1-[4-(2-aminopyrimidin-5-yl)phenyl]-N-hydroxy-3,3-dimethylcyclobutanecarboxamidine | 1361189-50-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1-[4-(2-aminopyrimidin-5-yl)phenyl]-N-hydroxy-3,3-dimethylcyclobutanecarboxamidine
• 英文别名: 1-[4-(2-aminopyrimidin-5-yl)phenyl]-N'-hydroxy-3,3-dimethylcyclobutane-1-carboximidamide
• CAS: 1361189-50-5
• 化学式: C₁₇H₂₁N₅O
• 分子量: 311.387
• InChiKey: QQBHPXJETZKDJD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  110
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-甲基吡唑-4-羧酸 、 1-[4-(2-aminopyrimidin-5-yl)phenyl]-N-hydroxy-3,3-dimethylcyclobutanecarboxamidine 在 N,N'-羰基二咪唑 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 0.5h， 以62%的产率得到5-(4-{3,3-dimethyl-1-[5-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]oxadiazol-3-yl]cyclobutyl}phenyl)pyrimidin-2-ylamine
  参考文献：
  名称：

  Synthesis, SAR, and Series Evolution of Novel Oxadiazole-Containing 5-Lipoxygenase Activating Protein Inhibitors: Discovery of 2-[4-(3-{(R)-1-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915)

  摘要：

  The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.

  DOI：

  10.1021/jm501185j
• 作为产物：
  描述：

  二溴新戊烷 在 bis-triphenylphosphine-palladium(II) chloride 、 羟胺 、 sodium hydride 、 sodium carbonate 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 32.33h， 生成 1-[4-(2-aminopyrimidin-5-yl)phenyl]-N-hydroxy-3,3-dimethylcyclobutanecarboxamidine
  参考文献：
  名称：

  Synthesis, SAR, and Series Evolution of Novel Oxadiazole-Containing 5-Lipoxygenase Activating Protein Inhibitors: Discovery of 2-[4-(3-{(R)-1-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915)

  摘要：

  The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.

  DOI：

  10.1021/jm501185j

文献信息

• [EN] OXADIAZOLE INHIBITORS OF LEUKOTRIENE PRODUCTION<br/>[FR] COMPOSÉS OXADIAZOLE, INHIBITEURS DE LA PRODUCTION DE LEUCOTRIÈNES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2012027322A1

  公开（公告）日：2012-03-01

  The present invention relates to compound of formula (I) and pharmaceutically acceptable salt thereof, wherein R1-R5 are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

  本发明涉及式(I)的化合物及其药用可接受盐，其中R1-R5如本文所定义。该发明还涉及包括这些化合物的药物组合物，使用这些化合物治疗各种疾病和疾病的方法，制备这些化合物的过程以及在这些过程中有用的中间体。
• OXADIAZOLE INHIBITORS OF LEUKOTRIENE PRODUCTION
  申请人：BARTOLOZZI Alessandra

  公开号：US20120214787A1

  公开（公告）日：2012-08-23

  The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 -R 5 are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

  本发明涉及式(I)的化合物及其药学上可接受的盐，其中R1-R5的定义如本文所述。本发明还涉及包含这些化合物的制药组合物，使用这些化合物治疗各种疾病和障碍的方法，制备这些化合物的方法以及在这些过程中有用的中间体。
• EP2609092B1
  申请人：——

  公开号：EP2609092B1

  公开（公告）日：2015-04-01
• US8580829B2
  申请人：——

  公开号：US8580829B2

  公开（公告）日：2013-11-12
• Synthesis, SAR, and Series Evolution of Novel Oxadiazole-Containing 5-Lipoxygenase Activating Protein Inhibitors: Discovery of 2-[4-(3-{(<i>R</i>)-1-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-<i>N</i>,<i>N</i>-dimethyl-acetamide (BI 665915)
  作者：Hidenori Takahashi、Doris Riether、Alessandra Bartolozzi、Todd Bosanac、Valentina Berger、Ralph Binetti、John Broadwater、Zhidong Chen、Rebecca Crux、Stéphane De Lombaert、Rajvee Dave、Jonathon A. Dines、Tazmeen Fadra-Khan、Adam Flegg、Michael Garrigou、Ming-Hong Hao、John Huber、J. Matthew Hutzler、Steven Kerr、Adrian Kotey、Weimin Liu、Ho Yin Lo、Pui Leng Loke、Paige E. Mahaney、Tina M. Morwick、Spencer Napier、Alan Olague、Edward Pack、Anil K. Padyana、David S. Thomson、Heather Tye、Lifen Wu、Renee M. Zindell、Asitha Abeywardane、Thomas Simpson

  DOI：10.1021/jm501185j

  日期：2015.2.26

  The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.