甲琥胺 | 77-41-8

• 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 - 吡咯烷类
• 中文名称: 甲琥胺
• 中文别名: 锡郎丁；1,3-二甲基-3-苯基-5-吡咯烷二酮
• 英文名称: methsuximide
• 英文别名: Methsuximid；N,α-Dimethyl-α-phenylsuccinimid；2-Methyl-2-phenyl-(N-methyl-succinimid)；Mesuximide；1,3-dimethyl-3-phenylpyrrolidine-2,5-dione
• CAS: 77-41-8
• 化学式: C₁₂H₁₃NO₂
• mdl: MFCD00072132
• 分子量: 203.241
• InChiKey: AJXPJJZHWIXJCJ-UHFFFAOYSA-N

物化性质

• 熔点：
  52-53°
• 沸点：
  bp0.1 121-122°
• 密度：
  1.1255 (rough estimate)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from dilute alcohol
• 气味：
  Odorless to slight odor
• 蒸汽压力：
  4.77X10-6 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Methsuximide has a relatively low melting range (50 to 56 °C or 122 to 133 °F). Improper storage may result in melting and subsequent impaired absorption of the capsule contents. /Methsuximide Capsules USP/
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/ .
• 保留指数：
  1597;1597;1595;1636.5;1591;1599;1615;1622

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.333
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

在服用极高剂量米托苏西米的病人中，有限的研究表明，米托苏西米通过N-去甲基化代谢为N-去甲基米托苏西米（NDM）。米托苏西米过量后出现的深度中枢神经系统抑制被认为是这种代谢物的结果，并且药物的抗惊厥效果可能来自NDM。米托苏西米过量可能呈现双相过程；病人在24小时内苏醒后又陷入昏迷。在一项对长期接受米托苏西米治疗的患者的研究中，NDM的血浆浓度是同期米托苏西米血浆浓度的700倍。基于这项研究，提出了一个暂定的治疗性血浆NDM浓度范围，为10-40微克/毫升；血浆NDM浓度超过40微克/毫升与毒性相关，并且有报道称血浆NDM浓度为150微克/毫升时出现昏迷。

Limited studies in patients who have taken extremely high doses of methsuximide and one study involving a small number of patients receiving methsuximide for the management of epilepsy indicate that the drug is metabolized via N-demethylation to N-demethylmethsuximide (NDM). Profound CNS depression following methsuximide overdosage has been attributed to this metabolite, and it is probable that the anticonvulsant effects of the drug result from NDM. Overdosage of methsuccimide may follow a biphasic course; patients have awakened and relapsed into coma within 24 hours. In one study in patients receiving methsuximide chronically, the plasma concentration of NDM was 700 times greater than the simultaneous plasma concentration of methsuximide. On the basis of this one study, a tentative therapeutic plasma NDM concentration of 10-40 ug/mL has been proposed; plasma NDM concentrations exceeding 40 ug/mL have been associated with toxicity and coma has been reported at plasma NDM concentrations of 150 ug/mL.

来源:Hazardous Substances Data Bank (HSDB)

代谢

甲琥胺及其主要代谢物2-甲基-2-苯基琥珀酰胺在一剂静脉给药后在犬体内的药代动力学进行了研究。甲琥胺的血药水平可以用双室开放模型描述，而代谢物的血药水平可以用单室开放模型描述。推导出了一个表达式，描述了甲琥胺给药后甲琥胺和代谢物血药水平。观察数据与模型预测的数据之间得到了很好的拟合。代谢物2-甲基-2-苯基琥珀酰胺占甲琥胺总消除的40%，且代谢物的半衰期（15小时）远大于母药（1-3.5小时）。结果表明，甲琥胺给药后的药理作用可能主要归因于代谢物，这种代谢物在重复给药期间可能会在体内积聚。

The pharmacokinetics of methsuximide and its major metabolite 2-methyl-2-phenylsuccinimide were studied in dogs after single intravenous doses. Plasma methsuximide levels were described by a two-compartment open model, and those of the metabolite were described by a one-compartment open model. An expression was derived that describes both methsuximide and metabolite plasma levels after methsuximide administration. Excellent fits were obtained between observed data and those predicted from the model. The metabolite, 2-methyl-2-phenylsuccinimide accounted for 40% of the overall elimination of methsuximide, and the half-life of the metabolite (15 hr) was much greater than that of the parent drug (1-3.5 hr). The results suggest that pharmacological effects after methsuximide administration may be due primarily to the metabolite, which may accumulate in the body during repeated doses.

来源:Hazardous Substances Data Bank (HSDB)

代谢

狗的肝脏微粒体酶代谢产生N-去甲基和對位羟基苯衍生物及其葡萄糖苷酸酯。

Metabolism by hepatic microsomal enzymes in dog yields n-demethyl & parahydroxyphenyl derivatives & their glucuronides. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给予狗口服1-2克甲琥酰胺后，从48小时尿液中分离出主要代谢物alpha-(对-羟基苯基)-alpha-甲基琥珀酰亚胺和N-甲基-alpha-(对-羟基苯基)-alpha-甲基琥珀酰亚胺，以及次要代谢物alpha-甲基-alpha-苯基琥珀酰亚胺。未发现母药。

Following oral admin of 1-2 g methsuximide to dogs, alpha-(p-hydroxyphenyl)-alpha-methylsuccinimide & n-methyl-alpha-(p-hydroxyphenyl)-alpha-methylsuccinimide isolated from 48 hr urine as major metab & alpha-methyl-alpha-phenylsuccinimide as minor. No parent drug found.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Metab, n-desmethylmethsuximide 在苯琥辛咪治疗的患者中的水平高于甲琥辛咪治疗的患者。血浆消除时间为32小时和1-2小时。

Metab, n-desmethylmethsuximide level higher in phensuximide than methsuximide treated patients. Plasma elimination was 32 & 1-2 hr.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

Methsuximide抑制与意识丧失相关的阵发性每秒三次的尖波和波形活动，这在失神（小发作）癫痫中很常见。癫痫样发作的频率降低了，这显然是通过抑制运动皮层和提高中枢神经系统对惊厥刺激的阈值来实现的。

Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

前瞻性研究表明，长期使用甲琥酰胺治疗并未伴随血清转氨酶水平的显著升高，尽管已在动物中显示出其具有肝毒性。临床上明显的甲琥酰胺肝毒性尚未有报道，尽管超敏反应伴有发热和皮疹并不少见（1%至5%）。甲琥酰胺的产品标签警告了肝功能障碍，并建议定期进行肝功能研究。尽管如此，如果真的发生，临床上明显的甲琥酰胺引起的肝损伤必须非常罕见。

Prospective studies suggest that chronic methsuximide therapy is not accompanied by significant elevations in serum aminotransferase levels, although it has been shown to have hepatotoxicity in animals. Clinically apparent hepatotoxicity from methsuximide has not been reported, although hypersensitivity reactions with fever and rash are not uncommon (1% to 5%). The product label for methsuximide warns of hepatic dysfunction and recommends periodic liver function studies. Nevertheless, clinically apparent liver injury from methsuximide must be very rare, if it occurs at all.

来源:LiverTox

毒理性

• 药物性肝损伤

甲琥胺

Compound:methsuximide

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

Methsuximide 从胃肠道吸收，血浆浓度在1-3小时内达到峰值。在一项研究中，单次服用600毫克Methsuximide后平均峰值血清浓度为3微克/毫升，单次服用1.2克Methsuximide后为6-7微克/毫升。

Methsuximide is absorbed from the GI tract and peak plasma concentrations are achieved in 1-3 hours. In one study, mean peak serum concentrations were 3 ug/mL following a single 600-mg dose and 6-7 ug/mL following a single 1.2-g dose of methsuximide.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Methsuximide is rapidly absorbed & metabolized. It is not bound significantly to plasma proteins. METHSUXIMIDE是一种治疗癫痫的药物，属于苯二氮䓬类药物。它主要通过肝脏代谢，可以迅速被吸收和代谢。此外，METHSUXIMIDE与血浆蛋白的结合率较低。

Methsuximide is rapidly absorbed & metabolized. It is not bound significantly to plasma proteins.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Methsuximide在给大鼠口服剂量后迅速分布到全身，并且它能自由地穿过血脑屏障。

Methsuximide is rapidly distributed throughout body after.../oral/ doses to rats, &.../it/ freely crosses blood-brain barrier.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

丁二酰亚胺抗惊厥药物可以自由分布到全身所有组织，除了脂肪。

Succinimide anticonvulsants are freely distributed to all body tissues, except fat.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2925190100
• WGK Germany：
  2
• 储存条件：
  Refrigerator

制备方法与用途

概述

甲琥胺属于二线抗癫痫药物，在其他抗癫痫药物无效时使用。然而，其疗效不佳且毒性反应较大，因此在临床中较少被采用。

用途

甲琥胺是一种琥珀酰亚胺类抗癫痫药，可用于治疗精神运动性发作，并可与其他抗癫痫药物联合使用。

反应信息

• 作为反应物：
  描述：

  甲琥胺 生成 (S)-Mesuximid
  参考文献：
  名称：

  Blaschke, Gottfried; Kraft, Horst Peter; Markgraf, Hildegunde, Chemische Berichte, 1983, vol. 116, # 11, p. 3611 - 3617

  摘要：

  DOI：
• 作为产物：
  描述：

  在 palladium on activated charcoal 、 2,9-二甲基-4,7二苯基-1,10-菲啰啉 、 氢气 、 氧气 、 copper (I) acetate 、 potassium carbonate 作用下， 以 丙酮 、 甲苯 为溶剂， 80.0 ℃ 、101.33 kPa 条件下， 生成 甲琥胺
  参考文献：
  名称：

  通过未活化的 C[双键，长度为 m-破折号]C 键断裂，铜催化烯烃束缚酰胺与 O2 的氧化：环状酰亚胺的直接方法。

  摘要：

  未活化烯烃通过 C[双键，长度为 m-dash]C 键双断裂的转化总是很有吸引力但非常具有挑战性。我们在此报告了一种化学选择性方法，通过未活化的 C[双键，长度为 m-dash]C 键的新型 Cu 催化的偕氨基氧化来制备有价值的环状酰亚胺。O2成功地用作氧化剂和O源，并通过C[双键，长度为m-dash]C键断裂结合到烯基酰胺中，用于有效制备琥珀酰亚胺或戊二酰亚胺衍生物。此外，该策略在简单条件下可用于生物活性化合物的后期修饰和药物合成，显示出潜在的应用前景。

  DOI：

  10.1039/c9sc03175h

文献信息

• 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。
• [EN] 2,3,5 TRISUBSTITUTED ARYL AND HETEROARYL AMINO DERIVATIVES, COMPOSITIONS, AND METHODS OF USE<br/>[FR] DÉRIVÉS AMINÉS D'HÉTÉROARYLE ET D'ARYLE 2,3,5 TRISUBSTITUÉS, COMPOSITIONS ET PROCÉDÉS D'UTILISATION ASSOCIÉS
  申请人：NEUROTHERAPEUTICS PHARMA INC

  公开号：WO2013059648A1

  公开（公告）日：2013-04-25

  Compounds are disclosed that have a formula represented by the following:(I) wherein Cy, L1 R1, R2a, R2b, R3, R4, n, and L2 are as described herein. These compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example addictive disorders, Alzheimer's Disease, anxiety disorders, ascites, autism, bipolar disorder, cancer, depression, endothelial corneal dystrophy, edema, epilepsy, glaucoma, Huntington's Disease, inflammatory pain, insomnia, ischemia, migraine, migraine with aura, migraine without aura, neuropathic pain, nociceptive neuralgia, nociceptive pain, ocular diseases, pain, itch, excessive itch, Pruritis, neuropathic pruritis, Parkinson's disease, personality disorders, postherpetic neuralgia, psychosis, schizophrenia, seizure disorders, tinnitus, and withdrawal syndromes.

  已披露具有以下表示的化合物的公式：(I)，其中Cy、L1、R1、R2a、R2b、R3、R4、n和L2如本文所述。这些化合物可以制备为药物组合物，并可用于预防和治疗包括人类在内的哺乳动物的各种疾病，例如成瘾障碍、阿尔茨海默病、焦虑障碍、腹水、自闭症、躁郁症、癌症、抑郁症、内皮角膜营养不良、水肿、癫痫、青光眼、亨廷顿病、炎症性疼痛、失眠、缺血、偏头痛、伴有先兆的偏头痛、无先兆的偏头痛、神经病性疼痛、伤害性神经痛、伤害性疼痛、眼部疾病、疼痛、瘙痒、过度瘙痒、瘙痒、神经性瘙痒、帕金森病、人格障碍、带状疱疹后神经痛、精神病、精神分裂症、癫痫障碍、耳鸣和戒断综合症等。

表征谱图