N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-chloro-3-nitrobenzamide | 1207534-91-5

• 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: N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-chloro-3-nitrobenzamide
• CAS: 1207534-91-5
• 化学式: C₂₃H₁₇ClN₆O₃
• 分子量: 460.879
• InChiKey: WTXZNEGCSMESNF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  33.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  122.94
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为产物：
  描述：

  N-(2-甲基-5-硝基苯基)-4-(3-吡啶基)-2-嘧啶胺 在 platinum(IV) oxide 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 27.5h， 生成 N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-chloro-3-nitrobenzamide
  参考文献：
  名称：

  伊马替尼中间体和类似物合成的优化方法† ‡

  摘要：

  我们回顾了伊马替尼合成的经典合成方法，为制备一系列新的伊马替尼类似物提供了一种改进和优化的方法。所提出的方法有效地克服了某些有问题的步骤，节省了时间和劳力，提供了很高的产率和纯度，并具有用于合成许多类似物的潜力。所需胍盐4的形成，是伊马替尼合成的关键步骤之一，几乎是通过合适的苯胺3的盐酸盐与过量的熔融氰胺在没有任何溶剂的情况下反应而定量进行的。纯芳基胺中间体6a–d在亚当催化剂上用氢气将中间体嘧啶5a-d的硝基还原后，可以在很短的反应时间内定量获得。此外，这种优化方法的应用可以扩展到尼罗替尼及其类似物中间体的合成中。

  DOI：

  10.1039/c6ra09812f

文献信息

• <p>Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib</p>
  作者：Despoina Pantazi、Nikoleta Ntemou、Alexios Brentas、Dimitrios Alivertis、Konstantinos Skobridis、Alexandros D Tselepis

  DOI：10.2147/dddt.s211907

  日期：——

  Background: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy.Purpose: The objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties.Methods: Based on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I-IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed.Results: The novel analogues V-VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC50 values of 13.30 mu M and 3.91 mu M, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds.Conclusion: Our results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation.