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Quinazoline derivatives containing hydroxamic acid side chain as well as preparation and application thereof

A technology of hydroxamic acid and quinazoline, applied in the field of quinazoline derivatives, can solve the problems of lung cancer treatment obstacles and the like, and achieve the effects of enhancing anti-drug resistance, preventing desensitization, and good inhibitory activity

Inactive Publication Date: 2016-12-07
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patented new chemical entity has two types - one with an alpha amino group attached to it called histidine or lysylargin (HAL) – while another molecule contains certain drugs like etanolide used for treatments such as chemotherapy drug resistances caused by overexpressed ErbB2 receptors. These combinations have been shown effective against cancer patients who are already being treated with these agents but they can be less effective when combined together due to their different mechanisms involved.

Problems solved by technology

This patented technical problem addressed in this patents relates to finding ways to prevent chemotherapeusis treatments from killing cells resistant to certain types of agents used during their use.

Method used

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  • Quinazoline derivatives containing hydroxamic acid side chain as well as preparation and application thereof
  • Quinazoline derivatives containing hydroxamic acid side chain as well as preparation and application thereof
  • Quinazoline derivatives containing hydroxamic acid side chain as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 4-(6-acrylamido-4-(3-chloro-4-fluoroanilino)quinazolin-7-yl)oxy-N-hydroxybutanamide;

[0032] step:

[0033] Raw material 1: 4-(3-chloro-4-fluoroanilino)-6-nitro-7-hydroxyquinazoline was prepared according to the method of document CN201210411352.7.

[0034] Raw material 2: Preparation of ethyl 4-(4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yl)oxybutyrate:

[0035]

[0036] Dissolve 4-(3-chloro-4-fluoroanilino)-6-nitro-7-hydroxyquinazoline (1.1 g, 3.3 mmol) and ethyl 4-bromobutyrate (3.3 mmol) in 10 mL of DMF , Potassium carbonate (0.45g, 3.3mmol) was added to the mixed system, and the reaction was stirred at room temperature for 36 hours. After the reaction was completed, a large amount of solid was precipitated by adding water, and the product was collected by suction filtration and purified by column chromatography.

[0037] 1 H NMR(500MHz,DMSO)δ9.58(s,1H),8.93(s,1H),8.54(s,1H),8.14(d,J=4.8Hz,1H),7.91–7.65(m,1H) ,7.43(t,J=9.0Hz,1H),7.28(s,1H),4....

Embodiment 2

[0059] Example 2 4-(6-acrylamido-4-(3-bromoanilino)quinazolin-7-yl)oxy-N-hydroxybutanamide

[0060] With reference to the method of Example 1, only 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-yl) oxy)-N-((tetrahydro -2H-pyran-2-yl)oxy)butanamide is replaced by 4-((6-acrylamido-4-(3-bromoanilino)quinazolin-7-yl)oxy)-N- ((Tetrahydro-2H-pyran-2-yl)oxy)butanamide, 88.3% yield. m.p.:200-202℃; 1 H-NMR(500MHz,DMSO)δ11.34(s,1H),10.60(s,1H),9.69(s,1H),9.28(s,1H),8.90(s,1H),7.96(t,J =1.9Hz,1H),7.71–7.68(m,1H),7.53–7.49(m,1H),7.45(m,2H),6.97(dd,J=17.0,10.2Hz,1H),6.37(dd, J=17.0,1.7Hz,1H),5.87(dd,J=10.2,1.7Hz,1H),4.27(t,J=5.8Hz,2H),2.27(t,J=6.7Hz,2H),2.18– 2.11(m,2H).HRMS(ESI)m / z calcdfor C 21 h 20 BrN 5 o4 [M+H] + :484.0872. Found: 484.0873.

Embodiment 3

[0061] Example 3 4-(6-acrylamido-4-(3-chloro-4-fluoroanilino)quinazolin-7-yl)oxy-N-hydroxycaproamide

[0062] With reference to the method of Example 1, only 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-yl) oxy)-N-((tetrahydro -2H-pyran-2-yl)oxy)butanamide was replaced by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino)quinazolin-7-yl)oxy )-N-((tetrahydro-2H-pyran-2-yl)oxy)pentanamide, yield 91.3%.

[0063] m.p.:174-176℃; 1 H-NMR(500MHz,DMSO)δ11.49(s,1H),10.58(s,1H),9.93(s,1H),9.21(s,1H),8.91(s,1H),7.96(dd,J =6.8,2.6Hz,1H),7.67(ddd,J=8.9,4.3,2.6Hz,1H),7.55(m,2H),6.85(dd,J=17.0,10.2Hz,1H),6.36(dd, J=17.0,1.8Hz,1H),5.87(dd,J=10.3,1.7Hz,1H),4.27(t,J=6.3Hz,2H),2.09(t,J=7.2Hz,2H),1.94– 1.81(m,2H),1.78–1.68(m,2H).HRMS(ESI)m / z calcd for C 22 h 21 ClFN 5 o 4 [M+H] + :472.1439. Found: 472.1435.

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Abstract

The invention provides quinazoline derivatives containing hydroxamic acid side chains, 4-arylamido quinazoline is used as a mother nucleus, and a target compound is obtained by one-step condensation of a special connecting group and hydroxylamine which is protected by THP as well as subsequent deprotection. Experiments prove that the product has substantial proliferation inhibition effects for EGFR tyrosine kinase activity related tumor cells (an epidermal carcinoma cancer cell line A431 with EGFR overexpression and human lung adenocarcinoma cell H1975 with drug resistance for Gefitinib) on the cell level, especially has good inhibition effects for H1975 with drug resistance, and at the same time the product has good inhibition effects for Hela, HepG2 and other tumor cells; the product is used for preparing corresponding medicaments for resisting tumor cells. The structural general formula is as follows.

Description

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Claims

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Application Information

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Owner ZHEJIANG UNIV
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