7-hydroxy-2-thioxo-2,3-dihydro-4H-1,3-benz[e]-1,3-oxazin-4-one

• 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-hydroxy-2-thioxo-2,3-dihydro-4H-1,3-benz[e]-1,3-oxazin-4-one
• 英文别名: 7-hydroxy-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one；7-Hydroxy-2-sulfanylidene-1,3-benzoxazin-4-one
• 化学式: C₈H₅NO₃S
• 分子量: 195.199
• InChiKey: PLMBOAIOWHYHOL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  90.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-hydroxy-2-thioxo-2,3-dihydro-4H-1,3-benz[e]-1,3-oxazin-4-one 在 碳酸氢钠 、 caesium carbonate 作用下， 以 甲醇 、 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
• 作为产物：
  描述：

  diisothiocyanato(triphenyl)-λ5-phosphane 、 2,4-二羟基苯甲酸 以 二氯甲烷 为溶剂， 以90%的产率得到7-hydroxy-2-thioxo-2,3-dihydro-4H-1,3-benz[e]-1,3-oxazin-4-one
  参考文献：
  名称：

  使用三苯基膦硫氰从 2-（羟基、硫代或氨基）芳香酸生产 1,3-苯并恶嗪、1,3-苯并噻嗪和喹唑啉衍生物的通用方法

  摘要：

  摘要 开发了一种改进的一锅法合成 1,3-苯并恶嗪，其中省略了不稳定硫氰的制备。发现该方法适用于取代（甲基、甲氧基、卤素和羟基）2-羟基苯甲酸和 2-羟基萘甲酸。该方法扩展到 2-硫代、2-氨基和 N-甲基氨基苯甲酸，分别实现了 1,3-苯并噻嗪和喹唑啉衍生物的合成。还发现使用改进方法的 3-羟基吡啶-2-羧酸和 2-羟基烟酸得到 2-硫代-2,3-二氢-4H-吡啶并[2,3-e][1,3]恶嗪-分别为 4-one 和 2-thioxo-2,3-dihydro-4H-pyrido[3,2-e][1,3]oxazin-4-one。新化合物的结构通过其 IR、1H 和 13C NMR 光谱的分析得到证实。

  DOI：

  10.1081/scc-200061564

文献信息

• Synthesis, toxicity and chemo-sensitization of HeLa cells to etoposide, of some 2-methyl amino acid ester-substituted-1,3-benzoxazines
  作者：Saleh K. Ihmaid、Cheree Fitzgibbon、Jasim M. A. Al-Rawi

  DOI：10.1007/s00044-015-1338-4

  日期：2015.7

  A number of new L- or LD-2-amino acid ester-(substituted)-benz[1,3]oxazines 12-17 were synthesized from the reaction of free L- or LD-amino acid ester 9a-d with 2-methylthio-1,3-benzoxazines 11a-g. The structures of the new products 12-17 were confirmed from their H-1, (CNMR)-C-13 and IR spectra and CHN microanalysis. Some of these compounds weakly inhibited DNA-PK and platelet aggregation. Studies of the toxicity for some of the new compounds showed mostly no inhibitory effects on HeLa cell growth at 1 and 10 A mu M and some up to 40 A mu M. The chemo-sensitization to etoposide by some of the compounds revealed that the most effective chemo-sensitizers at 10 A mu M were 14c (1.83 fold), 12e (1.42 fold), 15a (0.8 fold), 16d (0.76 fold) and 1c (0.74). However, at 1 A mu M in the presence of etoposide, some compounds were shown to be more effective. No direct link was observed between the type of the L-amino acid methyl ester as well as the 7-, 8-, or 7, 8-substitution on the aromatic ring on the effectiveness of the chemo-sensitizers; however, the 7-hydroxy group did lower the effective chemo-sensitizers values.
• Synthesis, structural elucidation and DNA-dependant protein kinase and antiplatelet studies of 2-amino-[5, 6, 7, 8-mono and 7, 8-di-substituted]-1,3-benzoxazines
  作者：Saleh Ihmaid、Jasim Al-Rawi、Christopher Bradley

  DOI：10.1016/j.ejmech.2010.07.066

  日期：2010.11

  A number of new 2-amino-[5, 6, 7 and 8]-O-substituted 1,3-benzoxazines, and 2-amino 8-methyl-7-O-substituted-1,3-benzoxazines were synthesized. Thirty one new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active compounds were 8-methyl-2-morpholin-4-yl-7-(pyridin-3-ylmethoxy)-4H-1,3-benzoxazin-4-one 9f and 8-methyl-2-morpholin-4-yl-7-(pyridin-4-ylmethoxy)-4H-1,3-benzoxazin-4-one 9j with IC(50) = 2 +/- 1.5 and 4 +/- 2 mu M respectively. Inhibition of DNA-PK activity at concentrations of 1.6-4 mu M were tested for 9 products 5i, 7a-e and 9b, 9f and 9j. Crown Copyright (C) 2010 Published by Elsevier Masson SAS. All rights reserved.
• Synthesis, identification and antiplatelet evaluation of 2-morpholino substituted benzoxazines
  作者：Kaylene M. Pritchard、Jasim Al-Rawi、Christopher Bradley

  DOI：10.1016/j.ejmech.2007.01.021

  日期：2007.9

  A number of 2-morpholino substituted benzoxazines have been prepared in order to test their effectiveness against ADP and collagen induced platelet aggregation. The reaction of 2-thio-1,3-benzoxazines with morpholine has been generalised to enable the use of substituted benzoxazines. Two separate methods were used to prepare 7-O-2-morpholino substituted benzoxazines from 7-hydroxy-2-morpholino benzoxazines. Antiplatelet testing was carried out on 15 of the title compounds. 7-(2-Chloroethoxy)-8-methyl-2-morpholin-4-yl-4H-1,3-benzoxazin-4-one 15d and 7-[2-(4-methylpiperazin-1-yl)ethoxy]-8-methyl-2-morpholin-4-yl-4H-1,3-benzoxazin-4-one 16d showed potent activity against ADP and collagen induced platelet aggregation. The structures of the newly prepared compounds were confirmed by microanalysis as well as the analysis of IR, H-1 and C-13 NMR. (c) 2007 Elsevier Masson SAS. All rights reserved.
• Generalized Method for the Production of 1,3‐Benzoxazine, 1,3‐Benzothiazine, and Quinazoline Derivatives from 2‐(Hydroxy, Thio, or Amino) Aromatic Acids Using Triphenylphosphine Thiocyanogen
  作者：Kaylene M. Pritchard、Jasim M. Al‐Rawi、Andrew B. Hughes

  DOI：10.1081/scc-200061564

  日期：2005.6.1

  derivatives has been achieved, respectively. It was also found that 3‐hydroxypyridine‐2‐carboxylic acid and 2‐hydroxynicotinic acid using a modified method gave 2‐thioxo‐2,3‐dihydro‐4H‐pyrido[2,3‐e][1,3]oxazin‐4‐one and 2‐thioxo‐2,3‐dihydro‐4H‐pyrido[3,2‐e][1,3]oxazin‐4‐one, respectively. The structures of the new compounds were confirmed by the analysis of their IR, 1H, and 13C NMR spectra.

  摘要 开发了一种改进的一锅法合成 1,3-苯并恶嗪，其中省略了不稳定硫氰的制备。发现该方法适用于取代（甲基、甲氧基、卤素和羟基）2-羟基苯甲酸和 2-羟基萘甲酸。该方法扩展到 2-硫代、2-氨基和 N-甲基氨基苯甲酸，分别实现了 1,3-苯并噻嗪和喹唑啉衍生物的合成。还发现使用改进方法的 3-羟基吡啶-2-羧酸和 2-羟基烟酸得到 2-硫代-2,3-二氢-4H-吡啶并[2,3-e][1,3]恶嗪-分别为 4-one 和 2-thioxo-2,3-dihydro-4H-pyrido[3,2-e][1,3]oxazin-4-one。新化合物的结构通过其 IR、1H 和 13C NMR 光谱的分析得到证实。
• 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.