N-[4-amino-3-(trifluoromethyl)phenyl]-4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide | 1089725-67-6

• 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-amino-3-(trifluoromethyl)phenyl]-4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide
• CAS: 1089725-67-6
• 化学式: C₂₄H₁₉F₃N₆O
• 分子量: 464.45
• InChiKey: LSAHHDSMQJIPAK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-[4-amino-3-(trifluoromethyl)phenyl]-4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide 、 氯乙酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以43%的产率得到US8586600, III-14
  参考文献：
  名称：

  HETEROCYCLIC COMPOUNDS AND USES THEREOF

  摘要：

  本发明提供了化合物、药学上可接受的组合物以及使用它们的方法。

  公开号：

  US20080300268A1
• 作为产物：
  描述：

  3-氨基-4-甲基苯甲酸乙酯 在 盐酸 、 potassium carbonate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 丙醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 50.5h， 生成 N-[4-amino-3-(trifluoromethyl)phenyl]-4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide
  参考文献：
  名称：

  <p>Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib</p>

  摘要：

  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.

  DOI：

  10.2147/dddt.s211907

文献信息

• ALGORITHM FOR DESIGNING IRREVERSIBLE INHIBITORS
  申请人：Singh Juswinder

  公开号：US20100185419A1

  公开（公告）日：2010-07-22

  The invention is an algorithm and method for designing an inhibitor that covalently binds a target polypeptide. The algorithm and method can be used to rapidly and efficiently convert reversible inhibitors into irreversible inhibitors.

  这项发明是一种用于设计与靶多肽共价结合的抑制剂的算法和方法。该算法和方法可用于快速高效地将可逆抑制剂转化为不可逆抑制剂。
• US8242271B2
  申请人：——

  公开号：US8242271B2

  公开（公告）日：2012-08-14
• [EN] HETEROCYCLIC COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES ET UTILISATIONS DE CEUX-CI
  申请人：AVILA THERAPEUTICS INC

  公开号：WO2008151183A1

  公开（公告）日：2008-12-11

  [EN] The present invention provides compounds, pharmaceutically acceptable compositions thereof, and
  [FR] La présente invention concerne des composés, des compositions pharmaceutiquement acceptables d
• HETEROCYCLIC COMPOUNDS AND USES THEREOF
  申请人：SINGH Juswinder

  公开号：US20080300268A1

  公开（公告）日：2008-12-04

  The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

  本发明提供了化合物、药学上可接受的组合物以及使用它们的方法。
• &lt;p&gt;Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib&lt;/p&gt;
  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.