1-[1-(3-methoxybenzyl)piperidin-4-yl]-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one

• 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: 1-[1-(3-methoxybenzyl)piperidin-4-yl]-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one
• 英文别名: 1-[1-(3-Methoxy-benzyl)-piperidin-4-yl]-5-methyl-4-phenyl-1,3-dihydro-imidazol-2-one；3-[1-[(3-methoxyphenyl)methyl]piperidin-4-yl]-4-methyl-5-phenyl-1H-imidazol-2-one
• 化学式: C₂₃H₂₇N₃O₂
• 分子量: 377.486
• InChiKey: SVAAEZGFWVDPDN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  44.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-溴苯丙酮 在 1-氯乙基氯甲酸酯 、 sodium methylate 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 50.5h， 生成 1-[1-(3-methoxybenzyl)piperidin-4-yl]-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one
  参考文献：
  名称：

  1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one:  A Selective High-Affinity Antagonist for the Human Dopamine D₄ Receptor with Excellent Selectivity over Ion Channels

  摘要：

  After the requirement of pseudocycle formation in the ureas 3 and 7 for hD(4) binding and selectivity was confirmed, structural hybridization with the known hD(4) ligand 2 led to the design and identification of the lead 4-(2-oxo-1,3-dihydroimidazol-2-yl)piperidine . Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD(4) over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective "four-step/one-pot'' procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1,3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or B-position of the 1,3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD(4) over hD(2) and hD(3). Greater Selectivity( > 1000-foId) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD(4) over the other dopamine subtypes, but only 32 has > 1000-fold selectivity over-all the key counterscreens we tested against. Compound 32 is an antagonist at hD(4) and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D-4 receptor.

  DOI：

  10.1021/jm991029k

文献信息

• IMIDAZOLONE AND OXAZOLONE DERIVATIVES AS DOPAMINE ANTAGONISTS
  申请人：MERCK SHARP & DOHME LTD.

  公开号：EP0719264B1

  公开（公告）日：1997-12-29
• US5698573A
  申请人：——

  公开号：US5698573A

  公开（公告）日：1997-12-16
• 1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one:  A Selective High-Affinity Antagonist for the Human Dopamine D₄ Receptor with Excellent Selectivity over Ion Channels
  作者：Robert W. Carling、Kevin W. Moore、Christopher R. Moyes、Elizabeth A. Jones、Katrine Bonner、Frances Emms、Rosemary Marwood、Shil Patel、Smita Patel、Alan E. Fletcher、Margaret Beer、Bindi Sohal、Andrew Pike、Paul D. Leeson

  DOI：10.1021/jm991029k

  日期：1999.7.1

  After the requirement of pseudocycle formation in the ureas 3 and 7 for hD(4) binding and selectivity was confirmed, structural hybridization with the known hD(4) ligand 2 led to the design and identification of the lead 4-(2-oxo-1,3-dihydroimidazol-2-yl)piperidine . Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD(4) over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective "four-step/one-pot'' procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1,3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or B-position of the 1,3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD(4) over hD(2) and hD(3). Greater Selectivity( > 1000-foId) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD(4) over the other dopamine subtypes, but only 32 has > 1000-fold selectivity over-all the key counterscreens we tested against. Compound 32 is an antagonist at hD(4) and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D-4 receptor.