(3Z)-3-(二苯并[b,e]氧杂卓-11(6H)-亚基)-N,N-二甲基-1-丙胺 | 3607-18-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噁庚英
• 中文名称: (3Z)-3-(二苯并[b,e]氧杂卓-11(6H)-亚基)-N,N-二甲基-1-丙胺
• 中文别名: 多塞平EP杂质D；西多塞平
• 英文名称: (Z)-doxepin
• 英文别名: doxepin；doxepine；cis-doxepin；Cidoxepin；(3Z)-3-(6H-benzo[c][1]benzoxepin-11-ylidene)-N,N-dimethylpropan-1-amine
• CAS: 3607-18-9
• 化学式: C₁₉H₂₁NO
• 分子量: 279.382
• InChiKey: ODQWQRRAPPTVAG-BOPFTXTBSA-N

物化性质

• 熔点：
  192-193°
• 颜色/状态：
  OILY LIQUID CONSISTING OF A MIXTURE OF CIS- & TRANS- ISOMERS
• 气味：
  ODORLESS
• 味道：
  BITTER
• 沸点：
  154-157 ºC at 0.03 mmHg
• 溶解度：
  31.6 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.
• 保留指数：
  2231;2210;2210;2194;2210;2239;2226;2215;2217;2191.6;2219.1;2219.8;2242;2220;2235;2217;2232.1

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

多塞平被广泛代谢成N-去甲基多塞平，这是一种生物活性代谢物，以及其他非活性代谢物。首过代谢占给药剂量的55-87%。之后，次要代谢是由N-去甲基多塞平转化为其葡萄糖苷酸结合物驱动的。参与多塞平转化的重要代谢酶是细胞色素P450家族的成员，CYP2C19和CYP2D6，以及CYP1A2和CYP2C9的少量参与。

Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates. The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9.

来源:DrugBank

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2-羟基多塞平和去甲多塞平。

Doxepin has known human metabolites that include 2-hydroxy-doxepin and Nordoxepin.

来源:NORMAN Suspect List Exchange

代谢

在肝脏中通过与其他三环类抗抑郁药相同的途径广泛代谢。<i>N</i>-脱甲基产生一个活性代谢物，<i>N</i>-去甲基多塞平。CYP2D6特异地羟基化E-对映体。 半衰期：6 - 24.5小时

Extensively metabolized in the liver via the same pathways as other TCAs. <i>N</i>-demethylation produces an active metabolite, <i>N</i>-desmethyldoxepin. CYP2D6 specifically hydroxylates the E-isomer. Half Life: 6 - 24.5 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

多塞平的作用机制尚未完全明了。人们认为，与阿米替林类似，多塞平通过阻断神经元膜上的去甲肾上腺素和5-羟色胺（血清素）的再摄取，增强它们的作用。然而，多塞平对多巴胺的再摄取仅有轻微的抑制作用。多塞平还可能作用于组胺H1受体，导致镇静效果，以及β-肾上腺素能受体。它还是5-羟色胺（血清素）受体、α-1肾上腺素能受体和毒蕈碱样胆碱受体的拮抗剂。

The mechanism of action of doxepin is not completely understood. It is thought that like amitriptyline, doxepin enhances the actions of norepinephrine and serotonin by blocking their reuptake at the neuronal membrane. However, doxepin weakly inhibits the reuptake of dopamine. Doxepin may also act on histamine H₁-receptors, resulting in sedative effects, and &beta;-adrenergic receptors. It is also an antagonist of 5-hydroxytryptamine (serotonin) receptors, alpha-1 adrenergic receptor, and muscarinic cholinergic receptors.

来源:Toxin and Toxin Target Database (T3DB)

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

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

低血压，体位性虚脱（如果患者从躺卧/坐位过快站立起来），心律失常（窦性心动过速、心动过缓、房室传导阻滞）。过敏/毒性反应还包括皮疹、光敏感性、胆汁淤积型肝损伤（罕见）、肝炎（极罕见）、白细胞减少或血小板减少（罕见）、粒细胞缺乏症（非常罕见）、再生障碍性贫血（罕见）。[维基百科]

hypotension, postural collapse (if patient arises too fast from lying/sitting position to standing), arrhythmias (sinus-tachycardia, bradycardia, av-blockade). Allergic/toxic effetcs also include skin rash, photosensitivity, liver damage of the cholostatic type (rarely), hepatitis (extremely rare), leuko- or thrombopenia (rarely), agranulocytosis (very rarely), hypoplastic anemia (rarely). [Wikipedia]

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：由于多塞平的镇静潜力、活性代谢物、在婴儿血清中的存在、两份报告称母乳喂养的婴儿出现了不良反应，以及只有一份报告称使用后没有明显不良反应，多塞平不是一个理想的选择，在哺乳期尤其是哺乳新生儿或早产儿时，应优先选择其他药物。一个安全评分系统发现，在哺乳期间不建议使用多塞平。 母亲使用外用多塞平乳膏，只要涂抹远离乳房，以免婴儿直接摄入药物，对哺乳婴儿来说不太可能构成问题。 对哺乳婴儿的影响：一名婴儿在母亲使用150毫克多塞平睡前服用，从产后30天开始的2个月期间被母乳喂养（程度未说明）。婴儿没有出现明显的不良反应。 一名婴儿出现了可能是由于母乳中多塞平引起的不良反应。一名8周大的母乳喂养婴儿在母亲剂量从每天10毫克增加到每天三次25毫克后的4天被发现面色苍白、软弱、嗜睡，几乎不呼吸。停止哺乳后24小时，婴儿恢复正常。 一名9天大的母乳喂养婴儿吸吮和吞咽困难、低张力、呕吐和体重下降。这种反应可能是由于母乳中的多塞平引起。婴儿的母亲每天睡前服用35毫克多塞平。 对泌乳和母乳的影响：一项观察性研究观察了在怀孕前2年服用抗抑郁药的2859名妇女的结局。与怀孕期间未服用抗抑郁药的妇女相比，整个孕期（3个季度）服用抗抑郁药的妇女出院时哺乳的可能性降低了37%。仅在第三季度服用抗抑郁药的妇女出院时哺乳的可能性降低了75%。仅在第一季度和第二季度服用抗抑郁药的妇女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，一组是晚期妊娠期间分发抗抑郁药的女性（n = 575），一组是有精神疾病但未接受抗抑郁药的女性（n = 1552），一组是没有精神疾病诊断的母亲（n = 30,535）。接受抗抑郁药的女性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多塞平。 在一项对1999年至2008年的80,882对挪威母婴对的研究中，392名妇女报告了产后新使用抗抑郁药，201名报告称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%，任何哺乳的几率降低51%，以及突然停止哺乳的风险增加2.6倍。具体抗抑郁药未提及。

◉ Summary of Use during Lactation:Because of its sedating potential, active metabolite, presence in infant serum, two reports of adverse effects in breastfed infants, and only one report of use without apparent adverse reactions, doxepin is a poor choice and other agents are preferred, especially while nursing a newborn or preterm infant. A safety scoring system finds doxepin to be not recommended during breastfeeding. Maternal use of topical doxepin cream is unlikely to pose a problem for a breastfed infant as long as it is applied away from the breasts so that the infant cannot ingest the drug directly. ◉ Effects in Breastfed Infants:One infant was breastfed (extent not stated) over a 2-month period during maternal use of doxepin 150 mg at bedtime, beginning at 30 days postpartum. The infant experienced no apparent adverse reactions. One infant had an adverse reaction that was probably caused by doxepin in breastmilk. An 8-week old breastfed infant was found pale, limp, somnolent and almost not breathing 4 days after the maternal dosage had been increased from 10 mg daily to 25 mg three times daily. The infant returned to normal 24 hours after discontinuing breastfeeding. A 9-day-old breastfed infant had poor sucking and swallowing, hypotonia, vomiting, and weight loss. The reaction was probably caused by doxepin in breastmilk. The infant's mother was taking 35 mg of doxepin at bedtime daily. ◉ Effects on Lactation and Breastmilk: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 doxepin. 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)

吸收、分配和排泄

• 吸收

多塞平口服后中等吸收，生物利用度为30%。多塞平的中位峰值浓度范围从8.8-45.8 ng/ml，首次给药后3.5小时达到。与高脂肪餐同服时，其吸收增加。

Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal.

来源:DrugBank

吸收、分配和排泄

• 消除途径

多塞平的消除曲线呈双相型。它主要以葡萄糖苷酸结合物的形式通过尿液排出。少于3%的多塞平剂量以原型药物或去甲多塞平的形式通过尿液排出。

The elimination profile of doxepin is presented as biphasic. It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin.

来源:DrugBank

吸收、分配和排泄

• 分布容积

盐酸多塞平的平均表观分布容积据报道为20 L/kg。

The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

单次口服50毫克多塞平后，健康个体的平均总表观血浆清除率为0.93升/小时/千克。

The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg.

来源:DrugBank

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)

反应信息

• 作为反应物：
  描述：

  (3Z)-3-(二苯并[b,e]氧杂卓-11(6H)-亚基)-N,N-二甲基-1-丙胺 在 双氧水 作用下， 以 水 为溶剂， 反应 120.0h， 生成 (Z)-doxepine-N-oxide
  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：

  多塞平EP杂质D 以 水 为溶剂， 生成 (3Z)-3-(二苯并[b,e]氧杂卓-11(6H)-亚基)-N,N-二甲基-1-丙胺
  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

文献信息

• Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short synthesis of doxepin
  作者：Jimena Scoccia、M. Julia Castro、M. Belén Faraoni、Cecilia Bouzat、Víctor S. Martín、Darío C. Gerbino

  DOI：10.1016/j.tet.2017.03.085

  日期：2017.5

  excellent yields and high regioselectivity. The synthetic application of new protocol was extended to the synthesis of known tricyclic drug doxepin as well as a small library of oxepin based derivatives. For the first time, the obtained dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-living nematode Caenorhabditis elegans as an effective and cost-efficient model

  通过直接的分子内邻位酰化反应，从容易获得的2-（苯氧基甲基）苯甲酸中合成了新颖高效的二苯并[ b，e ] oxepin-11（6H）-酮。该方法利用了由可持续的FeCl 2和Cl 2 CHOCH 3作为关键成分的新开发的协作系统。该方法与多种官能团兼容，具有良好的收率和极高的区域选择性。新方案的合成应用扩展到了已知的三环药物多塞平的合成，以及一个基于奥塞平的衍生物的小型文库。首次获得的二苯并[ b，e对] oxepinone衍生物在自由生活的线虫秀丽隐杆线虫上的生物学活性进行了评估，以此作为驱虫药发现的一种有效且具有成本效益的模型系统。
• The photochemical stability of <i>cis-</i> and <i>trans</i>- isomers of tricyclic neuroleptic drugs
  作者：A Li wan Po、W J Irwin

  DOI：10.1111/j.2042-7158.1980.tb12839.x

  日期：2011.4.12

  The irradiation of the tranquillizers flupenthixol, clopenthixol and chlorprothixene has been found to induce rapid cis-trans isomerization. The composition of the photostationary mixture is not that of the batch drug and hence this process may affect the activity. Further decomposition to a thioxanthone derivative occurs rapidly in the presence of air. Exclusion of oxygen, however, does not prevent further degradation and a slower secondary isomerization is observed on prolonged irradiation. Doxepin and dothiepin also undergo analogous reactions but the isomerizations are much slower and the oxidative degradation yields many products.

  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。
• COMPOSITIONS AND METHODS FOR THE TREATMENT OF MUCOSITIS
  申请人：CELLIX BIO PRIVATE LIMITED

  公开号：US20170327482A1

  公开（公告）日：2017-11-16

  The invention relates to the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII and formula VIII, 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, formula III, formula IV, formula V, formula VI, formula VII and formula VIII, and methods for the treatment of mucositis may be formulated for oral, mouth wash, buccal, rectal, topical, transdermal, transmucosal, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of oral and gastrointestinal mucositis, mucosal inflammatory and oral infectious diseases.

  本发明涉及式I、式II、式III、式IV、式V、式VI、式VII和式VIII的化合物，或其药学上可接受的多晶形、溶剂化物、对映体、立体异构体和水合物。该药物组合物包括有效量的式I、式II、式III、式IV、式V、式VI、式VII和式VIII化合物，以及用于口服、漱口、颊部、直肠、局部、经皮、经黏膜、静脉、口服溶液、颊粘膜层片剂、肌肉注射、糖浆或注射制剂的治疗口腔炎症的方法。这些组合物可用于治疗口腔和胃肠黏膜炎症和口腔感染性疾病。
• Pharmaceutical preparation comprising an active dispersed on a matrix
  申请人：——

  公开号：US20040058896A1

  公开（公告）日：2004-03-25

  The present invention relates to the field of pharmaceutical technology and describes a novel advantageous preparation for an active ingredient. The novel preparation is suitable for producing a large number of pharmaceutical dosage forms. In the new preparation an active ingredient is present essentially uniformly dispersed in an excipient matrix composed of one or more excipients selected from the group of fatty alcohol, triglyceride, partial glyceride and fatty acid ester.

  本发明涉及制药技术领域，描述了一种新的有利的活性成分制备方法。这种新的制备方法适用于生产大量的药物剂型。在这种新的制备方法中，活性成分基本上均匀地分散在由脂肪醇、甘油三酯、部分甘油酯和脂肪酸酯等多种赋形剂中选择的一种或多种赋形剂组成的赋形剂基质中。
• 一种以邻苯二甲醛为原料合成盐酸多塞平的方法
  申请人：苏州黄河制药有限公司

  公开号：CN105418577A

  公开（公告）日：2016-03-23

  本发明公开了以一种以邻苯二甲醛为原料合成盐酸多塞平的方法。该方法包括以来源广泛的邻苯二甲醛为起始原料，依次通过康尼查罗反应、分子内酯化、取代、环化、亲核加成、消除反应、亲核取代、亲核取代、中和反应，得到柳氮磺吡啶。于第8步的亲核取代反应步骤中，采用有机锂化合物于醚的溶剂中，这样使得机锂化合物与二甲胺形成铵锂盐，接着该铵锂盐与卤代物进行烷基化反应，提高三级胺的收率，由此保证了最终盐酸多塞平的收率和纯度。邻苯二甲醛价廉，从而降低了生产成本。

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