7-(pyridin-2-ylmethoxy)-3-(pyridin-2-ylmethyl)-2H-benz[e]-1,3-oxazine-2,4(3H)-dione | 1415672-49-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 7-(pyridin-2-ylmethoxy)-3-(pyridin-2-ylmethyl)-2H-benz[e]-1,3-oxazine-2,4(3H)-dione
• 英文别名: 7-(Pyridin-2-ylmethoxy)-3-(pyridin-2-ylmethyl)-1,3-benzoxazine-2,4-dione；7-(pyridin-2-ylmethoxy)-3-(pyridin-2-ylmethyl)-1,3-benzoxazine-2,4-dione
• CAS: 1415672-49-9
• 化学式: C₂₀H₁₅N₃O₄
• 分子量: 361.357
• InChiKey: YKZQEGJVGRDESG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  81.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,4-二羟基苯甲酸 在 碳酸氢钠 、 caesium carbonate 作用下， 以 甲醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 3.5h， 生成 7-(pyridin-2-ylmethoxy)-3-(pyridin-2-ylmethyl)-2H-benz[e]-1,3-oxazine-2,4(3H)-dione
  参考文献：
  名称：

  Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines

  摘要：

  A number of new 2-(pyridin-3-ylamino)-4H-(substituted) benz[e]-1,3-oxazin-4-ones were synthesized 10a-g. These were then reacted with the hydro-halogen salt of 2, 3 and 4-(halo-methyl) pyridine in the presence of Cs2CO3 to give eighteen new 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11a-i, 13a-c, and 15a-f). X-ray crystallography was used to confirm that the 2-N-substituted structures 11 and 13 were formed rather than the 3-N-substitution analogues 12 and 14. Eleven of the new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active inhibitory compound was 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl) amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 10 +/- 2 mu M. DNA-dependent protein kinase (DNA-PK) inhibition data for 12 previously prepared 2-morpholino substituted-1,3-benzoxazines (compounds 19-31) were measured and showed high to moderate activity where the most active compound was compound 27 with an IC50 of 0.28 mu M. Furthermore DNA-PK inhibition data for six newly prepared 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11b), 13a-b, 15a-b and 15e) and 8-methyl-7-(pyridin-3-ylmethoxy)-3-(pyridin-3-ylmethyl)-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 17d were measured and moderate to low inhibitory activity was observed, with the most active of the compounds in this series being 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 2.5 mu M. PI3K inhibition studies revealed that compound 27 is highly potent (IC50 for PI3K alpha = 0.13 mu M, PI3K beta = 0.14 mu M, PI3K gamma = 0.72 mu M, PI3K delta = 2.02 mu M). Compound 22 with 7-[2-(4-methylpiperazin-1-yl)ethoxy] group shows greater inhibition of DNA-PK over PI3K.Docking of some 2-morpholino-substituted-1,3-benzoxazine compounds 19-31 within the binding pocket and structure activity relationships (SAR) analyses were performed with results agreeing well with observed activities. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.08.035

文献信息

• Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines
  作者：Saleh K. Ihmaid、Jasim M.A. Al-Rawi、Christopher J. Bradley、Michael J. Angove、Murray N. Robertson

  DOI：10.1016/j.ejmech.2012.08.035

  日期：2012.11

  A number of new 2-(pyridin-3-ylamino)-4H-(substituted) benz[e]-1,3-oxazin-4-ones were synthesized 10a-g. These were then reacted with the hydro-halogen salt of 2, 3 and 4-(halo-methyl) pyridine in the presence of Cs2CO3 to give eighteen new 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11a-i, 13a-c, and 15a-f). X-ray crystallography was used to confirm that the 2-N-substituted structures 11 and 13 were formed rather than the 3-N-substitution analogues 12 and 14. Eleven of the new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active inhibitory compound was 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl) amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 10 +/- 2 mu M. DNA-dependent protein kinase (DNA-PK) inhibition data for 12 previously prepared 2-morpholino substituted-1,3-benzoxazines (compounds 19-31) were measured and showed high to moderate activity where the most active compound was compound 27 with an IC50 of 0.28 mu M. Furthermore DNA-PK inhibition data for six newly prepared 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11b), 13a-b, 15a-b and 15e) and 8-methyl-7-(pyridin-3-ylmethoxy)-3-(pyridin-3-ylmethyl)-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 17d were measured and moderate to low inhibitory activity was observed, with the most active of the compounds in this series being 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 2.5 mu M. PI3K inhibition studies revealed that compound 27 is highly potent (IC50 for PI3K alpha = 0.13 mu M, PI3K beta = 0.14 mu M, PI3K gamma = 0.72 mu M, PI3K delta = 2.02 mu M). Compound 22 with 7-[2-(4-methylpiperazin-1-yl)ethoxy] group shows greater inhibition of DNA-PK over PI3K.Docking of some 2-morpholino-substituted-1,3-benzoxazine compounds 19-31 within the binding pocket and structure activity relationships (SAR) analyses were performed with results agreeing well with observed activities. (C) 2012 Elsevier Masson SAS. All rights reserved.