tert-butyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate | 1426063-30-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: tert-butyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
• 英文别名: Tert-butyl 6-benzyl-4-oxo-2,3-dihydroquinoline-1-carboxylate；tert-butyl 6-benzyl-4-oxo-2,3-dihydroquinoline-1-carboxylate
• CAS: 1426063-30-0
• 化学式: C₂₁H₂₃NO₃
• 分子量: 337.419
• InChiKey: RXMYUYRVMRSPBM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate 在 titanium(IV) tetraethanolate 、 sodium tetrahydroborate 作用下， 以 四氢呋喃 为溶剂， 反应 51.0h， 生成 tert-butyl (R)-6-benzyl-4-(((R)-tert-butylsulfinyl)amino)-3,4-dihydroquinoline-1(2H)-carboxylate
  参考文献：
  名称：

  Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands

  摘要：

  N-Acetylation of the tetrahydroquinoline (THQ) core of a series of mu-opioid receptor (MOR) agonist/delta-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.

  DOI：

  10.1021/acs.jmedchem.6b00308
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 6-benzyl-2,3-dihydroquinolin-4(1H)-one 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 35.0h， 以77%的产率得到tert-butyl 6-Benzyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
  参考文献：
  名称：

  Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy μ Opioid Receptor (MOR) Agonist/δ Opioid Receptor (DOR) Antagonist Ligands

  摘要：

  We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood-brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.

  DOI：

  10.1021/jm400050y

文献信息

• Opioid Peptidomimetics: Leads for the Design of Bioavailable Mixed Efficacy μ Opioid Receptor (MOR) Agonist/δ Opioid Receptor (DOR) Antagonist Ligands
  作者：Henry I. Mosberg、Larisa Yeomans、Aubrie A. Harland、Aaron M. Bender、Katarzyna Sobczyk-Kojiro、Jessica P. Anand、Mary J. Clark、Emily M. Jutkiewicz、John R. Traynor

  DOI：10.1021/jm400050y

  日期：2013.3.14

  We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a mu opioid receptor (MOR) agonist, delta opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood-brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.
• Asymmetric Synthesis and in Vitro and in Vivo Activity of Tetrahydroquinolines Featuring a Diverse Set of Polar Substitutions at the 6 Position as Mixed-Efficacy μ Opioid Receptor/δ Opioid Receptor Ligands
  作者：Aaron M. Bender、Nicholas W. Griggs、Jessica P. Anand、John R. Traynor、Emily M. Jutkiewicz、Henry I. Mosberg

  DOI：10.1021/acschemneuro.5b00100

  日期：2015.8.19

  We previously reported a small series of mixed-efficacy mu opioid receptor (MOR) agonist/delta opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the kappa opioid receptor (KOR), and several of them (10j, 10k, 10m, and 10n) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for 10j, 10k, 10m, and 10n are also reported and show the antinociceptive potency and duration of action of compounds 10j and 10m to be comparable to those of morphine.
• Effects of <i>N</i>-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands
  作者：Aubrie A. Harland、Aaron M. Bender、Nicholas W. Griggs、Chao Gao、Jessica P. Anand、Irina D. Pogozheva、John R. Traynor、Emily M. Jutkiewicz、Henry I. Mosberg

  DOI：10.1021/acs.jmedchem.6b00308

  日期：2016.5.26

  N-Acetylation of the tetrahydroquinoline (THQ) core of a series of mu-opioid receptor (MOR) agonist/delta-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.