOCJLQIE-UHFFFAOYSA-N

物化性质

• 熔点：
  114°C
• 沸点：
  451.49°C (rough estimate)
• 密度：
  1.0202 (rough estimate)
• 溶解度：
  可溶于氯仿（轻微）、DMSO（轻微、超声）、甲醇（轻微、超声）
• 物理描述：
  Solid
• 颜色/状态：
  Crystals
• 蒸汽压力：
  5.42 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 9.74 (amine) (est)
• 碰撞截面：
  175.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
• 保留指数：
  2280;2284;2300;2245;2290;2267

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

双哌啶的代谢过程不完全清楚，但确实涉及羟基化。

The metabolism of biperiden is not completely understood, but does involve hydroxylation.

来源:DrugBank

代谢

双哌啶的代谢过程不完全清楚，但确实涉及羟基化。

The metabolism of biperiden is not completely understood, but does involve hydroxylation.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

帕金森病被认为是由于纹状体中兴奋性（胆碱能）和抑制性（多巴胺能）系统之间的失衡所致。中枢活性抗胆碱药物（如比哌立登）的作用机制被认为与纹状体中乙酰胆碱在胆碱能受体上的竞争性拮抗有关，这进而恢复平衡。

Parkinsonism is thought to result from an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the corpus striatum. The mechanism of action of centrally active anticholinergic drugs such as biperiden is considered to relate to competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

Biperiden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。尽管它已经被使用了50多年，但在文献中没有关于Biperiden导致肝损伤的报告，如果真的发生，它可能是非常罕见的肝损伤原因。 可能性评分：E（不太可能是明显临床肝损伤的原因）。 药物类别：抗帕金森病药物 同类其他药物，抗胆碱能药物：苯海拉明，三己苯多巴

Biperiden 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. Despite its use for more than 50 years, there have been no reports of biperiden liver injury in the literature and it must be a very rare cause of liver injury, if it occurs at all. Likelihood score: E (unlikely cause of clinically apparent liver injury). Drug Class: Antiparkinson Agents Other Drugs in the Subclass, Anticholinergic Agents: Benztropine, Trihexyphenidyl

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：比哌立登

Compound:biperiden

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI 关注

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

87% 生物利用度

87% bioavailability

来源:DrugBank

吸收、分配和排泄

单次口服4毫克剂量后1至1.5小时，血清浓度达到4-5 ng/mL。服药后48小时内可以测定到血浆水平（0.1-0.2 ng/mL）。在大鼠口服250毫克/公斤剂量6小时后，药物的吸收率为87%。

The serum concentration at 1 to 1.5 hours following a single, 4 mg oral dose was 4-5 ng/mL. Plasma levels (0.1-0.2 ng/mL) could be determined up to 48 hours after dosing. Six hours after an oral dose of 250 mg/kg in rats, 87% of the drug had been absorbed.

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，研究了比佩里登（BP）、三己氧苯酚（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一致，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。大脑和心脏中的亚细胞分布取决于每个组分的蛋白量。肺部的核后组分（P2）占总浓度的百分比特征性地比心脏大3-5倍。结果表明，肺部的分布与大脑和心脏的不同，具有高亲和力，这种亲和力不依赖于含有溶酶体的P2组分的蛋白量。另一方面，在3H-QNB低剂量（650 ng/kg）时，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。这些结果显示，尽管抗胆碱能药物的 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)

吸收、分配和排泄

双环维林（biperiden）的药代动力学进行了研究，并与药效学（瞳孔大小、调节能力、自我情绪评分量表）在6名健康志愿者中进行了比较。采用单盲交叉设计，使用安慰剂和双环维林（4毫克，市售片剂形式）。在0.5小时的潜伏期后，双环维林被迅速吸收，半衰期为0.3小时，血浆峰浓度在1.5小时后达到5纳克/毫升。双环维林显示出良好的组织渗透性（分布半衰期为0.6小时；总分布体积与中央分布体积之比为9.6），血浆浓度的终末半衰期为18小时，口服清除率为146升/小时。药效学的最大滞后于血浆峰浓度1（自我评分）至4小时（调节能力）。

The pharmacokinetics of biperiden were studied and compared with pharmacodynamics (pupil size, accommodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 hr, biperiden was rapidly absorbed with a half-life of 0.3 hr, plasma peak levels of 5 ng/mL being reached after 1.5 hr. Biperiden showed good tissue penetration (distribution half-life 0.6 hr; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 hr, and the oral clearance was 146 L/hr. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 hr (accommodation).

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933399090
• 储存条件：
  通风、低温、干燥

制备方法与用途

生物活性

Biperiden（KL 373）具有抗帕金森症活性，是中枢M1胆碱受体阻断剂。该药物为抗震颤麻痹药和解痉药，小鼠口服LD50值为545 mg/kg，静脉注射为56 mg/kg。

化学性质

Biperiden为白色结晶，熔点范围为112-116℃（或报道为238℃）。它不易溶于水，微溶于乙醇，但易溶于甲醇。其盐酸盐（C21H29NO·HCl）又称安克痉（Akineton、Akinophyl），约在275℃分解。

用途

Biperiden主要用于辅助治疗帕金森病的各种形式（包括后脑炎型、原发性及动脉硬化型）。此外，它也常用于改善抗精神病药物导致的帕金森症状和体征。

生产方法

以环戊二烯为原料，首先与氯乙烯合成氯代双环庚烯，再与镁和乙醚反应得到双环庚烯镁化氯。最终通过与β-哌啶苯丙酮缩合制得比哌立登。β-哌啶苯丙酮的制备：以苯乙酮为原料，与哌啶盐酸盐、甲醛及二甲胺通过曼氏反应获得。

类别

有毒物品

毒性分级

中毒

急性毒性

• 大鼠口服LD50: 750毫克/公斤
• 小鼠口服LD50: 530毫克/公斤

可燃性危险特性

可燃；燃烧时产生有毒氮氧化物烟雾

储运特性

通风、低温、干燥

灭火剂

干粉、泡沫、沙土、二氧化碳、雾状水

反应信息

• 作为产物：
  描述：

  1-(双环[2.2.1]庚-5-烯-2-基)-3-(1-哌啶基)-1-丙酮 、 phenyl magnesium 生成 比哌立登
  参考文献：
  名称：

  Method for the production of biperidin

  摘要：

  本发明涉及一种生产双氢异奎尼的方法，该方法是通过将1-(双环[2.2.1]庚-5-烯-2-基)-3-哌啶基-1-丙酮的外/内混合物与苯基镁化合物反应，形成1-(双环[2.2.1]庚-5-烯-2-基)-1-苯基-3-哌啶基-1-丙醇的异构体混合物，从而通过将该混合物转化为相应的盐酸盐，分离所述盐酸盐，再转化为游离基，并结晶化所述双氢异奎尼而获得。

  公开号：

  US07030247B2

文献信息

• [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。
• SUBSTITUTED BRIDGED UREA ANALOGS AS SIRTUIN MODULATORS
  申请人：GLAXOSMITHKLINE LLC

  公开号：US20150152108A1

  公开（公告）日：2015-06-04

  The present invention relates to novel substituted bridged urea compounds, corresponding related analogs, pharmaceutical compositions and methods of use thereof. Sirtuin-modulating compounds of the present invention may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders, which include, but are not limited to, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. The present invention also related to compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

  本发明涉及新型取代桥式脲化合物，相应的相关类似物，药物组合物以及其使用方法。本发明的抑制素调节化合物可用于延长细胞寿命，并治疗和/或预防各种疾病和疾病，包括但不限于与衰老或压力、糖尿病、肥胖、神经退行性疾病、心血管疾病、血液凝块疾病、炎症、癌症和/或潮红有关的疾病或疾病，以及那些会受益于增加线粒体活性的疾病或疾病。本发明还涉及包含抑制素调节化合物与另一治疗剂组合的组合物。
• [EN] SUBSTITUTED BRIDGED UREA ANALOGS AS SIRTUIN MODULATORS<br/>[FR] ANALOGUES D'URÉE PONTÉS SUBSTITUÉS EN TANT QUE MODULATEURS DE SIRTUINE
  申请人：GLAXOSMITHKLINE IP NO 2 LTD

  公开号：WO2016079709A1

  公开（公告）日：2016-05-26

  The present invention relates to novel substituted bridged urea analog compounds of Formula (I) or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, processes for making and use of such compounds, alone or in combination with other therapeutic agents, as Sirtuin Modulators useful for increasing lifespan of a cell, and for use in treating and/or preventing a wide variety of diseases and disorders, which include, but are not limited to, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity.

  本发明涉及一种新型的取代桥式脲类似物化合物，其化学式为（I）或其药学上可接受的盐，相应的药物组合物，制备这种化合物的方法以及单独使用或与其他治疗剂联合使用的这些化合物作为Sirtuin调节剂，可用于增加细胞寿命，并用于治疗和/或预防各种疾病和紊乱，包括但不限于与衰老或压力、糖尿病、肥胖、神经退行性疾病、心血管疾病、血液凝块紊乱、炎症、癌症和/或潮红有关的疾病或紊乱，以及那些会受益于增加线粒体活性的疾病或紊乱。
• [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