4,7-Dimethyl-pyrazolo[5,1-c][1,2,4]triazine-3-carboxylic acid ((R)-9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-amide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4,7-Dimethyl-pyrazolo[5,1-c][1,2,4]triazine-3-carboxylic acid ((R)-9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-amide
• 英文别名: 4,7-dimethyl-N-[(11R)-6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl]pyrazolo[5,1-c][1,2,4]triazine-3-carboxamide
• 化学式: C₂₆H₂₃N₇O₂
• 分子量: 465.514
• InChiKey: UEBKNPRUAVIUGP-DEOSSOPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  35
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime 在 5percent Ru/C O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N-乙酰-D-苯丙氨酸 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 80.0 ℃ 、800.01 kPa 条件下， 反应 2.0h， 生成 4,7-Dimethyl-pyrazolo[5,1-c][1,2,4]triazine-3-carboxylic acid ((R)-9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-amide
  参考文献：
  名称：

  Synthesis, Structure−Activity Relationships, and Pharmacological Profile of 9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indoles:  Discovery of Potent, Selective Phosphodiesterase Type 4 Inhibitors

  摘要：

  The synthesis, structure-activity relationships, and biological properties of a novel series of; potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC50 values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNF alpha release from hPBMC and; hWB with IC50:values of 0.34 and 0.84 muM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED50 = 3.2 mg/kg po) and in production of TNF alpha in Wistar fats (ED50 = 2.8; mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.

  DOI：

  10.1021/jm000315p

文献信息

• DIAZEPINO-INDOLES INHIBITEURS DE PHOSPHODIESTERASES IV
  申请人：Pfizer

  公开号：EP0785789B1

  公开（公告）日：2002-09-11
• Synthesis, Structure−Activity Relationships, and Pharmacological Profile of 9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-<i>h</i><i>i</i>]indoles:  Discovery of Potent, Selective Phosphodiesterase Type 4 Inhibitors
  作者：Catherine Burnouf、Eric Auclair、Nadine Avenel、Bernadette Bertin、Christèle Bigot、Alain Calvet、Kam Chan、Corinne Durand、Veronique Fasquelle、Frédéric Féru、Richard Gilbertsen、Henry Jacobelli、Adel Kebsi、Emmanuelle Lallier、Jacquie Maignel、Brigitte Martin、Stéphane Milano、Malika Ouagued、Yves Pascal、Marie-Pierre Pruniaux、Jocelyne Puaud、Marie-Noëlle Rocher、Christophe Terrasse、Roger Wrigglesworth、Annette M. Doherty

  DOI：10.1021/jm000315p

  日期：2000.12.1

  The synthesis, structure-activity relationships, and biological properties of a novel series of; potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC50 values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNF alpha release from hPBMC and; hWB with IC50:values of 0.34 and 0.84 muM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED50 = 3.2 mg/kg po) and in production of TNF alpha in Wistar fats (ED50 = 2.8; mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.