N-(3-bromophenyl)-8H-pyrrolo[3,2-g]quinazolin-4-amine

• 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: N-(3-bromophenyl)-8H-pyrrolo[3,2-g]quinazolin-4-amine
• 化学式: C₁₆H₁₁BrN₄
• 分子量: 339.194
• InChiKey: BBFWQWIFLDQYQQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  53.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(3-bromophenyl)-8H-pyrrolo[3,2-g]quinazolin-4-amine 在 sodium hydroxide 、 sodium hydride 作用下， 以 甲醇 为溶剂， 反应 2.08h， 生成 5-[(3-bromophenyl)amino]pyrrolo[3,2-g]quinazoline-1-acetic acid
  参考文献：
  名称：

  Tyrosine Kinase Inhibitors. 11. Soluble Analogues of Pyrrolo- and Pyrazoloquinazolines as Epidermal Growth Factor Receptor Inhibitors:  Synthesis, Biological Evaluation, and Modeling of the Mode of Binding

  摘要：

  A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the thioethers, N-1-alkylation, and coupling with 3-bromoaniline. C-S-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the isolated epidermal growth factor receptor (EGFR) and of its autophosphorylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays. A model for the binding of the general class of 4-anilinoquinazolines to the EGFR was constructed from structural information (particularly for the catalytic subunit of the cAMP-dependent protein kinase) and structure-activity relationships (SAR) in the series. In this model, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the entrance of the ATP binding pocket of the enzyme, with the pyrrole nitrogen located at the bottom of the cleft and the pyrrole C-3 position pointing toward a pocket corresponding to the ribose binding site of ATP. This allows considerable bulk tolerance for C-3 substituents and lesser but still significant bulk tolerance for N-1 substituents. The observed high selectivity of these compounds for binding to EGFR over other similar tyrosine kinases is attributed to the 4-anilino ring binding in an adjacent hydrophobic pocket which has an amino acid composition unique to the EGFR. The SAR seen for inhibition of the isolated enzyme by the pyrazolo- and pyrroloquinazolines discussed here is fully consistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with inhibition of the isolated enzyme, as seen previously for related pyridopyrimidines. However, the C-S-substituted pyrroloquinazolines show unexpectedly high potencies in the autophosphorylation assay, making them of particular interest.

  DOI：

  10.1021/jm960789h

文献信息

• US6596726B1
  申请人：——

  公开号：US6596726B1

  公开（公告）日：2003-07-22
• [EN] MODULATORS OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) PATHWAY FOR USE IN THE TREATMENT OR PREVENTION OF SUBSTANCE ABUSE<br/>[FR] MODULATEURS DE LA VOIE DES RÉCEPTEURS DU FACTEUR DE CROISSANCE ÉPIDERMIQUE (EGFR) POUR UTILISATION DANS LE TRAITEMENT OU LA PRÉVENTION DE LA CONSOMMATION EXCESSIVE D'ALCOOL OU D'AUTRES DROGUES
  申请人：UNIV CALIFORNIA

  公开号：WO2009070328A1

  公开（公告）日：2009-06-04

  The present invention provides methods of using modulators of the epidermal growth factor receptor (EGFR) pathway for treatment or prevention of substance abuse such as alcohol abuse. The modulators include small molecule inhibitors such as Erlotinib (TARCEVA®, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4- quinazolineamine) or a pharmaceutically acceptable salt, hydrate or prodrug thereof and Gefitinib [IRES S A®, N-(3 -chloro-4-fluoro-phenyl)-7-methoxy-6-(3 -morpholin-4- ylpropoxy)quinazolin-4-amine] or a pharmaceutically acceptable salt, hydrate or prodrug thereof and various macromolecular inhibitors of the EGFR pathway such as siRNAs and antibodies that target genes or proteins in the EGFR/ERK pathway such as one of the EGFR/ErbB protein or a homolog thereof.