2-(3-chlorophenyl)-1-(2,4,6-trihydroxyphenyl)ethanone

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 2-(3-chlorophenyl)-1-(2,4,6-trihydroxyphenyl)ethanone
• 英文别名: RM-6431；2-(3-Chlorophenyl)-1-(2,4,6-trihydroxyphenyl)ethan-1-one
• 化学式: C₁₄H₁₁ClO₄
• 分子量: 278.692
• InChiKey: UDMLVGSGFGXFEF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N,N-二甲基甲酰胺 、 2-(3-chlorophenyl)-1-(2,4,6-trihydroxyphenyl)ethanone 在 三氟化硼乙醚 、 甲基磺酰氯 作用下， 反应 2.0h， 以95%的产率得到3-(3-Chloro-phenyl)-5,7-dihydroxy-chromen-4-one
  参考文献：
  名称：

  Use of a Pharmacophore Model for the Design of EGFR Tyrosine Kinase Inhibitors:  Isoflavones and 3-Phenyl-4(1H)-quinolones

  摘要：

  Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the lick tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in I, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6,7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-clibydroxyisoflavone (fi) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of II did not further improve enzyme inhibitory activity but; led to derivatives with cellular activity in the lower micromolar range.

  DOI：

  10.1021/jm980551o
• 作为产物：
  描述：

  间苯三酚 、 间氯氰苄 在 盐酸 、 zinc(II) chloride 作用下， 生成 2-(3-chlorophenyl)-1-(2,4,6-trihydroxyphenyl)ethanone
  参考文献：
  名称：

  Use of a Pharmacophore Model for the Design of EGFR Tyrosine Kinase Inhibitors:  Isoflavones and 3-Phenyl-4(1H)-quinolones

  摘要：

  Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the lick tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in I, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6,7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-clibydroxyisoflavone (fi) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of II did not further improve enzyme inhibitory activity but; led to derivatives with cellular activity in the lower micromolar range.

  DOI：

  10.1021/jm980551o

文献信息

• [EN] PHENYL-SUBSTITUTED BICYCLIC HETEROCYCLYL DERIVATIVES AND THEIR USE<br/>[FR] DERIVES D'HETEROCYCLYLE BICYCLIQUE A SUBSTITUTION PHENYLE ET UTILISATION DE CES DERIVES
  申请人：NOVARTIS AG

  公开号：WO1998017662A1

  公开（公告）日：1998-04-30

  (EN) The invention relates to the use of a compound of formula (I), wherein R1 and R2, independently of each other, represent hydrogen, hydroxy or lower alkoxy, or R1 and R2 together form lower alkylenedioxy; R3 is halogen, lower alkyl, halogen-substituted lower alkyl, hydroxy, phenyloxy, C3-C7-cycloalkyloxy or lower alkoxy; any R4 is, independently of R3 and independently of any other R4 if present, selected from halogen, lower alkyl, halogen-substituted lower alkyl, hydroxy, phenyloxy, C3-C7-cycloalkyloxy or lower alkoxy; X is oxygen, imino or (halogen-substituted or unsubstituted lower alkanoyl, [lower alkyl or carboxy-, lower alkoxycarbonyl-, aminocarbonyl-, N-mono- or N,N-di-lower alkylamino carbonyl]-lower alkyl; or C6-C12-aryl)-substituted imino; and n is 0, 1, 3 or 4; or a salt thereof if at least one salt-forming group is present, in the treatment of certain diseases and the inhibition of protein kinases, as well as to new compounds of formula (I) and salts thereof.(FR) Cette invention concerne l'utilisation d'un composé de formule (I) dans laquelle R1 et R2 représentent indépendamment l'un de l'autre hydrogène, hydroxy ou alcoxy inférieur, ou bien R1 et R2 forment ensemble alkylènedioxy inférieur; R3 représente halogène, alkyle inférieur, alkyle inférieur à substitution halogène, hydroxy, phényloxy, cycloalkyloxy C3-C7 alcoxy inférieur; tout R4 indépendamment de R3 et indépendamment de tout autre R4 existant est sélectionné parmi halogène, alkyle inférieur, alkyle inférieur à substitution halogène, hydroxy, phényloxy, cycloalkyloxy C3-C7 alcoxy inférieur; X représente oxygène, imino ou imino à substitution (alcanoyle inférieur à substitution halogène ou non substitué, [alkyle inférieur ou carboxy-, alcoxycarbonyle inférieur, aminocarbonyle, N-mono- ou N,N,di-alkylamino inférieur-carbonyle] alkyle inférieur; ou aryle C6-C12); et n représente 0, 1, 3 ou 4. On peut utiliser ce composé ou un de ses sels s'il existe au moins un groupe formant un sel, dans le traitement de certaines maladies et pour inhiber des protéine kinases. Cette invention concerne également de nouveaux composés de formule (I) ainsi que leurs sels.