milnacipran | 136090-84-1

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: milnacipran
• 英文别名: 2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide
• CAS: 136090-84-1；92623-85-3
• 化学式: C₁₅H₂₂N₂O
• 分子量: 246.352
• InChiKey: GJJFMKBJSRMPLA-UHFFFAOYSA-N

物化性质

• 沸点：
  393.0±21.0 °C(Predicted)
• 密度：
  1.077±0.06 g/cm3(Predicted)
• 溶解度：
  H2O: 19 mg/mL
• 熔点：
  179°C
• 保留指数：
  1952

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  46.3
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

已确定左旋米那西普兰通过脱乙基化和羟基化分别生成去乙基左旋米那西普兰和对羟基左旋米那西普兰。这两种氧化代谢物进一步与葡萄糖醛酸结合，形成结合物米那西普兰羧酰胺-O-葡萄糖醛酸。脱乙基化主要由CYP3A4催化，CYP2C8、2C19、2D6和2J2也有少量贡献。此外，普遍认为米那西普兰对映体在体内不会相互转化。

It has been determined that levomilnacipran undergoes desethylation and hydroxylation to generate desethyl levomilnacipran and p-hydroxy-levomilnacipran, respectively. Both oxidative metabolites undergo further conjugation with glucuronide to form the conjugate milnacipran carbamoyl-O-glucuronide. The desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2. Additionally, it is the general understanding that there is no interconversion between the enantiomers of milnacipran in the body.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：米那西普兰在母乳中的含量较低，预计不会对哺乳婴儿产生任何不良反应。然而，在获得更多数据之前，哺乳期间应谨慎使用米那西普兰，特别是在哺乳新生儿或早产儿时。 对哺乳婴儿的影响：截至修订日期，未找到相关已发布信息。 对泌乳和母乳的影响：制造商报告称，乳汁分泌是米那西普兰的副作用之一。一名正在接受抑郁症治疗的女性故意过量服用了950毫克米那西普兰口服。在过量服用后的第5天到第15天，患者注意到左乳流出乳汁。乳汁分泌未经治疗即已解决。 在一项针对法国药物警戒中心报告的高催乳素血症及其症状（例如，男性乳房发育）病例的研究中，未发现米那西普兰与其他药物相比有增加引起高催乳素血症的风险。 一项观察性研究调查了在怀孕前两年内服用抗抑郁药的2859名女性的结果。与怀孕期间未服用抗抑郁药的女性相比，整个孕期（三个季度）都服用抗抑郁药的母亲在出院时哺乳的可能性降低了37%。仅在第三季度服用抗抑郁药的母亲在出院时哺乳的可能性降低了75%。仅在第一季度和第二季度服用抗抑郁药的母亲在出院时哺乳的可能性没有降低。母亲使用的抗抑郁药未具体说明。 一项回顾性队列研究比较了2001年至2008年的医院电子医疗记录，研究对象是晚期妊娠期间分发抗抑郁药的女性（n = 575）、患有精神疾病但未接受抗抑郁药的女性（n = 1552）以及没有精神疾病诊断的母亲（n = 30,535）。服用抗抑郁药的女性在出院时哺乳的可能性比没有精神疾病诊断的女性低37%，但与未接受治疗的精神疾病母亲相比，哺乳的可能性没有降低。这些母亲中没有人在服用米那西普兰。 在1999年至2008年的一项针对80,882对挪威母婴对的研究中，392名女性报告了产后新使用抗抑郁药，201名报告称她们从怀孕期间继续使用抗抑郁药。与未暴露的对照组相比，晚期妊娠使用抗抑郁药与哺乳开始的可能性降低7%有关，但对哺乳持续时间或专一性没有影响。与未暴露的对照组相比，新开始或重新开始使用抗抑郁药与6个月时主要哺乳的可能性降低63%和任何哺乳的可能性降低51%有关，以及突然停止哺乳的风险增加2.6倍。具体抗抑郁药未提及。

◉ Summary of Use during Lactation:Amounts of milnacipran in breastmilk are low and would not be expected to cause any adverse effects in breastfed infants. However, until more data become available, milnacipran should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Galactorrhea is reported by the manufacturer to be a side effect of milnacipran. One woman who was being treated for depression took an intentional overdose of 950 mg of milnacipran orally. From day 5 to day 15 after the overdose, the patient noted a flow of milk from her left breast. The galactorrhea resolved without treatment. In a study of cases of hyperprolactinemia and its symptoms (e.g., gynecomastia) reported to a French pharmacovigilance center, milnacipran was not found to have an increased risk of causing hyperprolactinemia compared to other drugs. An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified. A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking milnacipran. In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

米那西普兰的蛋白结合率测定为13%。相反，记录的左米那西普兰的血浆蛋白结合率为22%，浓度范围为10至1000 ng/mL。

The protein binding determined for racemic milnacipran is 13%. Conversely, the plasma protein binding documented for levomilnacipran is 22% over a concentration range of 10 to 1000 ng/mL.

来源:DrugBank

吸收、分配和排泄

• 吸收

消旋米那西帕明在口服给药后的绝对生物利用度约为85-90%。口服给药后2-4小时内达到消旋体药物的最大浓度，并且在36-48小时内达到稳态水平。相反，左旋米那西帕明的相对生物利用度已被记录为92%。左旋米那西帕明达到峰值浓度（Tmax）的中位时间大约是口服给药后6-8小时。在每日口服左旋米那西帕明120毫克后，平均Cmax值为341 ng/mL，平均稳态AUC值为5196 ng·h/mL。一般来说，无论是消旋米那西帕明还是左旋米那西帕明与食物一起服用，都不会影响药物的口服生物利用度。

Racemic milnacipram demonstrates an absolute bioavailability of about 85-90% following oral administration. Maximum concentrations of the racemic agent are reached within 2-4 hours after oral dosing, and steady-state levels are obtained by 36-48 hours. Conversely, the relative bioavailability of levomilnacipram has been documented as 92%. The median time to peak concentration Tmax for levomilnacipram is about 6-8 hours after oral administration. After daily dosing of levomilnacipram 120 mg, the mean Cmax value is 341 ng/mL, and the mean steady-state AUC value is 5196 ng.h/mL. In general, the administration of either racemic milnacipram or levomilnacipram with food does not affect the medication's oral bioavailability.

来源:DrugBank

吸收、分配和排泄

• 消除途径

左旋米那西普兰及其代谢物主要通过肾脏排泄。在口服14C-左旋米那西普兰溶液后，大约58%的剂量以未改变的左旋米那西普兰形式通过尿液排出。N-去乙基左旋米那西普兰是通过尿液排出的主要代谢物，约占剂量的18%。尿液中排出的其他可识别的代谢物包括左旋米那西普兰葡萄糖苷酸（4%）、去乙基左旋米那西普兰葡萄糖苷酸（3%）、对-羟基左旋米那西普兰葡萄糖苷酸（1%）和对-羟基左旋米那西普兰（1%）。

Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose. Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%).

来源:DrugBank

吸收、分配和排泄

• 分布容积

单次静脉给药给健康受试者后，记录的米尔纳昔普兰对映体的平均分布体积约为400升。另一方面，左旋米尔纳昔普兰的分布广泛，表观分布体积为387-473升。

The mean volume of distribution recorded for racemic milnacipran following a single intravenous dose to healthy subjects was approximately 400 L. Alternatively, levomilnacipran is widely distributed with an apparent volume of distribution of 387-473 L.

来源:DrugBank

吸收、分配和排泄

• 清除

米那西普兰的总体血浆清除率大约为40升/小时。

The total plasma clearance determined for milnacipran is approximately 40 L/h.

来源:DrugBank

制备方法与用途

生物活性方面，Milnacipran是一种5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRI），适用于治疗纤维肌痛。

反应信息

• 作为反应物：
  描述：

  milnacipran 在 silica gel 、 pyridinium chlorochromate 作用下， 以 氯仿 为溶剂， 生成 (1S,2R)-1-Phenyl-2-formyl-N,N-diethyl Cyclopropane Carboxamide
  参考文献：
  名称：

  一种式Ⅲ化合物及其制备方法和其用途

  摘要：

  本发明涉及一种式Ⅲ化合物及其制备方法,包括如下步骤：在搅拌、10‑40℃条件下，将羟胺或羟胺盐的任一种或其组合与式I化合物置于第一反应溶剂中,至反应完全，得含式Ⅲ化合物的完全反应液，本发明首次制备、分离、表征了米那普仑及制剂在制备和/或储存中产生的式Ⅲ化合物，式Ⅲ化合物纯度≥95％，并将式Ⅲ化合物用作检测米那普仑及制剂质量的标准品或对照品，实现药品质量监控，以保障药品的安全有效性。#imgabs0#

  公开号：

  CN117362194A
• 作为产物：
  描述：

  1-phenyl-1-diethylaminocarbonyl-2-chloromethylcyclopropane 在 sodium azide 、 四丁基溴化铵 、 三苯基膦 作用下， 以 甲苯 为溶剂， 反应 1.5h， 生成 milnacipran
  参考文献：
  名称：

  [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF 1-ARYL 2-AMINOMETHYL CYCLOPROPANE CARBOXYAMIDE (Z) DERIVATIVES, THEIR ISOMERS AND SALTS
  [FR] PROCÉDÉ PERFECTIONNÉ POUR LA PRÉPARATION DE DÉRIVÉS DE 1-ARYL-2-AMINOMÉTHYLCYCLOPROPANECARBOXAMIDE (Z), DE LEURS ISOMÈRES ET DE LEURS SELS

  摘要：

  本发明涉及一种改进的单锅法制备1-芳基2-氨甲基环丙烷羧酰胺（z）衍生物及其异构体的过程，其化学式为（I）或其药学上可接受的盐，其中R1和R2分别代表从氢、低烷基、低芳基和低烷基芳基中独立选择的基团，所述芳基或烷基芳基基团可选择性地被卤原子取代。

  公开号：

  WO2014009767A1

文献信息

• Indole derivatives for the treatment of depression and anxiety
  申请人：——

  公开号：US20040006229A1

  公开（公告）日：2004-01-08

  The present invention provides compounds of formula (I): which are useful for treating depression, anxiety, and alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine. 1

  本发明提供了以下化合物的公式（I）：这些化合物对治疗抑郁症、焦虑症，并缓解因戒烟或部分戒烟引起的症状非常有用。
• Benzofuran derivatives
  申请人：——

  公开号：US20030232833A1

  公开（公告）日：2003-12-18

  The present invention provides compounds of formula (I) which are useful for treating depression, anxiety, and alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine. 1

  本发明提供了一种化合物，其化学式为（I），可用于治疗抑郁症、焦虑症，并缓解因戒烟或部分戒烟引起的症状。
• Piperidines derivatives and their use as serotonin receptor antagonists
  申请人：——

  公开号：US20030225281A1

  公开（公告）日：2003-12-04

  The present invention provides compounds of formula (I): which are useful for treating depression, anxiety, and alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine. 1

  本发明提供了以下式(I)的化合物，用于治疗抑郁症、焦虑症，并缓解因戒烟或部分戒烟而引起的症状。
• Combination therapy for treatment of depression
  申请人：——

  公开号：US20030092770A1

  公开（公告）日：2003-05-15

  The present invention provides a method for treating depression, comprising administering to a patient an effective amount of a first component which is a suitable antidepressant, in combination with an effective amount of a second component which is a suitable AMPA receptor potentiator.

  本发明提供了一种治疗抑郁症的方法，包括向患者施用一种适量的第一成分，该成分是一种适当的抗抑郁药物，结合一种适量的第二成分，该成分是一种适当的AMPA受体增强剂。
• Benzodioxane and benzodioxolane derivatives and uses thereof
  申请人：Zhou Dahui

  公开号：US20060241172A1

  公开（公告）日：2006-10-26

  Compounds of formula I or pharmaceutically acceptable salts thereof are provided: wherein each of R 1 , R 2 , R 3 , R 4 , y, n, m, and Ar are as defined, and described in classes and subclasses herein, which are agonists or partial agonists of the 2C subtype of brain serotonin receptors. The compounds, and compositions containing the compounds, can be used to treat a variety of central nervous system disorders such as schizophrenia.

  提供了化学式I或其药用可接受盐的化合物：其中R1、R2、R3、R4、y、n、m和Ar中的每一个如所定义，并在此处描述的类和亚类中，它们是大脑5-羟色胺受体2C亚型的激动剂或部分激动剂。这些化合物和含有这些化合物的组合物可用于治疗多种中枢神经系统疾病，如精神分裂症。