2-methoxy-3-nitro-6-(piperidin-1-yl)pyridine | 526184-25-8

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 英文名称: 2-methoxy-3-nitro-6-(piperidin-1-yl)pyridine
• 英文别名: 6-methoxy-5-nitro-2-(piperidin-1-yl)pyridine；2-Methoxy-3-nitro-6-piperidin-1-ylpyridine
• CAS: 526184-25-8
• 化学式: C₁₁H₁₅N₃O₃
• 分子量: 237.258
• InChiKey: DOBMDZVXRYIZKB-UHFFFAOYSA-N

物化性质

• 沸点：
  419.5±45.0 °C(Predicted)
• 密度：
  1.243±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  71.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-methoxy-3-nitro-6-(piperidin-1-yl)pyridine 在 palladium on activated charcoal 、 氢气 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 异丙醇 为溶剂， 反应 6.0h， 生成 N-(2-((5-chloro-2-((2-methoxy-6-(piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide
  参考文献：
  名称：

  Dual potent ALK and ROS1 inhibitors combating drug-resistant mutants: Synthesis and biological evaluation of aminopyridine-containing diarylaminopyrimidine derivatives

  摘要：

  To identify ALK and ROS1 dual inhibitors conferring resistance to ALK secondary mutations, especially 'gatekeeper' L1196 M and the most predominant ceritinib-resistant G1202R mutations, a series of novel 2,4-diarylaminopyrimidine analogues were designed and synthesized by incorporating 2-alkoxy-6-alicyclic aminopyridinyl motifs. The biological evaluations on cellular and enzymatic assays led to identification of compound F-1, which turned out to be effective against ALK(WT), ROS1(WT), ALK(L1196M) and ALK(G1202R) kinases with IC50 of 2.1 nM, 2.3 nM, 1.3 nM and 3.9 nM, respectively, superior to crizotinib and ceritinib. Moreover, F-1 exhibited significant cytotoxicity on ALK-addicted Karpas299, H2228, and Ba/F3 cell expressing G1202R mutant, as well as ROS1-positive HCC78 cell with IC50 values ranging from 10 nM to 43 nM. Notably, F-1 was capable of suppressing phospho-ALK and its relative downstream signaling pathways, and eventually, inducing cell apoptosis in a dose-dependent manner in Karpas-299 cell. Together, F-1 is validated as a promising ALK/ROS1 dual inhibitor great potential for G1202R ALK mutation cancers. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.09.012
• 作为产物：
  描述：

  2,6-二氯-3-硝基吡啶 在 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 6.5h， 生成 2-methoxy-3-nitro-6-(piperidin-1-yl)pyridine
  参考文献：
  名称：

  Design, synthesis and biological evaluation N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD ‘head’ as potential ALK inhibitors

  摘要：

  Aiming to develop promising ALK inhibitors, two series of N-2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives (22a-x and 23a-d) were designed according to scaffold hopping and bioisosterism principles. All compounds were efficiently synthesized by concise reactions and anti-proliferative activities on ALK-addicted H2228, Karpas299 cells and EGFR-expressive A549 cell were evaluated by MTT assay. Several compounds exhibited potential cytotoxic activities with IC50 values below 0.10 mu M. Five compounds (22g, 22h, 22l, 22s and 23a) were selected for further enzymatic determination, resulting in the discovery of 22l against ALK and ALK(L1196M) with IC50 values of 2.1 nM and 3.8 nM. Particularly, western blot and cell apoptosis assays identified 22l as a promising ALK inhibitor, which was capable of obviously inhibiting cellular ALK activity and inducing cell apoptosis. Eventually, molecular docking modes of 22l with ALK confirmed structural basis in accordance with the SARs analysis.

  DOI：

  10.1016/j.bioorg.2018.09.019

文献信息

• Novel 2,5-diaminopyridine oxidation bases for the dyeing of keratin fibres
  申请人：——

  公开号：US20030163876A1

  公开（公告）日：2003-09-04

  Dyeing compositions for the dyeing of keratin fibres comprising at least one oxidation base chosen from formula (I), as defined herein and addition salts thereof. The use of the compositions for the dyeing of keratin fibres. Dyeing processes employing the compositions. Novel 2,5-diaminopyridine compounds and addition salts thereof and their use as oxidation bases.

  含有至少一种氧化碱的染色组合物，所述氧化碱选择自公式（I）中所定义的氧化碱及其盐。用于染色角蛋白纤维的组合物的使用。采用该组合物的染色过程。新型2,5-二氨基吡啶化合物及其盐以及它们作为氧化碱的用途。
• Nouvelles bases d'oxydation 2,5-diaminopyridine utiles pour la teinture des fibres kératiniques
  申请人：L'OREAL

  公开号：EP1312606A1

  公开（公告）日：2003-05-21

  L'invention a pour objet une composition tinctoriale utile pour la teinture des fibres kératiniques contenant une base d'oxydation du type 2,5-diaminopyridine, l'utilisation de cette composition pour la teinture des fibres kératiniques ainsi que le procédé de teinture mettant en oeuvre cette composition. L'invention a aussi pour objet des dérivés de 2,5-diaminopyridine de formule (I') suivante: dans laquelle Z'1 représente un radical OR'3 ou NR'4R'5; utiles comme base d'oxydation.

  本发明的目的是一种用于角蛋白纤维染色的染料组合物，其中含有一种 2,5-二氨基吡啶型氧化基，该组合物用于角蛋白纤维染色，以及使用该组合物的染色工艺。本发明还涉及下式（I'）的 2,5-二氨基吡啶衍生物： 其中 Z'1 代表 OR'3 或 NR'4R'5 基；可用作氧化碱。
• US6837908B2
  申请人：——

  公开号：US6837908B2

  公开（公告）日：2005-01-04
• Design, synthesis and biological evaluation N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD ‘head’ as potential ALK inhibitors
  作者：Lingyun Xing、Tongfei Jing、Junlong Zhang、Ming Guo、Xiuqi Miao、Feng Jiang、Xin Zhai

  DOI：10.1016/j.bioorg.2018.09.019

  日期：2018.12

  Aiming to develop promising ALK inhibitors, two series of N-2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives (22a-x and 23a-d) were designed according to scaffold hopping and bioisosterism principles. All compounds were efficiently synthesized by concise reactions and anti-proliferative activities on ALK-addicted H2228, Karpas299 cells and EGFR-expressive A549 cell were evaluated by MTT assay. Several compounds exhibited potential cytotoxic activities with IC50 values below 0.10 mu M. Five compounds (22g, 22h, 22l, 22s and 23a) were selected for further enzymatic determination, resulting in the discovery of 22l against ALK and ALK(L1196M) with IC50 values of 2.1 nM and 3.8 nM. Particularly, western blot and cell apoptosis assays identified 22l as a promising ALK inhibitor, which was capable of obviously inhibiting cellular ALK activity and inducing cell apoptosis. Eventually, molecular docking modes of 22l with ALK confirmed structural basis in accordance with the SARs analysis.
• Dual potent ALK and ROS1 inhibitors combating drug-resistant mutants: Synthesis and biological evaluation of aminopyridine-containing diarylaminopyrimidine derivatives
  作者：Ming Guo、Daiying Zuo、Junlong Zhang、Lingyun Xing、Wenfeng Gou、Feng Jiang、Nan Jiang、Dajun Zhang、Xin Zhai

  DOI：10.1016/j.ejmech.2018.09.012

  日期：2018.10

  To identify ALK and ROS1 dual inhibitors conferring resistance to ALK secondary mutations, especially 'gatekeeper' L1196 M and the most predominant ceritinib-resistant G1202R mutations, a series of novel 2,4-diarylaminopyrimidine analogues were designed and synthesized by incorporating 2-alkoxy-6-alicyclic aminopyridinyl motifs. The biological evaluations on cellular and enzymatic assays led to identification of compound F-1, which turned out to be effective against ALK(WT), ROS1(WT), ALK(L1196M) and ALK(G1202R) kinases with IC50 of 2.1 nM, 2.3 nM, 1.3 nM and 3.9 nM, respectively, superior to crizotinib and ceritinib. Moreover, F-1 exhibited significant cytotoxicity on ALK-addicted Karpas299, H2228, and Ba/F3 cell expressing G1202R mutant, as well as ROS1-positive HCC78 cell with IC50 values ranging from 10 nM to 43 nM. Notably, F-1 was capable of suppressing phospho-ALK and its relative downstream signaling pathways, and eventually, inducing cell apoptosis in a dose-dependent manner in Karpas-299 cell. Together, F-1 is validated as a promising ALK/ROS1 dual inhibitor great potential for G1202R ALK mutation cancers. (C) 2018 Elsevier Masson SAS. All rights reserved.