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Preparation method and application of quinazoline derivatives

A quinazoline and derivative technology, applied in the field of drug synthesis, can solve the problems of poor selectivity, easy drug resistance, strong toxic and side effects, etc.

Active Publication Date: 2019-03-08
FUJIAN INST OF RES ON THE STRUCTURE OF MATTER CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, most traditional anticancer drugs have poor selectivity, strong toxic and side effects, and are prone to drug resistance.

Method used

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  • Preparation method and application of quinazoline derivatives
  • Preparation method and application of quinazoline derivatives
  • Preparation method and application of quinazoline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1 Synthesis of intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole (II) or intermediate 3-substituted phenyl-5-aminomethyl-isoxazole (III):

[0076] where R 3 For H as an example:

[0077] (1) Synthesis of benzaldoxime

[0078]

[0079] 10.0mmol benzaldehyde was dissolved in 30mL30%CH 3 OH and H 2 Add O solution to a conical flask equipped with a magnetic stirrer, add 10.0 mmol of hydroxylammonium hydrochloride under stirring, and slowly add 5.0 mmol of dried and finely ground sodium carbonate after the hydroxylammonium hydrochloride is dissolved. After the reaction at room temperature, TLC detected that the reaction was complete, and the system was decompressed to remove methanol, and then 30 mL of H 2 O, extracted with dichloromethane (3×30mL), combined the organic layers, and dried the organic layer with anhydrous sodium sulfate. The solvent was removed to obtain the crude product of benzaldoxime with a yield of 86.2%. The crude product was di...

Embodiment 2

[0088] The synthesis of the quinazoline derivative shown in embodiment 2 formula I:

[0089] where R 3 Use H as an example to illustrate:

[0090] (1) Synthesis of 6,7-dimethoxy-2-chloro-4-[(3-phenyl-isoxazol-5-yl)-methoxy-]-quinazoline

[0091]

[0092] Dissolve 0.259g (1mmol) of 6,7-dimethoxy-2,4-dichloro-quinazoline in 5mL of dry isopropanol, and dissolve 0.175g (1mmol) of 5-hydroxymethyl 5 mL of isopropanol solution of phenyl-3-phenyl-isoxazole was slowly added dropwise to the reaction system, and then 0.101 g (1 mmol) of freshly steamed triethylamine was added, and the system was stirred at room temperature for 30 min, then reacted at 50 ° C, and the reaction was completed by TLC detection. Afterwards, the reaction solution was concentrated in vacuo, and the residue was directly separated from the column. （石油醚） :V （乙酸乙酯） =5:1~2:1) to obtain the target compound [6,7-di(methoxyethoxy)]-4-{[3-(4-methyl-phenyl)-isoxazole-5- Base]-methoxy-}-quinazoline (Q-1). The rest...

Embodiment 3

[0108] Embodiment 3 biological activity test

[0109] MTT method was used to screen the activity against colorectal cancer cell line HCT-116, human lung cancer cell line A549 and breast cancer cell line MCF-7. The specific screening process is as follows:

[0110] (1) Spread the lung cancer cell line A549 in a 96-well plate, add 100 μL of culture medium, and wait for the cells to grow to 90%, add 1 μL of drugs into the wells, and test 8 different concentrations of each drug (the initial concentration of the drug is respectively Concentration, 50μM, 5μM, 500nM, 50nM, 5nM, 500pM, 50Pm), for each drug concentration, do 3 replicate wells in parallel, after culturing for 18h, add 20μL of the prepared 5mg / mL MTT solution to each well for 4 hours Afterwards, the medium was aspirated, and 150 μL DMSO was added to each well, and the optical density (OD) value was measured at a wavelength of 595 nm. The negative control is DMSO. The inhibition rate was calculated according to the for...

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Abstract

The invention discloses a quinazoline derivative shown in formula (I) which is described in the specification and a salt thereof. In the formula, Z represents -NH- and -O-, R1 and R2 represent C1-3 alkoxy groups or hydrogen, R3 is selected from the group consisting of 4-fluoro-, 4-chloro-, 2-chloro-, 4-bromo-, 2, 4-dichloro-, 4-methyl, 4-methoxy, hydrogen, 4-trifluoromethyl and 2,4-dimethoxy. The invention relates to a preparation method and application of the compound shown in the formula (I) and the salt thereof. The compound or the salt thereof has strong inhibitory activity on colorectal cancer cell strains HCT-116, human lung cancer cell strains A549 and breast cancer cell strains MCF-7. The compound has wide spectrum antitumor activity and can be used as a drug or lead compound for treatment of diseases like tumors and cancers.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a class of quinazoline derivatives with novel structures, in particular to the preparation of quinazoline derivatives whose 4-position is substituted by isoxazole heterocycles and pharmaceutical compositions containing such derivatives and its uses. The compounds or salts thereof have strong inhibitory activity on colon cancer cell line HCT-116, human lung cancer cell line A549 and breast cancer cell line MCF-7. The compounds have broad-spectrum anticancer activities and can be used as drugs or lead compounds for treating diseases such as tumors and cancers. Background technique [0002] Cancer is a large class of diseases characterized by abnormal cell proliferation and metastasis, and is the second leading cause of death in humans, second only to cardiovascular and cerebrovascular diseases. According to the statistics of the World Health Organization, in 2008, about 7.6 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/12A61K31/517A61P35/00
CPCC07D413/12
Inventor 雍建平卢灿忠
Owner FUJIAN INST OF RES ON THE STRUCTURE OF MATTER CHINESE ACAD OF SCI
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