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Quinazoline derivative and preparation method and application thereof

A technology of quinazoline and derivatives, applied in the field of quinazoline derivatives and their preparation, can solve the problems of loss of drug efficacy, increase of EGFR and ATP binding ability and the like

Active Publication Date: 2016-11-23
GUANGZHOU HENOVCOM BIOSCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the acquired drug resistance mechanisms, the most common one (accounting for 50% of the total number of drug-resistant patients) is the secondary mutation T790M of EGFR, that is, the threonine at position 790 is mutated to methionine, which can increase The binding ability of EGFR and ATP makes it difficult for drug molecules such as Gefitinib to compete with the binding of ATP and EGFR, thus losing its efficacy

Method used

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  • Quinazoline derivative and preparation method and application thereof
  • Quinazoline derivative and preparation method and application thereof
  • Quinazoline derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Compound 7-1, N-(4-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(dimethylamino)ethoxy)quinazolin-6-yl) - Preparation of 2-methylbutyl-3-yn-2-yl)acrylamide.

[0107] Synthesize as follows:

[0108]

[0109] Step (1) prepares compound 2 (i.e. 2-amino-4-fluoro-5-iodobenzoic acid methyl ester), the method is as follows:

[0110] Take a 250mL clean two-necked round bottom flask, add 50g of raw material 1 (322.58mmol), 100mL of tert-butanol and 50mL of water in sequence, add 44.g (161.29mmol) of elemental iodine in batches under stirring, and then slowly add 40mL of 30% hydrogen peroxide dropwise , Heated to 50°C in an oil bath for 2h. The reaction was monitored by TLC. After the reaction, cool the system to room temperature, add 50mL saturated aqueous sodium bisulfite solution, let it extract three times with 150mL ethyl acetate, combine the organic phases, wash with 50mL saturated brine, dry over anhydrous sodium sulfate, and recrystallize to obtain Target compound 2 (59...

Embodiment 2

[0123] Compound 7-2, N-(3-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)propyl - Preparation of 2-yn-1-yl)acrylamide.

[0124] Preparation with reference to the method of Example 1, only select N-(2-hydroxyethyl) morpholine as raw material in step (3), the operation method is as in Example 1, step 5) adopts 6-2 as raw material, and prepares Target compound 7-2.

[0125]

[0126] The characterization data of this target compound are: 1 H NMR (400MHz, DMSO-d 6 )δ9.84(s,1H),8.69(t,J=5.6Hz,1H),8.63(s,1H),8.56(s,1H),8.19(dd,J=6.9,2.6Hz,1H), 7.82(ddd, J=9.0,4.3,2.7Hz,1H),7.42(t,J=9.1Hz,1H),7.23(s,1H),6.27(dd,J=17.1,10.0Hz,1H),6.16 (dd, J=17.1, 2.3Hz, 1H), 5.66(dd, J=10.0, 2.4Hz, 1H), 4.26-4.31(m, 4H), 3.60(q, J=4.7Hz, 4H), 2.79- 2.83(m,2H),2.57-2.62(m,4H).

Embodiment 3

[0128] Compound 7-3, N-(3-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(dimethylamino)ethoxy)quinazolin-6-yl) Preparation of Propyl-2-yn-1-yl)acrylamide.

[0129] Prepared with reference to the method of Example 1, only using compound 6-2 as a raw material in step 5) to prepare the target compound 7-3.

[0130]

[0131] The characterization data of this target compound are: 1 H NMR (400MHz, DMSO-d 6 )δ9.93(s,1H),8.78(t,J=5.8Hz,1H),8.69(s,1H),8.56(s,1H),8.21(dd,J=7.0,2.6Hz,1H), 7.84(dt,J=7.5,3.4Hz,1H),

[0132] 7.42(t, J=9.1Hz, 1H), 7.22(s, 1H), 6.29(dd, J=17.1, 10.1Hz, 1H), 6.16(d, J=16.9Hz, 1H),

[0133] 5.66(dd,J=10.0,2.4Hz,1H),4.21-4.29(m,4H),2.77(t,J=5.4Hz,2H),2.31(s,6H).

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Abstract

The invention relates to a quinazoline derivative and a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The structure of the quinazoline derivative is as shown in a formula I. The quinazoline derivative or a pharmaceutically acceptable salt thereof has an irreversible inhibition effect on tyrosine kinase, the compound can inhibit two kinds of tyrosine kinase of EGFR and HER2 simultaneously, and the compound has good inhibitory activity on multiple cancer cell lines. Please see the formula I in the description.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a quinazoline derivative and a preparation method and application thereof. Background technique [0002] Epidermal growth factor receptor (EGFR) is a member of the ErbB protein family, and the other three subtypes are HER2 (Neu, ErbB2), HER3 (ErbB3) and HER4 (ErbB4), which are involved in cell proliferation and differentiation It plays an important role in the process and is one of the most deeply studied tyrosine receptor proteins. EGFR widely exists in normal epidermal tissues such as skin, hair follicles and gastrointestinal tract, and plays an important role in maintaining normal physiological activities. However, the overexpression or continuous activation of EGFR can lead to many cancers, and EGFR abnormalities appear in cancers including colorectal cancer, lung cancer, breast cancer and head and neck cancer. [0003] From 2003 to 2004, the EGFR small molecule...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D401/12A61P35/00A61P15/00A61P35/02
CPCC07D239/94C07D401/12
Inventor 张健存彭江灵李宏
Owner GUANGZHOU HENOVCOM BIOSCI CO LTD
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