N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(pyridin-3-yl)phenoxy)acetamide | 1613167-89-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(pyridin-3-yl)phenoxy)acetamide
• 英文别名: N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-2-(4-pyridin-3-ylphenoxy)acetamide
• CAS: 1613167-89-7
• 化学式: C₂₇H₂₉F₃N₄O₂
• 分子量: 498.548
• InChiKey: UXNUQVZRIJPJBL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  57.7
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-(4-乙基哌嗪-1-甲基)-3-三氟甲基苯胺 、 2-(4-(pyridin-3-yl)phenoxy)acetic acid 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以5%的产率得到N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(pyridin-3-yl)phenoxy)acetamide
  参考文献：
  名称：

  Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells

  摘要：

  Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial structure activity relationship studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 and 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues. Kinase selectivity of these compounds is also presented.

  DOI：

  10.1021/acs.jmedchem.5b01712

文献信息

• [EN] COMPOUNDS INCLUDING MAP KINASE INTERACTING KINASES 1 AND 2 (MNK1 AND MNK2) MODULATORS AND ABL AND ABL (T315I) INHIBITORS, AND USES THEREOF<br/>[FR] COMPOSÉS COMPRENANT DES MODULATEURS DES KINASES INTERAGISSANT AVEC LES MAP KINASES 1 ET 2 (MNK1 ET MNK2) ET DES INHIBITEURS D'ABL ET ABL (T315I), ET LEURS UTILISATIONS
  申请人：AGENCY SCIENCE TECH & RES

  公开号：WO2014088519A1

  公开（公告）日：2014-06-12

  The present invention relates to certain piperazine-based compounds that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b and/or as ABL or ABL (T315I) inhibitors. The invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of cancer, inflammatory and Alzheimer disease conditions, as well as methods of treatment of these disorders.

  本发明涉及某些基于哌嗪的化合物，其作为MAP激酶相互作用激酶MNK2a、MNK2b、MNK1a和MNK1b的抑制剂，和/或作为ABL或ABL（T315I）抑制剂。本发明还涉及包含这些化合物的药物组合物，以及利用这些化合物制备用于预防和治疗癌症、炎症和阿尔茨海默病等疾病症状的药物的用途，以及治疗这些疾病的方法。
• Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells
  作者：Joseph Cherian、Kassoum Nacro、Zhi Ying Poh、Samantha Guo、Duraiswamy A. Jeyaraj、Yun Xuan Wong、Melvyn Ho、Hai Yan Yang、Joma Kanikadu Joy、Zekui Perlyn Kwek、Boping Liu、John Liang Kuan Wee、Esther HQ Ong、Meng Ling Choong、Anders Poulsen、May Ann Lee、Vishal Pendharkar、Li Jun Ding、Vithya Manoharan、Yun Shan Chew、Kanda Sangthongpitag、Sharon Lim、S. Tiong Ong、Jeffrey Hill、Thomas H. Keller

  DOI：10.1021/acs.jmedchem.5b01712

  日期：2016.4.14

  Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial structure activity relationship studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 and 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues. Kinase selectivity of these compounds is also presented.