(Z)-4-[3-[2-(三氟甲基)-9H-噻吨-9-亚基]丙基]哌嗪-1-乙醇 | 53772-82-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻喃类
• 中文名称: (Z)-4-[3-[2-(三氟甲基)-9H-噻吨-9-亚基]丙基]哌嗪-1-乙醇
• 英文名称: cis-(Z)-flupenthixol
• 英文别名: alpha-Flupenthixol；(Z)-Flupentixol；flupenthixol；α-flupenthixol；cis(Z)-flupentixol；cis-flupenthixol；Flupentixol；2-[4-[(3Z)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol
• CAS: 53772-82-0
• 化学式: C₂₃H₂₅F₃N₂OS
• 分子量: 434.526
• InChiKey: NJMYODHXAKYRHW-DVZOWYKESA-N

物化性质

• 溶解度：
  0.000346 mg/ml
• 保留指数：
  3052.6

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  52
• 氢给体数：
  1
• 氢受体数：
  7

ADMET

代谢

氟哌噻吨在肝脏通过亚磺酰化、脱烷基化和葡萄糖醛酸化代谢，形成药理学上不活跃的代谢物。肌内注射制剂中的活性成分氟哌噻吨癸酸酯被水解为氟哌噻吨。

Flupentixol is metabolized in the liver via sulfoxidation, dealkylation, and glucuronidation to form pharmacologically inactive metabolites. Flupentixol decanoate, the active ingredient in the intramuscular formulation, is hydrolyzed to flupentixol.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：氟奋乃静在美国尚未获得食品药品监督管理局的上市批准，但在其他国家可用。有限的信息表明，母亲每天口服剂量高达4毫克或每两周注射40毫克长效针剂，在母乳和哺乳婴儿的血清中产生的水平较低，并未引起不良发育后果。一个安全评分系统认为在母乳喂养期间可以谨慎使用氟奋乃静。在获得更多数据之前，应在仔细监测婴儿的情况下在母乳喂养期间使用氟奋乃静。 ◉ 对哺乳婴儿的影响：一名妇女在怀孕期间每天服用氟奋乃静1毫克和去甲替林100毫克，产后立即每天服用氟奋乃静4毫克和去甲替林125毫克。她完全用母乳喂养婴儿。在4个月的时间里，婴儿没有出现不良药物影响的迹象，并且在使用母亲每天服用氟奋乃静2毫克和去甲替林75毫克的情况下，运动发展正常。 ◉ 对泌乳和母乳的影响：氟奋乃静可以增加血清催乳素水平，并曾引起乳汁过多。在已建立泌乳的母亲中，催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Flupenthixol is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. Limited information indicates that maternal oral doses of up to 4 mg daily or depot injections of 40 mg every 2 weeks produced low levels in milk and breastfed infants' serum, and caused no adverse developmental consequences. A safety scoring system finds flupenthixol possible to use cautiously during breastfeeding. Until more data are available, flupenthixol should be used with careful infant monitoring during breastfeeding. ◉ Effects in Breastfed Infants:A woman took flupenthixol 1 mg and nortriptyline 100 mg daily during pregnancy and flupenthixol 4 mg and nortriptyline 125 mg daily immediately postpartum. She exclusively breastfed her infant. Over a 4-month period, the infant showed no signs of adverse drug effects and had normal motor development with a maternal dosage of flupenthixol 2 mg daily and nortriptyline 75 mg daily. ◉ Effects on Lactation and Breastmilk:Flupenthixol can increase serum prolactin and has caused galactorrhea. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

氟哌噻吨与血浆蛋白的结合率为99%。

Flupentixol is 99% bound to plasma proteins.

来源:DrugBank

吸收、分配和排泄

• 吸收

口服给药后，氟哌噻醇从胃肠道被迅速吸收，口服生物利用度约为40%。达峰时间（Tmax）为三到八小时。大约在七天左右达到稳态血浆水平，并且每日一次口服5毫克氟哌噻醇后，平均最低稳态水平约为1.7纳克/毫升（3.9纳米摩尔/升）。从肌肉注射部位，酯化的氟哌噻醇从油溶液中缓慢扩散，并缓慢释放到细胞外液和循环系统中，分布到不同的组织中。肌肉注射后四到七天达到药物浓度峰值。肌肉注射的氟哌噻醇在注射后三周内在血液中可检测到，并在大约三个月的重复给药后达到稳态浓度。

Following oral administration, flupentixol is readily absorbed from the gastrointestinal tract, with oral bioavailability of about 40%. Tmax ranges from three to eight hours. Steady-state plasma levels are achieved in about seven days and following once-daily oral administration of 5 mg flupentixol, the mean minimum steady-state level was about 1.7 ng/mL (3.9 nmol/L). From the site of intramuscular injection, esterified flupentixol diffuses slowly from the oil solution and is slowly released into the extracellular fluid and the circulation to be distributed to different tissues. Peak drug concentrations are reached between four and seven days following intramuscular injection. Intramuscularly administered flupentixol is detectable in the blood three weeks after injection and reaches steady-state concentrations after about three months of repeated administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

粪便排泄比肾排泄更为主要。在粪便中，氟哌噻醇主要以原形形式排出，以及其亲脂性代谢物，例如去烷基氟哌噻醇。氟哌噻醇在尿液中以原形以及其亲水性亚砜和葡萄糖苷酸代谢物形式排出。

Fecal excretion is more predominant than renal excretion. In the feces, flupentixol is recovered in the feces mainly as the unchanged form, as well as its lipophilic metabolites, such as dealkyl-flupentixol. Flupentixol is recovered in the urine as the unchanged form as well as its hydrophilic sulfoxide and glucuronide metabolites.

来源:DrugBank

吸收、分配和排泄

• 分布容积

表观分布容积约为14.1 L/kg。给药后，氟哌噻吨在肺、肝和脾中的含量最高。药物在血液和大脑中的浓度较低。

The apparent volume of distribution is about 14.1 L/kg. Following administration, the highest levels of flupentixol are found in the lungs, liver, and spleen. Lower concentrations of the drug are found in the blood and brain.

来源:DrugBank

吸收、分配和排泄

• 清除

口服给药后，平均系统清除率约为0.29升/分钟。

Following oral administration, the mean systemic clearance is about 0.29 L/min.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  癸酰氯 、 (Z)-4-[3-[2-(三氟甲基)-9H-噻吨-9-亚基]丙基]哌嗪-1-乙醇 在 盐酸 作用下， 以 丙酮 、 乙酸乙酯 为溶剂， 反应 1.5h， 以85%的产率得到(Z)-flupentixol decanoate dihydrochloride
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF Z-FLUPENTIXOL
  [FR] PROCEDE DE PREPARATION DE Z-FLUPENTIXOL

  摘要：

  本发明涉及一种用于分离氟哌替醇异构体的方法，特别是用于制备Z-氟哌替醇和癸酸酯及其新型合成中间体的方法。

  公开号：

  WO2005037820A1
• 作为产物：
  描述：

  (Z)-flupentixol p-chlorobenzoate dihydrochloride 在 氢氧化钾 、 环己烷 作用下， 以 甲醇 、 水 、 甲苯 为溶剂， 反应 1.0h， 以70%的产率得到(Z)-4-[3-[2-(三氟甲基)-9H-噻吨-9-亚基]丙基]哌嗪-1-乙醇
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF Z-FLUPENTIXOL
  [FR] PROCEDE DE PREPARATION DE Z-FLUPENTIXOL

  摘要：

  本发明涉及一种用于分离氟哌替醇异构体的方法，特别是用于制备Z-氟哌替醇和癸酸酯及其新型合成中间体的方法。

  公开号：

  WO2005037820A1

文献信息

• 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] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
• MACROCYCLES AS PDE1 INHIBITORS
  申请人：H. Lundbeck A/S

  公开号：US20190185489A1

  公开（公告）日：2019-06-20

  The present invention provides macrocycles of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.

  本发明提供了式(I)的大环化合物作为PDE1抑制剂，并将其用作药物，特别用于治疗神经退行性疾病和精神疾病。
• 1H-PYRAZOLO[4,3-B]PYRIDINES AS PDE1 INHIBITORS
  申请人：H. Lundbeck A/S

  公开号：US20190194189A1

  公开（公告）日：2019-06-27

  The present invention provides 1H-pyrazolo[4,3-b]pyridines of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.

  本发明提供了式(I)的1H-吡唑并[4,3-b]吡啶类化合物作为PDE1抑制剂，并将其用作药物，特别用于治疗神经退行性疾病和精神疾病。
• [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。