benzyl 1-[4-cyano-4-(3-ethoxy-4-methoxyphenyl)piperidin-1-yl]cyclopropanecarboxylate | 401518-86-3

• 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: benzyl 1-[4-cyano-4-(3-ethoxy-4-methoxyphenyl)piperidin-1-yl]cyclopropanecarboxylate
• 英文别名: 1-(4-(3-ethoxy-4-methoxyphenyl)-4-cyanopiperidin-1-yl)cyclopropanecarboxylic acid benzyl ester；Benzyl 1-[4-cyano-4-(3-ethoxy-4-methoxyphenyl)piperidin-1-yl]cyclopropane-1-carboxylate
• CAS: 401518-86-3
• 化学式: C₂₆H₃₀N₂O₄
• 分子量: 434.535
• InChiKey: KMFBJLSLCATXEJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  71.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  benzyl 1-[4-cyano-4-(3-ethoxy-4-methoxyphenyl)piperidin-1-yl]cyclopropanecarboxylate 在 palladium on activated charcoal 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成
  参考文献：
  名称：

  Highly potent PDE4 inhibitors with therapeutic potential

  摘要：

  The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo(TM) 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a-b, 11b-14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity. (2) Water-soluble piperidine analogs lacked the configurational isomerism of Ariflo 1 without loss of inhibitory activity. (3) Replacement of the 4-methoxy residue with a difluoromethoxy residue led to an increase of in vivo potency. Structure-activity relationships are presented. Single-dose rat pharmacokinetic data for 11b, 12b, and 17a are also presented. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.06.032
• 作为产物：
  描述：

  3-乙氧基-4-甲氧基苯乙腈 在 三乙酰氧基硼氢化钠 、 臭氧 、 溶剂黄146 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 7.42h， 生成 benzyl 1-[4-cyano-4-(3-ethoxy-4-methoxyphenyl)piperidin-1-yl]cyclopropanecarboxylate
  参考文献：
  名称：

  Highly potent PDE4 inhibitors with therapeutic potential

  摘要：

  The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo(TM) 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a-b, 11b-14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity. (2) Water-soluble piperidine analogs lacked the configurational isomerism of Ariflo 1 without loss of inhibitory activity. (3) Replacement of the 4-methoxy residue with a difluoromethoxy residue led to an increase of in vivo potency. Structure-activity relationships are presented. Single-dose rat pharmacokinetic data for 11b, 12b, and 17a are also presented. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.06.032

文献信息

• PIPERIDINE DERIVATIVES AND DRUGS CONTAINING THESE DERIVATIVES AS THE ACTIVE INGREDIENT
  申请人：ONO PHARMACEUTICAL CO., LTD.

  公开号：EP1308440B1

  公开（公告）日：2009-05-06
• US7649095B2
  申请人：——

  公开号：US7649095B2

  公开（公告）日：2010-01-19