2-(azepan-1-ylcarbonyl)-N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide | 403477-85-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-(azepan-1-ylcarbonyl)-N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide
• CAS: 403477-85-0
• 化学式: C₃₂H₃₆FN₃O₂
• 分子量: 513.655
• InChiKey: GIPFZYIDTGSYHG-CXAYTTCISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.92
• 重原子数：
  38.0
• 可旋转键数：
  5.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  52.65
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  2-(azepan-1-ylcarbonyl)benzoic acid 、 (3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以48%的产率得到2-(azepan-1-ylcarbonyl)-N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide
  参考文献：
  名称：

  Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition

  摘要：

  In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modi. cations on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using Clog D(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50) = 23 nM) with much reduced CYP2D6 inhibitory activity (IC50 = 29,000 nM) compared with 1. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.08.006

文献信息

• Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition
  作者：Ippei Sato、Koichiro Morihira、Hiroshi Inami、Hirokazu Kubota、Tatsuaki Morokata、Keiko Suzuki、Yosuke Iura、Aiko Nitta、Takayuki Imaoka、Toshiya Takahashi、Makoto Takeuchi、Mitsuaki Ohta、Shin-ichi Tsukamoto

  DOI：10.1016/j.bmc.2008.08.006

  日期：2008.9

  In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modi. cations on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using Clog D(7.4) values as the reference index of lipophilicity. This research led to the identification of N-(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50) = 23 nM) with much reduced CYP2D6 inhibitory activity (IC50 = 29,000 nM) compared with 1. (C) 2008 Elsevier Ltd. All rights reserved.