2-(2,6-dichloropyrimidin-4-yl)-1-(3-methoxy-5-methylphenyl)ethanone | 1188271-29-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(2,6-dichloropyrimidin-4-yl)-1-(3-methoxy-5-methylphenyl)ethanone
• CAS: 1188271-29-5
• 化学式: C₁₄H₁₂Cl₂N₂O₂
• 分子量: 311.167
• InChiKey: FOOKERAQXCVAEX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  52.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(2,6-dichloropyrimidin-4-yl)-1-(3-methoxy-5-methylphenyl)ethanone 在 bis-triphenylphosphine-palladium(II) chloride potassium carbonate 作用下， 以 四氢呋喃 、 水 、 丙酮 、 乙腈 为溶剂， 反应 42.0h， 生成 [4-[6-(2(S)-hydroxypropylamino)-2-pyridin-3-yl-pyrimidin-4-yl]-3-(3-methoxy-5-methylphenyl)-pyrazol-1-yl]acetonitrile
  参考文献：
  名称：

  PYRAZOLE COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST ROS KINASE

  摘要：

  本文披露了新型吡唑化合物，其药用盐，其制备方法，以及作为抗癌剂的用途。

  公开号：

  US20110015395A1
• 作为产物：
  描述：

  3-羟基-5-甲基苯甲酸 在 4-二甲氨基吡啶 potassium carbonate 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 36.0h， 生成 2-(2,6-dichloropyrimidin-4-yl)-1-(3-methoxy-5-methylphenyl)ethanone
  参考文献：
  名称：

  PYRAZOLE COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST ROS KINASE

  摘要：

  本文披露了新型吡唑化合物，其药用盐，其制备方法，以及作为抗癌剂的用途。

  公开号：

  US20110015395A1

文献信息

• ＲＯＳ 카이네이즈 저해활성을 갖는 2,4,6-삼치환된 피리미딘 화합물
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY 한국과학기술연구원(319980077518) BRN ▼209-82-03522

  公开号：KR101556317B1

  公开（公告）日：2015-10-01

  본 발명은 신규 2,4,6-삼치환된 피리미딘 화합물과 약제학적으로 허용 가능한 이의 염, 이 화합물의 제조방법, 그리고 이 화합물을 항암제로 사용하는 의약용도에 관한 것이다. 본 발명에 따른 신규 화합물들은 ROS 카이네이즈 엔자임에 대하여 매우 우수한 활성을 가지고 있으므로 뇌암, CNS 관련 암, 수막종 (meningiomas)과 역형성별 세포종 (astrocytomas), 다형성 교모세포종 (glioblastoma multiforme), 비소세포성 폐암 (NSCLC) 등의 질환을 치료 및 예방하는 항암제로 유용하다.

  This is the Chinese translation of the text you provided: 该发明涉及新型2,4,6-三取代嘧啶化合物及其药学上可接受的盐，该化合物的制备方法，以及将该化合物用作抗癌药物的药用用途。根据本发明，这些新型化合物对ROS激酶酶表现出非常优异的活性，因此对治疗和预防脑癌、与中枢神经系统相关的癌症、脑膜瘤（meningiomas）和星形胶质细胞瘤（astrocytomas）、多形性胶质母细胞瘤（glioblastoma multiforme）、非小细胞肺癌（NSCLC）等疾病具有用处。
• Design, synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor
  作者：Byung Sun Park、Ibrahim M. El-Deeb、Kyung Ho Yoo、Chang-Hyun Oh、Seung Joo Cho、Dong Keun Han、Hye-Seung Lee、Jae Yeol Lee、So Ha Lee

  DOI：10.1016/j.bmcl.2009.06.066

  日期：2009.8

  ROS1 protein is a receptor tyrosine kinase that has been reported mainly in meningiomas and astrocytomas, and until now, there is no selective inhibitor for this kinase. In this study, we illustrate for the synthesis of a highly potent and selective inhibitor for ROS1 kinase. The synthesized compound 1 was tested initially at a single dose concentration of 10 mu M over 45 different kinases. At this concentration, a 94% inhibition of the enzymatic activity of ROS1 kinase was observed, while the inhibition in activity was below 30% in all of the other kinases. The pyrazole compound 1 was further tested in a 10-dose IC50 mode and showed an IC50 value of 199 nM for ROS1 kinase. The compound 1 can be used as a promising lead for the development of new selective inhibitors for ROS1 kinase, and it may open the way for new selective therapeutics for astrocytomas. (C) 2009 Elsevier Ltd. All rights reserved.
• Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors
  作者：Ahmed Z. Abdelazem、Mohammad M. Al-Sanea、Byung Sun Park、Hye Mi Park、Kyung Ho Yoo、Taebo Sim、Jong Bae Park、Seung-Hoon Lee、So Ha Lee

  DOI：10.1016/j.ejmech.2014.11.023

  日期：2015.1

  With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silica modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Synthesis and biological evaluation of new pyrimidine-4-yl-ethanol derivatives as ROS1 kinase inhibitors
  作者：Ahmed Z. Abdelazem、So Ha Lee

  DOI：10.3109/14756366.2014.920838

  日期：2015.3.4

  As a part of trials to target ROS1 kinase with potential inhibitors, a novel series of pyrimidin-4-ylethanol and ethanone derivatives (4a-f, 5a-f, 6a-f and 7a-f) have been designed based on previously discovered lead compounds KIST301072 and KIST301080, and synthesized on 4-5 steps according to compounds. The structures of the newly synthesized compounds have been confirmed on H-1-NMR, C-13-NMR and IR. Most of the tested compounds showed ROS1 kinase inhibitory activity in micromolar range.
• Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors
  作者：Byung Sun Park、Mohammad M. Al-Sanea、Ahmed Z. Abdelazem、Hye Mi Park、Eun Joo Roh、Hyun-Mee Park、Kyung Ho Yoo、Taebo Sim、Jin Sung Tae、So Ha Lee

  DOI：10.1016/j.bmc.2014.06.020

  日期：2014.8

  Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC₅₀ values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC₅₀ values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC₅₀=13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value=0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM.