4-[(4-acetyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide | 1321600-77-4

• 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: 4-[(4-acetyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide
• 英文别名: 4-[(4-acetylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide
• CAS: 1321600-77-4
• 化学式: C₃₀H₃₁N₇O₂
• 分子量: 521.622
• InChiKey: HCSSWFKULPRADJ-UHFFFAOYSA-N

物化性质

• 密度：
  1.290±0.06 g/cm3(Predicted)
• 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
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  7

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 在 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.75h， 生成 4-[(4-acetyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide
  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

• [EN] HIGHLY PURE IMATINIB OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF<br/>[FR] IMATINIB DE GRANDE PURETÉ OU UN SEL PHARMACEUTIQUEMENT ACCEPTABLE DE CELUI-CI
  申请人：ACTAVIS GROUP PTC EHF

  公开号：WO2011095835A1

  公开（公告）日：2011-08-11

  Provided herein are impurities of imatinib, N-acetylpiperazine, N-acetylamino, N- chloromethylamino, formamide, 4-methylbenzamide and '2.24 RRt' impurities, and processes for the preparation and isolation thereof. Provided further herein is a highly pure imatinib or a pharmaceutically acceptable salt thereof substantially free of at least one, or two, or more, of the N-acetylpiperazine, N-acetylamino, N-chloromethylamino, formamide, 4-methylbenzamide, and '2.24 RRt' impurities, processes for the preparation, and pharmaceutical compositions comprising highly pure imatinib or a pharmaceutically acceptable salt thereof substantially free of impurities. Disclosed also herein is a process for preparing substantially pure α-form of imatinib mesylate.

  本文提供伊马替尼的杂质，包括N-乙酰哌嗪，N-乙酰氨基，N-氯甲基氨基，甲酰胺，4-甲基苯甲酰胺和'2.24 RRt'杂质，以及其制备和分离的方法。此外，本文还提供了一种高纯度的伊马替尼或其在药用上可接受的盐，基本上不含N-乙酰哌嗪，N-乙酰氨基，N-氯甲基氨基，甲酰胺，4-甲基苯甲酰胺和'2.24 RRt'杂质中的至少一个、两个或更多个，以及制备的方法，以及包含高纯度伊马替尼或其在药用上可接受的盐且基本上不含杂质的药物组合物。还公开了一种制备基本纯净的伊马替尼甲酸盐α型的方法。
• N-oxyde of n-phenyl-2-pyrimidine-amine derivatives
  申请人：Bornsen Olaf Klaus

  公开号：US20050209452A1

  公开（公告）日：2005-09-22

  The invention relates to N-phenyl-2-pyrimidine-amine derivatives in which at least one nitrogen atom carries an oxygen atom to form the corresponding N-oxides, to processes for the preparation thereof, to pharmaceutical compositions 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N-苯基-2-嘧啶胺衍生物，其中至少一个氮原子携带一个氧原子以形成相应的N-氧化物，以及制备这些化合物的过程，包括这些化合物的药物组成物和在制备温血动物，包括人类的治疗性药物组成物中的用途。
• N-OXIDES OF N-PHENYL-2-PYRIMIDINE-AMINE DERIVATIVES
  申请人：BORNSEN Klaus Olaf

  公开号：US20090239879A1

  公开（公告）日：2009-09-24

  The invention relates to N-phenyl-2-pyrimidine-amine derivatives derivatives in which at least one nitrogen atom carries an oxygen atom to form the corresponding N-oxides, to processes for the preparation thereof, to pharmaceutical compositions comprising those compounds, and to the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, including humans.

  该发明涉及N-苯基-2-嘧啶胺衍生物，其中至少有一个氮原子携带氧原子以形成相应的N-氧化物，以及其制备过程、包含这些化合物的制药组合物以及在制备治疗温血动物，包括人类的制药组合物时的使用。
• N-Oxides of n-Phenyl-2-pyrimidine-amine Derivatives
  申请人：Börnsen Klaus Olaf

  公开号：US20110294820A1

  公开（公告）日：2011-12-01

  The invention relates to N-phenyl-2-pyrimidine-amine derivatives derivatives in which at least one nitrogen atom carries an oxygen atom to form the corresponding N-oxides, to processes for the preparation thereof, to pharmaceutical compositions comprising those compounds, and to the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, including humans.

  该发明涉及N-苯基-2-嘧啶胺衍生物，其中至少一个氮原子携带氧原子以形成相应的N-氧化物，以及其制备方法、包含这些化合物的药物组合物和将其用于制备治疗温血动物，包括人类的药物组合物的用途。
• N-OXIDES OF N-PHENYL-2-PYRAMIDINE-AMINE DERIVATIVES
  申请人：Börnsen Klaus Olaf

  公开号：US20100222362A1

  公开（公告）日：2010-09-02

  The invention relates to N-phenyl-2-pyrimidine-amine derivatives derivatives in which at least one nitrogen atom carries an oxygen atom to form the corresponding N-oxides, to processes for the preparation thereof, to pharmaceutical compositions 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N-苯基-2-嘧啶胺衍生物，其中至少一个氮原子携带一个氧原子以形成相应的N-氧化物，其制备方法，包括这些化合物的药物组成物，以及在制备温血动物（包括人类）的治疗药物组成物中使用这些化合物的用途。