trans-N-({4-chloro-1-[3-(methyloxy)propyl]-1H-indol-3-yl}methyl)-N-cyclopropyl-4-(1-methyl 2-oxo-1,2-dihydro-4-pyridinyl)-3-piperidinecarboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: trans-N-({4-chloro-1-[3-(methyloxy)propyl]-1H-indol-3-yl}methyl)-N-cyclopropyl-4-(1-methyl 2-oxo-1,2-dihydro-4-pyridinyl)-3-piperidinecarboxamide
• 英文别名: (3R,4S)-N-[[4-chloro-1-(3-methoxypropyl)indol-3-yl]methyl]-N-cyclopropyl-4-(1-methyl-2-oxopyridin-4-yl)piperidine-3-carboxamide
• 化学式: C₂₈H₃₅ClN₄O₃
• 分子量: 511.064
• InChiKey: AUOWJTDDNOBEPP-PKTZIBPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-苄基-3-乙氧羰基-4-哌啶酮盐酸盐 在 甲醇 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 水 、 氢气 、 sodium ethanolate 、 potassium acetate 、 palladium(II) hydroxide 、 sodium hydride 、 sodium carbonate 、 magnesium 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium iodide 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 丙醇 、 乙醇 、 正己烷 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 、 乙腈 、 mineral oil 为溶剂， 80.0 ℃ 、344.75 kPa 条件下， 反应 140.0h， 生成 trans-N-({4-chloro-1-[3-(methyloxy)propyl]-1H-indol-3-yl}methyl)-N-cyclopropyl-4-(1-methyl 2-oxo-1,2-dihydro-4-pyridinyl)-3-piperidinecarboxamide
  参考文献：
  名称：

  Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of pyridone-substituted piperidines

  摘要：

  An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.05.013

文献信息

• 3,4-SUBSTITUTED PIPERIDINE DERIVATIVES AS RENIN INHIBITORS
  申请人：Chen Austin Chih-Yu

  公开号：US20110053940A1

  公开（公告）日：2011-03-03

  The present invention relates to 3,4-substituted piperidinyl-based renin inhibitor compounds bearing at 4-position oxopyridine and having the formula (I). The invention further relates to pharmaceutical compositions containing said compounds, as well as their use in treating cardiovascular events and renal insufficiency.

  本发明涉及一种以3,4-取代哌啶基为基础的肾素抑制剂化合物，其在4位上带有氧代吡啶，化学式为（I）。本发明还涉及含有上述化合物的制药组合物，以及它们在治疗心血管事件和肾功能不全方面的用途。
• 3, 4 - SUBSTITUTED PIPERIDINE DERIVATIVES AS RENIN INHIBITORS
  申请人：Actelion Pharmaceuticals Ltd.

  公开号：EP2274295B1

  公开（公告）日：2015-08-05
• US8889714B2
  申请人：——

  公开号：US8889714B2

  公开（公告）日：2014-11-18
• Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of pyridone-substituted piperidines
  作者：Austin Chen、Louis-Charles Campeau、Elizabeth Cauchon、Amandine Chefson、Yves Ducharme、Daniel Dubé、Jean-Pierre Falgueyret、Pierre-André Fournier、Sébastien Gagné、Erich Grimm、Yongxin Han、Robert Houle、Jing-Qi Huang、Patrick Lacombe、Sébastien Laliberté、Jean-François Lévesque、Susana Liu、Dwight MacDonald、Bruce Mackay、Dan McKay、M. David Percival、Chris Regan、Hillary Regan、René St-Jacques、Sylvie Toulmond

  DOI：10.1016/j.bmcl.2011.05.013

  日期：2011.7

  An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor. (C) 2011 Elsevier Ltd. All rights reserved.