N-Hydroxy-Mexiletine | 55304-17-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-Hydroxy-Mexiletine
• 英文别名: rac-N-[1-(2,6-dimethylphenoxy)propan-2-yl]hydroxylamine；(RS)-1-(2,6-dimethylphenoxy)-N-hydroxypropan-2-amine；1-(2,6-Dimethylphenoxy)-N-hydroxy-2-propanamine；N-[1-(2,6-dimethylphenoxy)propan-2-yl]hydroxylamine
• CAS: 55304-17-1
• 化学式: C₁₁H₁₇NO₂
• 分子量: 195.261
• InChiKey: ABMUWCMGKRQAIK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  41.5
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

N-羟基美西律已知的人类代谢物包括(2S,3S,4S,5R)-6-[1-(2,6-二甲基苯氧基)丙烷-2-基氨基]氧基-3,4,5-三羟基氧杂环己烷-2-羧酸。

N-hydroxy-mexiletine has known human metabolites that include (2S,3S,4S,5R)-6-[1-(2,6-dimethylphenoxy)propan-2-ylamino]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  美西律 生成 N-Hydroxy-Mexiletine
  参考文献：
  名称：

  1-芳基异丙基胺的伯和仲羟胺的旋光异构体的合成路线

  摘要：

  许多光学纯的初级1- arylisopropylamines的通过用相应的benzylimines的氧化转化为3-苯基-2-（1'-arylisopropyl）氧氮环丙烷米氯过苯甲酸。随后3-苯基氧氮丙啶的酸水解产生了光学纯的N-羟基-1-芳基异丙基胺。的作用米氯过苯甲酸对旋光纯的次要1- arylisopropylamines得到光学纯的N-羟基衍生物。通过使用N-三氟乙酰基-1-脯氨酰氯作为试剂的GLC分析羟胺的光学纯度。

  DOI：

  10.1016/0040-4020(75)87006-2

文献信息

• Addition of HO-Acids to <i>N</i> ,<i>N</i> -Bis(oxy)enamines: Mechanism, Scope and Application to the Synthesis of Pharmaceuticals
  作者：Yana A. Naumovich、Ivan S. Golovanov、Alexey Yu. Sukhorukov、Sema L. Ioffe

  DOI：10.1002/ejoc.201701266

  日期：2017.11.9

  calculations revealed that solvent affects the reaction pathway. In basic solvents (DMF, NMP, DMSO), N,N-bis(oxy)enamines were converted into nitrosoalkenes by a Lewis base promoted process followed by oxy-Michael addition of the HO-acid. In non-polar solvents (toluene, CH2Cl2), the reaction occurs by an acid-promoted SN′ substitution of the N-oxy-group via a highly reactive N-vinyl-N-alkoxynitrenium species.

  已发现将 HO-酸添加到 N,N-双（氧）烯胺中活化的 π 键的区域选择性极大地取决于溶剂。机理研究和量子化学计算表明，溶剂会影响反应途径。在碱性溶剂（DMF、NMP、DMSO）中，N,N-双（氧）烯胺通过路易斯碱促进的过程转化为亚硝基烯烃，然后是 H2O 酸的氧迈克尔加成。在非极性溶剂（甲苯、CH2Cl2）中，反应通过酸促进的 N-氧基团的 SN' 取代通过高反应性的 N-乙烯基-N-烷氧基硝基物质发生。基于这些研究，开发了使用现成的 N，N-双（氧）烯胺对各种 HO-酸（羧酸、酚类、异羟肟酸、磷酸和磺酸）进行肟基烷基化的通用和有效方案。这些方法被证明适用于带有酸性 OH 基团（如甾体激素、胆汁酸、受保护的氨基酸和肽）和配体 (BINOL) 的天然分子的后修饰。所得α-羟基肟被证明是有价值的1,2-氨基醇或1,2-羟基氨基醇衍生物的有用前体，包括抗心律失常药物美西律和有效的基质金属蛋白酶抑制剂。
• Role of specific cytochrome P450 enzymes in the N-oxidation of the antiarrhythmic agent mexiletine
  作者：L. LabbÈ、Z. Abolfathi、È. Lessard、H. Pakdel、P. Beaune、J. Turgeon

  DOI：10.1080/0049825021000017948

  日期：2003.1

  1. Mexiletine is extensively metabolized in man by C- and N-oxidation and the aim of the present study was to characterize major cytochrome P450 enzyme(s) involved in the formation of N-hydroxymexiletine.2. Incubations with genetically engineered microsomes indicated that the formation rate of N-hydroxymexiletine was highest in the presence of microsomes expressing high levels of either CYP1A2 or CYP2E1 and the formation of N-hydroxymexiletine by human liver microsomes was inhibited about 40% by antibodies directed against CYP1A1/1A2 or CYP2E1. Additional incubations demonstrated that formation of N-hydroxymexiletine was decreased 47 and 51% by furafylline, 40 muM and 120 muM, respectively, and decreased 55 and 67% by alpha-naphthoflavone, 1 muM and 3 muM, respectively (all p<0.05 versus control).3. The formation rate of N-hydroxymexiletine in human liver microsomes was highly correlated with CYP2B6 (RS-mexiletine, r=0.7827; R-(-)-enantiomer, r=0.7034; S-(+)-enantiomer, r=0.7495), CYP2E1 (S-(+)-enantiomer, r=0.7057) and CYP1A2 (RS-mexiletine, r=0.5334; S-(+)-enantiomer, r=0.6035).4. In conclusion, we have demonstrated that CYP1A2 is a major human cytochrome P450 enzyme involved in the formation of N-hydroxymexiletine. However, other cytochrome P450 enzymes (CYP2E1 and CYP2136) also appear to play a role in the N-oxidation of this drug.