methyl 4-chloro-2-(3-methoxyphenyl)acetamidobenzoate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl 4-chloro-2-(3-methoxyphenyl)acetamidobenzoate
• 英文别名: methyl 4-chloro-2-[[2-(3-methoxyphenyl)acetyl]amino]benzoate
• 化学式: C₁₇H₁₆ClNO₄
• 分子量: 333.771
• InChiKey: LIILTWVNAFXHIQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 4-chloro-2-(3-methoxyphenyl)acetamidobenzoate 在 双(三甲基硅烷基)氨基钾 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 1.0h， 生成 7-chloro-4-hydroxy-3-(3-methoxyphenyl)quinolin-2(1H)-one
  参考文献：
  名称：

  Effect of Plasma Protein Binding on in Vivo Activity and Brain Penetration of Glycine/NMDA Receptor Antagonists

  摘要：

  A major issue in designing drugs as antagonists at the glycine site of the NMDA receptor has been to achieve good in vivo activity. A series of 4-hydroxyquinolone glycine antagonists was found to be active in the DBA/2 mouse anticonvulsant assay, but improvements in in vitro affinity were not mirrored by corresponding increases in anticonvulsant activity. Here we show that binding of the compounds to plasma protein limits their brain penetration. Relative binding to the major plasma protein, albumin, was measured in two different ways: by a radioligand binding experiment or using an HPLC assay, for a wide structural range of glycine/NMDA site ligands. These measures of plasma protein binding correlate well (r = 0.84), and the HPLC assay has been used extensively to quantify plasma protein binding. For the 4-hydroxyquinolone series, binding to plasma protein correlates (r = 0.92) with log P (octanol/pH 7.4 buffer) over a range of log P values from 0 to 5. The anticonvulsant activity increases with in vitro affinity, but the slope of a plot of pED(50) versus pIC(50) is low (0.40); taking plasma protein binding into account in this plot increases the slope to 0.60. This shows that binding to albumin in plasma reduces the amount of compound free to diffuse across the blood-brain barrier. Further evidence comes from three other experiments: (a) Direct measurements of brain/blood ratios for three compounds (2, 16, 26) show the ratio decreases with increasing log P. (b) Warfarin, which competes for albumin binding sites dose-dependently, decreased the ED50 of 26 for protection against seizures induced by NMDLA. (c) Direct measurement of brain penetration using an in situ brain perfusion model in rat to measure the amount of drug crossing the blood/brain barrier showed that compounds 2, 26, and 32 penetrate the brain well in the absence of plasma protein, but this is greatly reduced when the drug is delivered in plasma. In the 4-hydroxyquinolones glycine site binding affinity increases with lipophilicity of the 3-substituent up to a maximum at a log P around 3, then does not improve further. When combined with increasing protein binding, this gives a parabolic relationship between predicted in vivo activity and log P, with a maximum log P value of 2.39. Finally, the plasma protein binding studies have been extended to other series of glycine site antagonists, and it is shown that for a. given log P these have similar protein binding to the 4-hydroxyquinolones, except for compounds that are not acidic. The results have implications for the design of novel glycine site antagonists, and it is suggested that it is necessary to either keep log P low or pK(a) high to obtain good central nervous system activity.

  DOI：

  10.1021/jm970417o
• 作为产物：
  描述：

  甲基2-胺-4-氯苯酚酯 、 3-甲氧基苯基乙酰氯 在 乙醚 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 以to afford methyl 4-chloro-2-(3-methoxyphenyl)acetamidobenzoate as a colourless solid (1.51 g), m.p. 144°-146° C.的产率得到methyl 4-chloro-2-(3-methoxyphenyl)acetamidobenzoate
  参考文献：
  名称：

  Hydroxyquinolone derivatives compounds which have pharmaceutical utility

  摘要：

  本发明涉及一类4-羟基-2-(1H)-喹啉衍生物，其在3位被一个可选择取代的芳基取代基所取代。这些化合物是选择性的非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。

  公开号：

  US05348962A1

文献信息

• Hydroxyquinolone derivatives compounds which have pharmaceutical utility
  申请人：Merck Sharpe & Dohme Ltd.

  公开号：US05348962A1

  公开（公告）日：1994-09-20

  This present invention relates to a class of 4-hydroxy-2-(1H)-quinolones which are substituted in the 3-position by an optionally substituted aryl substituent. These compounds are selective non-competitive antagonists of N-methyl-D-aspartate (NMDA) receptors.

  这项发明涉及一类在3位被可选择取代的芳基取代物所取代的4-羟基-2-(1H)-喹啉酮。这些化合物是N-甲基-D-天冬氨酸(NMDA)受体的选择性非竞争性拮抗剂。
• US5348962A
  申请人：——

  公开号：US5348962A

  公开（公告）日：1994-09-20
• US5559125A
  申请人：——

  公开号：US5559125A

  公开（公告）日：1996-09-24
• Effect of Plasma Protein Binding on in Vivo Activity and Brain Penetration of Glycine/NMDA Receptor Antagonists
  作者：Michael Rowley、Janusz J. Kulagowski、Alan P. Watt、Denise Rathbone、Graeme I. Stevenson、Robert W. Carling、Raymond Baker、George R. Marshall、John A. Kemp、Alan C. Foster、Sarah Grimwood、Richard Hargreaves、Catherine Hurley、Kay L. Saywell、Mark D. Tricklebank、Paul D. Leeson

  DOI：10.1021/jm970417o

  日期：1997.12.1

  A major issue in designing drugs as antagonists at the glycine site of the NMDA receptor has been to achieve good in vivo activity. A series of 4-hydroxyquinolone glycine antagonists was found to be active in the DBA/2 mouse anticonvulsant assay, but improvements in in vitro affinity were not mirrored by corresponding increases in anticonvulsant activity. Here we show that binding of the compounds to plasma protein limits their brain penetration. Relative binding to the major plasma protein, albumin, was measured in two different ways: by a radioligand binding experiment or using an HPLC assay, for a wide structural range of glycine/NMDA site ligands. These measures of plasma protein binding correlate well (r = 0.84), and the HPLC assay has been used extensively to quantify plasma protein binding. For the 4-hydroxyquinolone series, binding to plasma protein correlates (r = 0.92) with log P (octanol/pH 7.4 buffer) over a range of log P values from 0 to 5. The anticonvulsant activity increases with in vitro affinity, but the slope of a plot of pED(50) versus pIC(50) is low (0.40); taking plasma protein binding into account in this plot increases the slope to 0.60. This shows that binding to albumin in plasma reduces the amount of compound free to diffuse across the blood-brain barrier. Further evidence comes from three other experiments: (a) Direct measurements of brain/blood ratios for three compounds (2, 16, 26) show the ratio decreases with increasing log P. (b) Warfarin, which competes for albumin binding sites dose-dependently, decreased the ED50 of 26 for protection against seizures induced by NMDLA. (c) Direct measurement of brain penetration using an in situ brain perfusion model in rat to measure the amount of drug crossing the blood/brain barrier showed that compounds 2, 26, and 32 penetrate the brain well in the absence of plasma protein, but this is greatly reduced when the drug is delivered in plasma. In the 4-hydroxyquinolones glycine site binding affinity increases with lipophilicity of the 3-substituent up to a maximum at a log P around 3, then does not improve further. When combined with increasing protein binding, this gives a parabolic relationship between predicted in vivo activity and log P, with a maximum log P value of 2.39. Finally, the plasma protein binding studies have been extended to other series of glycine site antagonists, and it is shown that for a. given log P these have similar protein binding to the 4-hydroxyquinolones, except for compounds that are not acidic. The results have implications for the design of novel glycine site antagonists, and it is suggested that it is necessary to either keep log P low or pK(a) high to obtain good central nervous system activity.
• Hydroxyquinolone derivatives
  申请人：Merck, Sharp & Dohme Limited

  公开号：US05559125A1

  公开（公告）日：1996-09-24

  A class of 4-hydroxy-2-(1H)-quinolone derivatives, substituted at the 3-position by an optionally substituted aryl substituent, are selective non-competitive antagonists of NMDA receptors and/or are antagonists of AMPA receptors, and are therefore of utility in the treatment of conditions, such as neurodegenerative disorders, convulsions or schizophrenia, which require the administration of an NMDA and/or AMPA receptor antagonist.

  一类4-羟基-2-(1H)-喹啉衍生物，其在3位被可选择取代的芳基取代基所取代，是NMDA受体的选择性非竞争性拮抗剂和/或AMPA受体的拮抗剂，因此在治疗需要给予NMDA和/或AMPA受体拮抗剂的疾病，如神经退行性疾病、惊厥或精神分裂症等方面具有实用价值。