N-(3-氯苯基)-6,7-二甲氧基-4-喹唑啉胺盐酸盐 | 170449-18-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: N-(3-氯苯基)-6,7-二甲氧基-4-喹唑啉胺盐酸盐
• 英文名称: Tyrphostin hydrochloride
• 英文别名: 4-N-(3'-chloro-phenyl)amino-6,7-dimethoxyquinazoline hydrochloride；6,7-dimethoxy-4-(3'-chloroanilino)quinazoline hydrochloride；6, 7-dimethoxy-4-N-(3'-chlorine) phenylaminequinazoline hydrochloride；4-(3-chloroanilino)-6,7-dimethylquinoaline hydrochloride；N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine;hydron;chloride
• CAS: 170449-18-0
• 化学式: C₁₆H₁₄ClN₃O₂*ClH
• 分子量: 352.22
• InChiKey: WDJDYIUSDDVWKB-UHFFFAOYSA-N

物化性质

• 熔点：
  230-235 °C
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  4.47
• 重原子数：
  23
• 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：
  56.3
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 海关编码：
  2933990090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  储存温度为2-8°C，并需保存在惰性气体中。

制备方法与用途

生物活性

AG-1478 氢氯酸盐（Tyrphostin AG-1478 氢氯酸盐）是一种选择性的 EGFR 酪氨酸激酶抑制剂，IC50 为 3 nM。它对 HCV 和脑心肌炎病毒 (EMCV) 具有抗病毒作用。

目标	IC50
EGFR	3 nM
HCV	-
EMCV	-

体外研究

AG-1478 (AG1478) 不可逆地抑制人类肺 (A549) 和前列腺 (DU145) 癌细胞系的生长，这些细胞在化学定义的 DMEM/F12 培养基中培养。尽管 AG-1478 在较低浓度时效果更佳，但无法完全抑制 A549 细胞的生长。特异性酪氨酸激酶抑制剂 AG-1478 (AG1478) 通过显著减少血管紧张素 II 介导的 TGF-β 和纤维连接蛋白合成来抑制 EGFR。小分子抑制剂 AG-1478 的 IC50 为 4 nM。

聚fect (PF) 和 Superfect (SF) 治疗在流式细胞术评估下均显著增加了 HEK 293 细胞的凋亡率。抗氧化剂 tempol 显著减少了这两种治疗导致的凋亡，AG-1478 (AG1478)，以比信号研究中使用的剂量高 10 倍（100 μM）为阳性对照，显著诱导了 HEK 293 细胞的凋亡。

体内研究

AG-1478 (AG1478) 的给药显著减少了两种肥胖小鼠模型的心肌炎症、纤维化、凋亡和功能障碍。apoE-/- 小鼠首先以高脂肪饮食 (HFD) 喂养 8 周（ApoE-HFD），然后通过口服给予 AG-1478 (10 mg/kg/天) 或 542 (10 mg/kg/天) 另外 8 周。AG-1478 或 542 处理抑制了 HFD 引起的体内的心脏 EGFR 磷酸化，而不影响低密度脂蛋白 (LDL) 和总甘油三酯 (TG) 的血浆水平。EGF (10 nM) 的给药导致了 EGFR 磷酸化的显著和可重复的升高，这一效应可以被 AG-1478 (AG1478) 这种已知的 EGFR 磷酸化抑制剂所阻断。聚fect (PF) 剂量的增加导致 EGF 诱导的 EGFR 磷酸化显著减少（p<0.05），但这一效应不及 AG1478 所见的程度。

反应信息

• 作为反应物：
  描述：

  N-(3-氯苯基)-6,7-二甲氧基-4-喹唑啉胺盐酸盐 、 碘甲烷 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 21.0h， 生成 N-(3-chlorophenyl)-N-(6,7-dimethoxyquinazolin-4-yl)-N-methylamine
  参考文献：
  名称：

  Design, Synthesis, and DNA-Binding of N-Alkyl(anilino)quinazoline Derivatives

  摘要：

  New N-alkylanilinoquinazoline derivatives 5, 12, 20, and 22 have been prepared Crow 4-chloro-6, 7-dimethoxyquinazoline 3, 4-chloro-6,7-methylenedioxyquinazoline 19, and commercially available anilines. Differents classes of compounds substituted by an aryloxygroup (6a-c. 16a,b, and 17a,b). (aminophenyl)ureas (12a,b and 13a-f), anilines (4a-m, 20a,b), N-alkyl(aniline) (5a-m, 21a,b. 22a,d). and N-aminoalkyl(aniline) (22e-g) have been synthesized. These molecules were evaluated for then. cytotoxic activities and as potential DNA intercalating agents. We studied the strength and mode of binding to DNA of these molecules by DNA melting temperature measurements, fluorescence emission. and circular dichroism. The results of various spectral and gel electrophoresis techniques obtained with the different compounds, in particular compounds 5g and 22f, revealed significant DNA interaction. These experiments confirm that the N-aminoalkyl(anilino)-6,7-dimethoxyquinazoline nucleus is an efficient pharmacophore to trigger binding to DNA, via an intercalative binding process.

  DOI：

  10.1021/jm1009605
• 作为产物：
  描述：

  2-氨基-4,5-二甲氧基苯甲酸 在 氯化亚砜 作用下， 以 异丙醇 为溶剂， 反应 13.0h， 生成 N-(3-氯苯基)-6,7-二甲氧基-4-喹唑啉胺盐酸盐
  参考文献：
  名称：

  一些4-苯胺基喹唑啉衍生物的合成

  摘要：

  一些4-N-(3'-或4'-取代-苯基)氨基-6,7-二甲氧基喹唑啉和相应的未取代化合物由2-氨基-4,5-二甲氧基苯甲酸和适当的取代苯胺合成。还获得了其他相关的喹唑啉或其合成中间体。大量描述的喹唑啉是新化合物，而其余的则通过更有效的方法制备。合成这些化合物的主要目标是 4-苯胺基喹唑啉药效团是一个重要的单元，它存在于几种蛋白激酶的 ATP 竞争性抑制剂中。

  DOI：

  10.1055/s-2004-815949

文献信息

• 4-Anilinequinazolines with adenosine-kiase inhibitor properties
  申请人：Franchini Gomes Kleber

  公开号：US20070060600A1

  公开（公告）日：2007-03-15

  The present invention relates to the use of 4-anilinoquinazoline derivatives as adenosine-kinase inhibitors. The present invention also relates to a method for protecting tissues and organs like heart, brain and kidneys affected by ischemia, and for treating heart insufficiency, myocardium infarct, arrhythmia, arterial hypertension, atherosclerosis, coronary artery restenosis after angioplasty, chronic renal insufficiency, cerebral vascular accident, and chronic inflanunatory diseases (e.g., rheumatoid arthritis). The present invention also relates to the compound 6,7-dimethoxy-4-(3′-N′,N′-dimethylaminoanilino)quinazoline, or a pharmaceutically acceptable salt thereof, pharmaceutical composition comprising it and use of such compound in the manufacture of a medicament for treating or preventing diseases or conditions that are benefited from the adenosine-kinase inhibition.

  本发明涉及使用4-苯胺基喹唑啉衍生物作为腺苷激酶抑制剂。本发明还涉及一种保护受缺血影响的心脏、脑和肾等组织和器官，并治疗心力衰竭、心肌梗塞、心律失常、动脉高血压、动脉粥样硬化、血管成形术后冠状动脉再狭窄、慢性肾功能不全、脑血管意外和慢性炎症性疾病（如类风湿性关节炎）的方法。本发明还涉及化合物6,7-二甲氧基-4-(3'-N',N'-二甲基氨基苯基)喹唑啉或其药学上可接受的盐、包含它的制药组合物以及使用该化合物制造治疗或预防从腺苷激酶抑制中受益的疾病或病情的药物的用途。
• The preparation and sar of 4-(anilino), 4-(phenoxy), and 4-(thiophenoxy)-quinazolines: Inhibitors of p56lck and EGF-R tyrosine kinase activity
  作者：Michael R. Myers、Natalie N. Setzer、Alfred.P. Spada、Allison L. Zulli、Chin-Yi J. Hsu、Asher Zilberstein、Susan E. Johnson、Linda E. Hook、Mary V. Jacoski

  DOI：10.1016/s0960-894x(97)00034-6

  日期：1997.2

  We report herein our preliminary results of a SAR study of quinazoline-based inhibitors of p56(lck) and EGF-R tyrosine kinase activity.(1) The most potent inhibitor of p56(lck) identified, RPR-108518A (10), has an IC50 of 0.50 mu M. The 3-chlorophenoxy- and 3-chlorothiophenoxy- derivatives 5 and 6 were also shown to be extremely potent EGF-R inhibitors. (C) 1997, Elsevier Science Ltd.
• Anilinodialkoxyquinazolines:  Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Potential Tumor Imaging Probes
  作者：Henry F. VanBrocklin、John K. Lim、Stephanie L. Coffing、Darren L. Hom、Kitaw Negash、Michele Y. Ono、Jennifer L. Gilmore、Ianthe Bryant、David J. Riese

  DOI：10.1021/jm050607w

  日期：2005.11.1

  The epidermal growth factor receptor (EGFR), a long-standing drug development target, is also a desirable target for imaging. Sixteen dialkoxyquinazoline analogues, suitable for labeling with positron-emitting isotopes, have been synthesized and evaluated in a battery of in vitro assays to ascertain their chemical and biological properties. These characteristics provided the basis for the adoption of a selection schema to identify lead molecules for labeling and in vivo evaluation. A new EGER tyrosine kinase radiometric binding assay revealed that all of the compounds possessed suitable affinity (IC50 = 0.4-51 nM) for the EGFR tyrosine kinase. All of the analogues inhibited ligand-induced EGFR tyrosine phosphorylation (IC50 = 0.8-20 nM). The HPLC-estimated octanol/water partition coefficients ranged from 2 to 5.5. Four compounds, 4-(2'-fluoroanilino)- and 4-(3'-fluoroanilino)-6,7-diethoxyquinazoline as well as 4-(3'chloroanilino)- and 4-(3'-bromoanilino)-6,7-dimethoxyquinazoline, possess the best combination of characteristics that warrant radioisotope labeling and further evaluation in tumor-bearing mice.
• Tyrphostins IV—Highly potent inhibitors of EGF receptor kinase. Structure-activity relationship study of 4-anilidoquinazolines
  作者：Aviv Gazit、Jeffrey Chen、Harald App、Gerald McMahon、Peter Hirth、Irit Chen、Alexander Levitzki

  DOI：10.1016/0968-0896(96)00107-1

  日期：1996.8

  Potent 4-anilido-substituted quinazolines which potently inhibit epidermal growth factor receptor (EGFR) kinase were prepared. Structure-activity relationship studies reveal high sensitivity to substitution at the aniline ring. Copyright (C) 1996 Elsevier Science Ltd
• 4-ANILINOQUINAZOLINE DERIVATIVES WITH ADENOSINE-KINASE INHIBITORY PROPERTIES
  申请人：UNIVERSIDADE ESTADUAL DE CAMPINAS - UNICAMP

  公开号：EP1737832B1

  公开（公告）日：2011-12-14