7-(3H-benzimidazol-5-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine

• 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-(3H-benzimidazol-5-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine
• 化学式: C₁₆H₁₅N₃O
• 分子量: 265.315
• InChiKey: JZNHOBHWCWPHAD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  49.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  7-(3H-benzimidazol-5-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine 、 4-甲砜基苯甲酸 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 7-(1H-benzimidazol-6-yl)-4-{[4-(methylsulfonyl)phenyl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine
  参考文献：
  名称：

  Discovery of a Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)

  摘要：

  A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

  DOI：

  10.1021/jm3007933
• 作为产物：
  描述：

  4-bromo-2-[(2-hydroxyethyl)-iminomethyl]phenol 在 盐酸 、 sodium tetrahydroborate 、 正丁基锂 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 硼酸三异丙酯 、 偶氮二甲酸二异丙酯 、 三乙胺 、 三苯基膦 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙二醇二甲醚 、 水 为溶剂， 反应 6.5h， 生成 7-(3H-benzimidazol-5-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine
  参考文献：
  名称：

  Discovery of a Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)

  摘要：

  A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

  DOI：

  10.1021/jm3007933

文献信息

• Discovery of a Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)
  作者：Craig S. Takeuchi、Byung Gyu Kim、Charles M. Blazey、Sunghoon Ma、Henry W. B. Johnson、Neel K. Anand、Arlyn Arcalas、Tae Gon Baik、Chris A. Buhr、Jonah Cannoy、Sergey Epshteyn、Anagha Joshi、Katherine Lara、Matthew S. Lee、Longcheng Wang、James W. Leahy、John M. Nuss、Naing Aay、Ron Aoyama、Paul Foster、Jae Lee、Isabelle Lehoux、Narsimha Munagala、Arthur Plonowski、Sharmila Rajan、John Woolfrey、Kyoko Yamaguchi、Peter Lamb、Nicole Miller

  DOI：10.1021/jm3007933

  日期：2013.3.28

  A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.