氟奋乃静 | 69-23-8

• 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: 氟奋乃静
• 中文别名: 羟哌氟丙嗪；氟吩嗪；吉他霉素
• 英文名称: Fluphenazine
• 英文别名: fluphenazin；2-[4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol
• CAS: 69-23-8
• 化学式: C₂₂H₂₆F₃N₃OS
• 分子量: 437.529
• InChiKey: PLDUPXSUYLZYBN-UHFFFAOYSA-N

物化性质

• 熔点：
  268-274℃
• 沸点：
  bp0.5 268-274°; bp0.3 250-252°
• 密度：
  1.2156 (estimate)
• 闪点：
  9℃
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Dark brown viscous oil
• 蒸汽压力：
  1.11X10-10 mm Hg at 25 °C (est)
• 水溶性：
  -4.15
• 稳定性/保质期：
  Light sensitive. /Fluphenazine Decanoate/
• 分解：
  When heated to decomposition it emits very toxic fumes of /hydrogen fluoride/, /nitroge and sulfur/ oxides.
• 解离常数：
  pKa = 7.90
• 碰撞截面：
  198.1 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated]
• 保留指数：
  3045;3032;3015;3025;3045;3045;3045;3045;3050;3050;3050;3050;3050;3050;3050;3060;3060;3060;3060;3045;3056;3035;3085;3015.8;3065;3019.9

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  55.2
• 氢给体数：
  1
• 氢受体数：
  8

ADMET

代谢

在狗和恒河猴中，主要粪便代谢物7-羟基氟奋乃静通过质谱和核磁共振测量被分离和鉴定，涉及合成的7-和8-羟基氟奋乃静。7-羟基氟奋乃静以葡萄糖苷酸形式存在于处理过的狗和恒河猴的胆汁中。

In dogs and rhesus monkeys, the major fecal metabolite, 7-hydroxyfluphenazine, was isolated and identified by mass spectrometric and NMR measurements, involving synthetic 7- and 8-hydroxyfluphenazines. 7-hydroxyfluphenazine is present in bile of treated dogs and rhesus monkeys as glucuronide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氟奋乃静中的哌嗪环在体内降解，导致生成γ-(吩噻嗪基-10)-丙胺以及其环上取代类似物CF3-γ-(吩噻嗪基-10)-丙胺和C1-γ-(吩噻嗪基-10)-丙胺。

Degradation of piperazine ring in fluphenazine in vivo leads to formation of gamma-(phenothiazinyl-10)-propylamine and of its ring substituted analogs CF3-gamma-(phenothiazinyl-10)-propylamine and C1-gamma-(phenothiazinyl-10)-propylamine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氟奋乃静及其主要代谢物，包括氟奋乃静亚砜、7-羟基氟奋乃静和氟奋乃静结合物，在给人患者静脉注射和口服25毫克(14)C-氟奋乃静二盐酸后，可以在人类血浆、尿液和粪便中检测到。

Fluphenazine and its principal metabolites, fluphenazine sulfoxide, 7-hydroxyfluphenazine and fluphenazine conjugates were identified in human plasma, urine and feces, following im and oral administration of 25 mg of (14)C-fluphenazine dihydrochloride to patients.

来源:Hazardous Substances Data Bank (HSDB)

代谢

成鼠和新生鼠被用精神药物处理；抗精神病药（氟奋乃静，苯哌咪唑，哌咪清，硫噻嗪），一种镇静剂（奥沙西泮）和一种抗抑郁药（丙咪嗪）长达一年或更长时间的周期。监测了体重，并测量了脑重，总脑脂含量，个别磷脂的含量，(32)P掺入个别磷脂，以及磷脂酰乙醇胺的脂肪酸组成。长期使用抗精神病药和抗抑郁药，而不是奥沙西泮，导致了磷脂生物化学的深刻、通常是双相或多相变化。在讨论抗抑郁药和抗精神病药长期治疗的机制和副作用时，应考虑这些变化。

Adult and newborn rats were treated with psychotropic drugs; neuroleptics (fluphenazine, benperidol, pimozide, thiotixen), an ataractic (oxazepam) and an anti- depressant (protriptyline) for periods up to one year or longer. The body weight was monitored, and brain weight, total cerebral lipid content, content of individual phospholipids, incorporation of (32)P into individual phospholipids, and the fatty acids composition of phosphatidylethanolamine were measured. The prolonged treatment with neuroleptics and an antidepressant, but not with oxazepam, produced profound, often biphasic or multiphasic changes in the biochemistry of phospholipids. These changes should be taken into account in discussion of the mechanism of action and side-effects of prolonged treatment with antidepressants and neuroleptics.

来源:Hazardous Substances Data Bank (HSDB)

代谢

非那嗪有人体已知代谢物，包括10-{3-[4-(2-羟基乙基)哌嗪-1-基]丙基}-2-(三氟甲基)-10H-5'-吩噻嗪-5-酮。

Fluphenazine has known human metabolites that include 10-{3-[4-(2-hydroxyethyl)piperazin-1-yl]propyl}-2-(trifluoromethyl)-10H-5'-phenothiazin-5-one.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

氟奋乃静阻断脑内中脑边缘系统的多巴胺D1和D2受体；抑制下丘脑和垂体激素的释放，据信还能抑制网状激活系统，从而影响基础代谢率、体温、觉醒状态、血管紧张度和呕吐。

Fluphenazine 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

长期使用吩噻嗪类药物的患者中，据报道有高达40%的人会出现肝功能测试异常，但升高通常不会超过正常上限的3倍。转氨酶异常通常是轻微的、无症状的，并且是暂时的，即使继续用药也会逆转。已经报道了几例由于氟奋乃静引起的临床上明显的急性肝损伤，这些损伤类似于氯丙嗪和其他吩噻嗪类药物引起的肝损伤。吩噻嗪类药物相关的黄疸通常在1到4周内出现，血清酶升高的模式通常是胆汁淤积型或混合型。一些病例中存在免疫过敏特征（发热、皮疹和嗜酸性粒细胞增多），但它们通常是轻微的和自限性的；自身抗体罕见。最重要的是，吩噻嗪诱导的黄疸可能会延长，并可能与消失胆管综合征相关。所有吩噻嗪类抗精神病药物都可能引起胆汁淤积性肝损伤，但肝毒性的发生率似乎氯丙嗪远高于其他如氟奋乃静等药物。

Liver test abnormalities have been reported to occur in up to 40% of patients on long term therapy with phenothiazines, 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. Several instances of clinically apparent acute liver injury have been reported due to fluphenazine, which have resembled the liver injury caused by chlorpromazine and other phenothiazines. The onset of phenothiazide-related jaundice is usually within 1 to 4 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed. Immunoallergic features (fever, rash and eosinophilia) are present in some cases, but they are usually mild and self-limited; autoantibodies are rare. Most importantly, phenothiazide induced jaundice can be prolonged and associated with vanishing bile duct syndrome. All phenothiazine antipsychotic agents are probably capable of causing cholestatic liver injury, but the frequency of hepatotoxicity appears to be far greater with chlorpromazine than with others such as fluphenazine.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：氟奋乃静

Compound:fluphenazine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：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

盐酸氟奋乃静从胃肠道和注射部位迅速吸收。口服或肌肉注射盐酸氟奋乃静后，通常在1小时内起效；药效持续6-8小时。在一项有限的研究中，单次给予盐酸氟奋乃静后，肌肉注射或口服给药后分别在1.5-2小时或0.5小时内达到血清氟奋乃静浓度峰值。

Fluphenazine hydrochloride is rapidly absorbed from the GI tract and from parenteral sites. Following oral or im administration of fluphenazine hydrochloride, the onset of action usually occurs within 1 hour; the duration of action is 6-8 hours. Following administration of a single dose of fluphenazine hydrochloride in one limited study, peak serum fluphenazine concentrations were reached within 1.5-2 or 0.5 hours following im or oral administration, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

非那根的酯化作用可以减慢药物从脂肪组织释放的速度，从而延长药物的作用时间；将酯类药物溶于芝麻油中给药可以进一步延迟它们的释放速度。芝麻油中给予非那根癸酸酯后，作用发生时间在24-72小时内；作用持续时间通常为1-6周，平均为2周。

Esterification of fluphenazine slows the rate of release of the drug from fatty tissues, thus prolonging the drug's duration of action; administration of the esters in a sesame oil vehicle further delays their rate of release. Following im administration of fluphenazine decanoate in sesame oil, the onset of action occurs within 24-72 hours; the duration of action is usually 1-6 weeks, with an average of 2 weeks.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吩噻嗪类药物与血浆蛋白高度结合。

Phenothiazines are highly bound to plasma proteins.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚未完全阐明氟奋乃静的分布和代谢命运。据报道，氟奋乃静能够穿过血脑屏障；在2名个体中，给予放射性标记的氟奋乃静癸酸盐后，脑脊液中存在放射性。

The distribution and metabolic fate of fluphenazine have not been fully elucidated. Fluphenazine reportedly crosses the blood-brain barrier; radioactivity was present in CSF following im administration of radiolabeled fluphenazine decanoate in 2 individuals.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1
• 危险品标志：
  F,T
• 安全说明：
  S16,S36/37,S45
• 危险类别码：
  R11,R23/24/25,R39/23/24/25
• WGK Germany：
  1
• 储存条件：
  本品应避光密闭保存。

制备方法与用途

生产方法 

羟乙基哌嗪与溴代氯丙烷经过烷基化反应，再与2-三氟甲基吩噻嗪缩合生成盐类化合物。此外，也可通过间三氟甲基苯胺的缩合、消除和环合等步骤制得。

反应信息

• 作为反应物：
  描述：

  氟奋乃静 以 1,4-二氧六环 为溶剂， 生成 carbonic acid bis-(2-{4-[3-(2-trifluoromethyl-phenothiazin-10-yl)-propyl]-piperazin-1-yl}-ethyl) ester
  参考文献：
  名称：

  Synthesis of carbonates of 2-substituted 4-[3-(phenothiazinyl-10)-propyl]piperazin-1-ethanol

  摘要：

  DOI：

  10.1007/bf00757830
• 作为产物：
  描述：

  1-甲酰基-4-(3-氯丙基)哌嗪 以 甲醇 为溶剂， 反应 1.0h， 生成 氟奋乃静
  参考文献：
  名称：

  ANDERSON, Arzneimittel-Forschung/Drug Research, 1962, vol. 12, p. 937 - 942

  摘要：

  DOI：

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] 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）。
• [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。

表征谱图