2-氨基-4-氯-6-乙基苯甲酸甲酯 | 139422-20-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 2-氨基-4-氯-6-乙基苯甲酸甲酯
• 英文名称: methyl 2-amino-4-chloro-6-ethylbenzoate
• 英文别名: methyl 4-Chloro-6-ethylanthranilate
• CAS: 139422-20-1
• 化学式: C₁₀H₁₂ClNO₂
• 分子量: 213.664
• InChiKey: UXXGXOOHTIKGNV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  52.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-氨基-4-氯-6-乙基苯甲酸甲酯 在 双(2-氧代-3-恶唑烷基)次磷酰氯 、 双(三甲基硅烷基)氨基钾 、 三乙胺 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 、 甲苯 为溶剂， 反应 19.0h， 生成 L-701315
  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：

  methyl 2-amino-4-chloro-6-vinylbenzoate 在 铂 sulphide carbon 、 氮气 作用下， 以 乙酸乙酯 为溶剂， 反应 2.0h， 以to leave the desired methyl 2-amino-4-chloro-6-ethylbenzoate as a yellow oil (0.34 g)的产率得到2-氨基-4-氯-6-乙基苯甲酸甲酯
  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

• Dioxo-tetrahydroquinoline derivatives
  申请人：Merck Sharp & Dohme, Limited

  公开号：US05268378A1

  公开（公告）日：1993-12-07

  A class of 2,4-dioxo-1,2,3,4-tetrahydroquinoline derivatives, substituted at the 3-position by a range of carbonyl-containing substituents or by a five- or six-membered heteroaromatic moiety, 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 antagonist.

  一类2,4-二氧代-1,2,3,4-四氢喹啉衍生物，其在3位被一系列含羰基取代基团或五元或六元杂芳基取代，是NMDA受体的选择性非竞争性拮抗剂和/或是AMPA受体的拮抗剂，因此在治疗神经退行性疾病、癫痫或精神分裂症等需要给予NMDA和/或AMPA拮抗剂的情况下具有实用价值。
• 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。
• Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone derivatives as PET radioligands for the glycine-binding site of NMDA receptors
  作者：Takeshi Fuchigami、Terushi Haradahira、Noriko Fujimoto、Yumiko Nojiri、Takahiro Mukai、Fumihiko Yamamoto、Takashi Okauchi、Jun Maeda、Kazutoshi Suzuki、Tetsuya Suhara、Hiroshi Yamaguchi、Mikako Ogawa、Yasuhiro Magata、Minoru Maeda

  DOI：10.1016/j.bmc.2009.06.014

  日期：2009.8

  In this study, we synthesized and evaluated several amino 4-hydroxy-2(1H)-quinolone (4HQ) derivatives as new PET radioligand candidates for the glycine site of the NMDA receptors. Among these ligands, we discovered that 7-chloro-4-hydroxy-3-3-(4-methylaminobenzyl) phenyl}-2-(1H)-quinolone (12) and 5-ethyl-7-chloro-4-hydroxy-3-(3-methylaminophenyl)-2(1H)-quinolone (32) have high affinity for the glycine site (K-i values; 11.7 nM for 12 and 11.8 nM for 32). In vitro autoradiography experiments indicated that [C-11]12 and [C-11]32 showed high specific binding in the brain slices, which were strongly inhibited by both glycine agonists and antagonists. In vivo brain uptake of these C-11-labeled 4HQs were examined in normal mice. Cerebellum to blood ratio of accumulation, of both [C-11]12 and [C-11]32 at 30 min were 0.058, which were slightly higher than those of cerebrum to blood ratio (0.043 and 0.042, respectively). These results indicated that [C-11]12 and [C-11]32 have poor blood brain barrier permeability. Although the plasma protein-binding ratio of [C-11]32 was much lower than methoxy analogs (71% vs 94-98%, respectively), [C-11]32 still binds with plasma protein strongly. It is conjectured that still acidic moiety and high affinity with plasma protein of [C-11]32 may prevent in vivo brain uptake. In conclusion, [C-11]12 and [C-11]32 are unsuitable for imaging cerebral NMDA receptors. (C) 2009 Elsevier Ltd. All rights reserved.
• US5268378A
  申请人：——

  公开号：US5268378A

  公开（公告）日：1993-12-07
• US5348962A
  申请人：——

  公开号：US5348962A

  公开（公告）日：1994-09-20