伐诺司林 | 67469-69-6

• 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: 伐诺司林
• 英文名称: 1-(2-(di(4-fluorophenyl)-methoxy)-ethyl)-4-(3-phenylpropyl)piperazine
• 英文别名: Vanoxerine；1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine
• CAS: 67469-69-6
• 化学式: C₂₈H₃₂F₂N₂O
• 分子量: 450.572
• InChiKey: NAUWTFJOPJWYOT-UHFFFAOYSA-N

物化性质

• 沸点：
  542.7±50.0 °C(Predicted)
• 密度：
  1.135±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  15.7
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

体外研究表明，万诺赛林主要通过CYP3A4代谢。CYP2C8和CYP2E1也可能参与这种药物的代谢。CYP3A4选择性抑制剂可能与万诺赛林发生相互作用。

_In vitro_ studies suggest that vanoxerine is mostly metabolized by CYP3A4. CYP2C8 and CYP2E1 may also contribute to the metabolism of this drug. CYP3A4 selective-inhibitors may interact with vanoxerine.

来源:DrugBank

代谢

Vanoxerine 的人类已知代谢物包括 1-苯基-3-[4-[2-(4,4'-二氟苯基羟乙基)]哌嗪]-1-丙醇和 4-[3-[4-[2-[双(4-氟苯基)甲氧基]乙基]哌嗪]丙基]苯酚。

Vanoxerine has known human metabolites that include 1-Phenyl-3-[4-[2-(4,4'-difluorobenzhydryloxy)ethyl]piperazino]-1-propanol and 4-[3-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazino]propyl]phenol.

来源:NORMAN Suspect List Exchange

毒理性

• 蛋白质结合

Vanoxerine的血浆蛋白结合率在0.1、0.4和1微摩尔时为99%。

The plasma protein binding of vanoxerine is 99% at 0.1, 0.4 and 1 μM.

来源:DrugBank

吸收、分配和排泄

• 吸收

在25、75或125毫克的剂量下，健康男性志愿者（n=14）口服Vanoxerine后，其相应的Cmax分别为17.9、81.1和236.5纳摩尔/升，相应的AUC分别为81、365和1116小时·纳摩尔/升。在同一批志愿者中，25、75或125毫克口服剂量下的tmax分别达到0.91、0.93和1.13小时。这种药物的口服生物利用度取决于食物摄入。与禁食状态相比，志愿者在低脂和高脂餐后服用Vanoxerine的生物利用度分别高出76%和255%。

At doses of 25, 75 or 125 mg, vanoxerine had a corresponding Cmax of 17.9, 81.1 and 236.5 nmol/L and a corresponding AUC of 81, 365 and 1116 h⋅nmol/L when given orally to healthy male volunteers (n=14). In this same set of subjects, tmax was reached at 0.91, 0.93 and 1.13 h at oral doses of 25, 75 or 125 mg, respectively. The oral bioavailability of this drug depends on food intake. Compared with those fasting, the bioavailability of vanoxerine in volunteers taking a low-fat and a high-fat meal was 76% and 255% higher, respectively.

来源:DrugBank

吸收、分配和排泄

• 消除途径

万诺塞林主要通过尿液、胆汁和粪便排出。

The majority of vanoxerine is excreted in urine, bile and feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

Vanoxerine 能够穿过血脑屏障，并分布到包括脂肪组织、肺、肝脏和胃肠道的多个器官。Vanoxerine 具有较大的分布容积。

Vanoxerine is capable of crossing the blood-brain barrier and distributing to several organs such as fat tissue, lungs, liver and the gastrointestinal tract. Vanoxerine has a large volume of distribution.

来源:DrugBank

吸收、分配和排泄

• 清除

在25、75和125毫克/日的剂量下，Vanoxerine的相应口服清除率分别为660、478和250升/小时。

At 25, 75 and 125 mg/day, vanoxerine had a corresponding oral clearance of 660, 478 and 250 L/h.

来源:DrugBank

安全信息

• 储存条件：
  2-8℃

制备方法与用途

vanoxerine（GBR12909）是一种多巴胺重吸收抑制剂（DRI）。

反应信息

• 作为反应物：
  描述：

  伐诺司林 在 盐酸 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以116.9 g的产率得到1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride
  参考文献：
  名称：

  Scale-Up Synthesis of the Dopamine Uptake Inhibitor GBR-12909

  摘要：

  1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR-12909) is a dopamine uptake inhibitor. The development of a robust process for the preparation of this compound in kilogram quantities is described. The primary aims of the development work were to eliminate chromatographic purifications, to minimize the use of environmentally unacceptable reagents, and to improve the overall yield of the three-step convergent process. These objectives were met, with significant improvements obtained in the key coupling reaction of N-(3-phenylpropyl)piperazine dihydrochloride salt with 1-[bis(4-fluorophenyl)methoxy]-2-chloroethane, which was previously low-yielding and lacking in reproducibility.

  DOI：

  10.1021/op020211j
• 作为产物：
  描述：

  苯基丙基哌嗪 在 盐酸 、 sodium carbonate 作用下， 以 乙醇 、 水 、 丁酮 为溶剂， 反应 26.0h， 生成 伐诺司林
  参考文献：
  名称：

  Scale-Up Synthesis of the Dopamine Uptake Inhibitor GBR-12909

  摘要：

  1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR-12909) is a dopamine uptake inhibitor. The development of a robust process for the preparation of this compound in kilogram quantities is described. The primary aims of the development work were to eliminate chromatographic purifications, to minimize the use of environmentally unacceptable reagents, and to improve the overall yield of the three-step convergent process. These objectives were met, with significant improvements obtained in the key coupling reaction of N-(3-phenylpropyl)piperazine dihydrochloride salt with 1-[bis(4-fluorophenyl)methoxy]-2-chloroethane, which was previously low-yielding and lacking in reproducibility.

  DOI：

  10.1021/op020211j

文献信息

• SUBSTITUTED TRIAZOLOPYRIDINES
  申请人：Gant Thomas G.

  公开号：US20090209550A1

  公开（公告）日：2009-08-20

  Disclosed herein are substituted triazolopyridine serotonin reuptake modulators and/or 5-HT receptor modulators of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

  本文披露了Formula I的替代三唑吡啶类血清素再摄取调节剂和/或5-HT受体调节剂，其制备方法，药物组合物以及使用方法。
• 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。
• [EN] 5-HT2C RECEPTOR AGONISTS AND COMPOSITIONS AND METHODS OF USE<br/>[FR] AGONISTES DE RÉCEPTEUR 5-HT2C ET COMPOSITIONS ET PROCÉDÉS D'UTILISATION
  申请人：ARENA PHARM INC

  公开号：WO2017023679A1

  公开（公告）日：2017-02-09

  Provided in some embodiments are compounds of Formula A, as defined herein, that modulate the activity of 5-HT2C receptor. Also provided in some embodiments are methods, such as, for weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction, pathological gambling, reward deficiency syndrome, and sex addiction), obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders (including insomnia, fragmented sleep architecture, and disturbances of slow-wave sleep), urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea.

  在某些实施例中提供了一些符合本文所定义的A式化合物，其调节5-HT2C受体的活性。在某些实施例中还提供了一些方法，例如用于体重管理、诱导饱腹感、减少食物摄入，以及预防和治疗肥胖、抗精神病药物引起的体重增加、2型糖尿病、普拉德-威利综合征、烟草/尼古丁依赖、药物成瘾、酒精成瘾、病理性赌博、奖赏缺乏综合征和性成瘾，强迫症谱系障碍和冲动控制障碍（包括咬指甲和咬甲症），睡眠障碍（包括失眠、睡眠结构碎裂和慢波睡眠紊乱），尿失禁，精神障碍（包括精神分裂症、厌食症和暴食症），阿尔茨海默病，性功能障碍，勃起功能障碍，癫痫，运动障碍（包括帕金森病和抗精神病药物引起的运动障碍），高血压，血脂异常，非酒精性脂肪肝病，肥胖相关肾脏疾病和睡眠呼吸暂停症。
• N-and o-substituted 4-[2-( diphenylmethoxy) -ethyl]-1- (phenyl) methyl) piperidine analogs and methods of treating cns disorders therewith
  申请人：——

  公开号：US20030225133A1

  公开（公告）日：2003-12-04

  N- and O-substituted 4[2-diaromaticmethoxy and methylamino)alkyl]piperidines exhibit high CNS activity with respect to the dopamine transporter (DAT) and serotonin transporter (SERT). Preferred compounds exhibit highly differential behavior as between the DAT and SERT and between the DAT and the norepinephrine transporter (NET). The compounds have utility in treating CNS disorders, including but not limited to cocaine addiction, depression, and Parkinson's disease. 1 2

  N-和O-取代的4-[2-二芳基甲氧基和甲氨基)烷基]哌啶具有高中枢神经系统活性，与多巴胺转运蛋白（DAT）和5-羟色胺转运蛋白（SERT）相关。优选化合物在DAT和SERT之间以及DAT和去甲肾上腺素转运蛋白（NET）之间表现出高度差异行为。这些化合物在治疗中枢神经系统疾病方面具有用途，包括但不限于可卡因成瘾、抑郁症和帕金森病。
• AMINO-HETEROCYCLIC COMPOUNDS
  申请人：Claffey Michelle M.

  公开号：US20100190771A1

  公开（公告）日：2010-07-29

  The invention provides PDE9-inhibiting compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , A, and n are as defined herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in treating neurodegenerative and cognitive disorders, such as Alzheimer's disease and schizophrenia, are also provided.

  这项发明提供了式（I）中的PDE9抑制化合物，以及其药学上可接受的盐，其中R1、R2、R3、A和n的定义如本文所述。还提供了含有式I中化合物的药物组合物，并且提供了在治疗神经退行性和认知障碍疾病，如阿尔茨海默病和精神分裂症中的用途。