1-(4-Bromo-2-fluorophenyl)methyl-6-chloro-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetic acid | 133166-49-1

• 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: 1-(4-Bromo-2-fluorophenyl)methyl-6-chloro-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetic acid
• 英文别名: 2-[1-[(4-bromo-2-fluorophenyl)methyl]-6-chloro-2,4-dioxoquinazolin-3-yl]acetic acid
• CAS: 133166-49-1
• 化学式: C₁₇H₁₁BrClFN₂O₄
• 分子量: 441.641
• InChiKey: QSTJBCAKTXXQKM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  77.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  N-<2-<<(4-bromo-2-fluorophenyl)methyl>amino>-6-chlorobenzoyl>glycine 1,1-dimethylethyl ester 在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 为溶剂， 反应 4.5h， 生成 1-(4-Bromo-2-fluorophenyl)methyl-6-chloro-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetic acid
  参考文献：
  名称：

  Quinazolineacetic acids and related analogs as aldose reductase inhibitors

  摘要：

  A variety of 2,4-dioxoquinazolineacetic acids (10, 11) were synthesized as hybrids of the known aldose reductase inhibitors alrestatin (8), ICI-105,552 (9), and ICI-128,436 (2) and evaluated for their ability to inhibit partially purified bovine lens aldose reductase (in vitro) and their effectiveness to decrease galactitol accumulation in the 4-day galactosemic rat model (in vivo). In support to SAR studies, related analogues pyrimidinediones (12), dihydroquinazolones (13), and indazolidinones (14, 15) were synthesized and tested in the in vitro and in vivo assays. All prepared compounds (10-15) have shown a high level of in vitro activity (IC50 approximately 10(-6) to 4 x 10(-8) M). However, only the 2,4-quinazolinedione analogues 10 and 11, with similar N-aralkyl substitution found in 2 and 9, have exhibited good oral potency. The remaining compounds were either inactive or had only a marginal in vivo activity. The structure-activity data support the presence of a secondary hydrophobic pocket in the vicinity of the primary lipophilic region of the enzyme.

  DOI：

  10.1021/jm00108a038

文献信息

• Quinazoline-3-alkanoic acid derivatives, their salts and their
  申请人：Kyorin Pharmaceutical Co., Ltd.

  公开号：US05234928A1

  公开（公告）日：1993-08-10

  The present invention relates to quinazoline-3-alkanoic acid derivatives having both an inhibitory effect on platelet aggregation and a hindering effect on aldose reductase together, represented by a general formula [I] ##STR1## [wherein R is hydrogen or a protecting group for carboxyl group, R.sup.1 is a lower alkyl group, alkenyl group, alkinyl group, lower alkoxy group, lower alkylthio group, halogen, phenyl group (this phenyl group may be substituted by one to three of lower alkyls, lower alkoxys, halogens, trifluoromethyls, carboxyethylenes or ethoxycarbonylethylenes, naphthyl group, heterocycle (this heterocycle may be substituted by one to three of lower alkyls), cycloalkyl group or benzoyl group (this benzoyl group may be substituted by lower alkyl or halogen), R.sup.2 and R.sup.3 are identically or differently hydrogens, halogens, lower alkyl groups, lower alkoxy groups, aralkyl groups which may be substituted, nitro groups, imidazolyl groups, imidazolylmethyl groups or ##STR2## (R.sup.4 and R.sup.5 indicate identically or differently hydrogens or lower alkyl groups, or connected with each other to make five- or six-membered heterocycles which may contain other hetero atom, X is carbonyl, thiocarbonyl or methylene group (this methylene group may be substituted by lower alkyl group), A is lower alkylene or lower alkenylene, and n indicates an integer of 1 to 3], their salts, their preparation processes and medicinal drugs containing them.

  本发明涉及具有对血小板聚集的抑制作用和对醛糖还原酶的阻碍作用的喹唑啉-3-烷酸衍生物，其通式[I]所代表，其中R是氢或羧基的保护基，R.sup.1是较低的烷基、烯基、炔基、较低的烷氧基、较低的烷硫基、卤素、苯基（该苯基可能被一个至三个较低的烷基、较低的烷氧基、卤素、三氟甲基、羧基乙烯基或乙氧基羰基乙烯基取代），萘基、杂环（该杂环可能被一个至三个较低的烷基取代）、环烷基或苯甲酰基（该苯甲酰基可能被较低的烷基或卤素取代），R.sup.2和R.sup.3是相同或不同的氢、卤素、较低的烷基、较低的烷氧基、可能被取代的芳基、硝基、咪唑基、咪唑基甲基或##STR2##（R.sup.4和R.sup.5表示相同或不同的氢或较低的烷基，或彼此连接以形成含有其他杂原子的五元或六元杂环，X是羰基、硫代羰基或亚甲基（该亚甲基可能被较低的烷基取代），A是较低的烷基或较低的烯基，n为1至3的整数，它们的盐、制备方法和含有它们的药物。
• QUINAZOLINE-3-ALKANOIC ACID DERIVATIVE, SALT THEREOF, AND PRODUCTION THEREOF
  申请人：KYORIN PHARMACEUTICAL CO., LTD.

  公开号：EP0456835A1

  公开（公告）日：1991-11-21

  A quinazoline-3-alkanoic acid derivative of general formula (I), which has both of platelet agglutination inhibition and aldose reductase inhibition activities, salts thereof, process for producing the same, and a medicine containing the same, wherein R represents hydrogen or a protective group of the carboxyl group; R' represents lower alkyl, alkenyl, alkynyl, lower alkoxy, lower alkylthio, halogen, phenyl (which may be substituted with 1 to 3 substituents selected from among lower alkyl, lower alkoxy, halogen, trifluoromethyl, carboxyethylene, and ethoxy-carbonylethylene groups), naphthyl, heterocycle (which may be substituted with 1 to 3 lower alkyl groups), cycloalkyl, or benzoyl (which may be substituted with lower alkyl or halogen); R² and R³ may be the same or different from each other and each represents hydrogen, halogen, lower alkyl, lower alkoxy, optionally substituted aralkyl, nitro, imidazolyl, imidazolylmethyl, or -NR⁴R⁵ wherein R⁴ and R⁵ may be the same or different from each other and each represents hydrogen or lower alkyl, or they are combined with each other to form a 5- or 6-membered heterocycle which may contain other heteroatom(s); X represents carbonyl, thiocarbonyl or methylene (which may be substituted with lower alkyl); A represents lower alkylene or lower alkenylene; and n is an integer of 1 to 3.

  一种同时具有血小板凝集抑制活性和醛糖还原酶抑制活性的通式(I)的喹唑啉-3-烷酸衍生物、其盐类、生产工艺以及含有该衍生物的药物，其中 R 代表氢或羧基的保护基团；R'代表低级烷基、烯基、炔基、低级烷氧基、低级烷硫基、卤素、苯基（可被 1 至 3 个选自低级烷基、低级烷氧基、卤素、三氟甲基、羧基乙烯和乙氧基羰基乙烯基团的取代基取代）、萘基、杂环（可被 1 至 3 个低级烷基取代）、环烷基或苯甲酰基（可被低级烷基或卤素取代）；R² 和 R³ 可以相同或互不相同，各自代表氢、卤素、低级烷基、低级烷氧基、任选取代的芳烷基、硝基、咪唑基、咪唑甲基或 -NR⁴R⁵，其中 R⁴ 和 R⁵ 可以相同或互不相同，各自代表氢或低级烷基，或者它们相互结合形成 5 或 6 元杂环，该杂环可含有其他杂原子；X 代表羰基、硫代羰基或亚甲基（可被低级烷基取代）；A 代表低级亚烷基或低级亚烯基；n 是 1 至 3 的整数。
• US5234928A
  申请人：——

  公开号：US5234928A

  公开（公告）日：1993-08-10
• Quinazolineacetic acids and related analogs as aldose reductase inhibitors
  作者：Michael S. Malamas、Jane Millen

  DOI：10.1021/jm00108a038

  日期：1991.4

  A variety of 2,4-dioxoquinazolineacetic acids (10, 11) were synthesized as hybrids of the known aldose reductase inhibitors alrestatin (8), ICI-105,552 (9), and ICI-128,436 (2) and evaluated for their ability to inhibit partially purified bovine lens aldose reductase (in vitro) and their effectiveness to decrease galactitol accumulation in the 4-day galactosemic rat model (in vivo). In support to SAR studies, related analogues pyrimidinediones (12), dihydroquinazolones (13), and indazolidinones (14, 15) were synthesized and tested in the in vitro and in vivo assays. All prepared compounds (10-15) have shown a high level of in vitro activity (IC50 approximately 10(-6) to 4 x 10(-8) M). However, only the 2,4-quinazolinedione analogues 10 and 11, with similar N-aralkyl substitution found in 2 and 9, have exhibited good oral potency. The remaining compounds were either inactive or had only a marginal in vivo activity. The structure-activity data support the presence of a secondary hydrophobic pocket in the vicinity of the primary lipophilic region of the enzyme.