methyl 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine-8-carboxylate 4,4-dioxide | 1426683-38-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: methyl 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine-8-carboxylate 4,4-dioxide
• 英文别名: Methyl 1,5-dimethyl-4,4-dioxopyrazolo[4,3-c][2,1]benzothiazine-8-carboxylate；methyl 1,5-dimethyl-4,4-dioxopyrazolo[4,3-c][2,1]benzothiazine-8-carboxylate
• CAS: 1426683-38-6
• 化学式: C₁₃H₁₃N₃O₄S
• 分子量: 307.33
• InChiKey: NSXFENUFULOSEG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  89.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine-8-carboxylate 4,4-dioxide 在 lithium aluminium tetrahydride 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 (1,5-dimethyl-4,4-dioxido-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-yl)methylmethanesulfonate
  参考文献：
  名称：

  Structure-based discovery of cellular-active allosteric inhibitors of FAK

  摘要：

  In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[ 4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50 = 0.64 mu M) and in cellular assays (IC50 = 7.1 mu M). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.01.047
• 作为产物：
  描述：

  dimethyl 4-[methyl(methylsulfonyl)amino]isophthalate 在 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 6.0h， 生成 methyl 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine-8-carboxylate 4,4-dioxide
  参考文献：
  名称：

  Structure-based discovery of cellular-active allosteric inhibitors of FAK

  摘要：

  In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[ 4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50 = 0.64 mu M) and in cellular assays (IC50 = 7.1 mu M). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.01.047

文献信息

• Structure-based discovery of cellular-active allosteric inhibitors of FAK
  作者：Naoki Tomita、Yoko Hayashi、Shinkichi Suzuki、Yoshimasa Oomori、Yoshio Aramaki、Yoshihiro Matsushita、Misa Iwatani、Hidehisa Iwata、Atsutoshi Okabe、Yoshiko Awazu、Osamu Isono、Robert J. Skene、David J. Hosfield、Hiroshi Miki、Tomohiro Kawamoto、Akira Hori、Atsuo Baba

  DOI：10.1016/j.bmcl.2013.01.047

  日期：2013.3

  In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[ 4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50 = 0.64 mu M) and in cellular assays (IC50 = 7.1 mu M). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents. (C) 2013 Elsevier Ltd. All rights reserved.