4-[(4-methyl-3-oxo-1-piperazinyl)methyl]-benzoic acid | 571187-05-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-[(4-methyl-3-oxo-1-piperazinyl)methyl]-benzoic acid
• 英文别名: 4-[(4-Methyl-3-oxo-1-piperazinyl)methyl]benzoic acid；4-[(4-methyl-3-oxopiperazin-1-yl)methyl]benzoic acid
• CAS: 571187-05-8
• 化学式: C₁₃H₁₆N₂O₃
• mdl: MFCD20596229
• 分子量: 248.282
• InChiKey: SAMUFAQDDMPNPO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.384
• 拓扑面积：
  60.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[(4-methyl-3-oxo-1-piperazinyl)methyl]-benzoic acid 、 N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-氨基嘧啶 在 1-丙基磷酸酐 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 4-[(4-methyl-3-oxo-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
• 作为产物：
  描述：

  3-溴甲基苯甲酸 、 1-甲基哌嗪-2-酮 在 potassium carbonate 作用下， 以 乙醇 为溶剂， 反应 17.0h， 生成 4-[(4-methyl-3-oxo-1-piperazinyl)methyl]-benzoic acid
  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-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-pyrimidine-amine derivatives
  申请人：Novartis AG

  公开号：US07557105B2

  公开（公告）日：2009-07-07

  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，以及其制备过程，包括这些化合物的制药组合物，以及它们在制备治疗温血动物，包括人类的药物组合物中的用途。
• 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。