7-(4-{[(4-carboxyphenylamino)carbonylamino]methyl}imidazol-1-yl)-3,4-dihydro-3-oxo-6-(trifluoromethyl)quinoxaline-2-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 7-(4-{[(4-carboxyphenylamino)carbonylamino]methyl}imidazol-1-yl)-3,4-dihydro-3-oxo-6-(trifluoromethyl)quinoxaline-2-carboxylic acid
• 英文别名: 7-(4-(((4-Carboxyphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylic acid；7-[4-[[(4-carboxyphenyl)carbamoylamino]methyl]imidazol-1-yl]-3-oxo-6-(trifluoromethyl)-4H-quinoxaline-2-carboxylic acid
• 化学式: C₂₂H₁₅F₃N₆O₆
• 分子量: 516.393
• InChiKey: KEPYXBRRBZFMQU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  175
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  4-fluoro-3-(trifluoromethyl)acetanilide 在 palladium on activated charcoal 、 Pd/Ac 盐酸 、 manganese(IV) oxide 、 sodium hydroxide 、 盐酸羟胺 、 氢气 、 硝酸 、 sodium acetate 、 potassium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 140.0 ℃ 、405.3 kPa 条件下， 反应 73.5h， 生成 7-(4-{[(4-carboxyphenylamino)carbonylamino]methyl}imidazol-1-yl)-3,4-dihydro-3-oxo-6-(trifluoromethyl)quinoxaline-2-carboxylic acid
  参考文献：
  名称：

  Design and synthesis of novel 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group as superior AMPA receptor antagonists with good physicochemical properties

  摘要：

  We describe the design, synthesis, and physicochemical and biological properties of a novel series of 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group joined through a urethane or urea linkage to the heterocycle at the 7 position. Introduction of the trifluoromethyl group at the 6 position conferred good biological activity, including neuroprotective effects, as well as good physicochemical properties. In terms of alpha-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) affinity, a urea linkage was equivalent to a urethane linkage and a pyrrole ring at the 7 position reduced affinity in comparison with an imidazole ring. Among this series, compound 14h (KRP-199), which has a 4-carboxyphenyl group joined through a urethane linkage to a 7-imidazolyl heterocycle, was found to possess high potency and selectivity for the AMPA-R in vitro and to exhibit good neuroprotective effects in vivo. Furthermore, the compound showed good physicochemical properties, including stability to light and good solubility in aqueous solutions. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.08.060

文献信息

• 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives, addition salts thereof, and processes for the preparation of both
  申请人：Kyorin Pharmaceutical Co., Ltd.

  公开号：US06348461B1

  公开（公告）日：2002-02-19

  The present invention provides 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compounds and their addition salts, and processes for preparing them, which have antagonism against excitatory amino acid receptors, in particular, an AMPA receptor. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compounds and their addition salts of the present invention are represented by formula (1) wherein Q, R, R1 and R2 are as described in the specification.

  本发明提供了6,7-不对称二取代喹喔啉羧酸化合物及其加合盐，以及制备它们的方法，这些化合物对兴奋性氨基酸受体，特别是AMPA受体具有拮抗作用。本发明的6,7-不对称二取代喹喔啉羧酸化合物及其加合盐由下式表示（1式），其中Q、R、R1和R2如规范中所述。
• 6,7-ASYMMETRICALLY DISUBSTITUTED QUINOXALINECARBOXYLIC ACID DERI VATIVES, ADDITION SALTS THEREOF, AND PROCESSES FOR THE PREPARATION OF BOTH
  申请人：KYORIN PHARMACEUTICAL CO., LTD.

  公开号：EP1020453A1

  公开（公告）日：2000-07-19

  The present invention provides compounds with antagonism against excitatory amino acid receptors, in particular, AMPA receptor, having 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives and their addition salts as effective ingredients, and processes for preparing them, and relates to 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives represented by a general formula (1) [wherein, Q denotes a halogen atom, lower alkyl group which may be substituted with halogen atom, general formula (2)         Ar-P-     (2) (wherein Ar denotes a phenyl group or naphthyl group which may have one or more substituents, and P denotes a lower alkylene, lower alkenylene, lower alkynylene, oxygen or sulfur atom), or general formula (3);         L-A-     (3) R denotes a nitro group, trifluoromethyl group, amino group which may be substituted, or general formula (7), R1 denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), hydrogen atom, lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and R2 denotes a hydroxyl group, lower alkoxy group or general formula (6) ], and their addition salts.

  本发明提供了以6，7-不对称二取代的喹喔啉羧酸衍生物及其加成盐为有效成分的对兴奋性氨基酸受体，特别是AMPA受体具有拮抗作用的化合物及其制备工艺，并涉及通式(1)表示的6，7-不对称二取代的喹喔啉羧酸衍生物 [其中，Q 表示卤素原子、可被卤素原子取代的低级烷基、通式 (2) Ar-P- (2) (其中 Ar 表示苯基或萘基，可带有一个或多个取代基，P 表示低级亚烷基、低级亚烯基、低级亚炔基、氧原子或硫原子）或通式（3）； L-A- (3) R 表示硝基、三氟甲基、可被取代的氨基或通式（7）、 R1 表示芳烷基、苯基、萘基、5 或 6 元杂环及其缩合环（可在芳香环或杂环上有一个或多个取代基）、氢原子、可被卤素原子取代的低级烷基或环烷基，R2 表示羟基、低级烷氧基或通式（6）。 ] 以及它们的加成盐。
• 6,7-ASYMMETRICALLY DISUBSTITUTED QUINOXALINECARBOXYLIC ACID DERIVATIVES, ADDITION SALTS THEREOF, AND PROCESSES FOR THE PREPARATION OF BOTH
  申请人：KYORIN PHARMACEUTICAL CO., LTD.

  公开号：EP1020453B1

  公开（公告）日：2004-05-19
• US6348461B1
  申请人：——

  公开号：US6348461B1

  公开（公告）日：2002-02-19
• Design and synthesis of novel 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group as superior AMPA receptor antagonists with good physicochemical properties
  作者：Yasuo Takano、Futoshi Shiga、Jun Asano、Wataru Hori、Kazunori Fukuchi、Tsuyoshi Anraku、Takashi Uno

  DOI：10.1016/j.bmc.2005.08.060

  日期：2006.2

  We describe the design, synthesis, and physicochemical and biological properties of a novel series of 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group joined through a urethane or urea linkage to the heterocycle at the 7 position. Introduction of the trifluoromethyl group at the 6 position conferred good biological activity, including neuroprotective effects, as well as good physicochemical properties. In terms of alpha-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) affinity, a urea linkage was equivalent to a urethane linkage and a pyrrole ring at the 7 position reduced affinity in comparison with an imidazole ring. Among this series, compound 14h (KRP-199), which has a 4-carboxyphenyl group joined through a urethane linkage to a 7-imidazolyl heterocycle, was found to possess high potency and selectivity for the AMPA-R in vitro and to exhibit good neuroprotective effects in vivo. Furthermore, the compound showed good physicochemical properties, including stability to light and good solubility in aqueous solutions. (c) 2005 Elsevier Ltd. All rights reserved.