6-amino-4-[(3-chlorophenyl)amino]quinazoline | 153436-71-6

• 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: 6-amino-4-[(3-chlorophenyl)amino]quinazoline
• 英文别名: N⁴-(3-chlorophenyl)quinazoline-4,6-diamine；4-N-(3-chlorophenyl)quinazoline-4,6-diamine；FD 105；N4-(3-chlorophenyl)quinazoline-4,6-diamine
• CAS: 153436-71-6
• 化学式: C₁₄H₁₁ClN₄
• 分子量: 270.721
• InChiKey: AWAYNEMCHILZCF-UHFFFAOYSA-N

物化性质

• 熔点：
  186-189 °C
• 沸点：
  472.5±40.0 °C(Predicted)
• 密度：
  1.422±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  63.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-amino-4-[(3-chlorophenyl)amino]quinazoline 在 吡啶 、 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 3-(2-Chloro-ethyl)-1-[4-(3-chloro-phenylamino)-quinazolin-6-yl]-1-methyl-urea
  参考文献：
  名称：

  The Combi-Targeting Concept:  Synthesis of Stable Nitrosoureas Designed to Inhibit the Epidermal Growth Factor Receptor (EGFR)

  摘要：

  According to the "combi-targeting" concept, the EGFR tyrosine kinase ( TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds ( 3'-Cl and Br series) with small angles ( 0.5-3 degrees) were generally stronger EGFR TK inhibitors than those with large angles ( 18-21 degrees). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC50 values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line ( Pearson r = 0.8). On the basis of stability ( t(1/2)), EGFR TK inhibitory potency ( IC50), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.

  DOI：

  10.1021/jm0600390
• 作为产物：
  描述：

  2-氰基-4-硝基苯胺 在 乙酸酐 、 溶剂黄146 、 tin(ll) chloride 作用下， 以 甲醇 为溶剂， 反应 17.5h， 生成 6-amino-4-[(3-chlorophenyl)amino]quinazoline
  参考文献：
  名称：

  (4-苯氨基)喹唑啉烷基硫脲衍生物作为新型 NF-κB 抑制剂的开发

  摘要：

  对于许多炎症性疾病，需要新的、副作用较少的有效药物。虽然它似乎有希望靶向激活中枢促炎转录因子 NF-κB，但许多先前发现的药物都具有细胞毒性。在这项研究中，开发了新的烷基硫脲喹唑啉衍生物，可选择性地抑制巨噬细胞样 THP-1 细胞中 NF-κB 的活化，同时显示出较低的一般细胞毒性。最好的化合物之一19强烈抑制 IL-6 (IC 50 = 0.84 µM) 的产生，而对 TNFα (IC 50 = 4.0 µM) 的抑制作用较弱；相比之下，参比化合物咖啡酸苯乙酯 (CAPE) 的 IC 50 s 分别为 1.1 和 11.4 µM。有趣的是，19发现阻断 NF-κB 二聚体向细胞核的易位，尽管其从 IκB 复合物的释放不受影响。此外，19抑制了 NF-κB-p65 在 Ser468 位点的磷酸化，而不是在 Ser536 位点；然而，19没有抑制任何参与 NF-κB 活化的激酶。p65 磷酸

  DOI：

  10.3390/ph15070778

文献信息

• The combination of 4-anilinoquinazoline and cinnamic acid: A novel mode of binding to the epidermal growth factor receptor tyrosine kinase
  作者：Dong-Dong Li、Peng-Cheng Lv、Hui Zhang、Hong-Jia Zhang、Ya-Ping Hou、Kai Liu、Yong-Hao Ye、Hai-Liang Zhu

  DOI：10.1016/j.bmc.2011.06.044

  日期：2011.8

  A novel type of cinnamic acid quinazoline amide derivatives (20–42), which designed the combination between quinazoline as the backbone and various substituted cinnamic acid as the side chain, have been synthesized and their biological activities were evaluated within cytotoxicity assay firstly and then potent EGFR inhibitory activity. Compound 42 demonstrated the most potent inhibitory activity (IC50 = 0

  一种新的类型的肉桂酸喹唑啉酰胺衍生物（的20 - 42），其设计喹唑啉作为骨架和各种取代的肉桂酸作为侧链之间的组合，已被合成和它们的生物活性进行了细胞毒性测定法中评价首先，然后有力EGFR抑制活性。化合物42表现出最强的抑制活性（ EGFR的IC 50 = 0.94μM），可以在进一步的研究中将其优化为潜在的EGFR抑制剂。进行对接模拟以将化合物42定位在EGFR活性位点中以确定可能的结合模型。42的结合构象分析在活性位点显示，化合物42通过与Lys822的氢键相互作用而稳定，这与其他衍生物不同。在进一步的研究中，合成了化合物43和44，并评估了其生物学活性，与我们预期的相同。化合物43 作为潜在的抗癌剂已显示出显着的EGFR（IC 50 = 0.12μM）和抑制肿瘤生长的活性。
• Identification of 4-anilino-6-aminoquinazoline derivatives as potential MERS-CoV inhibitors
  作者：Jun Young Lee、Young Sup Shin、Jihye Lee、Sunoh Kwon、Young-hee Jin、Min Seong Jang、Seungtaek Kim、Jong Hwan Song、Hyoung Rae Kim、Chul Min Park

  DOI：10.1016/j.bmcl.2020.127472

  日期：2020.10

  New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N4-(3-Chloro-4-fluorophenyl)-N6-(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was

  迫切需要治疗冠状病毒的新疗法。合成并评估了一系列 4-苯胺基-6-氨基喹唑啉衍生物，显示出高抗 MERS-CoV 活性。N 4 -(3-氯-4-氟苯基)- N 6 -(3-甲氧基苄基)喹唑啉-4,6-二胺 ( 1 ) 已在随机筛选中被鉴定为抑制 MERS-CoV 感染的热门化合物。在整个优化过程中，发现化合物20表现出高抑制作用（IC 50 = 0.157 μM，SI = 25），无细胞毒性，体内PK 特性适中。
• Design, Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives as Anti-inflammatory Agents against Lipopolysaccharide-induced Acute Lung Injury in Rats
  作者：Jie Hu、Yali Zhang、Lili Dong、Zhe Wang、Lingfeng Chen、Dandan Liang、Dengjian Shi、Xiaoou Shan、Guang Liang

  DOI：10.1111/cbdd.12454

  日期：2015.6

  inhibition against lipopolysaccharide‐induced TNF‐α and IL‐6 release. Then, the preliminary structure–activity relationship and quantitative structure–activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide‐induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation

  据报道，喹唑啉具有多种生物活性。这项研究的目的是发现新的喹唑啉衍生物通过抗炎作用对脂多糖诱导的急性肺损伤具有预防作用。合成了33种4-氨基喹唑啉衍生物，并筛选了脂多糖诱导的巨噬细胞的抗炎活性。最有效的四种化合物6h，6m，6p和6q对脂多糖诱导的TNF-α和IL-6释放具有剂量依赖性抑制作用。然后，进行了初步的结构-活性关系和定量的结构-活性关系分析。为了进一步确定喹唑啉类药物对急性肺损伤的治疗作用，采用了脂多糖诱导的急性肺损伤模型。在滴注脂多糖之前，先对雄性Sprague Dawley大鼠进行6m或6q预处理。结果表明，6m和6q，尤其是6q明显减轻了脂多糖引发的肺组织病理学变化，炎性细胞浸润和细胞因子mRNA表达。两者合计，这项工作表明，6m和6q通过抑制体内和体外的炎症反应来抑制脂多糖诱导的急性肺损伤，表明喹唑啉可能作为治疗急性肺损伤的潜在药物，值得继续进行药物开发和研究。
• Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells
  作者：Rania S.M. Ismail、Sahar M. Abou-Seri、Wagdy M. Eldehna、Nasser S.M. Ismail、Sara M. Elgazwi、Hazem A. Ghabbour、Mahmoud Salama Ahmed、Fathi T. Halaweish、Dalal A. Abou El Ella

  DOI：10.1016/j.ejmech.2018.06.024

  日期：2018.7

  Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and

  先前已经研究了表皮生长因子受体（EGFR）信号传导途径在不同类型的恶性肿瘤进展中的重要作用，其中靶向EGFR的小分子的发展是设计抗肿瘤药物的众所周知的策略。在这里，我们报告设计和合成的两个系列的6-（2-取代的乙酰胺基）-4-苯胺基喹唑啉（6a-x和13a-d）作为EGFR抑制剂。在体外评估所有新合成的喹唑啉衍生物对MCF-7（乳腺癌）和HepG2（肝细胞癌）细胞系的抗增殖活性。特别是，化合物6n对MCF-7和HepG2细胞系具有明显的抑制活性（IC 50 分别与埃洛替尼（IC 50  = 20和25μM ）相比分别为3和16μM ）。在MCF-7细胞系中6n的蛋白质印迹显示6n对减少EGFR和ERK磷酸化水平的双重抑制活性。此外，ELISA分析证实了化合物6n的抗EGFR活性（IC 50  = 0.037μM）。最后，一项分子对接研究表明，在EGFR的ATP催化结合位点内可能存在6n的结
• Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity
  作者：Yun-Yun Xu、Si-Ning Li、Gao-Jian Yu、Qing-Hua Hu、Huan-Qiu Li

  DOI：10.1016/j.bmc.2013.06.070

  日期：2013.10

  to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR–TK inhibitory activity. Especially, N6-((5-bromothiophen-2-yl)methyl)-N4-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50 = 3.11 μM for Hep G2, IC50 = 0.82 μM for A549). The EGFR molecular docking

  已发现含有与4-苯胺基喹唑啉核连接的6-氨基取代基或6-丙烯酰胺取代基的两个新系列新化合物。这些化合物被证明对抗增殖活性和EGFR-TK抑制活性有效。尤其是N 6 -（（5-溴噻吩-2-基）甲基）-N 4-（3-氯苯基）喹唑啉-4,6-二胺（5e）表现出最强的抑制活性（IC 50  = 3.11μM Hep G2，IC 50 对于A549 = 0.82μM）。EGFR分子对接模型表明该新化合物与EGFR区域结合良好，Hoechst染色实验的细胞形态表明这些化合物可有效诱导A549细胞凋亡。