乙苯妥英 | 86-35-1

• 物质功能分类: 原料药 - 神经系统用药 - 抗癫痫及抗惊厥药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 中文名称: 乙苯妥英
• 中文别名: 乙基苯妥英
• 英文名称: ethotoin
• 英文别名: 3-ethyl-5-phenylimidazolidine-2,4-dione；3-ethyl-5-phenylhydantoin；Ethotoinum；Pegoanone；Etotoina
• CAS: 86-35-1
• 化学式: C₁₁H₁₂N₂O₂
• 分子量: 204.228
• InChiKey: SZQIFWWUIBRPBZ-UHFFFAOYSA-N

物化性质

• 熔点：
  94°C
• 沸点：
  342.72°C (rough estimate)
• 密度：
  1.1754 (rough estimate)
• 溶解度：
  二氯甲烷（少许）、DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Stout prisms from water.
• 蒸汽压力：
  5.5X10-8 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Ethotoin darkens on exposure to light or extreme heat.
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 保留指数：
  1790;1800

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

肝脏。该药物在形成主要代谢物N-去乙基和p-羟基乙妥因方面表现出饱和代谢。

Hepatic. The drug exhibits saturable metabolism with respect to the formation of N-deethyl and p-hydroxyl-ethotoin, the major metabolites.

来源:DrugBank

代谢

乙妥英通过肝脏代谢，经过N-脱乙基化后转化为p-羟基化和m-羟基化衍生物；这些代谢物与葡萄糖醛酸结合。N-脱乙基化的代谢物还可能进一步代谢为2-苯基乙内酰脲酸。乙妥英在形成p-羟基化和N-脱乙基化代谢物方面表现出饱和代谢的特性。

Ethotoin is metabolized by the liver to p-hydroxylated and m-hydoxylated derivatives following N-deethylation; these metabolites are conjugated with glucuronic acid. The N-deethylated metabolite may also be metabolized to 2-phenylhydantoic acid. Ethotoin appears to exhibit saturable metabolism with respect to the formation of the p-hydroxylated and N-deethylated metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏生物转化的速率在年幼儿童、孕妇、月经期妇女以及急性创伤患者中增加；随着年龄的增长，速率会降低。/乙内酰脲类抗惊厥药/

The rate of hepatic biotransformation is increased in younger children, in pregnant women, in women during menses, and in patients with acute trauma; rate decreases with advancing age. /Hydantoin anticonvulsants/

来源:Hazardous Substances Data Bank (HSDB)

代谢

乙妥英及其五种代谢物在三个接受乙妥英连续治疗的病人中的尿排泄模式被研究，以探讨这种抗惊厥药物剂量依赖性动力学背后的机制。结果表明，在三个病人中，在高剂量水平下，脱烷基过程部分饱和。尝试对不同的酶促过程进行Michaelis-Menten常数的粗略估计。根据所获得的结果，p-羟基化可能是一个可饱和的过程。乙妥英在人体中的剂量依赖性动力学似乎可以通过存在部分可饱和的酶促途径来解释。

The urinary excretion pattern of ethotoin and five metabolites were examined in three patients receiving continuous treatment with ethotoin at two dose levels, in order to investigate the mechanism behind the dose-dependent kinetics of this anticonvulsant drug. The results suggest a partial saturation in the dealkylation process at high dose levels in three patients. A rough approximation of the Michaelis-Menten constants for different enzymatic processes was attempted. On the basis of the results obtained, the p-hydroxylation may be a saturable process. The dose-dependent kinetics of ethotoin in man seem to be explicable by the existence of partly saturable enzymatic pathways.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏。该药物在形成主要代谢物N-去乙基和p-羟基乙妥因方面表现出饱和代谢。 半衰期：3至9小时

Hepatic. The drug exhibits saturable metabolism with respect to the formation of N-deethyl and p-hydroxyl-ethotoin, the major metabolites. Half Life: 3 to 9 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

作用机制可能和苯妥英钠非常相似。后者药物似乎更倾向于稳定正常癫痫阈值而不是提高它，并且阻止癫痫活动的扩散而不是消除癫痫放电的初级焦点。乙妥英通过降低钠离子流入，限制痉挛性刺激，从而抑制运动皮层的神经冲动。

The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. Ethotoin inhibits nerve impulses in the motor cortex by lowering sodium ion influx, limiting tetanic stimulation.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

乙妥英

Compound:ethotoin

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

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

相当迅速地被吸收，然而，口服吸收的程度尚不清楚。

Fairly rapidly absorbed, however, the extent of oral absorption is not known.

来源:DrugBank

吸收、分配和排泄

Ethotoin口服给药后从胃肠道相当快地被吸收；吸收程度尚不清楚。

Ethotoin is fairly rapidly absorbed from the GI tract following oral administration; the extent of absorption is not known.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

用于治疗的地高辛血清浓度范围为0.5至2.0 ng/mL。

Therapeutic serum concentrations range from 15 to 50 ug/mL (74 to 245 umol/L) for ethotoin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

乙妥英和苯妥英会分布到母乳中...

Ethotoin and phenytoin are distributed into breast milk...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

有限的数据表明，乙妥英以及更小程度的5-苯基乙内酰脲（N-去乙基化代谢物）在单次口服500、1000和1500毫克剂量的乙妥英后，可能表现出非线性药代动力学。与单次剂量相比，多次口服给药（给药间隔为4-6小时）乙妥英的非线性程度可能会增加，这可能是由于药物在血浆中的积累。

Limited data suggest that ethotoin and, to a lesser degree, 5-phenylhydantoin (the N-deethylated metabolite) may exhibit nonlinear pharmacokinetics following oral administration of single 500-, 1000-, and 1500-mg doses of ethotoin. The degree of nonlinearity may increase following oral administration of multiple doses (with a dosing interval of 4-6 hours) of ethotoin when compared with single doses, probably secondary to accumulation of the drug in plasma.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险类别码：
  R22
• 海关编码：
  2933210000
• 储存条件：
  -20°C，密封保存，置于干燥处。

制备方法与用途

乙素（聚乙二醇酮）是一种用于癫痫研究的口服活性抗惊厥剂，它属于乙内酰脲类药物，类似于苯妥英钠。

反应信息

• 作为反应物：
  描述：

  乙苯妥英 在 溴 、 溶剂黄146 作用下， 生成 1,1'-diethyl-4,4'-diphenyl-tetrahydro-[4,4']biimidazolyl-2,5,2',5'-tetraone
  参考文献：
  名称：

  二苯基乙二胺。

  摘要：

  DOI：

  10.1021/jo01256a083
• 作为产物：
  描述：

  在 吡啶 、 三氟甲磺酸酐 作用下， 以 二氯甲烷 为溶剂， 反应 2.08h， 以60%的产率得到乙苯妥英
  参考文献：
  名称：

  通过Tf 2 O介导的Boc保护的二肽化合物的双重活化合成高度取代的咪唑烷-2,4-二酮（乙内酰脲）

  摘要：

  高取代度的手性乙内酰脲很容易在温和的条件下一步一步由简单的二肽合成。该反应通过Tf 2 O-吡啶双重活化酰胺和叔丁氧羰基（Boc）保护基而进行。该方法已成功地用于制备多种生物活性化合物，包括药物类似物和天然产物。

  DOI：

  10.1021/ol502900j

文献信息

• BENZAZEPINE DERIVATIVE, PROCESS FOR PRODUCING THE SAME, AND USE
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP1422228A1

  公开（公告）日：2004-05-26

  The present invention provides a novel benzazepine derivative represented by formula : wherein, R1 is a 5- or 6-membered aromatic ring, R2 is lower alkyl group, etc., Y is an optionally substituted imino group, ring A and ring B are independently an optionally substituted aromatic ring, W is formula -W1-X2-W2- (W1 and W2 are independently S(O)m1 (m1 is 0, 1 or 2), etc., and X2 is an optionally substituted alkylene groupetc. ), a preparation method and use thereof.

  本发明提供了一种新型的苯并氮杂环衍生物，其由以下公式表示： 其中，R1是一个5-或6-成员的芳香环，R2是低级烷基团等，Y是可选地取代的亚氨基，环A和环B是独立地选自一个可选地取代的芳香环，W是公式-W1-X2-W2-（W1和W2是独立地为S(O)m1（m1是0、1或2）等，X2是一个可选地取代的亚烷基团等），其制备方法及其用途。
• 1-(2-PHENOXYMETHYLHETEROARYL)PIPERIDINE AND PIPERAZINE COMPOUNDS
  申请人：Stangeland Eric L.

  公开号：US20110230495A1

  公开（公告）日：2011-09-22

  The invention relates to compounds of formula I: where X, HAr, a, and R 1 through R 6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake inhibitors. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

  本发明涉及如下公式I的化合物： 其中X，HAr，a，以及R1至R6如说明书所述，或其药用可接受的盐。公式I的化合物是5-羟色胺和去甲肾上腺素再摄取抑制剂。本发明还涉及包含这些化合物的药物组合物；使用这些化合物的方法；以及制备这些化合物的方法和中间体。
• [EN] BUPRENORPHINE ANALOGS<br/>[FR] ANALOGUES DE BUPRÉNORPHINE
  申请人：PURDUE PHARMA LP

  公开号：WO2012038813A1

  公开（公告）日：2012-03-29

  The present invention is directed to Buprenorphine Analog compounds of the Formula (I), Formula (IA) or Formula (IB) shown below, wherein R1, R2, R8, R 3a, R 3b, G, X, Z and Y are as defined herein. Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors.

  本发明涉及如下所示的公式(I)、公式(IA)或公式(IB)的丁丙诺啡类似物化合物，其中R1、R2、R8、R 3a、R 3b、G、X、Z和Y的定义如本文所述。本发明的化合物可用于治疗疼痛、便秘以及通过阿片类和ORL-1受体的活性调节的其他状况。
• PYRIDINE AND PIPERIDINE DERIVATIVES AND USE THEREOF
  申请人：Purdue Pharma L.P.

  公开号：US20150141434A1

  公开（公告）日：2015-05-21

  The invention provides compounds that are useful as sodium channel blockers. In one aspect, the invention provides compounds of Formula I: or pharmaceutically acceptable salts, solvates, hydrates, or diastereomers thereof, wherein R 1 , R 4 , X, G, n, p, W 1 , W 2 , W 3 , W 4 , and the E ring are defined in the disclosure. In certain embodiments, the invention provides compounds of Formulae II-XIII as set forth supra. The invention also provides the use of compounds of any of the above discussed formulae to treat a disorder responsive to blockade of sodium channels. In one embodiment, Compounds of the Invention are useful for treating pain.

  本发明提供了一种用作钠通道阻断剂的化合物。在一方面，本发明提供了公式I的化合物： 或其药用可接受的盐、溶剂化物、水合物或对映异构体，其中R1、R4、X、G、n、p、W1、W2、W3、W4和E环在公开中定义。在某些实施例中，本发明提供了上述公式II-XIII的化合物。本发明还提供了使用上述任何讨论公式的化合物来治疗对钠通道阻断有反应的疾病。在一个实施例中，发明化合物用于治疗疼痛。
• 2,5-DIALKYL-4-H/HALO/ETHER-PHENOL COMPOUNDS
  申请人：Tansna Therapeutics Inc.

  公开号：US20150148430A1

  公开（公告）日：2015-05-28

  The present disclosure provides phenolic compounds useful in the treatment of neurological conditions such as convulsions and tremors, having the structure of Formula (I): wherein R 2 , R 4 , & R 5 , are as defined in the detailed description; pharmaceutical compositions comprising at least one of the compounds; and methods for treating neurological conditions.

  本公开提供用于治疗诸如惊厥和震颤等神经学状况的酚类化合物，其具有公式（I）的结构： 其中R2、R4和R5如详细描述中定义；包含至少一种该化合物的药物组合物；以及用于治疗神经学状况的方法。

表征谱图