氟提肟氨 | 54739-18-3

• 物质功能分类: 原料药 - 神经系统用药 - 抗抑郁、躁狂药
• 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: 氟提肟氨
• 中文别名: (E)-5-甲氧基-4-三氟甲基苯戊酮氧-2-氨乙酰基肟；氟伏沙明
• 英文名称: fluvoxamine
• 英文别名: 2-[(E)-[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine
• CAS: 54739-18-3
• 化学式: C₁₅H₂₁F₃N₂O₂
• 分子量: 318.339
• InChiKey: CJOFXWAVKWHTFT-XSFVSMFZSA-N

物化性质

• 熔点：
  120-122.5°C
• 沸点：
  370.6±52.0 °C(Predicted)
• 密度：
  1.16±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少量）、DMSO（少量）、甲醇（少量）

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  7

ADMET

代谢

氟伏沙明主要通过肝脏代谢。

Fluvoxamine is metabolized extensively by the liver.

来源:DrugBank

代谢

氟伏沙明已知的人类代谢物包括氟伏沙明醇。

Fluvoxamine has known human metabolites that include Fluvoxamino alcohol.

来源:NORMAN Suspect List Exchange

代谢

肝脏 消除途径：主要的人体代谢物是氟伏沙明酸，连同其N-乙酰化类似物，约占尿液排泄产物的60%。大约2%的氟伏沙明以未改变的形式从尿液中排出。在给予14C标记的氟伏沙明马来酸盐（5毫克）后，平均有94%的药物相关产物在71小时内通过尿液回收。 半衰期：15.6小时

Hepatic Route of Elimination: The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. Approximately 2% of fluvoxamine was excreted in urine unchanged. Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours. Half Life: 15.6 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

氟伏沙明的作用机制尚未完全确定，但似乎与其抑制中枢神经系统神经元对血清素的摄取有关。氟伏沙明阻断了神经元膜上血清素再摄取泵的血清素再摄取，增强了血清素对5HT_1A自受体的作用。体外研究表明，作为血清素再摄取抑制剂，氟伏沙明比氯米帕明、氟西汀和去甲丙咪嗪更有效。研究还证实，氟伏沙明对α₁-或α₂-肾上腺素能、β-肾上腺素能、毒蕈碱、多巴胺D₂、组胺H₁、GABA-苯二氮卓、阿片、5-HT₁或5-HT₂受体的亲和力几乎为零。

The exact mechanism of action of fluvoxamine has not been fully determined, but appears to be linked to its inhibition of CNS neuronal uptake of serotonin. Fluvoxamine blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT_1A autoreceptors. In-vitro studies suggest that fluvoxamine is more potent than clomipramine, fluoxetine, and desipramine as a serotonin-reuptake inhibitor. Studies have also demonstrated that fluvoxamine has virtually no affinity for alpha₁- or alpha₂-adrenergic, beta-adrenergic, muscarinic, dopamine D₂, histamine H₁, GABA-benzodiazepine, opiate, 5-HT₁, or 5-HT₂ receptors.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在服用氟伏沙明（fluvoxamine）的患者中，已报告有高达1%的患者出现肝功能测试异常，但这些升高通常较为轻微，通常不需要调整剂量或停药。在服用氟伏沙明的患者中，有少数病例报告出现了急性、临床上明显的肝脏损伤，伴有明显的肝酶升高，黄疸很少或几乎没有。损伤的发生通常在开始治疗后的几天内，血清酶升高的模式是肝细胞型或混合型。自体免疫（自身抗体）和免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）并未提及。由于报告的病例太少，无法详细描述肝脏损伤的临床特征。在对抗抑郁药和SSRIs引起肝脏不良事件的大规模分析中，氟伏沙明很少被提及。

Liver test abnormalities have been reported to occur in up to 1% patients on fluvoxamine, but elevations are usually modest and usually do not require dose modification or discontinuation. A few instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with no or minimal jaundice have been reported in patients on fluvoxamine. The onset of injury was within a few days of starting therapy and the pattern of serum enzyme elevations was hepatocellular or mixed. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were not mentioned. Too few cases have been reported to characterize the clinical features of the liver injury in any detail. In large scale analyses of hepatic adverse events due to antidepressants and SSRIs, fluvoxamine is rarely mentioned.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：氟伏沙明

Compound:fluvoxamine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

吸收良好，马来酸氟伏沙明的生物利用度为53%。

Well absorbed, bioavailability of fluvoxamine maleate is 53%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

给予马来酸氟伏沙明5毫克放射性标记剂量后，鉴定出9种代谢物，大约占氟伏沙明尿液排泄产物的大约85%。主要的人体代谢物是氟伏沙明酸，其与它的N-乙酰化类似物共同占据了大约60%的尿液排泄产物。大约2%的氟伏沙明以不变的形式在尿液中排出。在给予14C标记的口服马来酸氟伏沙明（5毫克）后，平均有94%的药物相关产物在71小时内通过尿液回收。

Nine metabolites were identified following a 5 mg radio labelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. Approximately 2% of fluvoxamine was excreted in urine unchanged. Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours.

来源:DrugBank

吸收、分配和排泄

• 分布容积

25 升/千克。

25 L/kg.

来源:DrugBank

安全信息

• 海关编码：
  2928000090
• 储存条件：
  -20°C冷冻存储，置于惰性气氛中

制备方法与用途

生物活性

Fluvoxamine (DU-23000) 是一种5-羟色胺再吸收抑制剂，具有抗抑郁活性。

靶点

SSRIs

体内研究

Fluvoxamine (DU-23000) 在抑制血小板和脑突触囊泡中的5-HT摄取方面表现出有效性。氟伏沙明对抗萝巴新诱导的戊四氮惊厥阈值降低的现象可以视为其对5-HT摄取的影响所致。与去甲替林和丙咪嗪的作用不同，快速作用的萝巴新样化合物在给予氟伏沙明后，并未在大鼠中发现刺激效应。Fluvoxamine (DU-23000) 被发现可以改善与战斗相关的PTSD症状，但对抑郁症状无明显改善。由于高脱落率和缺乏安慰剂对照组，我们的研究结论受到限制。进行氟伏沙明治疗PTSD的受控研究是必要的。

在有食物同时提供的条件下，Fluvoxamine (DU-23000) 减少乙醇自我给药的作用不如乙醇单独提供时显著 [ED50: 4.0 (2.7-5.9) 和 5.1 (4.3-6.0)]。在食物可用的条件下，对食物的影响在两种条件下都是相似的。研究结果表明，氟伏沙明减少维持乙醇行为的有效性取决于乙醇是单独提供还是与同时安排的食物强化共存。

反应信息

• 作为反应物：
  描述：

  氟提肟氨 在 三乙胺 、 N,N-二异丙基乙胺 、 potassium iodide 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 26.5h， 生成 (E)-2-(((5-methoxy-1-(4-(trifluoromethyl)phenyl)pentylidene)amino)oxy)ethyl 4-chlorobenzoate
  参考文献：
  名称：

  通过可自动化的酯化反应重新利用胺和羧酸结构单元

  摘要：

  结合胺和羧酸的新方法补充了流行的酰胺偶联，如果它们产生的产物不同于经典的 R-NHC(O)-R' 酰胺排列，则可以显着扩展可及的化学空间。在这里，我们开发了一种基于胺 C-N 键的吡啶盐活化的胺-酸酯化反应，在与烷基和芳基羧酸反应时产生 R-OC(O)-R' 类型的产物。正如开源机器人的自动化所证明的那样，该协议是健壮和简便的。

  DOI：

  10.1039/d2cc05670d
• 作为产物：
  描述：

  5-甲氧基-1-[4-(三氟甲基)苯基]-1-戊酮 在 盐酸羟胺 、 sodium acetate 、 potassium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 氟提肟氨
  参考文献：
  名称：

  通过引入卤素原子调整已知药物的活性，SERT 配体 - 氟西汀和氟伏沙明的案例研究

  摘要：

  作用于血清素转运蛋白 (SERT) 的选择性血清素再摄取抑制剂 (SSRI) 是处方最广泛的抗抑郁药物之一。所有五种获批的 SSRI 都含有氟或氯原子，并且描述它们与较重卤素（即溴和碘）类似物的报告数量有限。为了阐明卤素原子在 SSRIs 与 SERT 结合中的作用，我们设计了一系列 22 种氟西汀和氟伏沙明类似物，它们被氟、氯、溴和碘原子取代，它们在苯环上的排列不同。获得的生物活性数据，得到了全面的计算机支持结合模式分析，允许识别卤素键相互作用的两个伙伴：E493 和 T497 的骨架羰基氧原子。此外，发现具有较重卤素原子的化合物通过明显不同的结合模式与 SERT 结合，这一结果未在别处介绍。对制备的 XSAR 集的后续分析表明，E493 和 T497 参与形成的卤键数量最多。XSAR 库分析导致合成了两种最活跃的化合物（3,4-diCl-氟西汀42、SERT K i = 5 nM 和 3

  DOI：

  10.1016/j.ejmech.2021.113533

文献信息

• [EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2010104818A1

  公开（公告）日：2010-09-16

  MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.

  MCHR1拮抗剂具有以下化学式（I）：A1和A2独立地为C或N；E为C或N；Q1、Q2和Q3独立地为C或N，但至少其中一个为N，但不超过一个为N；D1为键，-CR8R9 X-，-XCR8R9-，-CHR8CHR9-，-CR10=CR10'-，-C≡C-，或1,2-环丙基；X为O、S或NR11；R1、R2和R3独立地从氢、卤素、低烷基、低环烷基、-CF3、-O 、-OR12和-SR12组成的群体中选择；G为O、S或-NR15；D2为低烷基、低环烷基、低烷基环烷基、低环烷基烷基、低环烷氧基烷基或低烷基环烷氧基，或当G为NR15时，G和D2一起可以选择形成氮杂环丙烷、吡咯烷或哌啶环；Z1和Z2独立地为氢、低烷基、低环烷基、低烷氧基、低环烷氧基、卤素、- 、-OCONR14R14'、-CN、-CONR14R14'、-SOR12、-SO2R12、-NR14COR14'、-NR14CO2R14'、-CO2R12、NR14SO2R12或COR12；R5、R6和R7独立地从氢、低烷基、低环烷基、- 、-SR12、低烷氧基、低环烷氧基、-CN、-CONR14R14'、SOR12、SO2R12、NR14COR14'、NR14CO2R12、CO2R12、NR14SO2R12和-COR12组成的群体中选择；R8、R9、R10、R10'、R11独立地为氢或低烷基；R12为低烷基或低环烷基；R14和R14'独立地为H、低烷基、低环烷基或R14和R14'与其连接的N一起形成具有4至7个原子的环；R15独立地从氢和低烷基组成的群体中选择。这些化合物对于治疗MCHR1介导的疾病，如肥胖症、糖尿病、炎症性肠病、抑郁症和焦虑症非常有用。
• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [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。
• NAPHTHALENE-BASED INHIBITORS OF ANTI-APOPTOTIC PROTEINS
  申请人：Pellecchia Maurizio

  公开号：US20090105319A1

  公开（公告）日：2009-04-23

  Methods of using apogossypol and its derivatives for treating inflammation is disclosed. Also, there is described a group of compounds having structure A, or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof are provided: wherein each R is independently selected from the group consisting of H, C(O)X, C(O)NHX, NH(CO)X, SO 2 NHX, and NHSO 2 X, wherein X is selected from the group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, an alkylaryl, and a heterocycle. Compounds of group A may be used for treating various diseases or disorders, such as cancer.

  使用阿波戈司宝及其衍生物治疗炎症的方法被披露。此外，还描述了一组具有结构A的化合物，或其药学上可接受的盐、水合物、N-氧化物或溶剂化合物： 其中每个R独立地选自H、C(O)X、C(O)NHX、NH(CO)X、SO2NHX和NHSO2X组成的组，其中X选自烷基、取代烷基、芳基、取代芳基、烷基芳基和杂环的组。A组化合物可用于治疗各种疾病或疾病，如癌症。