methyl (trans-4-{4-[[4,6-dichloropyrimidin-5-ylcarbonyl](2-hydroxyethyl)amino]phenyl}cyclohexyl)acetate | 1109277-52-2

• 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: methyl (trans-4-{4-[[4,6-dichloropyrimidin-5-ylcarbonyl](2-hydroxyethyl)amino]phenyl}cyclohexyl)acetate
• CAS: 1109277-52-2
• 化学式: C₂₂H₂₅Cl₂N₃O₄
• 分子量: 466.364
• InChiKey: QSFWXZFUSUIIFC-SHTZXODSSA-N

物化性质

• 沸点：
  642.4±55.0 °C(Predicted)
• 密度：
  1.332±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.26
• 重原子数：
  31.0
• 可旋转键数：
  7.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  92.62
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  methyl (trans-4-{4-[[4,6-dichloropyrimidin-5-ylcarbonyl](2-hydroxyethyl)amino]phenyl}cyclohexyl)acetate 在 三乙胺 作用下， 以 乙腈 为溶剂， 反应 6.0h， 生成 methyl {trans-4-[4-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-(5H)-yl)phenyl]cyclohexyl}acetate
  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
• 作为产物：
  描述：

  methyl [trans-4-(4-{(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)[(4,6-dichloropyrimidin-5-yl)carbonyl]amino}phenyl)cyclohexyl]acetate 在 盐酸 、 碳酸氢钠 作用下， 以 甲醇 、 水 、 乙酸乙酯 为溶剂， 反应 0.5h， 生成 methyl (trans-4-{4-[[4,6-dichloropyrimidin-5-ylcarbonyl](2-hydroxyethyl)amino]phenyl}cyclohexyl)acetate
  参考文献：
  名称：

  SUBSTITUTED BICYCLOLACTAM COMPOUNDS

  摘要：

  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。

  公开号：

  US20090036425A1

文献信息

• 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。
• 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.
• Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1
  作者：Robert L. Dow、Jian-Cheng Li、Michael P. Pence、E. Michael Gibbs、Jennifer L. LaPerle、John Litchfield、David W. Piotrowski、Michael J. Munchhof、Tara B. Manion、William J. Zavadoski、Gregory S. Walker、R. Kirk McPherson、Susan Tapley、Eliot Sugarman、Angel Guzman-Perez、Paul DaSilva-Jardine

  DOI：10.1021/ml200051p

  日期：2011.5.12

  Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in the biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant to diet-induced obesity and have increased insulin sensitivity. Thus, inhibition of DGAT-1 may represent an attractive target for the treatment of obesity or type II diabetes. Herein, we report the discovery and characterization of a potent and selective DGAT-1 inhibit or PF-04620110 (3). Compound 3 inhibits DGAT-1 with an IC50 of 19 nM and shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of >= 0.1 mg/kg following a lipid challenge. On the basis of this pharmacologic and pharmacokinetic profile, compound 3 has been advanced to human clinical studies.
• US7718645B2
  申请人：——

  公开号：US7718645B2

  公开（公告）日：2010-05-18