1-(1-甲基乙基)-1H-苯并三唑-6-羧酸 | 467235-05-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并三唑类
• 中文名称: 1-(1-甲基乙基)-1H-苯并三唑-6-羧酸
• 英文名称: 3-isopropyl-3H-benzotriazole-5-carboxylic acid
• 英文别名: 3-propan-2-ylbenzotriazole-5-carboxylic acid
• CAS: 467235-05-8
• 化学式: C₁₀H₁₁N₃O₂
• 分子量: 205.216
• InChiKey: SCPIIACVIRPBIK-UHFFFAOYSA-N

物化性质

• 熔点：
  229-230°C
• 沸点：
  413.9±18.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  68
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险品标志：
  Xi

反应信息

• 作为反应物：
  描述：

  1-(1-甲基乙基)-1H-苯并三唑-6-羧酸 在 草酰氯 、 二异丁基氢化铝 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 22.5h， 生成 1-异丙基-1H-苯并[d][1,2,3]噻唑-5-甲醛
  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：

  3-氨基-4-(异丙基氨基)苯甲酸 在 盐酸 、 sodium nitrite 作用下， 反应 1.0h， 生成 1-(1-甲基乙基)-1H-苯并三唑-6-羧酸
  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

• Novel benzotriazoles anti-inflammatory compounds
  申请人：Pfizer Inc.

  公开号：US20030078432A1

  公开（公告）日：2003-04-24

  The present invention relates to novel benzotriazoles of the formula I 1 wherein Het is an optionally substituted 5-membered heterocycle containing one to two heteroatoms selected from nitrogen, sulfur and oxygen wherein at least one of said heteroatoms atoms must be nitrogen; R 2 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl or other suitable substituents; R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl or other suitable substituents; s is an integer from 0-5; to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, repurfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

  本发明涉及公式I的新型苯并三唑 其中Het是一个可选择取代的含有一个到两个来自氮、硫和氧的杂原子的5元杂环，其中至少一个杂原子必须是氮; R 2 选自由氢、(C 1 -C 6 )烷基或其他适当的取代基组成的群; R 3 选自由氢、(C 1 -C 6 )烷基或其他适当的取代基组成的群; s是0-5之间的整数; 用于它们的制备的中间体，含有它们的药物组合物以及它们的药用。本发明的化合物是MAP激酶，优选p38激酶的有效抑制剂。它们在治疗炎症、骨关节炎、类风湿性关节炎、癌症、中风或心脏病发作中的再灌注或缺血、自身免疫疾病和其他疾病中有用。
• Benzotriazoles anti-inflammatory compounds
  申请人：Pfizer Inc

  公开号：US06664395B2

  公开（公告）日：2003-12-16

  The present invention relates to novel benzotriazoles of the formula I wherein Het is an optionally substituted 5-membered heterocycle containing one to two heteroatoms selected from nitrogen, sulfur and oxygen wherein at least one of said heteroatoms atoms must be nitrogen; R2 is selected from the group consisting of hydrogen, (C1-C6)alkyl or other suitable substituents; R3 is selected from the group consisting of hydrogen, (C1-C6)alkyl or other suitable substituents; s is an integer from 0-5; to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, repurfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

  本发明涉及公式I的新型苯并三唑，其中Het是一种含有1-2个异原子（氮、硫和氧）的可选取代的5元杂环，其中至少一个异原子必须是氮；R2选自氢、（C1-C6）烷基或其他适当的取代基；R3选自氢、（C1-C6）烷基或其他适当的取代基；s是0-5的整数；以及制备它们的中间体、含有它们的制药组合物以及它们的药用用途。本发明的化合物是MAP激酶的强效抑制剂，优选为p38激酶。它们在治疗炎症、骨关节炎、类风湿性关节炎、癌症、中风或心脏病发作的再灌注或缺血、自身免疫性疾病和其他疾病方面有用。
• US6664395B2
  申请人：——

  公开号：US6664395B2

  公开（公告）日：2003-12-16
• 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.