(1R,2S)-cis-milnacipran hydrochloride

• 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: (1R,2S)-cis-milnacipran hydrochloride
• 英文别名: (-)-Milnacipran hydrochloride；(1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide;hydron;chloride
• 化学式: C₁₅H₂₂N₂O*ClH
• 分子量: 282.813
• InChiKey: XNCDYJFPRPDERF-PBCQUBLHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.94
• 重原子数：
  19
• 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：
  48
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

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，患者注意到左乳有乳汁流出。乳汁分泌未经治疗即已解决。 在一项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）案例的研究中，与其它药物相比，米那西普兰并未发现增加引起高催乳素血症的风险。 在一项观察性研究中，调查了2859名在怀孕前两年内服用抗抑郁药的妇女的结果。与怀孕期间未服用抗抑郁药的妇女相比，整个孕期都服用抗抑郁药的妇女在出院时哺乳的可能性降低了37％。仅在第三孕期服用抗抑郁药的妇女在出院时哺乳的可能性降低了75％。仅在第一和第二孕期服用抗抑郁药的妇女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妇女（n = 575），有精神疾病但未接受抗抑郁药的妇女（n = 1552），以及没有精神疾病诊断的妇女（n = 30,535）。服用抗抑郁药的妇女在出院时哺乳的可能性比没有精神疾病诊断的妇女低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。母亲中没有人在服用米那西普兰。 在1999年至2008年的一项对80,882对挪威母婴对的研究中，392名妇女报告了产后新开始使用抗抑郁药，201名妇女报告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几率降低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个月时主要哺乳的几率降低63％和任何哺乳的几率降低51％有关，以及突然停止哺乳的风险增加2.6倍。具体的抗抑郁药未提及。

◉ 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)

反应信息

• 作为反应物：
  描述：

  (1R,2S)-cis-milnacipran hydrochloride 在 sodium hydroxide 作用下， 以 二氯甲烷 、 水 为溶剂， 生成 (1S,2R)-cis-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (D)-(-)-mandelate
  参考文献：
  名称：

  PROCESS FOR PREPARING OPTICALLY PURE MILNACIPRAN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

  摘要：

  本发明涉及一种改进的商业化可行的过程，用于分离式解决式I的顺式米纳西普兰的外消旋体和其药用可接受盐II。本发明包括使用外消旋式顺式米纳西普兰或其药用可接受盐作为起始物质，采用具有低成本和商业化可用性的分离剂III的工业安全和经济低成本材料，例如水作为溶剂。所述过程导致具有优异光学纯度的外消旋式顺式米纳西普兰的光学异构体，而无需进行多次结晶步骤。本发明还包括绿色化学的概念，因为该发明在水作为溶剂的情况下运作良好，从而最大限度地减少了对任何其他溶剂的使用。其中X是从Cl、Br、I、HSO4、磷酸盐或有机酸中选择的阴离子。III的化学式应插入此处，*代表不对称中心，化合物III的化学式代表苹果酸及其衍生物。

  公开号：

  US20120289744A1
• 作为产物：
  描述：

  (1R,2S)-cis-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (L)-(+)-mandelate 在 盐酸 作用下， 以 甲基叔丁基醚 、 异丙醇 为溶剂， 反应 4.5h， 以79%的产率得到(1R,2S)-cis-milnacipran hydrochloride
  参考文献：
  名称：

  PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE SALTS OF RACEMIC MILNACIPRAN AND ITS OPTICAL ENANTIOMERS THEREOF

  摘要：

  本发明涉及一种通过酸基交换改进的制备米氮西普兰药用可接受盐的方法。

  公开号：

  US20120184774A1

文献信息

• Piperazine derivatives and the use thereof as medicament
  申请人：HOENKE Christoph

  公开号：US20150105397A1

  公开（公告）日：2015-04-16

  The present inventions relate to substituted piperazine derivatives of general formula (I) and to the manufacture of said compounds, pharmaceutical compositions comprising a compound according to general formula (I), and the use of said compounds for the treatment of various medical conditions related to glycine transporter-1 (GlyT1).

  这些发明涉及一般式(I)的取代哌嗪衍生物，以及所述化合物的制备，包括符合一般式(I)的化合物的药物组合物，以及利用这些化合物治疗与甘氨酸转运蛋白-1（GlyT1）相关的各种医疗状况。
• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• Heteroaryl-Substituted Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
  申请人：Pfizer Inc.

  公开号：US20140228356A1

  公开（公告）日：2014-08-14

  The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I, and the variables R 1 and R 2 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本发明涉及所披露的化合物、互变异构体和该化合物的药用可接受盐，其中该化合物具有如下式的结构， 变量R1和R2如规范中所定义。还披露了相应的药用组合物、治疗方法、合成方法和中间体。
• Heterocyclic Substituted Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
  申请人：PFIZER INC.

  公开号：US20130296308A1

  公开（公告）日：2013-11-07

  Compounds, tautomers and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I, as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  揭示了化合物、互变异构体和该化合物的药学上可接受的盐，其中该化合物具有如规范中定义的Formula I的结构。还披露了相应的药物组合物、治疗方法、合成方法和中间体。
• AMINO-HETEROCYCLIC COMPOUNDS
  申请人：Claffey Michelle M.

  公开号：US20100190771A1

  公开（公告）日：2010-07-29

  The invention provides PDE9-inhibiting compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , A, and n are as defined herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in treating neurodegenerative and cognitive disorders, such as Alzheimer's disease and schizophrenia, are also provided.

  这项发明提供了式（I）中的PDE9抑制化合物，以及其药学上可接受的盐，其中R1、R2、R3、A和n的定义如本文所述。还提供了含有式I中化合物的药物组合物，并且提供了在治疗神经退行性和认知障碍疾病，如阿尔茨海默病和精神分裂症中的用途。