5-bromo-3-ethoxycarbonyl-2-hydroxyacetophenone | 185347-31-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 5-bromo-3-ethoxycarbonyl-2-hydroxyacetophenone
• 英文别名: Ethyl 3-acetyl-5-bromo-2-hydroxybenzoate
• CAS: 185347-31-3
• 化学式: C₁₁H₁₁BrO₄
• 分子量: 287.11
• InChiKey: UROABOHFTYMYBH-UHFFFAOYSA-N

物化性质

• 熔点：
  64.0-65.2 °C
• 沸点：
  353.0±42.0 °C(Predicted)
• 密度：
  1.511±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-bromo-3-ethoxycarbonyl-2-hydroxyacetophenone 在 甲酸 、 硫酸 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.5h， 生成 6-bromo-8-ethoxycarbonyl-3'-(2-benzothiazolylmethoxy)flavone
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of Carboxyflavones as Structurally Rigid CysLT₁ (LTD₄) Receptor Antagonists

  摘要：

  The synthesis and CysLT(1) receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted 6-, 7-, or 8-carboxylated flavones are described. CysLT(1) receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [H-3]LTD4 from its receptor in guinea pig lung membranes. Structure-affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT(1) affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT(1) affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity to the quinoline. Flavones having CysLT(1) receptor affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD4-induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF 5087) was selected for further research because of its high potency in the functional assay. This series contains the most rigid CysLT(1) receptor antagonists known to date, and they are useful in the development of a CysLT(1) antagonist model, which is discussed in the companion paper.

  DOI：

  10.1021/jm970179x
• 作为产物：
  描述：

  乙醇 、 3-acetyl-5-bromo-2-hydroxybenzoic acid 在 硫酸 作用下， 反应 5.0h， 以75%的产率得到5-bromo-3-ethoxycarbonyl-2-hydroxyacetophenone
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of Carboxyflavones as Structurally Rigid CysLT₁ (LTD₄) Receptor Antagonists

  摘要：

  The synthesis and CysLT(1) receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted 6-, 7-, or 8-carboxylated flavones are described. CysLT(1) receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [H-3]LTD4 from its receptor in guinea pig lung membranes. Structure-affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT(1) affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT(1) affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity to the quinoline. Flavones having CysLT(1) receptor affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD4-induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF 5087) was selected for further research because of its high potency in the functional assay. This series contains the most rigid CysLT(1) receptor antagonists known to date, and they are useful in the development of a CysLT(1) antagonist model, which is discussed in the companion paper.

  DOI：

  10.1021/jm970179x

文献信息

• Flavone derivative and medicine comprising the same
  申请人：Kowa Co., Ltd.

  公开号：US06136848A1

  公开（公告）日：2000-10-24

  This invention relates to a flavone derivative represented by the formula (1) or a salt thereof, and also to a medicine containing the same. ##STR1## wherein A represents H, halogen, phenyl, naphthyl, a group of the formula (2) in which X is H or halogen, B is --CH.dbd.CH--, --CH.dbd.N--, --N(R.sup.7)-- (R.sup.7 : lower alkyl or alkoxyalkyl), --O-- or --S--; W represents a single bond, --CH.sub.2 O-- or --CH.dbd.CH--; at least one of R.sup.1 to R.sup.4 represents --COOH, --CN, alkyloxycarbonyl, tetrazolyl or --CONHR.sup.8 (R.sup.8 : H, lower alkyl or phenylsulfonyl), the remainder thereof individually represent H, halogen, --OH, lower alkyl or lower alkoxyl; R.sup.5 represents H, --OH, lower alkoxyl, --O(CH.sub.2).sub.m NR.sup.9 R.sup.10 (R.sup.9,R.sup.10 : H or lower alkyl, or coupled together with the adjacent N to form a phthalimido group; m: 1-5), or a group of the formula (3) (n: 1-5, l: 2-3; and R.sup.6 represents H, halogen, lower alkyl or lower alkoxyl. A situation where A is H or halogen, W is a single bond and R.sup.5 is H is excluded. The compound (1) has excellent cys-LT.sub.1 receptor antagonism.

  本发明涉及一种由式（1）表示的黄酮衍生物或其盐，以及包含该衍生物的药物。其中A代表H，卤素，苯基，萘基，式（2）中的一个基团，其中X为H或卤素，B为--CH.dbd.CH--，--CH.dbd.N--，--N(R.sup.7)--（R.sup.7：低碳基或烷氧基烷基），--O--或--S--；W代表单键，--CH.sub.2 O--或--CH.dbd.CH--；R.sup.1至R.sup.4中的至少一个代表--COOH，--CN，烷氧羰基，四唑基或--CONHR.sup.8（R.sup.8：H，低碳基或苯基磺酰基），其余各自代表H，卤素，--OH，低碳基或低烷氧基；R.sup.5代表H，--OH，低烷氧基，--O(CH.sub.2).sub.m NR.sup.9 R.sup.10（R.sup.9，R.sup.10：H或低碳基，或与相邻的N结合形成邻苯二甲酰亚胺基；m：1-5），或式（3）中的一个基团（n：1-5，l：2-3；R.sup.6代表H，卤素，低碳基或低烷氧基。排除A为H或卤素，W为单键且R.sup.5为H的情况。该化合物（1）具有优异的cys-LT.sub.1受体拮抗作用。
• Synthesis of carboxylated flavonoids as new leads for LTD4 antagonists
  作者：ME Zwaagstra、H Timmerman、RS Abdoelgafoer、MQ Zhang

  DOI：10.1016/s0223-5234(97)89849-2

  日期：1996.1

  A series of 3'- and 5'-carboxylated chalcones, 6- or 8-carboxylated flavones and 6-carboxylated flavanones, -flavanols and -flavans were prepared. The compounds were tested for their inhibitory activities against leukotriene D-4 (LTD(4)) induced contraction of guinea-pig ileum. A new and convenient synthetic route to 3-acetyl-2-hydroxybenzoic acid (1d), a key intermediate for the synthesis of 3'-carboxy-2'-hydroxychalcones and 8-carboxylated flavones, was developed. The activities of the tested compounds ranged from 0 to 63% inhibition at 10(-5) M drug concentration against a single challenge of 10(-8) M LTD(4). Several compounds were tested in a radioligand binding assay against [H-3]LTD(4) on guinea-pig lung membrane. The quinoline-containing chalcone 12 and flavone 17 were found to exhibit significant but weak affinities for LTD(4) receptors with pK(D)-values of 4.95 and 4.83, respectively, and are interesting lead structures for the development of rigid LTD(4) antagonists. In contrast, the rest of the compounds tested in the binding assay did not show significant displacement of the radioligand, implying that for these compounds the functional activity is probably not caused by competitive antagonism at the LTD(4) receptor. The exact mechanism of the relaxant activity remains unclear.
• Synthesis of 3-and 5′-substituted flavone-8-carboxylic acids as ‘three-armed’ leukotriene CysLT1 receptor antagonists
  作者：Mariël E. Zwaagstra、Ronald E.M. Korthouwer、Henk Timmerman、Ming-Qiang Zhang

  DOI：10.1016/s0223-5234(98)80034-2

  日期：1998.2

  Molecular modelling of leukotriene CysLT(1) receptor antagonists have suggested that in addition to the two binding sites for a lipophilic and an acidic group, the receptor has a 'third pocket' to accommodate 'three-armed' ligands such as montelukast 1. Based on the most rigid CysLT(1) receptor antagonist 3'-[2-(2-quinolinyl)ethenyl]flavone-8-carboxylic acid 2, we have synthesised 3- and 5'-substituted flavone derivatives to probe this additional binding pocket. Introduction of large substituents, e.g. 2-quinolinyl-methoxy, to the C5' position of the flavone skeleton abolished the CysLT(1) receptor affinity whereas the same modification at the C3 position yielded a potent CysLT antagonist. This observation implies that the third binding pocket of the receptor has considerable steric tolerance, probably corresponding to the substituents at C3 of the flavone skeleton. Further modification by introducing a C3 substituent containing a basic nitrogen resulted in compound 6g with potent H-1 antihistaminic activity although the CysLT(1) antagonistic activity was much reduced. Further study on the CysLT(1) receptor recognition of three armed antagonists may facilitate the design of more effective antiasthmatic agents, e.g. dual antagonists of histamine H-1 and leukotriene CysLT(1) receptors. (C) Elsevier, Paris.
• US6136848A
  申请人：——

  公开号：US6136848A

  公开（公告）日：2000-10-24
• Synthesis and Structure−Activity Relationships of Carboxyflavones as Structurally Rigid <i>CysLT</i><i>₁</i> (LTD₄) Receptor Antagonists
  作者：Mariël E. Zwaagstra、Henk Timmerman、Andrea C. van de Stolpe、Frans J. J. de Kanter、Masahiro Tamura、Yasushi Wada、Ming-Qiang Zhang

  DOI：10.1021/jm970179x

  日期：1998.4.1

  The synthesis and CysLT(1) receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted 6-, 7-, or 8-carboxylated flavones are described. CysLT(1) receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [H-3]LTD4 from its receptor in guinea pig lung membranes. Structure-affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT(1) affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT(1) affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity to the quinoline. Flavones having CysLT(1) receptor affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD4-induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF 5087) was selected for further research because of its high potency in the functional assay. This series contains the most rigid CysLT(1) receptor antagonists known to date, and they are useful in the development of a CysLT(1) antagonist model, which is discussed in the companion paper.