三甲双酮 | 127-48-0

• 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: 三甲双酮
• 中文别名: 3,5,5-三甲基恶唑-2,4-二酮；三甲唑烷双酮；3,5,5-三甲基噁唑烷-2,4-二酮
• 英文名称: trimethadione
• 英文别名: 3,5,5-trimethyloxazolidine-2,4-dione；3,5,5-trimethyl-oxazolidine-2,4-dione；3,5,5-Trimethyl-oxazolidin-2,4-dion；3,5,5-trimethyl-1,3-oxazolidine-2,4-dione
• CAS: 127-48-0
• 化学式: C₆H₉NO₃
• mdl: MFCD00047084
• 分子量: 143.142
• InChiKey: IRYJRGCIQBGHIV-UHFFFAOYSA-N

物化性质

• 熔点：
  45-46°C
• 沸点：
  78-80°C 5mm
• 密度：
  1.3075 (rough estimate)
• 闪点：
  78-80°C/5mm
• 溶解度：
  易溶于水，极易溶于乙醇（96%）。
• 物理描述：
  Solid
• 保留指数：
  1080;1100

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  10
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.666
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

三甲双酮已知的人类代谢物包括二甲双酮。

Trimethadione has known human metabolites that include Dimethadione.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

Dione抗惊厥药通过抑制电压依赖性T型钙通道，减少丘脑神经元中的T型钙电流，包括丘脑中继神经元。这提高了丘脑重复活动的阈值，并抑制了皮层到丘脑的传递。因此，被认为是在失神发作时脑电图（EEG）上看到的3赫兹尖波和慢波放电基础的异常丘脑皮质节律性活动得到了抑制。

Dione anticonvulsants reduce T-type calcium currents in thalamic neurons, including thalamic relay neurons. It does so via the inhibition of voltage dependent T-type calcium channels. This raises the threshold for repetitive activity in the thalamus, and inhibits corticothalamic transmission. Thus, the abnormal thalamocortical rhythmicity, which is thought to underlie the 3-Hz spike-and-wave discharge seen on electroencephalogram(EEG) with absence seizures, is dampened.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

三甲双酮

Compound:trimethadione

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

严重程度等级：5

Severity Grade:5

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

安全信息

• 危险品标志：
  T
• 安全说明：
  S22,S36/37/39,S45,S53
• 危险类别码：
  R61
• WGK Germany：
  3
• RTECS号：
  RQ2100000
• 海关编码：
  2934999090
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P201,P280,P308+P313
• 危险品运输编号：
  2811
• 危险性描述：
  H312,H332,H360
• 储存条件：
  2-8℃

制备方法与用途

生物活性

Trimethadione（3,5,5-Trimethyloxazolidine-2,4-dione）是一种恶唑烷二酮类抗惊厥剂，广泛用于研究失神发作。此外，Trimethadione还是一种T型钙通道阻滞剂，并具有抗痛觉过敏作用。

反应信息

• 作为反应物：
  描述：

  三甲双酮 在 human liver microsomes 作用下， 以 various solvent(s) 为溶剂， 反应 0.33h， 生成 5,5-二甲基噁唑烷-2,4-二酮
  参考文献：
  名称：

  Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1

  摘要：

  1. Caucasian liver samples were used in this study. N-demethylation of trimethadione (TMO) to dimethadione (DMO) was monitored in the presence of chemical inhibitors of CYPs, such as fluconazole, quinidine, dimethyl-nitrosamine, acetaminophen, phenacetin, chlorzoxazone and mephenytoin. Trimethadione N-demethylation was selectively inhibited by dimethylnitrosamine and chlorzoxazone (> 50%) and weakly inhibited by tolbutamide (12 %) and fluconazole (22 %), whereas other inhibitors showed no effect. This result suggested that TMO metabolism to DMO is mainly mediated by CYP2E1 and marginally by CYP2C and CYP3A4.2. Fifteen human livers were screened and interindividual variability of TMO N-demethylation activity was 3-fold. Chlorzoxazone 6-hydroxylation activity was also measured and both activities were significantly correlated (r = 0.735, p < 0.01).3. DMO production by human cDNA expressed CYP enzymes was observed mainly for CYP2E1 (10.8 nmol/tube), marginally for CYP2C8 (0.22 nmol/tube) and not detectable for other CYP enzymes.4. These results indicate that TMO metabolism is primarily catalysed by CYP2E1 and that trimethadione would be a suitable selective probe drug for the estimation of human CYP2E1 activity in vivo.

  DOI：

  10.1080/004982598238930
• 作为产物：
  描述：

  3,5,5-trimethyl-oxazolidine-2,4-dione 2-[(1-phenyl-ethylidene)-hydrazone] 在 盐酸 作用下， 以 乙醇 为溶剂， 生成 三甲双酮
  参考文献：
  名称：

  Beyer,H.; Spoerl,R., Chemische Berichte, 1966, vol. 99, p. 2719 - 2724

  摘要：

  DOI：

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。
• [EN] HETEROCYCLIC COMPOUNDS AND THEIR USE AS RETINOID-RELATED ORPHAN RECEPTOR (ROR) GAMMA-T INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES ET LEUR UTILISATION EN TANT QU'INHIBITEURS GAMMA-T DU RÉCEPTEUR ORPHELIN APPARENTÉ AUX RÉCEPTEURS DES RÉTINOÏDES (ROR) )
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2016002968A1

  公开（公告）日：2016-01-07

  Provided are heterocyclic compounds having a RORγt inhibitory action represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.

  提供的是具有RORγt抑制作用的杂环化合物，其由公式(I)表示：其中每个符号如说明书中定义，或其盐。
• 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。

表征谱图