N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]-4-(1-piperazinylmethyl)benzamide methanesulphonate | 404844-03-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]-4-(1-piperazinylmethyl)benzamide methanesulphonate
• 英文别名: CGP 74588；N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide methanesulfonate；N-Desmethyl imatinib mesylate；methanesulfonic acid;N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]-4-(piperazin-1-ylmethyl)benzamide
• CAS: 404844-03-7
• 化学式: CH₄O₃S*C₂₈H₂₉N₇O
• 分子量: 575.692
• InChiKey: BRTOZFXRYMYSOF-UHFFFAOYSA-N

物化性质

• 熔点：
  140-150°C
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3.75
• 重原子数：
  41
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  158
• 氢给体数：
  4
• 氢受体数：
  10

制备方法与用途

生物活性方面，N-去甲伊马替尼甲磺酸盐（Norimatinib mesylate）是伊马替尼（HY-15463）的代谢物。伊马替尼是一种针对v-Abl、c-Kit和PDGFR等多个靶点的抑制剂。

反应信息

• 作为产物：
  描述：

  N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-氨基嘧啶 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 16.75h， 生成 N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]-4-(1-piperazinylmethyl)benzamide methanesulphonate
  参考文献：
  名称：

  The kinetic deuterium isotope effect as applied to metabolic deactivation of imatinib to the des-methyl metabolite, CGP74588

  摘要：

  There has recently been a burgeoning interest in impeding drug metabolism by replacing hydrogen atoms with deuterium to invoke a kinetic isotope effect. Imatinib, a front-line therapy for both chronic myeloid leukemia and of gastrointestinal stromal tumours, is often substantially metabolised via N-demethylation to the significantly less active CGP74588. Since deuterium-carbon bonds are stronger than hydrogen-carbon bonds, we hypothesised that the N-trideuteromethyl analogue of imatinib might be subject to a reduced metabolic turnover as compared to imatinib and lead to different pharmacokinetic properties, and hence improved efficacy, in vivo. Consequently, we investigated whether the N-trideuteromethyl analogue would maintain target inhibition and show a reduced propensity for N-demethylation in in vitro assays with liver microsomes and following oral administration to rats. The N-trideuteromethyl compound exhibited similar activity as a tyrosine kinase inhibitor as imatinib and similar efficacy as an antiproliferative in cellular assays. In comparison to imatinib, the trideuterated analogue also showed reduced N-demethylation upon incubation with both rat and human liver microsomes, consistent with a deuterium isotope effect. However, the reduced in vitro metabolism did not translate into increased exposure of the N-trideuteromethyl analogue following intravenous administration of the compound to rats and no significant difference was observed for the formation of the N-desmethyl metabolite from either parent drug. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.03.038

文献信息

• N-phenyl-2-pyrimidine-amine derivatives
  申请人：——

  公开号：US20040102453A1

  公开（公告）日：2004-05-27

  The invention relates to N-phenyl-2-pyrimidine-amine derivatives of formula (I) wherein the substituents are defined as indicated in the description, to processes for the preparation thereof, to medicaments comprising those compounds, and the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, including humans.

  这项发明涉及式（I）的N-苯基-2-嘧啶胺衍生物，其中取代基如描述中所示定义，以及其制备方法，包括这些化合物的药物、以及在制备用于治疗温血动物，包括人类的药物组合物中的应用。
• N-PHENYL-2-PYRIMIDINE-AMINE DERIVATIVES
  申请人：Buerger Michael Hans

  公开号：US20070265292A1

  公开（公告）日：2007-11-15

  The invention relates to N-phenyl-2-pyrimidine-amine derivatives of formula I wherein the substituents are defined as indicated in the description, to processes for the preparation thereof, to medicaments comprising those compounds, and to the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, including humans.

  本发明涉及式I的N-苯基-2-嘧啶胺衍生物，其中取代基如描述中所示，涉及其制备方法，包括这些化合物的药物，以及在制备治疗温血动物，包括人类的药物组合物的治疗中使用它们。
• N-phenyl-3-pyrimidine-amine derivatives
  申请人：Novartis AG

  公开号：US07329661B2

  公开（公告）日：2008-02-12

  The invention relates to N-phenyl-2-pyrimidine-amine derivatives of formula I wherein the substituents are defined as indicated in the description, to processes for the preparation thereof, to medicaments comprising those compounds, and to the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, including humans.

  本发明涉及化合物式I中的N-苯基-2-嘧啶胺衍生物，其中取代基如说明书中所示，以及其制备方法，包括这些化合物的药物和在制备治疗温血动物，包括人类的制药组合物的治疗用途。
• US7081532B2
  申请人：——

  公开号：US7081532B2

  公开（公告）日：2006-07-25
• US7329661B2
  申请人：——

  公开号：US7329661B2

  公开（公告）日：2008-02-12