4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (2-dimethylamino-ethyl)-amide | 340021-19-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (2-dimethylamino-ethyl)-amide
• 英文别名: N-[2-(dimethylamino)ethyl]-4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)bicyclo[2.2.2]octane-1-carboxamide
• CAS: 340021-19-4
• 化学式: C₂₄H₃₈N₆O₃
• 分子量: 458.604
• InChiKey: VUNOGVXKRYEQTC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]octane-1-carboxylic acid 、 N,N-二甲基乙二胺 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 乙腈 为溶剂， 反应 16.0h， 生成 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (2-dimethylamino-ethyl)-amide
  参考文献：
  名称：

  Potent and Orally Bioavailable 8-Bicyclo[2.2.2]octylxanthines as Adenosine A₁ Receptor Antagonists

  摘要：

  In the search for a selective adenosine A(1) receptor antagonist with greater aqueous solubility than the compounds currently in clinical trials as diuretics, a series of 1,4- substituted 8-cyclohexyl and 8-bicyclo-[2.2.2] octylxanthines were investigated. The binding affinities of a variety of cyclohexyl and bicyclo[2.2.2]octylxanthines for the rat and human adenosine A(1), A(2A), A(2B), and A(3) receptors are presented. Bicyclo[ 2.2.2] octylxanthine 16 exhibited good pharmaceutical properties and in vivo activity in a rat diuresis model (ED50=0.3 mg/ kg po). Optimization of the bridgehead substituent led to propionic acid 29 ( BG9928), which retained high potency ( hA(1), K-i=7 nM) and selectivity for the adenosine A1 receptor (915-fold versus adenosine A2A receptor; 12-fold versus adenosine A2B receptor) with improved oral efficacy in the rat diuresis model (ED50=0.01 mg/ kg) as well as high oral bioavailability in rat, dog, and cynomolgus monkey.

  DOI：

  10.1021/jm0605381

文献信息

• Poycyloalkylpurines as adenosine receptor antagonists
  申请人：Biogen Idec MA Inc.

  公开号：EP2305684A1

  公开（公告）日：2011-04-06

  The invention is based on the discovery that compounds of Formula (I) are unexpectedly highly potent and selective inhibitors of the adenosine A1 receptor. Adenosine A1 antagonists can be useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable. In one embodiment, the invention features a compound of formula (I).

  本发明的基础是发现式（I）化合物是出乎意料的腺苷 A1 受体的高效选择性抑制剂。腺苷 A1 拮抗剂可用于预防和/或治疗多种疾病，包括心脏和循环系统疾病、中枢神经系统退行性疾病、呼吸系统疾病以及许多适合利尿剂治疗的疾病。在一个实施方案中，本发明以式（I）化合物为特征。
• Potent and Orally Bioavailable 8-Bicyclo[2.2.2]octylxanthines as Adenosine A₁ Receptor Antagonists
  作者：William F. Kiesman、Jin Zhao、Patrick R. Conlon、James E. Dowling、Russell C. Petter、Frank Lutterodt、Xiaowei Jin、Glenn Smits、Mary Fure、Andrew Jayaraj、John Kim、Gail Sullivan、Joel Linden

  DOI：10.1021/jm0605381

  日期：2006.11.30

  In the search for a selective adenosine A(1) receptor antagonist with greater aqueous solubility than the compounds currently in clinical trials as diuretics, a series of 1,4- substituted 8-cyclohexyl and 8-bicyclo-[2.2.2] octylxanthines were investigated. The binding affinities of a variety of cyclohexyl and bicyclo[2.2.2]octylxanthines for the rat and human adenosine A(1), A(2A), A(2B), and A(3) receptors are presented. Bicyclo[ 2.2.2] octylxanthine 16 exhibited good pharmaceutical properties and in vivo activity in a rat diuresis model (ED50=0.3 mg/ kg po). Optimization of the bridgehead substituent led to propionic acid 29 ( BG9928), which retained high potency ( hA(1), K-i=7 nM) and selectivity for the adenosine A1 receptor (915-fold versus adenosine A2A receptor; 12-fold versus adenosine A2B receptor) with improved oral efficacy in the rat diuresis model (ED50=0.01 mg/ kg) as well as high oral bioavailability in rat, dog, and cynomolgus monkey.