1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde | 865443-86-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde
• 英文别名: 3-Methyl-2-oxo-1-propan-2-ylbenzimidazole-5-carbaldehyde
• CAS: 865443-86-3
• 化学式: C₁₂H₁₄N₂O₂
• 分子量: 218.255
• InChiKey: LKHNZCTUYBKGAX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde 、 Α-(对甲苯磺酰基)-4-氟苄基异腈 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 36.0h， 以11%的产率得到5-[4-(4-Fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-3-methyl-1,3-dihydrobenzoimidazol-2-one
  参考文献：
  名称：

  Theoretical and Experimental Design of Atypical Kinase Inhibitors:  Application to p38 MAP Kinase

  摘要：

  Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.

  DOI：

  10.1021/jm050346q
• 作为产物：
  描述：

  4-异丙基氨基-3-硝基苯甲酸甲酯 在 palladium on activated charcoal 、 四丁基氯化铵 、 碳酸氢钠 2,2,6,6-tetramethyl-piperidine-N-oxyl 、 N-氯代丁二酰亚胺 、 锂硼氢 、 氢气 、 sodium hydride 、 sodium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 二甲基亚砜 、 甲苯 为溶剂， 22.0~80.0 ℃ 、275.79 kPa 条件下， 反应 118.0h， 生成 1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde
  参考文献：
  名称：

  Theoretical and Experimental Design of Atypical Kinase Inhibitors:  Application to p38 MAP Kinase

  摘要：

  Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.

  DOI：

  10.1021/jm050346q

文献信息

• Theoretical and Experimental Design of Atypical Kinase Inhibitors:  Application to p38 MAP Kinase
  作者：Kim F. McClure、Yuriy A. Abramov、Ellen R. Laird、John T. Barberia、Weiling Cai、Thomas J. Carty、Santo R. Cortina、Dennis E. Danley、Alan J. Dipesa、Kathleen M. Donahue、Mark A. Dombroski、Nancy C. Elliott、Christopher A. Gabel、Seungil Han、Thomas R. Hynes、Peter K. LeMotte、Mahmoud N. Mansour、Eric S. Marr、Michael A. Letavic、Jayvardhan Pandit、David B. Ripin、Francis J. Sweeney、Douglas Tan、Yong Tao

  DOI：10.1021/jm050346q

  日期：2005.9.1

  Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.