(+)-(1S,2R)-米那普仑 | 96847-54-0

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (+)-(1S,2R)-米那普仑
• 中文别名: 米那普仑杂质2；左旋米那普仑
• 英文名称: (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide
• 英文别名: levomilnacipran；(+)-Milnacipran；(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide；(1S,2R)-milnacipran；(1S,2R)-N,N-diethyl-2-aminomethyl-1-phenylcyclopropanamide
• CAS: 96847-54-0
• 化学式: C₁₅H₂₂N₂O
• 分子量: 246.352
• InChiKey: GJJFMKBJSRMPLA-DZGCQCFKSA-N

物化性质

• 沸点：
  393.0±21.0 °C(Predicted)
• 密度：
  1.077±0.06 g/cm3(Predicted)
• 保留指数：
  2362.2

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

肝脏的。左旋米那西拉潘经过脱乙基化生成脱乙基左旋米那西拉潘，并经过羟基化生成对-羟基-左旋米那西拉潘。脱乙基化主要由CYP3A4催化，CYP2C8、2C19、2D6和2J2也在一定程度上参与。这两种代谢物都会进一步与葡萄糖醛酸结合形成结合物。

Hepatic. Levomilnacipran undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran. Desethylation is facilitated primarily by CYP3A4 and by CYP2C8, 2C19, 2D6, and 2J2 to a lesser extent. Both metabolites undergo further conjugation with glucuronide to form conjugates.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概要：左旋米那西普兰尚未在哺乳期母亲中进行研究。然而，米那西普兰的消旋形式在母乳中的水平较低，预计不会对哺乳婴儿造成任何不良影响。在获得更多数据之前，哺乳期间应谨慎使用左旋米那西普兰，尤其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，没有找到相关的已发布信息。 对泌乳和母乳的影响：截至修订日期，没有找到关于左旋米那西普兰的具体已发布信息。 一项观察性研究调查了在怀孕前两年内使用抗抑郁药的2859名女性的结果。与怀孕期间未使用抗抑郁药的女性相比，整个孕期（三个季度）都使用抗抑郁药的母亲在出院时哺乳的可能性降低了37%。仅在第三季度使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使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）、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）。使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。 在一项对1999年至2008年的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名女性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。没有提到具体的抗抑郁药。

◉ Summary of Use during Lactation:Levomilnacipran has not been studied in nursing mothers. However, the racemic form of milnacipran has low levels in breastmilk are low and would not be expected to cause any adverse effects in breastfed infants. Until more data become available, levomilnacipran 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:Specific published information on levomilnacipran was not found as of the revision date. 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

22% 在10至1000纳克/毫升的浓度范围内与人血浆蛋白结合。

22% bound to human plasma protein over concentration range of 10 to 1000 ng/mL.

来源:DrugBank

吸收、分配和排泄

• 吸收

延时释放胶囊给药后的相对生物利用度与口服溶液相比为92%。食物不影响左旋米那西普兰的浓度。每日给药左旋米那西普兰（延时释放胶囊）后，平均Cmax为341 ng/mL，平均稳态AUC值为5196 ng·h/mL。口服给药后Tmax为6 - 8小时。在人中不存在立体异构体之间的相互转化。

The relative bioavailability after administration of the extended-release capsule was 92% when compared to oral solution. Food does not affect the concentration of levomilnacipran. After daily dosing of levomilnacipran (extended-release capsule) the mean Cmax is 341 ng/mL, and the mean steady-state AUC value is 5196 ng·h/mL. The Tmax is 6 - 8 hours after oral administration. Interconversion of stereoisomers does not occur in humans.

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。58%的剂量以未改变的左旋米那西普兰形式在尿液中排出。N-去乙基左旋米那西普兰是尿液中排出的主要代谢物，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%）。这些代谢物是无效的。

Levomilnacipran and its metabolites are eliminated primarily by renal excretion. 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-hydroxylevomilnacipran (1%). The metabolites are inactive.

来源:DrugBank

吸收、分配和排泄

• 分布容积

387 - 473 L [表观分布容积]

387 - 473 L [apparent volume of distribution]

来源:DrugBank

吸收、分配和排泄

• 清除

21 - 29 升/小时 [平均表观总清除率]

21 - 29 L/h [mean apparent total clearance]

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  (+)-(1S,2R)-米那普仑 在 盐酸 作用下， 以 乙醚 为溶剂， 生成 左旋米那普仑盐酸盐
  参考文献：
  名称：

  Enantioselective synthesis of levomilnacipran

  摘要：

  报告采用一种新方法不对称地合成了抗抑郁药物米那西普兰的活性 (1S,2R)-对映体。从苯乙酸开始，依次安装环丙烷环上的两个立体中心。

  DOI：

  10.1039/c2cc33743f
• 作为产物：
  描述：

  (1S5R)-1-苯基-3-氧杂双环[3.1.0]己烷-2-酮（左米那普仑中间体A） 在 aluminum (III) chloride 、 氯化亚砜 、 C.I.酸性橙108 作用下， 以 甲苯 为溶剂， 反应 20.0h， 生成 (+)-(1S,2R)-米那普仑
  参考文献：
  名称：

  Enantioselective synthesis of levomilnacipran

  摘要：

  报告采用一种新方法不对称地合成了抗抑郁药物米那西普兰的活性 (1S,2R)-对映体。从苯乙酸开始，依次安装环丙烷环上的两个立体中心。

  DOI：

  10.1039/c2cc33743f

文献信息

• [EN] A NEW PROCESS FOR PREPARING OPTICALLY PURE MILNACIPRAN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS.<br/>[FR] NOUVEAU PROCÉDÉ DE PRÉPARATION DE MILNACIPRAN OPTIQUEMENT PUR ET DE SES SELS DE QUALITÉ PHARMACEUTIQUE
  申请人：ARCH PHARMALABS LTD

  公开号：WO2012059933A1

  公开（公告）日：2012-05-10

  The present invention relates to an improved and commercially, viable process for the resolution of racemic cis milnacipran of formula I and its pharmaceutically acceptable salts of formula II. The present invention comprises using racemic cis milnacipran or its pharmaceutically acceptable salts as starting material, a low cost and commercially available resolving agent of formula III and industrially safe and economically low cost material such as water as a solvent. The said process results into optical isomers of racemic cis milnacipran having excellent optical purity without involving multiple crystallization steps. The present invention also comprises the concept of green chemistry as the invention works well with water as a solvent thereby minimizing the use of any other solvent. (Formular I and II should be inserted here) Wherein X is anion selected from Cl, Br, I, HSO4, Phosphate or organic acid(Formular III should be inserted here) *represent asymmetric centre Compound of formula III represent mandelic acid and its derivatives.

  本发明涉及一种改进的商业可行的过程，用于分离式异构体顺式米纳西普兰（化学式I）及其药用可接受盐（化学式II）。本发明包括使用顺式米纳西普兰的异构体或其药用可接受盐作为起始物质，以及具有低成本且商业上可获得的分离剂（化学式III）和工业安全以及经济低成本材料（如水）作为溶剂。该过程导致顺式米纳西普兰的光学异构体具有优异的光学纯度，而无需进行多次结晶步骤。本发明还包括绿色化学概念，因为该发明与水作为溶剂良好配合，从而最小化了对任何其他溶剂的使用。 （化学式I和II应在此处插入） 其中X是从Cl、Br、I、HSO4、磷酸盐或有机酸中选择的阴离子 （化学式III应在此处插入） *代表不对称中心，化合物的化学式III代表苯乙酸及其衍生物。
• PROCESS FOR PREPARING OPTICALLY PURE MILNACIPRAN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
  申请人：Pai Ganesh Gurpur

  公开号：US20120289744A1

  公开（公告）日：2012-11-15

  The present invention relates to an improved and commercially, viable process for the resolution of racemic cis milnacipran of formula I and its pharmaceutically acceptable salts of formula II. The present invention comprises using racemic cis milnacipran or its pharmaceutically acceptable salts as starting material, a low cost and commercially available resolving agent of formula III and industrially safe and economically low cost material such as water as a solvent. The said process results into optical isomers of racemic cis milnacipran having excellent optical purity without involving multiple crystallization steps. The present invention also comprises the concept of green chemistry as the invention works well with water as a solvent thereby minimizing the use of any other solvent. (Formular I and II should be inserted here) Wherein X is anion selected from Cl, Br, I, HSO 4 , Phosphate or organic acid (Formular III should be inserted here) *represent asymmetric centre Compound of formula III represent mandelic acid and its derivatives.

  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。
• PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE SALTS OF RACEMIC MILNACIPRAN AND ITS OPTICAL ENANTIOMERS THEREOF
  申请人：Jagtap Vikram Sarjerao

  公开号：US20120184774A1

  公开（公告）日：2012-07-19

  The present invention relates to an improved process for the preparation of pharmaceutically acceptable salts of milnacipran by mutual acid radical exchange.

  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。
• [EN] COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS<br/>[FR] COMPOSITIONS ET MÉTHODES DE TRAITEMENT D'AFFECTIONS NEUROLOGIQUES
  申请人：KANDULA MAHESH

  公开号：WO2013168002A1

  公开（公告）日：2013-11-14

  The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of neurological conditions may he formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may he used to treatment: of fibromyalgia, depression, neuropathic pain, severe pain, chronic pain, generalized pain, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multipie sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.

  该发明涉及公式(I)的化合物或其药用可接受的盐，以及其多晶型、溶剂合物、对映体、立体异构体和水合物。包括有效量的公式(I)化合物的药物组合物，以及用于治疗神经系统疾病的方法可以制备用于口服、颊粘膜、直肠、局部、经皮、经粘膜、静脉、肠道、糖浆或注射的制剂。这些组合物可用于治疗：纤维肌痛、抑郁症、神经病性疼痛、严重疼痛、慢性疼痛、全身性疼痛、损伤、术后疼痛、骨关节炎、类风湿性关节炎、多发性硬化、脊髓损伤、偏头痛、HIV相关神经病性疼痛、带状疱疹后神经痛、糖尿病性神经病变、癌症疼痛、纤维肌痛和腰背痛。
• COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
  申请人：Kandula Mahesh

  公开号：US20150119452A1

  公开（公告）日：2015-04-30

  The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of neurological conditions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of fibromyalgia, depression, neuropathic pain, severe pain, chronic pain, generalized pain, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.

  本发明涉及化合物I的公式或其药用可接受的盐，以及其多型、溶剂合物、对映体、立体异构体和水合物。包含化合物I的有效量的药物组合物，以及用于治疗神经系统疾病的方法可以制成口服、颊内、直肠、局部、经皮、经粘膜、静脉、肠道、糖浆或注射剂形式。这种组合物可以用于治疗纤维肌痛、抑郁症、神经病性疼痛、严重疼痛、慢性疼痛、全身疼痛、损伤、术后疼痛、骨关节炎、类风湿性关节炎、多发性硬化、脊髓损伤、偏头痛、HIV相关神经病性疼痛、带状疱疹后神经痛、糖尿病性神经病、癌症疼痛、纤维肌痛和腰背痛的治疗。