5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz [2,3:6,7] oxepino [4,5-c] pyrrol-1-one | 158018-50-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噁庚英
• 英文名称: 5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz [2,3:6,7] oxepino [4,5-c] pyrrol-1-one
• 英文别名: 9-chloro-4-methyl-13-oxa-4-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),7(12),8,10,14,16-hexaene
• CAS: 158018-50-9
• 化学式: C₁₇H₁₆ClNO
• 分子量: 285.773
• InChiKey: VSWBSWWIRNCQIJ-UHFFFAOYSA-N

物化性质

• 沸点：
  357.9±42.0 °C(Predicted)
• 密度：
  1.231±0.06 g/cm3(Predicted)
• 颜色/状态：
  White to off-white powder
• 溶解度：
  In water, 0.98 mg/L at 25 °C (est)
• 蒸汽密度：
  1.83X10-6 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 9.64 (amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  20
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

在大约50%的循环物种中，已经确定了主要物种为阿塞那平N+-葡萄糖苷酸；其他包括N-去甲基阿塞那平，N-去甲基阿塞那平N-羧基葡萄糖苷酸，以及少量未改变的阿塞那平。阿塞那平的活性主要归因于原型药物。

About 50% of the circulating species in plasma have been identified. The predominant species was asenapine N+-glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine in smaller amounts. Asenapine activity is primarily due to the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

阿森纳平[(3aRS,12bRS)-5-氯-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂[4,5-c]吡咯(2Z)-2-丁烯二酸盐(1:1)]在健康男性志愿者舌下给药(14)C-阿森纳平后的代谢和排泄进行了研究。使用带有放射性检测的高效液相色谱法在血浆、尿液和粪便中确定代谢轮廓。在大约50%的人血浆中识别或量化了与药物相关的物质。剩余的循环放射性对应至少15个非常极性的小峰(主要是II期产品)。总的来说，>70%的循环放射性与结合代谢物有关。主要的代谢途径是直接葡萄糖醛酸化和N-脱甲基化。主要的循环代谢物是阿森纳平N(+)-葡萄糖苷酸；其他循环代谢物包括N-去甲基阿森纳平-N-羧基葡萄糖苷酸、N-去甲基阿森纳平和阿森纳平11-O-硫酸盐。除了母化合物阿森纳平外，主要的排泄代谢物是阿森纳平N(+)-葡萄糖苷酸。其他排泄代谢物包括N-去甲基阿森纳平-N-羧基葡萄糖苷酸、11-羟基阿森纳平随后发生结合、10,11-二羟基-N-去甲基阿森纳平、10,11-二羟基阿森纳平随后发生结合(发现了这些途径的几种组合)以及N-甲酰阿森纳平与多种羟基化反应的组合，以及很可能是阿森纳平N-氧化物与10,11-羟基化反应随后发生结合。总之，阿森纳平被广泛而迅速地代谢，产生了几种区域异构羟基化和结合代谢物。

The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of (14)C-asenapine to healthy male volunteers. ... Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

肝脏测试异常在接受阿塞纳平的患者中发生的概率为1%到2.5%，但安慰剂治疗（0.6%到1.3%）和比较剂也有类似的报告率。ALT升高通常是轻微的、暂时的，并且常常在不修改剂量或停药的情况下解决。曾有一个病例报告，在开始使用阿塞纳平后3到4周出现了胆汁淤积性血清酶升高，停药后一个月内解决。因此，阿塞纳平可能是轻度胆汁淤积性肝损伤的罕见原因。

Liver test abnormalities occur in 1% to 2.5% of patients receiving asenapine, but similar rates are reported with placebo therapy (0.6% to 1.3%) and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There has been a single case report of cholestatic serum enzyme elevations arising 3 to 4 weeks after starting asenapine, resolving within a month of stopping. Thus, asenapine may be a rare cause of mild cholestatic liver injury.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：目前没有关于哺乳期使用阿舍那平的信息。如果母亲需要阿舍那平，这并不是停止哺乳的理由。然而，可能会更倾向于使用另一种药物，特别是在哺乳新生儿或早产儿时。 ◉ 对哺乳婴儿的影响：在国家非典型抗精神病药物妊娠登记处登记的患者中，有576名在哺乳期间正在服用第二代抗精神病药物的患者与818名未接受第二代抗精神病药物治疗的对照组哺乳患者进行了比较。在服用第二代抗精神病药物的患者中，60.4%的人正在服用一种以上的精神药物。在儿科病历回顾中，暴露于第二代抗精神病药物单药治疗或多药治疗的婴儿中没有记录到不良影响。没有报告服用阿舍那平的妇女数量。 ◉ 对泌乳和乳汁的影响：根据制造商的报告，阿舍那平与乳汁分泌过多有关。高催乳素血症似乎是乳汁分泌过多的原因。高催乳素血症是由药物在结节-漏斗通路中的多巴胺阻断作用引起的。在已建立泌乳的母亲中，母体催乳素水平可能不会影响她的哺乳能力。 在国家非典型抗精神病药物妊娠登记处登记的患者中，有576名在哺乳期间正在服用第二代抗精神病药物的患者与818名主要诊断为重性抑郁障碍和焦虑障碍、通常使用SSRI或SNRI类抗抑郁药治疗但未使用第二代抗精神病药物的对照组哺乳患者进行了比较。在服用第二代抗精神病药物的妇女中，60.4%的人正在服用一种以上的精神药物，而对照组中这一比例为24.4%。在服用第二代抗精神病药物的妇女中，59.3%的人报告“曾经哺乳”，而对照组中这一比例为88.2%。在产后3个月，服用第二代抗精神病药物的妇女中，23%的人正在纯母乳喂养，而对照组中这一比例为47%。没有报告服用阿舍那平的妇女数量。

◉ Summary of Use during Lactation:No information is available on the use of asenapine during breastfeeding. If asenapine is required by the mother, it is not a reason to discontinue breastfeeding. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who were not treated with a second-generation antipsychotic (n = 818). Of the patients who were taking a second-generation antipsychotic drug, 60.4% were on more than one psychotropic. A review of the pediatric medical records, no adverse effects were noted among infants exposed or not exposed to second-generation antipsychotic monotherapy or to polytherapy. The number of women taking asenapine was not reported. ◉ Effects on Lactation and Breastmilk:Galactorrhea has been reported with asenapine according to the manufacturer. Hyperprolactinemia appears to be the cause of the galactorrhea. The hyperprolactinemia is caused by the drug's dopamine-blocking action in the tuberoinfundibular pathway. The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed. Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who had primarily diagnoses of major depressive disorder and anxiety disorders, most often treated with SSRI or SNRI antidepressants, but not with a second-generation antipsychotic (n = 818). Among women on a second-generation antipsychotic, 60.4% were on more than one psychotropic compared with 24.4% among women in the control group. Of the women on a second-generation antipsychotic, 59.3% reported “ever breastfeeding” compared to 88.2% of women in the control group. At 3 months postpartum, 23% of women on a second-generation antipsychotic were exclusively breastfeeding compared to 47% of women in the control group. The number of women taking asenapine was not reported.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

Potential pharmacologic interaction (possible disruption of body temperature regulation); use asenapine with caution in patients concurrently receiving drugs with anticholinergic activity. 可能的药物相互作用（可能干扰体温调节）；在接受具有抗胆碱活性的药物的患者中谨慎使用阿塞那平。

Potential pharmacologic interaction (possible disruption of body temperature regulation); use asenapine with caution in patients concurrently receiving drugs with anticholinergic activity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

可能的药物相互作用（增加中枢神经系统和呼吸抑制的效果）。与其他可能引起中枢神经系统抑制的药物一起使用时需谨慎。在阿塞纳平治疗期间避免使用酒精。

Potential pharmacologic interaction (additive CNS and respiratory depressant effects). Use with caution with other drugs that can produce CNS depression. Avoid use of alcohol during asenapine therapy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of other drugs known to prolong the corrected QT (QTc) interval, including class Ia antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, olanzapine, pimozide, paliperidone, quetiapine, ziprasidone), some antibiotics (e.g., gatifloxacin, moxifloxacin), and tetrabenazine. 可能的药物相互作用（对QT间期延长的叠加效应）；避免同时使用其他已知可延长校正QT（QTc）间期的药物，包括Ia类抗心律失常药（例如，奎尼丁，普鲁卡因胺），III类抗心律失常药（例如，胺碘酮，索他洛尔），一些抗精神病药（例如，氯丙嗪，硫利达嗪，氯哌醇，奥氮平，匹莫齐特，帕利哌酮，喹硫平，齐拉西酮），一些抗生素（例如，加替沙星，莫西沙星）和四苯氮唑。

Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of other drugs known to prolong the corrected QT (QTc) interval, including class Ia antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, olanzapine, pimozide, paliperidone, quetiapine, ziprasidone), some antibiotics (e.g., gatifloxacin, moxifloxacin), and tetrabenazine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

阿塞那平通过舌下给药，因为口服给药后观察到生物利用度较低（小于2%）和广泛的首过代谢。

Asenapine is administered sublingually because of the low bioavailability (less than 2%) and extensive first-pass metabolism observed following oral administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

药物舌下片在舌下、舌上和颊粘膜处迅速吸收，峰值血药浓度在0.5-1.5小时内出现。

Sublingual tablets of the drug are rapidly absorbed in the sublingual, supralingual, and buccal mucosa following sublingual administration, with peak plasma concentrations occurring within 0.5-1.5 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

舌下含服阿塞那平（5毫克）的绝对生物利用度为35%。在每日两次的舌下给药下，稳态血浆浓度在3天内达到。

The absolute bioavailability of sublingual asenapine (5 mg) is 35%. Steady-state plasma concentrations are reached within 3 days with twice-daily sublingual administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在服用单次5毫克阿塞纳平后，平均Cmax大约为4 ng/mL，在平均tmax为1小时时观察到。

Following a single 5-mg dose of asenapine, the mean Cmax was approximately 4 ng/mL and was observed at a mean tmax of 1 hour.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz [2,3:6,7] oxepino [4,5-c] pyrrol-1-one 在 氢氧化钾 、 盐酸 作用下， 以 乙醇 、 水 、 甲苯 为溶剂， 反应 18.0h， 以22%的产率得到trans-2-chloro-10,11-dihydro-11-[(methylamino)methyl]-dibenz[b,f]oxepin-11-carboxylic acid hydrochloride
  参考文献：
  名称：

  Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole

  摘要：

  公开号：

  EP1710241B1
• 作为产物：
  描述：

  trans-N-methyl-3-(2-iodophenyl)-4-(2-hydroxy-5-chlorophenyl)-pyrrolidine 在 copper(l) iodide 、 2,2,4,4-tetramethyl-3,5-heptanedione 、 caesium carbonate 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 1.0h， 生成 5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz [2,3:6,7] oxepino [4,5-c] pyrrol-1-one
  参考文献：
  名称：

  WO2008/3460

  摘要：

  公开号：

文献信息

• [EN] PROCESS FOR THE PREPARATION OF ASENAPINE AND INTERMEDIATE PRODUCTS USED IN SAID PROCESS<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ASÉNAPINE ET PRODUITS INTERMÉDIAIRES UTILISÉS DANS LEDIT PROCÉDÉ
  申请人：ORGANON NV

  公开号：WO2009087058A1

  公开（公告）日：2009-07-16

  The invention relates to a novel process for the preparation of asenapine, i.e. trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, as well as to novel intermediate products for use in said process.

  该发明涉及一种新型制备阿塞那平的方法，即trans-5-氯-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂环[4,5-c]吡咯的方法，以及用于该方法的新型中间产物。
• [EN] HYDROXYASENAPINE COMPOUNDS, DERIVATIVES THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME<br/>[FR] COMPOSES D'HYDROXY-ASENAPINE, LEURS DERIVES ET LES COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT
  申请人：ORGANON NV

  公开号：WO2011012654A1

  公开（公告）日：2011-02-03

  The present invention provides isolated or purified hydroxyasenapine compounds, derivatives thereof, especially ester derivatives thereof, and pharmaceutical compositions comprising the same. The present invention provides also methods of treatment using the same.

  本发明提供了已分离或纯化的羟基阿塞那平化合物，其衍生物，特别是其酯衍生物，以及包含它们的制药组合物。本发明还提供了使用这些化合物的治疗方法。
• [EN] COMPRESSED ORAL DOSAGE FORM FOR ASENAPINE MALEATE<br/>[FR] FORME POSOLOGIQUE ORALE COMPRIMÉE DE MALÉATE D'ASÉNAPINE
  申请人：HEXAL AG

  公开号：WO2013041435A1

  公开（公告）日：2013-03-28

  The present invention relates to a compressed pharmaceutical dosage form intended for sublingual or buccal administration and capable of being rapidly disintegrated, the compressed pharmaceutical dosage form containing asenapine maleate in a microcrystalline monoclinic form. It further relates to a method of preparing the same and to a container comprising the dosage form.

  本发明涉及一种压缩的药物剂型，用于舌下或颊内给药，并能够快速分解，该压缩的药物剂型包含微晶单斜形式的阿塞那平男酸盐。本发明还涉及制备该剂型的方法以及包含该剂型的容器。
• Tartrate Salt of (7S)-7-[(5-Fluoro-2-Methyl-Benzyl)oxy]-2-[(2R)-2-Methylpiperazin-1-YL]-6,7-Dihydro-5H-Cyclopenta[B]Pyridine
  申请人：Liu Kevin Kun-Chin

  公开号：US20100004259A1

  公开（公告）日：2010-01-07

  The present invention provides a tartrate salt of Formula (I), Formula I is also known as (7S)-7-[(5-fluoro-2-methyl-benzyl)oxy]-2-[(2R)-2-methylpiperazin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridine. The tartrate salt is preferably crystalline. The tartrate salt of Formula I of the invention is useful in the treatment of diseases linked to activation of the 5HT2c receptor in animals including humans, for example, in the treatment of schizophrenia, cognitive deficits including cognitive deficits associated with schizophrenia, anxiety, depression, obsessive-compulsive disorder, epilepsy, obesity, sexual dysfunction, and urinary incontinence, among others.

  本发明提供了公式（I）的酒石酸盐，公式I也被称为（7S）-7-[(5-氟-2-甲基苯基)氧基]-2-[(2R)-2-甲基哌嗪-1-基]-6,7-二氢-5H-环戊[b]吡啶。该酒石酸盐最好是结晶性的。本发明的公式I的酒石酸盐对于治疗与动物包括人类的5HT2c受体激活有关的疾病非常有用，例如治疗精神分裂症、认知缺陷包括与精神分裂症有关的认知缺陷、焦虑症、抑郁症、强迫症、癫痫、肥胖症、性功能障碍和尿失禁等。
• Asenapine Prodrugs
  申请人：Blumberg Laura Cook

  公开号：US20110166194A1

  公开（公告）日：2011-07-07

  Compounds of Formula I and their use for the treatment of neurological and psychiatric disorders including schizophrenia and manic or mixed episodes associated with bipolar I disorder with or without psychotic features is disclosed: wherein R 1 -R 8 , G, N and A − are as defined in the written description.

  公开了式I的化合物及其用于治疗神经和精神障碍，包括精神分裂症和与带或不带精神症状的双相I障碍相关的躁狂或混合发作：其中R1-R8，G，N和A-如书面描述中所定义。