6-carbomethoxy-7-chloro-4-hydroxy-3-(3,4,5-trimethylphenyl)-1H-quinolin-2-one | 335293-17-9

• 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: 6-carbomethoxy-7-chloro-4-hydroxy-3-(3,4,5-trimethylphenyl)-1H-quinolin-2-one
• 英文别名: methyl 7-chloro-4-hydroxy-2-oxo-3-(3,4,5-trimethylphenyl)-1H-quinoline-6-carboxylate
• CAS: 335293-17-9
• 化学式: C₂₀H₁₈ClNO₄
• 分子量: 371.82
• InChiKey: AKFDSDAAMSUOFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-carbomethoxy-7-chloro-4-hydroxy-3-(3,4,5-trimethylphenyl)-1H-quinolin-2-one 在 4-二甲氨基吡啶 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 46.5h， 生成 4-(2-(N-tert-butoxycarbonylazetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide
  参考文献：
  名称：

  A Potent, Nonpeptidyl 1H-Quinolone Antagonist for the Gonadotropin-Releasing Hormone Receptor

  摘要：

  Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the g-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 104-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.

  DOI：

  10.1021/jm000275p
• 作为产物：
  描述：

  4-(乙酰氨基)-6-氯-1,3-苯二甲酸二甲酯 在 甲醇 、 硫酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 为溶剂， 反应 14.0h， 生成 6-carbomethoxy-7-chloro-4-hydroxy-3-(3,4,5-trimethylphenyl)-1H-quinolin-2-one
  参考文献：
  名称：

  A Potent, Nonpeptidyl 1H-Quinolone Antagonist for the Gonadotropin-Releasing Hormone Receptor

  摘要：

  Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the g-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 104-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.

  DOI：

  10.1021/jm000275p

文献信息

• Identification of neutral 4-O-alkyl quinolone nonpeptide GnRH receptor antagonists
  作者：Robert J. DeVita、Mamta Parikh、Jinlong Jiang、Jason A. Fair、Jonathan R. Young、Thomas F. Walsh、Mark T. Goulet、Jane-L. Lo、Ning Ren、Joel B. Yudkovitz、Jisong Cui、Yi T. Yang、Kang Cheng、Susan P. Rohrer、Matthew J. Wyvratt

  DOI：10.1016/j.bmcl.2004.08.056

  日期：2004.11

  A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists. (C) 2004 Elsevier Ltd. All rights reserved.
• [EN] ANTAGONISTS OF GONADOTROPIN RELEASING HORMONE<br/>[FR] ANTAGONISTES DE L'HORMONE DE LIBERATION DE LA GONADOTROPHINE
  申请人：MERCK & CO INC

  公开号：WO2001070228A1

  公开（公告）日：2001-09-27

  There are disclosed compounds of formula (I) or pharmaceutically acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related conditions in both men and women.