tert-butyl 8-benzoyl-2,8-diazaspiro[4.5]decane-2-carboxylate | 1539278-08-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 8-benzoyl-2,8-diazaspiro[4.5]decane-2-carboxylate
• CAS: 1539278-08-4
• 化学式: C₂₀H₂₈N₂O₃
• 分子量: 344.454
• InChiKey: GUZPDKOVQHELNJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.55
• 重原子数：
  25.0
• 可旋转键数：
  1.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  49.85
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  tert-butyl 8-benzoyl-2,8-diazaspiro[4.5]decane-2-carboxylate 在 盐酸 、 sodium cyanoborohydride 、 N,N-二异丙基乙胺 作用下， 以 2-甲基四氢呋喃 、 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 97.75h， 生成 (8-benzoyl-2,8-diazaspiro[4.5]decan-2-yl)(1-cyclobutylpiperidin-4-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
• 作为产物：
  描述：

  2,8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯盐酸盐 、 苯甲酸 在 N,N-二异丙基乙胺 、 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium 作用下， 以 2-甲基四氢呋喃 为溶剂， 反应 1.0h， 以61.8%的产率得到tert-butyl 8-benzoyl-2,8-diazaspiro[4.5]decane-2-carboxylate
  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

• Core chemotype diversification in the HIV-1 entry inhibitor class using field-based bioisosteric replacement
  作者：Marina Tuyishime、Rae Lawrence、Simon Cocklin

  DOI：10.1016/j.bmcl.2015.10.080

  日期：2016.1

  Demand remains for new inhibitors of HIV-1 replication and the inhibition of HIV-1 entry is an extremely attractive therapeutic approach. Using field-based bioisosteric replacements, we have further extended the chemotypes available for development in the HIV-1 entry inhibitor class. Moreover, using field-based disparity analysis of the compounds, 3D structure-activity relationships were derived that will be useful in the further development of these inhibitors towards clinical utility. (C) 2015 Elsevier Ltd. All rights reserved.