三氟拉嗪 | 117-89-5

• 物质功能分类: 原料药 - 神经系统用药 - 抗精神病药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 中文名称: 三氟拉嗪
• 中文别名: 10-[3-(4-甲基哌嗪-1-基丙基]-2-三氟甲基-10H-吩噻嗪；三氟比拉嗪
• 英文名称: Trifluoperazine
• 英文别名: TFP；10-[3-(4-methylpiperazin-1-yl)propyl]-2-(trifluoromethyl)phenothiazine
• CAS: 117-89-5
• 化学式: C₂₁H₂₄F₃N₃S
• 分子量: 407.503
• InChiKey: ZEWQUBUPAILYHI-UHFFFAOYSA-N

物化性质

• 熔点：
  232°C
• 沸点：
  bp0.6 202-210°
• 密度：
  1.2060 (estimate)
• 溶解度：
  DMSO（少许）、甲醇（少许）、水（少许）
• 物理描述：
  Solid
• 水溶性：
  -4.52
• 稳定性/保质期：

  In aqueous solution, trifluoperazine HCl is readily oxidized by atmospheric oxygen. /Trifluoperazine HCl/

• 分解：
  When heated to decomposition it emits very toxic fumes of /hydrogen fluoride/, nitroxides, and sulfoxides.
• 解离常数：
  pKa1= 3.9; pKa2= 8.1 /Dihydrochloride/
• 碰撞截面：
  188.1 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2688;2666;2662;2662;2641;2685;2691;2683;2684.6;2661.8;2710;2683;2650;2695;2683;2704.5;2682;2707;2685;2685;2677.1

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  35
• 氢给体数：
  0
• 氢受体数：
  7

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

在长期给予哌嗪取代的吩噻嗪类药物给大鼠后，组织中含有了药物代谢物，其中哌嗪环通过多次氧化N-脱烷基化反应裂解，生成了取代的乙二胺。类似的，三氟甲基的类似物也以相同的方式从三氟哌嗪形成。

AFTER CHRONIC ADMIN OF PIPERAZINE-SUBSTITUTED PHENOTHIAZINE DRUGS...TO RATS, TISSUES CONTAINED DRUG METABOLITES, IN WHICH PIPERAZINE RING FISSION BY MULTIPLE OXIDATIVE N-DEALKYLATION HAD OCCURRED TO GIVE SUBSTITUTED ETHYLENEDIAMINE. ...2-TRIFLUOROMETHYL ANALOGUE WAS FORMED SIMILARLY FROM TRIFLUPERAZINE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体内 trifluoperazine 的哌嗪环降解导致形成 gamma-(苯并噻唑基-10)-丙胺及其环上取代类似物 CF3- 和 Cl-. 这些代谢物的砜化物在大鼠(慢性)尿液中被识别为生物转化产物。

IN VIVO DEGRADATION OF PIPERAZINE RING OF TRIFLUOPERAZINE LEADS TO FORMATION OF GAMMA-(PHENOTHIAZINYL-10)-PROPYLAMINE & ITS RING SUBSTITUTED ANALOGS CF3- & CL-. SULFOXIDES OF THESE METABOLITES HAVE BEEN IDENTIFIED AS URINARY BIOTRANSFORMATION PRODUCTS IN RATS (CHRONIC).

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏的。 半衰期：10-20小时

Hepatic. Half Life: 10-20 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

三氟拉嗪阻断了大脑中突触后的中脑边缘多巴胺能D1和D2受体；抑制了下丘脑和垂体激素的释放，并且据信它抑制了网状激活系统，从而影响基础代谢率、体温、觉醒状态、血管运动张力和呕吐。

Trifluoperazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

肝脏测试异常在长期使用吩噻嗪类药物的患者中报告发生率较高，但升高的情况很少超过正常上限的3倍。转氨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。已经报告了在使用三氟拉嗪治疗中出现临床明显的急性肝损伤的罕见病例，这种损伤类似于氯丙嗪引起的。黄疸的出现通常在1到4周内，血清酶升高的模式通常是胆汁淤积型或混合型。一些病例中出现了免疫过敏特征（皮疹、发热和嗜酸性粒细胞增多），但这些都是轻微和自限性的；自身抗体罕见。

Liver test abnormalities have been reported to occur in a high proportion of patients on long term phenothiazine therapy, 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, resembling that due to chlorpromazine, have been reported with trifluoperazine therapy. The onset of jaundice is usually within 1 to 4 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed. Immunoallergic features (rash, fever and eosinophilia) were present in some cases but were mild and self-limited; autoantibodies were rare.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：三氟拉嗪

Compound:trifluoperazine

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

严重程度等级：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

吩噻嗪类药物在体内的最终停留时间非常长。/吩噻嗪类/

ULTIMATE SOJOURN OF PHENOTHIAZINE DRUGS IN BODY IS EXCEEDINGLY LONG. /PHENOTHIAZINES/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品运输编号：
  small
• 海关编码：
  2934300000

制备方法与用途

生物活性方面，三氟哌啶醇（NSC-17474、RP-7623、SKF-5019）是FDA认证的抗精神病药物，用于治疗精神分裂症。它同时是一种钙调蛋白(CaM)和多巴胺D2受体抑制剂，对D2受体的IC50值为1.2 nM。

反应信息

• 作为反应物：
  描述：

  三氟拉嗪 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以38%的产率得到trifluoperazine N^4'-oxide
  参考文献：
  名称：

  吩噻嗪抗精神病药N氧化物的合成。

  摘要：

  通过用相应母体药物的N-10侧链上的指定氮原子进行氧化合成氯丙嗪N-氧化物，氟奋乃静N4'-氧化物，丙氯嗪N4'-氧化物，磺胺嘧啶N-氧化物和三氟哌嗪N4'-氧化物。 3-氯过氧苯甲酸。在三氟哌嗪的情况下，氧化剂量的逐步增加产生了N1'，N4'-二氧化物和N1'，N4'，S-三氧化物。氯丙嗪和磺胺哒嗪的N'，S-二氧化物通过适当母体药物的过氧化氢氧化获得。

  DOI：

  10.1002/jps.2600820323
• 作为产物：
  描述：

  2-三氟甲基吩噻嗪 在 potassium phosphate 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 52.0h， 生成 三氟拉嗪
  参考文献：
  名称：

  Synthesis and antitubercular activity of phenothiazines with reduced binding to dopamine and serotonin receptors

  摘要：

  Analogs of the psychotropic phenothiazines were synthesized and examined as antitubercular agents against Mycobacterium tuberculosis H37Rv. The compounds were subsequently counter-screened for binding to the dopaminergic-receptor subtypes D1, D2, D3 and the serotonergic-receptor subtypes 5-HT1A, 5-HT2A, and 5-HT2C. The most active compounds showed MICs from 2 to 4 mu g/mL and had overall reduced binding to the dopamine and serotonin receptors compared to chlorpromazine and trifluoperazine. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.064
• 作为试剂：
  描述：

  吗啉-4-基苯甲酸酯 、 2-碘代甲苯 、 苯丙酸,a-重氮基-,乙基酯 在 norbornene 、 palladium diacetate 、 caesium carbonate 、 三氟拉嗪 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 30.25h， 以57%的产率得到(E)-ethyl 2-(2-methyl-6-morpholinophenyl)-3-phenylacrylate
  参考文献：
  名称：

  Palladium-Catalyzed/Norbornene-Mediated ortho-Amination/N-Tosylhydrazone Insertion Reaction: An Approach to the Synthesis of ortho-Aminated Vinylarenes

  摘要：

  ortho-Aminated vinylarene derivatives were obtained via a reaction of aryl iodides, N-benzoyloxyamines, and N-tosylhydrazones. This approach involves a palladium-catalyzed, norbomene-mediated ortho-amination/N-tosylhydrazone insertion reaction. In this transformation, one C-N bond and one C-C bond are formed and an amine group is introduced at the ortho position successfully.

  DOI：

  10.1021/jo501125b

文献信息

• [EN] BENZAMIDE OR BENZAMINE COMPOUNDS USEFUL AS ANTICANCER AGENTS FOR THE TREATMENT OF HUMAN CANCERS<br/>[FR] COMPOSÉS BENZAMIDE OU BENZAMINE À UTILISER EN TANT QU'ANTICANCÉREUX POUR LE TRAITEMENT DE CANCERS HUMAINS
  申请人：UNIV TEXAS

  公开号：WO2017007634A1

  公开（公告）日：2017-01-12

  The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not affect normally dividing cells.

  所描述的发明提供了用于治疗对胆固醇生物合成抑制作出反应的肿瘤的小分子抗癌化合物。这些化合物选择性地抑制肿瘤来源的癌细胞中的胆固醇生物合成途径，但不影响正常分裂的细胞。
• [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。
• [EN] PHENOTHIAZINE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE PHÉNOTHIAZINE ET LEURS UTILISATIONS
  申请人：CAMP4 THERAPEUTICS CORP

  公开号：WO2019195789A1

  公开（公告）日：2019-10-10

  The present invention provides phenothiazine compounds, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment of various diseases or conditions, for example ribosomal disorders and ribosomopathies, e.g. Diamond Blackfan anemia (DBA).

  本发明提供了吩噻嗪化合物，其制备方法，包含该化合物的药物组合物，以及在治疗各种疾病或症状中使用该化合物或组合物，例如核糖体紊乱和核糖体病，例如钻石-布莱克范贫血（DBA）。

表征谱图