4-amino-6-{4-[trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl]phenyl}-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one | 1236356-01-6

• 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-[trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl]phenyl}-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one
• CAS: 1236356-01-6
• 化学式: C₂₃H₃₀N₄O₃
• 分子量: 410.516
• InChiKey: FNQZTVFWIXAXPH-WKILWMFISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.53
• 重原子数：
  30.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  101.57
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  4-amino-6-{4-[trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl]phenyl}-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one 在 叠氮基三甲基硅烷 、 三氟化硼乙醚 、 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 反应 50.0h， 以21 mg的产率得到4-amino-6-{4-[trans-4-(2-amino-2-methylpropyl)cyclohexyl]phenyl}-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-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
• 作为产物：
  描述：

  methyl {trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-(5H)-yl)phenyl]cyclohexyl}acetate 、 甲基溴化镁 在 水 作用下， 以 甲苯 、 乙酸乙酯 为溶剂， 生成 4-amino-6-{4-[trans-4-(2-hydroxy-2-methylpropyl)cyclohexyl]phenyl}-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one
  参考文献：
  名称：

  [EN] 4-AMINO-5-OXO-7, 8-DIHYDROPYRIMIDO [5,4-F] [1,4] OXAZEPIN-6 (5H) -YL) PHENYL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
  [FR] DÉRIVÉS DE 4-AMINO-5-OXO-7,8-DIHYDROPYRIMIDO[5,4-F][1,4]OXAZÉPIN-6(5H)-YL)PHÉNYLE

  摘要：

  该发明提供了式（I）的化合物，其中R1、R2a、R2b、R3、m和A如本文所定义，以及这些化合物的组合物和通过给予本发明的化合物和/或其组合物来调节通过抑制二酰基甘油酯O-酰基转移酶1（DGAT-1）酶而调节的疾病、状况或紊乱的治疗方法。

  公开号：

  WO2010086820A1

文献信息

• [EN] 4-AMINO-5-OXO-7, 8-DIHYDROPYRIMIDO [5,4-F] [1,4] OXAZEPIN-6 (5H) -YL) PHENYL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF<br/>[FR] DÉRIVÉS DE 4-AMINO-5-OXO-7,8-DIHYDROPYRIMIDO[5,4-F][1,4]OXAZÉPIN-6(5H)-YL)PHÉNYLE
  申请人：PFIZER

  公开号：WO2010086820A1

  公开（公告）日：2010-08-05

  The invention provides compounds of Formula (I), wherein R1, R2a, R2b, R3, m and A are as defined herein, as well as compositions thereof and methods for treating a disease, condition or disorder that is modulated by the inhibition of the diacylglycerol O-acyltransferase 1 (DGAT-1) enzyme by administering the compounds of the present invention and/or compositions thereof.

  该发明提供了式（I）的化合物，其中R1、R2a、R2b、R3、m和A如本文所定义，以及这些化合物的组合物和通过给予本发明的化合物和/或其组合物来调节通过抑制二酰基甘油酯O-酰基转移酶1（DGAT-1）酶而调节的疾病、状况或紊乱的治疗方法。
• 4-AMINO-5-OXO-7,8-DIHYDROPYRIMIDO[5,4-F][1,4]OXAZEPIN-6(5H)-YL PHENYL DERIVATIVES
  申请人：Aspnes Gary E.

  公开号：US20100204119A1

  公开（公告）日：2010-08-12

  The invention provides compounds of Formula (I), wherein R 1 , R 2a , R 2b , R 3 , m and A are as defined herein, as well as compositions thereof and methods for treating a disease, condition or disorder that is modulated by the inhibition of the diacylglycerol O-acyltransferase 1 (DGAT-1) enzyme by administering the compounds of the present invention and/or compositions thereof.

  本发明提供了式（I）的化合物，其中R1，R2a，R2b，R3，m和A如本文所定义，以及它们的组合物和通过给予本发明的化合物和/或组合物来抑制二酰甘油O-酰基转移酶1（DGAT-1）酶而治疗受DGAT-1调节的疾病，情况或紊乱的方法。
• 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.