维洛沙秦 | 46817-91-8

• 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 - 苯酚醚
• 中文名称: 维洛沙秦
• 中文别名: 苯氧吗啉；苯甲吗啉；2-((2-乙氧基苯氧基)甲基)吗啉；吗啉苯二醚
• 英文名称: viloxazine
• 英文别名: 2-(o-ethoxyphenoxymethyl)morpholine；2-((2-ethoxyphenoxy)methyl)morpholine；(±)-viloxazine；vivalan；2-(2-ethoxy-phenoxymethyl)-morpholine；2-[(2-ethoxyphenoxy)methyl]morpholine
• CAS: 46817-91-8
• 化学式: C₁₃H₁₉NO₃
• 分子量: 237.299
• InChiKey: YWPHCCPCQOJSGZ-UHFFFAOYSA-N

物化性质

• 熔点：
  176-179 °C
• 沸点：
  379.83°C (rough estimate)
• 密度：
  1.0942 (rough estimate)
• 保留指数：
  1860;1864.9;1860.5

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  39.7
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

Viloxazine 经由 CYP2D6 介导的 5-羟基化反应生成 5-羟基viloxazine。这个代谢物可以通过 UGT1A9 和 UGT2B15 进行葡萄糖醛酸化，形成 5-羟基viloxazine 葡萄糖醛酸苷，这是在血浆中检测到的主要代谢物。Viloxazine 也可以通过葡萄糖醛酸化反应形成 Viloxazine N-羧基葡萄糖醛酸苷。

Viloxazine undergoes CYP2D6-mediated 5-hydroxylation to form 5-hydroxyviloxazine. This metabolite can be glucuronidated by UGT1A9 and UGT2B15 to form 5-hydroxyviloxazine glucuronide, which is the major metabolite detected in plasma. Viloxazine can also be glucuronidated to form Viloxazine N-carbamoyl glucuronide.

来源:DrugBank

毒理性

• 肝毒性

在四项针对患有ADHD儿童的viloxazine安慰剂对照试验中，5%至10%的受试者出现了轻微的血清转氨酶升高，但超过正常上限两倍的情况不到1%。在预注册试验中，没有出现归因于viloxazine的临床明显肝损伤或伴有黄疸的血清转氨酶升高的情况。自从在欧洲作为治疗抑郁症的疗法获得批准已有30多年，以及2021年在美国作为ADHD的疗法以来，没有文献描述由于viloxazine引起的临床明显肝损伤。此外，viloxazine的疗效和安全性的总结并未提到肝脏不良事件。然而，viloxazine在儿童中的长期临床经验有限，其他SNRIs（如阿托莫斯特）已与罕见的临床明显肝损伤病例有关联。

In four placebo-controlled trials of viloxazine in children with ADHD, minor serum aminotransferase elevations occurred in 5% to 10% of recipients but were more than 2 times the upper limit of normal in less than 1%. In the preregistration trials, there were no instances of clinically apparent liver injury or serum aminotransferase elevations with jaundice attributable to viloxazine. Since its approval as therapy for depression in Europe more than 30 years ago and as therapy of ADHD in the United States in 2021, there have been no publications describing clinically apparent liver injury due to viloxazine. Furthermore, summaries of the efficacy and safety of viloxazine do not mention hepatic adverse events. Nevertheless, long term clinical experience with viloxazine in children is limited, and other SNRIs (such as atomoxetine) have been linked to rare instances of clinically apparent liver injury.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间的使用总结：目前没有关于母乳喂养期间使用维洛沙嗪的已发表经验。如果母亲需要维洛沙嗪，这并不是停止母乳喂养的理由，但在更多数据可用之前，尤其是当哺乳新生儿或早产儿时，可能更倾向于使用替代药物。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发表信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发表信息。

◉ Summary of Use during Lactation:There is no published experience with viloxazine during breastfeeding. If viloxazine is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, 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:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

Viloxazine在血液浓度范围为0.5 mcg/mL至10 mcg/mL时，与人体血浆蛋白的结合率为76-82%。

Viloxazine is 76-82% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 10 mcg/mL.

来源:DrugBank

吸收、分配和排泄

• 吸收

Viloxazine口服给药后可迅速吸收。与速释制剂相比，Viloxazine缓释制剂的相对生物利用度约为88%。Viloxazine的Cmax和AUC在100 mg至600 mg每日一次的剂量范围内成比例增加。Cmax的范围在540至1600 ng/mL之间。在单次给予200 mg剂量后，中位Tmax大约为五小时，范围在三至九小时。在每日一次给药两天后达到稳态，未观察到累积。高脂肪餐会使Cmax和AUC分别降低约9%和8%，并将Tmax推迟两小时。

Viloxazine is rapidly absorbed following oral administration. The relative bioavailability of viloxazine extended-release relative to an immediate-release formulation was about 88%. Viloxazine Cmax and AUC increase proportionally over a dosage range from 100 mg to 600 mg once daily. The Cmax ranges between 540 and 1600 ng/mL. Following administration of a single 200 mg dose, the median Tmax was approximately five hours, with a range of three to nine hours. Steady-state was reached after two days of once-daily administration, and no accumulation was observed. A high-fat meal decreases Cmax and AUC by about 9% and 8%, respectively, and delays Tmax by two hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Viloxazine主要通过肾脏消除。在给予放射性标记的Viloxazine后，90%的剂量在首次给药后的24小时内通过尿液回收。不到1%的剂量通过粪便排出。大约12-15%的总药物以未改变的原药形式消除。

Viloxazine is primarily excreted via renal elimination. After administration of radiolabeled viloxazine, 90% of the dose was recovered in urine within the first 24 hours post-dose. Less than 1% of the dose is excreted in the feces. About 12-15% of the total drug is eliminated as unchanged parent drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

分布容积为0.73 ± 0.28 L/kg，是在静脉给药后测定的。

The volume of distribution was 0.73 ± 0.28 L/kg following intravenous administration.

来源:DrugBank

吸收、分配和排泄

• 清除

静脉给药后的清除率为124 ± 11 mL/小时/千克。

The clearance rate was 124 ± 11 mL/hour/kg following intravenous administration.

来源:DrugBank

制备方法与用途

维洛嗪是一种去甲肾上腺素再摄取抑制剂，同时也是有效的5-HT2C激动剂和5-HT2B拮抗剂，其EC50值分别为32μM和27μM。它的作用机制主要涉及5-羟色胺能和去甲肾上腺素能途径。维洛嗪可用于研究抑郁症。

反应信息

• 作为反应物：
  描述：

  维洛沙秦 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 生成 2-[(2-乙氧基苯氧基)甲基]吗啉盐酸盐
  参考文献：
  名称：

  [EN] PROCESS AND INTERMEDIATES FOR THE PREPARATION OF VILOXAZINE AND OTHER 2-SUBSTITUTED MORPHOLINE DERIVATIVES
  [FR] PROCÉDÉ ET INTERMÉDIAIRES POUR LA PRÉPARATION DE VILOXAZINE ET D'AUTRES DÉRIVÉS DE MORPHOLINE SUBSTITUÉS EN POSITION 2

  摘要：

  The present invention relates to an efficient and industrially applicable process for the preparation of 2-substituted morpholine derivatives such as viloxazine and to intermediates useful therefor.

  公开号：

  WO2024028423A1
• 作为产物：
  描述：

  (+/-)-4-benzyl-2-(2-ethoxyphenoxymethyl)morpholine 在 palladium on activated charcoal 盐酸 、 氢气 作用下， 以 乙醇 为溶剂， 以96%的产率得到维洛沙秦
  参考文献：
  名称：

  作为多巴胺D4受体配体的新系列吗啉和1,4-恶唑烷衍生物：合成和3D-QSAR模型。

  摘要：

  自多巴胺D（4）受体亚型的鉴定和关于其可能参与精神分裂症的推测以来，选择性D（4）配体的开发已投入大量工作。这些选择性配体可能是没有锥体束外副作用的有效抗精神病药。这项工作描述了对多巴胺D（4）受体具有选择性的新系列的2,4-二取代的吗啉和2,4-二取代的1,4-恶唑酮的合成。进行了使用GRID / GOLPE方法的3D-QSAR分析，目的是更好地了解化学结构与生物活性之间的关系。通过查看系数图，我们可以确定对于亲和力至关重要的区域位于两个苯环系统（对氯苄基）周围，和属于吗啉或1，4-氧杂庚烷体系的脂族胺。另外，吗啉或1，4-氧杂庚烷环的大小对于亲和力似乎很重要。

  DOI：

  10.1021/jm031111m

文献信息

• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
  申请人：UNIV EMORY

  公开号：WO2013181135A1

  公开（公告）日：2013-12-05

  The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.

  该披露涉及喹唑啉衍生物、组合物以及相关方法。在某些实施例中，该披露涉及NADPH-氧化酶（Nox酶）和/或髓过氧化物酶的抑制剂。
• [EN] NMDA RECEPTOR MODULATORS AND USES THEREOF<br/>[FR] MODULATEURS DES RÉCEPTEURS NMDA ET UTILISATIONS DE CEUX-CI
  申请人：CADENT THERAPEUTICS

  公开号：WO2018119374A1

  公开（公告）日：2018-06-28

  Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated to modulate the NMDA receptor.

  本文披露了部分杂芳化合物及其在治疗神经精神障碍，例如精神分裂症和重度抑郁症中的用途方法。提供了药物组合物和制备杂芳化合物的方法。这些化合物被认为可以调节NMDA受体。
• [EN] COMT INHIBITING METHODS AND COMPOSITIONS<br/>[FR] PROCÉDÉS D'INHIBITION DE LA COMT ET COMPOSITIONS ASSOCIÉES
  申请人：LIEBER INST FOR BRAIN DEV

  公开号：WO2016123576A1

  公开（公告）日：2016-08-04

  The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinson's disease and/or schizophrenia.

  这些发明包括一种抑制受试者中COMT酶的方法，以及式I的化合物或其药用可接受盐，这些化合物在治疗由COMT介导的各种疾病中有用，包括帕金森病和/或精神分裂症。

表征谱图