(4-cyclobutyl-1,4-diazepan-1-yl)(6-(tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octan-1-yl)methanone | 1539277-69-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂卓
• 英文名称: (4-cyclobutyl-1,4-diazepan-1-yl)(6-(tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octan-1-yl)methanone
• 英文别名: (4-Cyclobutyl-1,4-diazepan-1-yl)-[6-(oxan-4-yl)-6-azaspiro[2.5]octan-2-yl]methanone；(4-cyclobutyl-1,4-diazepan-1-yl)-[6-(oxan-4-yl)-6-azaspiro[2.5]octan-2-yl]methanone
• CAS: 1539277-69-4
• 化学式: C₂₂H₃₇N₃O₂
• 分子量: 375.555
• InChiKey: BDOPQVFPHYQRME-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  36
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  ethyl 6-azaspiro[2.5]octane-1-carboxylate 在 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 甲醇 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.42h， 生成 (4-cyclobutyl-1,4-diazepan-1-yl)(6-(tetrahydro-2H-pyran-4-yl)-6-azaspiro[2.5]octan-1-yl)methanone
  参考文献：
  名称：

  Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine-3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition

  摘要：

  A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only sigma 2 (62% at 10 mu M). Compound 6s demonstrated free-plasma exposures above the IC50 (similar to 50x) with a brain-to-plasma ratio of similar to 3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H-3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.

  DOI：

  10.1021/jm4014828

文献信息

• Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine-3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition
  作者：Dean G. Brown、Peter R. Bernstein、Andrew Griffin、Steve Wesolowski、Denis Labrecque、Maxime C. Tremblay、Mark Sylvester、Russell Mauger、Phillip D. Edwards、Scott R. Throner、James J. Folmer、Joseph Cacciola、Clay Scott、Lois A. Lazor、Mehrnaz Pourashraf、Vijayaratnam Santhakumar、William M. Potts、Simon Sydserff、Pascall Giguère、Carine Lévesque、Mohammed Dasser、Thierry Groblewski

  DOI：10.1021/jm4014828

  日期：2014.2.13

  A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only sigma 2 (62% at 10 mu M). Compound 6s demonstrated free-plasma exposures above the IC50 (similar to 50x) with a brain-to-plasma ratio of similar to 3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H-3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.