(2S)-2-(2-氯苯基)-2-(甲基氨基)-环己酮 | 33643-46-8

• 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: (2S)-2-(2-氯苯基)-2-(甲基氨基)-环己酮
• 英文名称: (S)-ketamine
• 英文别名: esketamine；(S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone；(-)-Ketamine；[11C]-(-)-Ketamine；(2S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
• CAS: 33643-46-8
• 化学式: C₁₃H₁₆ClNO
• 分子量: 237.729
• InChiKey: YQEZLKZALYSWHR-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

esketamine主要通过细胞色素P450（CYP）酶CYP2B6和CYP3A4，以及较小程度的CYP2C9和CYP2C19，代谢为_noresketamine_代谢物。Norsetamine通过细胞色素依赖性代谢途径代谢，随后代谢物发生葡萄糖苷酸化。

Esketamine is mainly metabolized to the _noresketamine_ metabolite by cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A4, and to a lesser extent, CYP2C9 and CYP2C19. Noresketamine is metabolized by cytochrome-dependent metabolic pathways followed by subsequent glucuronidation of metabolites.

来源:DrugBank

毒理性

• 肝毒性

在口服抗抑郁药的患者中，与安慰剂相比，添加鼻腔喷雾剂艾司氯胺酮并没有更频繁的肝功能检测异常。在艾司氯胺酮作为治疗难治性抑郁症的关键试验中，活动治疗期间平均血清ALT、AST和碱性磷酸酶水平降低，没有血清酶升高、黄疸、肝炎、因血清酶升高而停药或严重肝不良事件的报告。尽管已知长期使用氯胺酮与胆管损伤和胆汁淤积性黄疸发作有关，但在医疗监督下使用艾司氯胺酮治疗抑郁症尚未发现与类似的胆道损伤或胆汁淤积性肝炎的联系。艾司氯胺酮的长期使用临床经验很少，但迄今为止尚未有在使用中出现的明显肝损伤的报告。

In patients on oral antidepressants, liver test abnormalities were no more frequent with the addition of nasal spray esketamine than with placebo. In the pivotal trials of esketamine as therapy of treatment- resistant depression, mean serum ALT, AST and alkaline phosphatase levels decreased during active therapy and there were no reports of serum enzyme elevations, jaundice, hepatitis, discontinuations for serum enzyme elevations or serious hepatic adverse events. Although long term ketamine use is known to be associated with bile duct injury and episodes of cholestatic jaundice, esketamine has not been linked to a similar pattern of biliary injury or cholestatic hepatitis when used under medical supervision to treat depression. There has been little clinical experience with long term use of esketamine, but no instances of clinically apparent liver injury have as yet been reported with its use.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：艾司氯胺酮是氯胺酮的S型异构体，后者是一种消旋药物。艾司氯胺酮鼻喷剂作为抗抑郁药在母乳喂养期间尚未进行研究。有限的数据表明，在剖宫产手术中单次静脉注射艾司氯胺酮或氯胺酮可能不会影响哺乳的婴儿或泌乳。在获得更多信息之前，重复剂量的艾司氯胺酮鼻喷剂在哺乳期间应尽量避免使用。如果使用艾司氯胺酮，监测婴儿是否出现镇静、进食不良和体重增长不良的情况。 ◉ 对哺乳婴儿的影响：四名接受硬脊膜外麻醉（利多卡因和布比卡因）进行剖宫产的母亲也接受了氯胺酮和咪达唑仑（剂量未指定）的全身麻醉。他们的婴儿要么母乳喂养，要么通过奶瓶接受母亲的母乳。报告称婴儿没有出现不良反应。 ◉ 对泌乳和母乳的影响：一名孕妇在足月时遭受了28%的体表面积烧伤。她在预产期接受了氯胺酮麻醉下的紧急剖宫产。尽管婴儿需要剧烈的复苏，但婴儿立即开始母乳喂养。婴儿出现了短暂的黄疸，几天后自行消退。 一项研究比较了接受剖宫产的母亲，她们分别接受了安慰剂或S-氯胺酮（艾司氯胺酮）0.5毫克/千克肌肉注射，随后以2微克/千克/分钟的速度连续输注12小时。这种低剂量用于增强镇痛和减少残余疼痛，而不是提供麻醉。所有母亲都接受了硬脊膜内注射布比卡因8至10毫克和舒芬太尼5微克进行镇痛，以及在S-氯胺酮或安慰剂注射前静脉注射咪达唑仑0.02毫克/千克。术后，患者接受了24小时的患者控制静脉吗啡，随后根据需要使用对乙酰氨基酚、口服酮洛酸和单剂量静脉注射昂丹司琼8毫克。在研究的56名患者中（每组28人），每组有13人在产后3年进行了联系。接受安慰剂的患者平均母乳喂养了10.5个月，而接受S-氯胺酮的患者平均母乳喂养了8个月；然而，差异在统计学上并不显著。 一项随机双盲研究比较了静脉注射丙泊酚0.25毫克/千克、氯胺酮0.25毫克/千克、氯胺酮25毫克加丙泊酚25毫克以及生理盐水安慰剂对剖宫产后母亲疼痛控制的效果。单次剂量在脐带结扎后立即给予。接受安慰剂的患者第一次母乳喂养的时间为58分钟，使用氯胺酮的患者为31.9分钟，使用氯胺酮加丙泊酚的患者为25.8分钟。与其他组相比，组合使用的时间显著缩短。

◉ Summary of Use during Lactation:Esketamine is the more potent S-isomer of the racemic drug, ketamine. Esketamine nasal spray used as an antidepressant has not been studied during breastfeeding. Minimal data indicate that single doses of intravenous esketamine or ketamine use during cesarean section delivery may not affect the breastfed infant or lactation. Until more data are available, repeated doses esketamine nasal spray should probably be avoided during breastfeeding. If esketamine is used, monitor the infant for sedation, poor feeding and poor weight gain. ◉ Effects in Breastfed Infants:Four mothers who received epidural analgesia with lidocaine and bupivacaine for cesarean section also received general anesthesia with ketamine and midazolam (dosages not specified). Their infants were either breastfed or received their mother's breastmilk by bottle. No adverse effects were reported in the infants. ◉ Effects on Lactation and Breastmilk:A pregnant woman sustained 28% body surface area burns near term. She underwent an emergency cesarean section on her due date under ketamine anesthesia. Although the infant required vigorous resuscitation, the infant began breastfeeding immediately. The infant had transient jaundice that resolved in a few days. A study compared women undergoing cesarean section who received either placebo or S-ketamine (esketamine) 0.5 mg/kg intramuscularly, followed by a continuous infusion of 2 mcg/kg/minute for 12 hours. This low dose was used to enhance analgesia and reduce residual pain rather than to provide anesthesia. All women received intraspinal bupivacaine 8 to10 mg and sufentanil 5 mcg for analgesia, as well as midazolam 0.02 mg/kg intravenously before the S-ketamine or placebo injection. Postoperatively, patients received patient-controlled intravenous morphine for 24 hours, followed by acetaminophen, oral ketorolac and a single dose of ondansetron 8 mg intravenously as needed. Of the 56 patients enrolled in the study (28 in each group), 13 in each group were contacted at 3 years postpartum. Patients who received placebo reported breastfeeding for an average of 10.5 months and those who received S-ketamine reported breastfeeding for an average of 8 months; however, the difference was not statistically significant. A randomized, double-blind study compared the effects of intravenous propofol 0.25 mg/kg, ketamine 0.25 mg/kg, ketamine 25 mg plus propofol 25 mg, and saline placebo for pain control in mothers post-cesarean section. A single dose was given immediately after clamping of the umbilical cord. The time to the first breastfeeding was 58 minutes in those who received placebo, 31.9 minutes with ketamine and 25.8 minutes with propofol plus ketamine. The time was significantly shorter than the other groups with the combination.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

esketamine的蛋白质结合率大约为43%到45%。

The protein binding of esketamine is about 43% to 45%.

来源:DrugBank

吸收、分配和排泄

• 吸收

由于这种药物是通过鼻喷剂给药的，因此吸收迅速。在 esketamine 鼻喷剂给药后，平均绝对生物利用度约为 48%。在最后一次 esketamine 鼻喷剂给药后，达到 esketamine 血浆浓度峰值的时间为 20 至 40 分钟。esketamine 的受试者间变异性在 Cmax（最大浓度）为 27% 至 66%，在 AUC（药时曲线下面积）为 18% 至 45%。esketamine 的受试者内变异性对于 Cmax 大约为 15%，对于 AUC 大约为 10%。

Due to the fact that this drug is administered via nasal spray, absorption is rapid. The mean absolute bioavailability is approximately 48% after esketamine nasal spray administration. The time to achieve peak esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of esketamine. Inter-subject variability of esketamine ranges from 27% to 66% for Cmax (maximum concentration) and 18% to 45% for AUC (area under the curve). The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC.

来源:DrugBank

吸收、分配和排泄

• 消除途径

不足1%的鼻腔给药剂量以未改变的药物形式在尿液中排出。静脉注射（IV）或口服（PO）给药后， esketamine的代谢物主要在尿液中回收（占放射性标记剂量的78%以上），一小部分在粪便中测量（占放射性标记剂量的2%以下）。

Less than 1% of a dose of nasal esketamine is measured as unchanged drug, excreted in the urine. Following intravenous (IV) or oral (PO) administration, esketamine-derived metabolites were mainly recovered in urine (≥ 78% of a radiolabeled dose), and a smaller percentage was measured in the feces (≤ 2% of a radiolabeled dose).

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉给药时，艾司氯胺的平均稳态分布容积为709升。

The average steady-state volume of distribution of esketamine administered by the intravenous route is 709 L.

来源:DrugBank

吸收、分配和排泄

• 清除

esketamine的平均清除率约为89升/小时，静脉给药后。主要代谢物 esketamine, _noresketamine_, 从血浆中消除的速度比 esketamine 慢。 noresketamine 血浆浓度的降低呈双相方式，给药后前4小时下降较快，平均终末半衰期约为8小时。

The average clearance of esketamine is approximately 89 L/hour following intravenous administration. Elimination of the major esketamine metabolite, _noresketamine_, from plasma is slower than esketamine. The decrease of noresketamine plasma concentrations occurs in a biphasic fashion, with a more rapid decline for the first 4 hours post-administration, and an average terminal t1/2 of approximately 8 hours.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  (2S)-2-(2-氯苯基)-2-(甲基氨基)-环己酮 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 1.0h， 以79%的产率得到克他命
  参考文献：
  名称：

  氯胺酮的工艺研究和杂质控制策略

  摘要：

  已经开发了一种改进的（S）-氯胺酮（esketamine）合成方法，该方法成本效益高，不需要的异构体可通过外消旋作用回收。确定每个步骤的关键工艺参数以及与工艺相关的杂质。首先讨论了大多数杂质的形成机理和控制策略。此外，（S）-酒石酸氯胺酮是二水合物，这是首次公开。由氯化铝催化的可行外消旋以定量收率进行，纯度为99％。ICH级质量（S通过手性拆分和三倍的母液回收率，可得到5-氯胺酮盐酸盐，总产率为51.1％（无外消旋作用为14.0％）。氯胺酮的稳健工艺可以在工业上推广。

  DOI：

  10.1021/acs.oprd.9b00553
• 作为产物：
  描述：

  氯胺酮 在 sodium hydroxide 作用下， 以 水 、 丙酮 为溶剂， 反应 2.0h， 生成 (2S)-2-(2-氯苯基)-2-(甲基氨基)-环己酮
  参考文献：
  名称：

  氯胺酮的工艺研究和杂质控制策略

  摘要：

  已经开发了一种改进的（S）-氯胺酮（esketamine）合成方法，该方法成本效益高，不需要的异构体可通过外消旋作用回收。确定每个步骤的关键工艺参数以及与工艺相关的杂质。首先讨论了大多数杂质的形成机理和控制策略。此外，（S）-酒石酸氯胺酮是二水合物，这是首次公开。由氯化铝催化的可行外消旋以定量收率进行，纯度为99％。ICH级质量（S通过手性拆分和三倍的母液回收率，可得到5-氯胺酮盐酸盐，总产率为51.1％（无外消旋作用为14.0％）。氯胺酮的稳健工艺可以在工业上推广。

  DOI：

  10.1021/acs.oprd.9b00553

文献信息

• [EN] PRODRUGS OF KETAMINE, COMPOSITIONS AND USES THEREOF<br/>[FR] PROMÉDICAMENTS À BASE DE KÉTAMINE, COMPOSITIONS ET UTILISATIONS DE CEUX-CI
  申请人：XW LAB INC

  公开号：WO2019137381A1

  公开（公告）日：2019-07-18

  Provided are prodrugs of (S) -or (R) -ketamine, including isotopically labeled ketamine,composition and uses thereof. Compounds having formula (Ia) or (Ib) as the prodrugs of (S) -or (R) -ketamine, including isotopically labeled ketamine, and pharmaceutical compositions comprising the compounds provided herein are used for treating or preventing a CNS disease.More particularly, the related diseases include depression and pain. (Ia) (Ib)

  提供了（S）-或（R）-氯胺酮的前药，包括同位素标记的氯胺酮，其组成和用途。具有化学式（Ia）或（Ib）的化合物作为（S）-或（R）-氯胺酮的前药，包括同位素标记的氯胺酮，以及包含本文提供的化合物的药物组合物用于治疗或预防中枢神经系统疾病。更具体地，相关疾病包括抑郁症和疼痛。（Ia）（Ib）
• [EN] COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DISEASES<br/>[FR] COMPOSITIONS ET PROCÉDÉS POUR LE TRAITEMENT DE MALADIES NEUROLOGIQUES
  申请人：CELLIX BIO PRIVATE LTD

  公开号：WO2019186357A1

  公开（公告）日：2019-10-03

  The invention relates to the compounds or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, formula II and formula III and the methods for the treatment of neurological diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, nasal spray, oral solution, suspension, oral spray, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of neurological diseases.

  该发明涉及化合物或其药用可接受的多型体、溶剂合物、对映体、立体异构体及其水合物。包括化合物I、化合物II和化合物III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、颊下、直肠、局部、经皮、经粘膜、含片、喷雾、静脉注射、口服溶液、鼻喷雾、口服溶液、悬浮液、口腔喷雾、颊下粘膜层片剂、肠外给药、糖浆或注射剂。这些组合物可用于治疗神经系统疾病。
• Enantioselective Syntheses of (<i>S</i>)-Ketamine and (<i>S</i>)-Norketamine
  作者：Cheng-yi Chen、Xiaowei Lu

  DOI：10.1021/acs.orglett.9b02575

  日期：2019.8.16

  (S)-ketamine (esketamine) based on catalytic enantioselective transfer hydrogenation of cyclic enone and [3,3]-sigmatropic rearrangement of allylic cyanate to isocyanate is described. The catalytic asymmetric route afforded esketamine (99.9% ee) in 50% overall yield over four steps and forms the basis for the future development of the drug substance. Furthermore, the route was applicable to the synthesis

  描述了基于环烯酮的催化对映选择性转移氢化和烯丙基氰酸酯的[3,3]-σ重排为异氰酸酯的有效的不对称合成（S）-氯胺酮（esketamine）。催化不对称路线通过四个步骤以50％的总收率提供了esketamine（99.9％ee），并为原料药的未来开发奠定了基础。此外，该途径适用于通过倒数第二个异氰酸酯的简单水解来合成（S）-去甲氯胺酮。
• [EN] (S)-CSA SALT OF S-KETAMINE, (R)-CSA SALT OF S-KETAMINE AND PROCESSES FOR THE PREPARATION OF S-KETAMINE<br/>[FR] SEL (S)-CSA DE S-KÉTAMINE, SEL (R)-CSA DE S-KÉTAMINE ET PROCÉDÉS PERMETTANT LA PRÉPARATION DE S-KÉTAMINE
  申请人：CHEN CHENG YI

  公开号：WO2016180984A1

  公开（公告）日：2016-11-17

  The present invention is directed to processes for the preparation of esketamine. The present invention is further directed to processes for the resolution of S-ketamine from a racemic or enantiomerically enriched mixture of ketamine. The present invention is further directed to an (S)-CSA salt of S-ketamine, more particularly a monohydrate form of the (S)-CSA salt of S-ketamine; and to an (R)-CSA salt of R-ketamine.

  本发明涉及制备左旋氯胺酮的方法。本发明进一步涉及从消旋或对映体富集混合物中分离S-氯胺酮的方法。本发明还涉及S-氯胺酮的(S)-CSA盐，更具体地是(S)-CSA盐的单水合物形式；以及R-氯胺酮的(R)-CSA盐。
• Halogen Substitution Influences Ketamine Metabolism by Cytochrome P450 2B6: In Vitro and Computational Approaches
  作者：Pan-Fen Wang、Alicia Neiner、Thomas R. Lane、Kimberley M. Zorn、Sean Ekins、Evan D. Kharasch

  DOI：10.1021/acs.molpharmaceut.8b01214

  日期：2019.2.4

  ketamine effects, influencing both systemic elimination and bioactivation. CYP2B6 is the major catalyst of hepatic ketamine N-demethylation and metabolism at clinically relevant concentrations. Numerous CYP2B6 substrates contain halogens. CYP2B6 readily forms halogen-protein (particularly Cl-π) bonds, which influence substrate selectivity and active site orientation. Ketamine is chlorinated, but little is

  氯胺酮在麻醉和亚麻醉剂量下具有镇痛作用，最近已用于治疗抑郁症。生物转化介导氯胺酮作用，影响全身消除和生物激活。 CYP2B6 是临床相关浓度下肝氯胺酮N-去甲基化和代谢的主要催化剂。许多 CYP2B6 底物含有卤素。 CYP2B6 很容易形成卤素-蛋白质（特别是 Cl-π）键，这会影响底物选择性和活性位点方向。氯胺酮是氯化的，但人们对卤化类似物的代谢知之甚少。这项研究评估了卤素取代对 CYP2B6 催化的氯胺酮类似物N-去甲基化的体外影响，并使用各种计算方法模拟了与 CYP2B6 的相互作用。邻苯环卤素取代基的变化导致K m存在显着差异（18 倍），其顺序为 Br（溴氯胺酮，10 μM）< Cl < F < H（去氯氯胺酮，184 μM）。相反， V max变化最小（83-103 pmol/min/pmol CYP）。因此，表观底物结合亲和力是卤素取代的主要结果和N-去甲基化的主要决定因素。氯胺酮和类似物的对接姿势相似，与