(E)-doxepin | 3607-34-9

• 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: (E)-doxepin
• 英文别名: doxepin；doxepine；trans-doxepin；(3E)-3-(6H-benzo[c][1]benzoxepin-11-ylidene)-N,N-dimethylpropan-1-amine
• CAS: 3607-34-9
• 化学式: C₁₉H₂₁NO
• 分子量: 279.382
• InChiKey: ODQWQRRAPPTVAG-GZTJUZNOSA-N

物化性质

• 沸点：
  413.3±44.0 °C(Predicted)
• 密度：
  1.122±0.06 g/cm3(Predicted)
• 颜色/状态：
  OILY LIQUID CONSISTING OF A MIXTURE OF CIS- & TRANS- ISOMERS
• 气味：
  ODORLESS
• 味道：
  BITTER
• 溶解度：
  In water, 31.57 mg/l at 25 °C.
• 稳定性/保质期：

  DECOMP SLOWLY IN LIGHT, NONHYGROSCOPIC UP TO 75% RELATIVE HUMIDITY, RELATIVELY STABLE IN HEAT /HYDROCHLORIDE/

• 分解：
  When heated to decomposition it emits toxic fumes of nitroxides.

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

在人类口服盐酸多塞平后，产生了代谢物去甲基多塞平。

AFTER ORAL DOSING OF DOXEPIN-HCL TO HUMANS, METABOLITE DESMETHYLDOXEPIN WAS PRODUCED.

来源:Hazardous Substances Data Bank (HSDB)

代谢

多塞平已知的人类代谢物包括多塞平N-葡萄糖苷酸。

Doxepin has known human metabolites that include Doxepin N-glucuronide.

来源:NORMAN Suspect List Exchange

毒理性

• 肝毒性

三环类抗抑郁药治疗的患者中有报道称肝功能测试异常发生率高达16%，但升高的情况很少超过正常上限的3倍。氨基转移酶异常通常是轻微的、无症状的且短暂的，即使在继续用药的情况下也会逆转。由于多虑平导致的临床上明显的急性肝损伤的罕见病例已有报道，但病例数量太少，无法描述其临床特征。重复接触多虑平后出现复发性黄疸和显著氨基转移酶升高的报道。大多数病例都是轻微的，尚未有因急性肝衰竭或慢性损伤导致死亡的报道。

Liver test abnormalities have been reported to occur in up to 16% of patients being treated with tricyclic antidepressants, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to doxepin, but the number of cases have been too few to characterize the clinical features. Recurrent jaundice and marked aminotransferase elevations with repeated exposures to doxepin has been reported. Most cases have been mild and deaths from acute liver failure or chronic injury have not been reported.

来源:LiverTox

毒理性

• 药物性肝损伤

多塞平

Compound:doxepin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：4

Severity Grade:4

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

多塞平具有...对葡萄膜黑色素有特殊的亲和力...同样...在体内和体外都能与眼黑色素结合。

/DOXEPIN HAS/...A PECULIAR AFFINITY FOR UVEAL MELANIN...ALSO...BOUND BY OCULAR MELANIN BOTH IN VIVO & IN VITRO.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在人类口服75毫克多塞平盐酸盐后，估计首次通过肝脏的代谢率为55-87%，假设完全吸收。

AFTER HUMAN ORAL DOSE 75 MG DOXEPIN-HCL, EST 1ST-PASS METAB RANGED FROM 55-87% OF ORAL DOSE ASSUMING COMPLETE ABSORPTION.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

多塞平的药代动力学尚未广泛研究，但该药物在动物体内能很好地从胃肠道吸收。口服给药后，药物在2小时内达到血浆峰值浓度。

The pharmacokinetics of doxepin have not been extensively studied, but the drug is well absorbed from the GI tract in animals. Peak plasma concentrations occur within 2 hours after oral administration of the drug.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

有限的数据表明，多塞平和其活性代谢物N-去甲基多塞平会分布到乳汁中，据报道其浓度分别约为母体血清中浓度的30-140%和10-115%，并且在接受每日75-150毫克多塞平的母亲所哺乳的婴儿的血清和尿液中检测到了活性代谢物的实质性浓度。

Limited data indicate that doxepin and its active N-demethylated metabolite are distributed into milk in concentrations reportedly ranging from about 30-140% and 10-115%, respectively, of those in maternal serum and that substantial concentrations of the active metabolite have been detected in the serum and urine of nursing infants whose mothers were receiving 75-150 mg daily.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  (E)-doxepin 在 双氧水 作用下， 以 水 为溶剂， 反应 120.0h， 生成 杂质多塞平2
  参考文献：
  名称：

  Methods of using low-dose doxepin for the improvement of sleep

  摘要：

  通过使用低剂量多塞平（例如1-6毫克），可以预防早醒，并提高睡眠效率，使睡眠周期中第7和第8小时的睡眠更好。

  公开号：

  US20070281990A1
• 作为产物：
  描述：

  (3Z)-3-(二苯并[b,e]氧杂卓-11(6H)-亚基)-N,N-二甲基-1-丙胺 以 水 为溶剂， 反应 1.0h， 生成 (E)-doxepin
  参考文献：
  名称：

  The photochemical stability of cis- and trans- isomers of tricyclic neuroleptic drugs

  摘要：

  标题：摘要 三种镇静剂氟硫氧噻唑、氯硫氧噻唑和氯丙硫氧噻唑的辐照发现会诱导快速的顺-反异构化。光平衡混合物的组成不同于批量药物，因此这个过程可能会影响其活性。在空气存在的情况下，进一步分解为硫氧噻唑衍生物迅速发生。然而，排除氧气并不能阻止进一步降解，长时间辐照观察到较慢的次级异构化。多塞平和多硫平也会发生类似的反应，但异构化速度较慢，氧化降解产生多种产物。

  DOI：

  10.1111/j.2042-7158.1980.tb12839.x

文献信息

• [EN] DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS<br/>[FR] DÉRIVÉS DE DIAZABICYCLO[4.3.1]DÉCANE POUR LE TRAITEMENT DE TROUBLES PSYCHIATRIQUES
  申请人：MAX PLANCK GES ZUR FÖRDERUNG DER WISSENSCHAFTEN E V

  公开号：WO2015110271A1

  公开（公告）日：2015-07-30

  The present invention relates to diazabicyclo[4.3.1 ]decane derivatives (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are specific inhibitors of the FK506 binding proteins (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.

  本发明涉及二氮杂双环[4.3.1]癸烷衍生物(I)，这些化合物的药用盐以及含有至少一种这些化合物的药用载体、赋形剂和/或稀释剂的药物组合物。所述的二氮杂双环[4.3.1]癸烷衍生物是FK506结合蛋白(FKBP)的特异性抑制剂，可用于预防和/或治疗精神障碍和神经退行性疾病、障碍和症状。
• Diazabicyclo[4.3.1]decane derivatives for treatment of psychiatric disorders
  申请人：Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.

  公开号：EP2899192A1

  公开（公告）日：2015-07-29

  The present invention relates to diazabicyclo[4.3.1]decane derivatives of formula (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are inhibitors of the FK506 binding protein (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.

  本发明涉及式(I)的二氮杂双环[4.3.1]癸烷衍生物，这些化合物的药用盐以及含有至少一种这些化合物的药用载体、赋形剂和/或稀释剂的药物组合物。所述的二氮杂双环[4.3.1]癸烷衍生物是FK506结合蛋白（FKBP's）的抑制剂，可用于预防和/或治疗精神障碍和神经退行性疾病、障碍和症状。
• DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS
  申请人：MAX-PLANCK-GESELLSCHAFT ZUR FÖRDERUNG DER WISSENSCHAFTEN E.V.

  公开号：US20170002003A1

  公开（公告）日：2017-01-05

  The present invention relates to diazabicyclo[4.3.1]decane derivatives, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.

  本发明涉及二氮杂双环[4.3.1]癸烷衍生物，这些化合物的药用盐以及含有至少一种这些化合物的药用载体、赋形剂和/或稀释剂的药物组合物。所述的二氮杂双环[4.3.1]癸烷衍生物可用于预防和/或治疗精神障碍和神经退行性疾病、障碍和症状。
• 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。