洛非帕明 | 23047-25-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 中文名称: 洛非帕明
• 中文别名: 氯苯咪嗪；氯苯酰丙咪嗪
• 英文名称: lofepramine
• 英文别名: CPD000469292；1-(4-chloro-phenyl)-2-{[3-(10,11-dihydro-dibenzo[b,f]azepin-5-yl)-propyl]-methyl-amino}-ethanone；4'-chloro-2-{[3-(10,11-dihydro-5H-dibenz[b,f]-azepinyl)-(5)-propyl]-methylamino}-acetophenone；lofepramine base；1-(4-chlorophenyl)-2-[3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)propyl-methylamino]ethanone
• CAS: 23047-25-8
• 化学式: C₂₆H₂₇ClN₂O
• 分子量: 418.966
• InChiKey: SAPNXPWPAUFAJU-UHFFFAOYSA-N

物化性质

• 熔点：
  103-105°C
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 颜色/状态：
  Crystals from methanol or acetone
• 蒸汽压力：
  1.5X10-9 mm Hg @ 25 °C /Estimated/

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  23.6
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

体外研究中，比较了洛非普拉明（lofepramine）与依米帕明（imipramine）的代谢情况。两种化合物在大鼠和人体肝脏微粒体中通过NADPH生成系统被羟基化和去甲基化。两种药物共有的三种代谢物分别是去甲丙咪嗪（DMI）、2-羟基去甲丙咪嗪（2-OH-DMI）和二去甲基依米帕明（DDMI）。洛非普拉明还代谢为三种独特的三环代谢物。与真实参考化合物的比较表明，其中两种代谢物是2-羟基洛非普拉明和去甲基洛非普拉明。DDMI与DMI的浓度比值在洛非普拉明中高于依米帕明。这可能是由于洛非普拉明通过两条平行代谢途径形成DDMI，即DMI和去甲基洛非普拉明。推测洛非普拉明与去甲丙咪嗪和依米帕明不同的代谢模式对药物的治疗特性具有重要意义。

The in vitro metabolism of lofepramine was studied in comparison with imipramine. Both compounds were hydroxylated and demethylated by a NADPH-generating system in rat and human liver microsomes. Three metabolites were in common for the two drugs, namely desipramine (DMI), 2-hydroxydesipramine (2-OH-DMI) and didesmethylimipramine (DDMI). Lofepramine was also metabolized to three unique tricyclic metabolites. Comparisons with authentic reference compounds suggested that two of these metabolites were 2-hydroxylofepramine and desmethyllofepramine. The ratio between the concentrations of DDMI and DMI was higher for lofepramine than imipramine. This is probably due to DDMI formation via two parallel metabolic pathways of lofepramine, i.e. DMI and desmethyllofepramine, respectively. It is speculated that the different metabolic pattern of lofepramine as compared with desipramine and imipramine is of importance for the therapeutic profile of the drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

乐非拉明部分通过肝脏首次通过时的细胞色素P450依赖酶系统代谢为去甲丙咪嗪。它通过N-脱烷基化、羟基化和葡萄糖苷酸化进行代谢。乐非拉明的血浆清除率为686升/小时。其主要尿代谢物为去甲丙咪嗪、2-羟基去甲丙咪嗪及其葡萄糖苷酸（2-羟基异莫苯甲）和p-氯苯甲酸的甘氨酸结合物。

Lofepramine is partially metabolized to desipramine by a cytochrome p450 dependent enzyme system on first pass through the liver. It is metabolized by N-dealkylation, hydroxylation, and glucuronidation. The plasma clearance of lofepramine is 686 L/hr. Its main urinary metabolites are desipramine, 2-hydroxydesipramine, and its glucuronide (2-hydroxyimodibenzyl), and the glycine conjugate of p-chlorobenzoic acid.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

乐费拉明可能增强酒精的镇静作用。

Lofepramine may potentiate alcohol sedation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

癫痫或心律失常可能会在服用大量循环性抗抑郁药的患者中由氟马西尼诱发。/氟马西尼/

Seizures or arrhythmias may be precipitated /SRP: by flumazenil/ in patients with a serious cyclic antidepressant overdose. /Flumazenil/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

鉴于蛋白质结合度高和分布体积广泛，血液透析和血液灌流等措施不太可能具有价值。

Measures such as hemodialysis and hemoperfusion are not likely to be of value in view of the high degree of protein binding and the extensive volume of distribution.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

乐伯品（lofepramine）过量的治疗主要是对症和支持性的。在有必要的情况下应提供气管插管和通气。

Treatment of lofepramine overdose is largely symptomatic and supportive. Intubation and ventilation should be provided where indicated.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道。如有必要，进行吸痰。观察呼吸不足的迹象，并在需要时辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预期癫痫发作，并在必要时进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在转运过程中，用生理盐水连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的呕吐反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在健康受试者单次口服210毫克剂量后，氯丙咪嗪迅速被吸收，1小时和4小时分别达到血浆峰浓度，分别为140纳克/毫升（氯丙咪嗪）和5纳克/毫升（去甲丙咪嗪）。

Following oral administration of a single dose of 210 mg to healthy subjects, lofepramine is rapidly absorbed, with peak plasma concentrations of 140 ng/ml(lofepramine) and 5 ng/ml (desipramine) achieved within 1 and 4 hours, respectively.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  存储条件：2-8°C，密封保存，置于干燥处。

制备方法与用途

生物活性

Lofepramine（洛普拉明）是一种有效的三环类抗抑郁药，广泛代谢为去甲替林。Lofepramine 的抗抑郁活性主要通过抑制去神经传导物质的摄取来促进去甲肾上腺素能神经传递，并且还能通过抑制神经元摄取 5-羟色胺和色氨酸吡咯酶来增强 5-羟色胺能神经传递。除了具有显著的抗抑郁作用外，Lofepramine 还具备明显的抗焦虑功效。

反应信息

• 作为反应物：
  描述：

  洛非帕明 、 顺丁烯二酸 以 乙酸乙酯 为溶剂， 反应 1.08h， 以95%的产率得到lofepramine maleate
  参考文献：
  名称：

  WO2008/139484

  摘要：

  公开号：
• 作为产物：
  描述：

  地昔帕明 、 2'-溴-4-氯苯乙酮 在 potassium carbonate 、 potassium hydrogencarbonate 作用下， 以 甲基叔丁基醚 为溶剂， 生成 洛非帕明
  参考文献：
  名称：

  WO2008/139484

  摘要：

  公开号：

文献信息

• NAPHTHALENE-BASED INHIBITORS OF ANTI-APOPTOTIC PROTEINS
  申请人：Pellecchia Maurizio

  公开号：US20090105319A1

  公开（公告）日：2009-04-23

  Methods of using apogossypol and its derivatives for treating inflammation is disclosed. Also, there is described a group of compounds having structure A, or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof are provided: wherein each R is independently selected from the group consisting of H, C(O)X, C(O)NHX, NH(CO)X, SO 2 NHX, and NHSO 2 X, wherein X is selected from the group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, an alkylaryl, and a heterocycle. Compounds of group A may be used for treating various diseases or disorders, such as cancer.

  使用阿波戈司宝及其衍生物治疗炎症的方法被披露。此外，还描述了一组具有结构A的化合物，或其药学上可接受的盐、水合物、N-氧化物或溶剂化合物： 其中每个R独立地选自H、C(O)X、C(O)NHX、NH(CO)X、SO2NHX和NHSO2X组成的组，其中X选自烷基、取代烷基、芳基、取代芳基、烷基芳基和杂环的组。A组化合物可用于治疗各种疾病或疾病，如癌症。
• [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。
• [EN] NMDA RECEPTOR MODULATORS AND USES THEREOF<br/>[FR] MODULATEURS DES RÉCEPTEURS NMDA ET UTILISATIONS DE CEUX-CI
  申请人：CADENT THERAPEUTICS

  公开号：WO2018119374A1

  公开（公告）日：2018-06-28

  Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated to modulate the NMDA receptor.

  本文披露了部分杂芳化合物及其在治疗神经精神障碍，例如精神分裂症和重度抑郁症中的用途方法。提供了药物组合物和制备杂芳化合物的方法。这些化合物被认为可以调节NMDA受体。
• Chemical Compounds
  申请人：Brown Alan Daniel

  公开号：US20120010182A1

  公开（公告）日：2012-01-12

  The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to new sulfonamide Nav1.7 inhibitors of formula (I): or pharmaceutically acceptable salts thereof, wherein Z 1 , R a , R b , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain.

  该发明涉及磺胺衍生物，其在医学上的应用，含有它们的组合物，其制备方法以及用于这些方法的中间体。 更具体地，该发明涉及公式（I）的新磺胺基Nav1.7抑制剂： 或其药学上可接受的盐，其中Z 1 ，R a ，R b ，R 1 ，R 2 ，R 3 ，R 4 和R 5 如描述中所定义。 Nav 1.7抑制剂在治疗各种疾病，特别是疼痛方面具有潜在用途。
• [EN] TREATMENT OF AUTISM SPECTRUM DISORDERS, OBSESSIVE-COMPULSIVE DISORDER AND ANXIETY DISORDERS<br/>[FR] TRAITEMENT DE TROUBLES DU SPECTRE AUTISTIQUE, DE TROUBLES OBSESSIVO-COMPULSIFS ET DE TROUBLES DE L'ANXIÉTÉ
  申请人：RUGEN HOLDINGS CAYMAN LTD

  公开号：WO2018098128A1

  公开（公告）日：2018-05-31

  Disclosed are methods for treating NMDA receptor-mediated disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. NMDA receptor-mediated disorders include autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders.

  揭示了通过给予特定NR2B亚单位选择性NMDA（N-甲基-D-天冬氨酸）拮抗剂来治疗NMDA受体介导的疾病的方法。NMDA受体介导的疾病包括自闭症谱系障碍、强迫症和焦虑症。