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Quinazoline derivatives and their application as antitumor drugs

A quinazoline and derivative technology, applied in the field of drug synthesis, can solve the problems of drug resistance, poor clinical efficacy and the like, and achieve the effects of good inhibitory activity, good selectivity and good selectivity

Active Publication Date: 2022-02-15
SHENYANG POLYTECHNIC UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Non-small cell lung cancer is one of the currently known cancers with EGFR mutation characteristics, but the drug resistance of marketed drugs needs to be solved urgently, and the current targets for gastric cancer and lung cancer treatment mainly include HER1, HER2, VEGF, VEGFR, HGF, etc. , but the clinical efficacy is not good, therefore, it is necessary to develop a quinazoline derivative that is resistant to drug resistance and has strong inhibitory activity against gastric cancer and lung cancer cell lines

Method used

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  • Quinazoline derivatives and their application as antitumor drugs
  • Quinazoline derivatives and their application as antitumor drugs
  • Quinazoline derivatives and their application as antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis of 2-(7-methoxy-4-anilino)quinazolin-6-yl)-1-morpholin-1-one (I-a);

[0044]

[0045] With toluene (30mL) as solvent, 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate 1 (3.0g, 12.81mmol), triethylamine (3.1 mL, 21.78mmol) and phosphorus oxychloride (3mL, 32.02mmol) were sequentially added into a 150mL single-necked bottle, and reacted for about 3 hours under constant temperature stirring and reflux at 78°C. The progress of the reaction was monitored by TLC (ethyl acetate / petroleum ether=1 / 1). After the raw materials are completely reacted, the suspension in the bottle is not processed, and the second-step reaction is carried out directly. A solution of aniline a (1.55 g, 16.67 mmol) diluted with toluene (40 mL) was slowly dropped into the above suspension, and stirring was continued for 4 h, resulting in a large amount of solids. TLC monitoring (ethyl acetate / petroleum ether=2 / 1). After the reaction was completed, the reaction liquid was lowered to roo...

Embodiment 2

[0050] Synthesis of 2-(4-(2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-1-morpholin-1-one (I-b);

[0051]

[0052] Prepared according to the same method as in Example 1, replacing the raw material aniline with o-fluoroaniline, and synthesized 0.109 g of the target compound (I-b) through 5 steps of chlorination, amination, ester hydrolysis, amidation, and alkylation, with a yield of 73 %; m.p.: 105.7~106.6℃; IR(v,cm -1 ):3293.84, 2918.66, 2854.35, 1640.20, 1504.79, 1424.69, 1206.89, 998.80, 844.15; 1 H-NMR(600MHz,DMSO-d6):δ9.38(s,1H,NH),8.36(s,1H,C=NH),7.78(s,1H,ArH),7.57(s,1H,ArH) ,7.32(d,J=7.3Hz,2H,ArH),7.26(s,1H,ArH),7.22(s,1H,ArH),4.96(s,2H,OCH 2 C=O),3.95(s,3H,OCH 3 ),3.66(s,2H,OCH 2 ),3.60(s,2H,OCH 2 ),3.53(s,2H,NCH 2 ),3.50(s,2H,NCH 2 ).

Embodiment 3

[0054] Synthesis of 2-(4-(4-fluoro-2-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-1-morpholin-1-one (I-c);

[0055]

[0056] Prepared according to the same method as in Example 1, the raw material aniline was replaced by 4-fluoro-2-methylaniline, and the target compound (I-c) was synthesized through 5 steps of chlorination, amination, ester hydrolysis, amidation, and alkylation. 0.118g, yield 77%; m.p.:98.5~100.9℃; IR(v,cm -1 ):3397.98, 3005.33, 2969.50, 2913.54, 1650.50, 1418.90, 1229.24, 997.61, 839.55; 1 H-NMR(600MHz,DMSO-d6):δ9.19(s,1H,NH),8.25(s,1H,C=NH),7.73(s,1H,ArH),7.31(s,1H,ArH) ,7.15(d,J=7.0Hz,2H,ArH),7.05(s,1H,ArH),4.91(s,2H,OCH 2 C=O),3.91(s,3H,OCH 3 ),3.62(s,2H,OCH 2 ),3.56(s,2H,OCH 2 ),3.49(s,2H,NCH 2 ),3.46(s,2H,NCH 2 ),2.14(s,3H,ArCH 3 ).

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Abstract

The present invention belongs to the technical field of medicinal chemistry, and relates to quinazoline derivatives of general formula (I) and their physiologically acceptable salts formed with inorganic or organic acids, pharmaceutical compositions containing them, and their preparation for the treatment of tumors. The use of drugs for diseases, especially diseases characterized by abnormal EGFR family. Said compounds have valuable pharmacological properties, especially the inhibition of signal transduction by tyrosine kinases.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to quinazoline derivatives and their application as antitumor drugs. Background technique [0002] Tyrosine Kinase Inhibitor (Tyrosine Kinase Inhibitor) mainly acts on the kinase domain of Epidermal Growth Factor Receptor (EGFR / HER1) to block cell growth signals. Epidermal growth factor receptor is one of the four major receptors of human epidermal growth factor receptor (HER), and the other three are HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). EGFR spans the cell membrane and consists of an extramembrane ligand receptor-binding domain, a single transmembrane segment, and an intracellular domain containing a tyrosine kinase domain. From the structural point of view, EGFR is a glycoprotein with kinase activity. It acts as a receptor and an enzyme, and plays an important role in physiological activities such as cell proliferation, differentiation, and apoptosis. There is evidence that...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94A61K31/5377A61K31/517A61P35/00
CPCC07D239/94A61P35/00
Inventor 蔡志强韩晓丁海关赵臣康王博郝林林
Owner SHENYANG POLYTECHNIC UNIV
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