磷苯妥英 | 93390-81-9

• 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: 磷苯妥英
• 中文别名: 柠檬酸咖啡因
• 英文名称: fosphenytoin
• 英文别名: 3-(hydroxymethyl)-5,5-diphenylhydantoin phosphate ester；5,5-diphenyl-3-[(phosphono)oxymethyl]-2,4-imidazolidinedione；5,5-diphenyl-3-[(phosphonooxy)methyl]imidazolidine-2,4-dione；3-phosphoryloxymethyl-5,5-diphenylhydantoin；3-Phosphoryloxymethyl-diphenylhydantoin；oxcarbamazepine；(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl dihydrogen phosphate
• CAS: 93390-81-9
• 化学式: C₁₆H₁₅N₂O₆P
• 分子量: 362.279
• InChiKey: XWLUWCNOOVRFPX-UHFFFAOYSA-N

物化性质

• 熔点：
  173-176.5°
• 密度：
  1.495±0.06 g/cm3(Predicted)
• 物理描述：
  Solid
• 颜色/状态：
  White crystals from acetone
• 溶解度：
  In water, 349 mg/L at 25 °C (est)
• 蒸汽压力：
  6.1X10+11 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 1.20 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

福斯苯妥英通过磷酸酶代谢为苯妥英、磷酸和甲醛；随后甲醛转化为甲酸。产生的苯妥英通过CYP2C9在肝脏中代谢，在一定程度上也通过CYP2C19。

Fosphenytoin is metabolized, likely by phosphatases, to phenytoin, phosphate, and formaldehyde; the formaldehyde is subsequently converted into formate. The phenytoin produced is metabolized hepatically by CYP2C9 and, to a lesser extent, by CYP2C19.

来源:DrugBank

代谢

Fosphenytoin 经快速水解转化为苯妥英。… Fosphenytoin 的转化还产生两种额外的代谢物，磷酸和甲醛。甲醛随后转化为甲酸，甲酸再通过叶酸依赖机制进行代谢。… 磷酸酶酶在 Fosphenytoin 转化为苯妥英的过程中可能发挥主要作用。

Fosphenytoin undergoes rapid hydrolysis to phenytoin. ... Conversion of fosphenytoin also yields two additional metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which in turn is metabolized via a folate-dependent mechanism. ... Phosphatase enzymes probably play a major role in the conversion of fosphenytoin to phenytoin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项调查旨在确定一种新的免疫反应代谢物的结构，该代谢物来自fosphenytoin，之前假设存在于接受这种前药治疗的肾损害患者的血清中。该代谢物通过固相提取和高效液相色谱（HPLC）从尿毒症血清中分离出来。结构分析采用高效液相色谱-串联质谱、核磁共振（NMR）、氘交换和化学衍生化方法进行。免疫反应性通过荧光偏振免疫分析评估。该代谢物在负离子模式下有一个m/z 457的母离子，并断裂产生m/z 251的苯妥英以及苯妥英的其他质量碎片。与葡萄糖醛酸相关的质量碎片也存在。与此代谢物对应的色谱峰显示出足够的免疫反应性，导致苯妥英免疫分析假性升高。观察到的免疫反应性与收集馏分中代谢物的相对浓度成正比。NMR分析表明存在与苯妥英化学位移相同的苯基团，以及存在一个亚甲基桥，这与fosphenytoin的磷酸酯上的同一亚甲基桥一致。使用多反应监测定量分析比较接受苯妥英和fosphenytoin治疗的肾损害患者的血清样本，表明这种代谢物与fosphenytoin给药有关。已经从接受这种前药治疗的尿毒症患者的血清中分离出一种独特的免疫反应性羟基甲基葡萄糖醛酸代谢物，该代谢物来自fosphenytoin。

This investigation was undertaken to identify the structure of a novel immunoreactive metabolite derived from fosphenytoin that has been hypothesized previously as present in sera from renally impaired patients receiving this prodrug. The metabolite was isolated from uremic sera using solid-phase extraction and HPLC. Structural analysis was performed using HPLC-tandem mass spectrometry, nuclear magnetic resonance (NMR), deuterium exchange, and chemical derivatization. Immunoreactivity was evaluated using a fluorescence polarization immunoassay. The metabolite had a parent ion at m/z 457 in the negative-ion mode and fragmented to yield the m/z 251 of phenytoin, as well as other mass fragments of phenytoin. Mass fragments associated with glucuronic acid were also present. The chromatographic peak corresponding to this metabolite demonstrated immunoreactivity sufficient to lead to falsely increased reported values for phenytoin immunoassays. The observed immunoreactivity was also proportional to the relative concentration of the metabolite in collected fractions. Analysis by NMR indicated the presence of phenyl groups with chemical shifts identical to those of phenytoin, as well as the presence of a methylene bridge, which was consistent with the same methylene bridge present on the phosphate ester of fosphenytoin. Comparative analysis of serum samples from renally impaired patients receiving phenytoin vs fosphenytoin using multiple reaction monitoring quantification demonstrated that this metabolite was associated with fosphenytoin administration. A unique immunoreactive oxymethylglucuronide metabolite derived from fosphenytoin has been isolated from sera from uremic patients receiving this prodrug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

苯妥英钠磷酸酯是一种酰亚胺衍生物抗惊厥药。苯妥英钠磷酸酯是苯妥英的水溶性磷酸酯前药，在体内水解成苯妥英之前，几乎没有抗惊厥活性。苯妥英磷酸酯的药理作用包括苯妥英的药理作用。

Fosphenytoin sodium is a hydantoin-derivative anticonvulsant. Fosphenytoin sodium, a water-soluble phosphate ester of phenytoin, is a prodrug and has little, if any, anticonvulsant activity until hydrolyzed in vivo to phenytoin. Pharmacologic effects of fosphenytoin include those of phenytoin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏。 消除途径：从Cerebyx给药中得到的苯妥英在肝脏广泛代谢，并主要作为5-(对-羟基苯基)-5-苯基乙内酰脲及其葡萄糖苷酸在尿液中排泄；很少有不改变的苯妥英（Cerebyx剂量的1%-5%）在尿液中回收。 半衰期：磷苯妥英的半衰期大约为15分钟。

Hepatic. Route of Elimination: Phenytoin derived from administration of Cerebyx is extensively metabolized in the liver and excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1%-5% of the Cerebyx dose) is recovered in urine. Half Life: Fosphenytoin has a half-life of approximately 15 minutes.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

Fosphenytoin 是苯妥英的前药，因此，其抗惊厥效果归因于苯妥英。苯妥英作用于神经元细胞膜上的钠通道，限制癫痫活动的传播并减少癫痫的扩散。通过促进神经元中的钠离子外流，苯妥英倾向于稳定阈值，防止由于过度刺激或能够减少膜钠梯度的环境变化引起的过度兴奋性。这包括减少突触后的张力增强。失去后张力增强可以防止皮质癫痫病灶引爆邻近的皮质区域。

Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

肝脏损伤并未特别归因于使用磷酸氟苯妥英，但由于它代谢为苯妥英，因此很可能引起类似的肝脏损伤。在接受磷酸氟苯妥英初始治疗并随后转换为口服形式的患者的报告中，已经出现了典型的免疫过敏性肝炎和药物超敏反应综合症（DRESS 综合症）的案例。

Hepatic injury has not been specifically ascribed to use of fosphenytoin, but because it is metabolized to phenytoin, it is likely to cause similar hepatic injury. Cases of typical immunoallergic hepatitis and DRESS syndrome have been reported in patients initially treated with fosphenytoin and then converted to the oral form.

来源:LiverTox

毒理性

• 药物性肝损伤

复合物：磷苯妥英

Compound:fosphenytoin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：最令人关注的药物性肝损伤

DILI Annotation:Most-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：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

以15至20 mg PE/kg的速度静脉输注Fosphenytoin，每分钟100至150 mg PE，可以得到与以50 mg/min的速度给药的相同剂量的苯妥英钠相似的游离血浆苯妥英浓度。单次静脉给药的Fosphenytoin在平均最高总苯妥英浓度方面呈线性增长，而平均最高未结合苯妥英浓度随着剂量和输注速率的增加而增加。静脉给药后，Fosphenytoin迅速转化为苯妥英，半衰期为15分钟；如果肌内给药，血浆中苯妥英的峰值浓度直到三小时后才达到。

Fosphenytoin at 15 to 20 mg PE/kg infused at 100 to 150 mg PE/min intravenously yields free plasma phenytoin concentrations similar to an equivalent dose of phenytoin sodium administered at 50 mg/min. Single intravenous administration of fosphenytoin shows a linear increase in mean maximum total phenytoin concentration while the mean maximum unbound phenytoin concentrations increase with both dose and infusion rate. Fosphenytoin is rapidly converted to phenytoin following intravenous administration with a half-life of 15 minutes; if administered intramuscularly, the peak plasma phenytoin concentration is not reached until three hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

从磷酸苯妥英给药中衍生出的苯妥英主要通过尿液排出，主要以5-(对-羟基苯基)-5-苯基乙内酰脲及其葡萄糖苷酸形式排出。尿液中几乎没有未改变的苯妥英（占给药剂量的1%-5%），实际上没有检测到磷酸苯妥英的回收。

Phenytoin derived from fosphenytoin administration is excreted in the urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide. There is little unchanged phenytoin (1%–5% of the administered dose), and essentially no fosphenytoin recovered in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

磷酸苯妥英的分布体积随剂量和给药速率的增加而增加，范围在4.3到10.8升之间。

The volume of distribution of fosphenytoin increases with dose and rate, ranging between 4.3 and 10.8 L.

来源:DrugBank

吸收、分配和排泄

无论是静脉注射还是肌肉注射，生物利用度基本上是100%。

Bioavailability from either intravenous or intramuscular route is essentially 100%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

/Fosphenytoin是/ 最可能在人类中分布到心脏、肾脏、小肠、肝脏、肺、脾，在那里它被磷酸酶水解为苯妥英。主要分布在中央（血浆）室。

/Fosphenytoin is/ most likely distributed in humans to heart, kidneys, small intestine, liver, lungs, spleen, where it is hydrolyzed by phosphatases to phenytoin. Predominately distributed in the central (plasma) compartment.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933990090

制备方法与用途

磷苯妥英钠是一种磷酸酯前药，可以替代静脉注射苯妥英钠用于急性癫痫发作的治疗。与苯妥英钠相比，磷苯妥英钠具有以下优点：静脉给药更加方便快捷，并且还可以进行肌肉注射；此外，其在注射部位引起不良反应的可能性较低。

反应信息

• 作为反应物：
  描述：

  磷苯妥英 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 生成 Fosphenytoin
  参考文献：
  名称：

  Process for the preparation of sodium fosphenytoin

  摘要：

  磷酸二酯2,5-二氧代-4,4-二苯基咪唑烷-1-甲酯，其两个酯基可选择性地被裂解，通过将3-(羟甲基)-5,5-二苯基咪唑烷-2,4-二酮转化为烷磺酸酯或芳基磺酸酯，并将其与一个磷酸二酯反应而获得。从所得的磷酸二酯中可以选择性地裂解两个酯基，得到的产物可以转化为5,5-二苯基-3-[(磷酸酯氧)甲基]咪唑烷-2,4-二酮二钠盐。后者是一种抗抽搐、抗癫痫和抗心律失常药物，简称为磷酸美多嗪钠。

  公开号：

  US20050272706A1
• 作为产物：
  描述：

  3-(chloromethyl)-5,5-diphenylhydantoin 在 palladium on activated charcoal 氢气 作用下， 以 乙酸乙酯 、 苯 为溶剂， 反应 2.42h， 生成 磷苯妥英
  参考文献：
  名称：

  苯妥英前药III：口服和/或肠胃外使用的水溶性前药。

  摘要：

  合成了苯妥英钠的各种生物可逆衍生物，苯妥英钠是口服和胃肠外给药后水溶性差且易失性的药物。对这些预期的前药的初步评估，即它们的水溶性，在各种动物组织中的裂解以及在小鼠中的抗惊厥活性，证实了许多衍生物确实起了前药的作用。最有前途的前药是磷酸二钠酯和3-（羟甲基）-5,5-二苯基乙内酰脲的各种含氨基的酰基酯。

  DOI：

  10.1002/jps.2600730812

文献信息

• [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] 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] PROCESSES USEFUL FOR THE SYNTHESIS OF (R)-1-{2-[4'-(3-METHOXYPROPANE-1-SULFONYL)-BIPHENYL-4-YL]-ETHYL}-2-METHYL-PYRROLIDINE<br/>[FR] PROCÉDÉS UTILES POUR LA SYNTHÈSE DE LA (R)-1-{2-[4'-(3-MÉTHOXYPROPANE-1-SULFONYL)-BIPHÉNYL-4-YL]-ÉTHYL}-2-MÉTHYL-PYRROLIDINE
  申请人：ARENA PHARM INC

  公开号：WO2009128907A1

  公开（公告）日：2009-10-22

  Processes useful for making a pharmaceutically useful compound according to Formula (I), forms of such a compound, and intermediates useful in such processes are described.

  根据公式（I）制备药用化合物的有用过程，以及该化合物的形式和在这些过程中有用的中间体被描述。
• [EN] HETEROCYCLIC LSF INHIBITORS AND THEIR USES<br/>[FR] INHIBITEURS DE LSF HÉTÉROCYCLES ET LEURS UTILISATIONS
  申请人：UNIV BOSTON

  公开号：WO2021150835A1

  公开（公告）日：2021-07-29

  The present invention is directed to heterocyclic SV40 Factor (LSF) inhibitors and their uses. In some implementations, the present invention discloses small-molecule compounds of Formula (I). In some implementations, the compounds of Formula (I) are used in methods for inhibiting LSF in a subject. In some implementations, the compounds of Formula (I) are used in methods for treating cancer in a subject.

  本发明涉及杂环SV40因子（LSF）抑制剂及其用途。在某些实施例中，本发明揭示了化合物的分子式（I）。在某些实施例中，分子式（I）的化合物用于抑制受试者中的LSF。在某些实施例中，分子式（I）的化合物用于治疗受试者中的癌症。
• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。