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Quinazoline derivative and application thereof

A technology of quinazoline and isoxazole, which is applied in the field of quinazoline derivatives and applications, and can solve problems such as uncontrollable cell division

Active Publication Date: 2013-10-23
FUJIAN INST OF RES ON THE STRUCTURE OF MATTER CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Overexpression and enhanced activity of EGFR can eventually lead to uncontrolled cell division

Method used

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  • Quinazoline derivative and application thereof
  • Quinazoline derivative and application thereof
  • Quinazoline derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 16

[0242] The synthesis of embodiment 16,7-dimethoxy-4-chloro-quinazoline

[0243] Add 4.12g (20mmol) of 6,7-dimethoxy-quinazolinone into a 500mL single-necked round low flask, then slowly add 120mL of redistilled thionyl chloride containing 1 drop of DMF, reflux reaction, TLC detection After the reaction was completed, excess thionyl chloride was distilled off under reduced pressure, and the residue was dissolved in 300 mL of ethyl acetate, washed with saturated sodium bicarbonate solution to neutrality, and the organic layer was dried over anhydrous sodium sulfate, concentrated and separated by column (V 石油醚 :V 乙酸乙酯 :4:1~2:1) to get 6,7-dimethoxy-4-chloro-quinazoline, yield: 85%, 1 H NMR (DMSO-d 6 ,400MHz):4.01(s,6H,2CH 3 ),7.38(s,1H),7.45(s,1H),8.88(s,1H);ESI-MS(100%):224([M] + ,100).

Embodiment 27

[0244] The synthesis of embodiment 27-nitro-quinazolone

[0245] Add 46g (0.25mol) of 2-amino-4-nitrobenzoic acid and 52g (0.5mol) of formamidine acetate into a 500mL single-necked round-bottomed flask, add 200mL of absolute ethanol, and reflux for 4 to 6 hours. There will be A large number of khaki precipitates. Stop heating at this time, cool the system to about 50°C, remove part of the ethanol in vacuum to about 50mL of the system, add 30mL of water to the system, stir the system for a few minutes, refrigerate for 1h, filter, and filter the cake with refrigerated ethanol (3×10mL) Washing, washing with water (2×10mL), drying in vacuo to give 7-nitro-quinazolinone 2, 39.6g khaki needle-like solid, yield: 82.8%, m.p: 282~284°C, IR(KBr) ν: 3174, 3064, 2960, 1683, 1613, 1528, 803; this compound can be directly used in the next chlorine substitution reaction without further purification.

Embodiment 37

[0246] The synthesis of embodiment 37-nitro-4-chloro-quinazoline

[0247] Take 19.1g (0.1mol) of 7-nitro-quinazolinone in a 250mL three-neck flask, slowly add 60mL of freshly steamed SOCl containing 2 drops of DMF dropwise under stirring 2 , reflux reaction after adding, TLC monitors the progress of the reaction, after the reaction is completed, excess SOCl is evaporated under reduced pressure 2 , the residue was washed with refrigerated ether (5×20mL) to obtain the crude product, and the crude product was recrystallized with petroleum ether and ethyl acetate to obtain 19.0g of the compound intermediate 7-nitro-4-chloro-quinazoline, white needles shape crystal. Yield: 90.6%, m.p: 150~151℃, 1 H NMR (CDCl 3 ,400MHz)δ:8.55(s,2H,Ph-H),8.98(s,1H,Ph-H),9.23(s,1H,Ar-H);IR(KBr)ν:3057,2959,1528, 1469, 1357, 805, 743.

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Abstract

The present invention provides a quinazoline compound shown in formula (I), or pharmaceutically acceptable salt thereof. R1, R2 and R7 are independently and respectively selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, halogenate C1-6 alkyl, halogenate C1-6 alkoxy, hydroxyl C1-6 alkyl, hydroxyl C1-6 alkoxy, C1-6 alkoxy C1-6 alkoxy, C3-8 cycloalkyloxy, optional aryl or heteroaryl substituted by R6, nitryl, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino; it comprises at least one C3-8 heterocycloalkyloxy selected from N, O, S heteroatoms; Z is -NR4-, C(R5)2, S or -O-, R4 being hydrogen or C1-3 alkyl, and R5 being selected from hydrogen or C1-3 alkyl; R3 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or halogenate C1-6 alkyl; R6 is selected from hydrogen, C1-3 alkyl, hydroxyl, halogen, C1-3 alkoxy; and n is 0 to 5. The present invention further provides a preparation method of the compound shown in formula (I) or the pharmaceutically acceptable salt and pharmaceutical usage thereof, which can be used as medicines or lead compounds for curing diseases such as tumour and cancer related to protein tyrosine kinase.

Description

technical field [0001] The present invention relates to a class of novel structure quinazoline derivatives containing isoxazole heterocycles and pharmaceutical compositions containing such derivatives and their uses, in particular, relates to the ability to inhibit epidermal growth factor protein tyrosine kinase ( EGFR-TK) active quinazoline compound or its pharmaceutical composition, this type of compound or its salt has the activity of inhibiting colorectal cancer cell line (HCT-116) and human lung cancer cell line (A549), and some compounds are effective against epidermal growth factor Human tyrosine kinase (EGFR-TK) has a strong inhibitory activity, and this type of substance can be used as a drug or lead compound for the treatment of tumors, cancers and other diseases related to protein tyrosine kinase. Background technique [0002] Binding of Epidermal Growth Factor (EGF) to Epidermal Growth Factor Receptor (EGFR) activates the activity of tyrosine kinases and thus act...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/06A61K31/517A61P35/00
CPCA61K31/517C07D413/12C07D413/06A61P35/00
Inventor 卢灿忠雍建平
Owner FUJIAN INST OF RES ON THE STRUCTURE OF MATTER CHINESE ACAD OF SCI
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