dimethyl 6-amino-4-chloro-1,3-isophthalate | 335293-15-7

• 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: dimethyl 6-amino-4-chloro-1,3-isophthalate
• 英文别名: Dimethyl 4-amino-6-chloroisophthalate；dimethyl 4-amino-6-chlorobenzene-1,3-dicarboxylate
• CAS: 335293-15-7
• 化学式: C₁₀H₁₀ClNO₄
• 分子量: 243.647
• InChiKey: KQRFZPRAOOBLCE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  78.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  dimethyl 6-amino-4-chloro-1,3-isophthalate 在 三苯基膦 、 lithium hexamethyldisilazane 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 为溶剂， 反应 35.5h， 生成 4-(2-(N-tert-butoxycarbonylazetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydoquinoline-6-carboxylic acid
  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 作用下， 反应 1.0h， 以80%的产率得到dimethyl 6-amino-4-chloro-1,3-isophthalate
  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

• [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.
• A Potent, Nonpeptidyl 1<i>H</i>-Quinolone Antagonist for the Gonadotropin-Releasing Hormone Receptor
  作者：Robert J. DeVita、Thomas F. Walsh、Jonathan R. Young、Jinlong Jiang、Feroze Ujjainwalla、Richard B. Toupence、Mamta Parikh、Song X. Huang、Jason A. Fair、Mark T. Goulet、Matthew J. Wyvratt、Jane-L. Lo、Ning Ren、Joel B. Yudkovitz、Yi T. Yang、Kang Cheng、Jisong Cui、George Mount、Susan P. Rohrer、James M. Schaeffer、Linda Rhodes、Jennifer E. Drisko、Erin McGowan、D. Euan MacIntyre、Styliani Vincent、Josephine R. Carlin、Judith Cameron、Roy G. Smith

  DOI：10.1021/jm000275p

  日期：2001.3.1

  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.