methyl (E)-3-(3-benzyl-4-oxo-3,4-dihydrospiro[benzo[e][1,3]oxazine-2,4'-piperidin]-6-yl)acrylate hydrochloride | 1192127-66-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: methyl (E)-3-(3-benzyl-4-oxo-3,4-dihydrospiro[benzo[e][1,3]oxazine-2,4'-piperidin]-6-yl)acrylate hydrochloride
• CAS: 1192127-66-4
• 化学式: C₂₃H₂₄N₂O₄*ClH
• 分子量: 428.915
• InChiKey: VDLHEBPYKODJFJ-VRTOBVRTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.41
• 重原子数：
  30.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  67.87
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  methyl (E)-3-(3-benzyl-4-oxo-3,4-dihydrospiro[benzo[e][1,3]oxazine-2,4'-piperidin]-6-yl)acrylate hydrochloride 在 盐酸 、 三乙酰氧基硼氢化钠 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 、 水 、 溶剂黄146 为溶剂， 反应 7.0h， 生成 (E)-3-{1'-methyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzooxaazine-2,4'-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-propenamide
  参考文献：
  名称：

  Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors

  摘要：

  Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.061
• 作为产物：
  描述：

  (E)-3-{1'-tert-butoxycarbonyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 4.0h， 以89%的产率得到methyl (E)-3-(3-benzyl-4-oxo-3,4-dihydrospiro[benzo[e][1,3]oxazine-2,4'-piperidin]-6-yl)acrylate hydrochloride
  参考文献：
  名称：

  Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors

  摘要：

  Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.061