4-amino-6-{4-[4-(1H-tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-7,8-dihydro-6H-9-oxa-1,3,6-triaza-benzocyclohepten-5-one | 1109277-42-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-amino-6-{4-[4-(1H-tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-7,8-dihydro-6H-9-oxa-1,3,6-triaza-benzocyclohepten-5-one
• 英文别名: 6-(4-(trans-4-((2H-tetrazol-5-yl)methyl)cyclohexyl)phenyl)-4-amino-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one
• CAS: 1109277-42-0
• 化学式: C₂₁H₂₄N₈O₂
• 分子量: 420.474
• InChiKey: IBRWLUSJPIEFEC-HDJSIYSDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.13
• 重原子数：
  31.0
• 可旋转键数：
  4.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  135.8
• 氢给体数：
  2.0
• 氢受体数：
  8.0

反应信息

• 作为产物：
  描述：

  2-[4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-yl)phenyl]cyclohexyl]acetic acid 在 草酰氯 、 叠氮基三甲基硅烷 、 三甲基铝 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 60.0h， 生成 4-amino-6-{4-[4-(1H-tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-7,8-dihydro-6H-9-oxa-1,3,6-triaza-benzocyclohepten-5-one
  参考文献：
  名称：

  Defining the key pharmacophore elements of PF-04620110: Discovery of a potent, orally-active, neutral DGAT-1 inhibitor

  摘要：

  DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.045

文献信息

• SUBSTITUTED BICYCLOLACTAM COMPOUNDS
  申请人：Dow Robert L.

  公开号：US20090036425A1

  公开（公告）日：2009-02-05

  The invention provides compounds of formula (1), and the pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 5d , Q, A, Z, and R 7 are as described herein; compositions thereof; and uses thereof.

  该发明提供了式（1）的化合物及其药用盐，其中R1、R2、R3、R4、R5a、R5b、R5c、R5d、Q、A、Z和R7如本文所述；以及其组合物和用途。
• Substituted Bicyclolactam Compounds
  申请人：Dow Robert L.

  公开号：US20090137551A1

  公开（公告）日：2009-05-28

  The invention provides compounds of formula (1), and the pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 5d , Q, A, Z, and R 7 are as described herein; compositions thereof; and uses thereof.

  本发明提供了式（1）的化合物及其药学上可接受的盐，其中R1，R2，R3，R4，R5a，R5b，R5c，R5d，Q，A，Z和R7如本文所述；其组合物；以及其用途。
• US7718645B2
  申请人：——

  公开号：US7718645B2

  公开（公告）日：2010-05-18
• [EN] SUBSTITUTED BICYCLOLACTAM COMPOUNDS<br/>[FR] BICYCLOLACTAMES SUBSTITUÉS
  申请人：PFIZER PROD INC

  公开号：WO2009016462A2

  公开（公告）日：2009-02-05

  The invention provides compounds of formula (1), and the pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5a, R5b, R5c, R5d, Q, A, Z, and R7 are as described herein; compositions thereof; and uses thereof for the treatment of diabetes and obesity.
• Defining the key pharmacophore elements of PF-04620110: Discovery of a potent, orally-active, neutral DGAT-1 inhibitor
  作者：Robert L. Dow、Melissa P. Andrews、Jian-Cheng Li、E. Michael Gibbs、Angel Guzman-Perez、Jennifer L. LaPerle、Qifang Li、Dawn Mather、Michael J. Munchhof、Mark Niosi、Leena Patel、Christian Perreault、Susan Tapley、William J. Zavadoski

  DOI：10.1016/j.bmc.2013.06.045

  日期：2013.9

  DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures. (C) 2013 Elsevier Ltd. All rights reserved.