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2,4-diaminopyrimidine containing dihydropyran thiazole and application of 2,4-diaminopyrimidine

A technology of dihydropyranothiazole and diaminopyrimidine, which is applied in the field of 2,4-diaminopyrimidine and can solve the problems of unsatisfactory effect and the like

Active Publication Date: 2019-09-20
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the effect of the above two compounds on inhibiting the proliferation of cervical, liver cancer or colon tumor cells is still not satisfactory.

Method used

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  • 2,4-diaminopyrimidine containing dihydropyran thiazole and application of 2,4-diaminopyrimidine
  • 2,4-diaminopyrimidine containing dihydropyran thiazole and application of 2,4-diaminopyrimidine
  • 2,4-diaminopyrimidine containing dihydropyran thiazole and application of 2,4-diaminopyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1 [preparation compound N 2 -(4-sulfonamidophenyl)-N 4 -(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-methyl-2,4-diaminopyrimidine (Ia)]

[0023] 2.2mmol N 4 -(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2-chloro-5-methylpyrimidine, 2.0mmol 4-sulfonamidoaniline and 4.4mmol Add aluminum chloride hydrochloride to 15ml of anhydrous ethylene glycol methyl ether, stir in ice bath for 1 hour, add 2.2mmol DIPEA, continue stirring in ice bath for 30 minutes, then start to heat up to 120°C for 15-20 hours. TLC detection, after the reaction, the reaction solution was poured into 100mL water, extracted with ethyl acetate (100mL × 3), left to separate the liquid, the organic phase was washed with saturated brine (80mL × 3), and then washed with anhydrous magnesium sulfate Dry, filter with suction, and remove ethyl acetate under reduced pressure to obtain a white solid, which is subjected to column chromatography with petroleum ether: ethyl acetate to obtain 0.135 g of wh...

Embodiment 2

[0025] Embodiment 2 [preparation N 2 -(4-Methanesulfonylphenyl)-N 4 -(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-5-methyl-2,4-diaminopyrimidine (Ib)]

[0026] 2.2mmol N 4 -(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2-chloro-5-methylpyrimidine, 2.0mmol 4-methanesulfonylanilide and 4.4mmol Add aluminum chloride hydrochloride to 15ml of anhydrous ethylene glycol methyl ether, stir in ice bath for 1 hour, add 2.2mmol DIPEA, continue stirring in ice bath for 30 minutes, then start to heat up to 120°C for 15-20 hours. TLC detection, after the reaction, the reaction solution was poured into 100mL water, extracted with ethyl acetate (100mL × 3), left to separate the liquid, the organic phase was washed with saturated brine (80mL × 3), and then washed with anhydrous magnesium sulfate Dry, filter with suction, and remove ethyl acetate under reduced pressure to obtain a white solid, which is subjected to column chromatography with petroleum ether: ethyl acetate to obtain 0.129 g of whi...

Embodiment 3

[0028] Embodiment 3 (antitumor activity research)

[0029] The antitumor activity of the compounds of the present invention is demonstrated by the following method test. These effects indicate that the compounds of the present invention are useful in the treatment of cancer, especially solid tumors such as colon cancer, cervical cancer and liver cancer. The specific test method is as follows:

[0030] The in vitro antitumor activity of the compounds prepared in Examples 1-4 (numbered sequentially Ia-Id) was detected by MTT method. Collect logarithmic phase cells, adjust the concentration of cell suspension to 4×10 3 -5×10 3 cells / mL were inoculated in 96-well plates and incubated for 12-24 hours. After the cells adhered to the wall, drugs of different concentrations were added, and a total of 6 concentration gradients of 1.875, 3.75, 7.5, 15, 30, and 60 μmol / l were set, with 4 replicate wells for each concentration. Set at 37°C, 5% CO 2 Incubator, start timing cultivatio...

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Abstract

The invention relates to 2,4-diaminopyrimidine containing dihydropyran thiazole. The chemical structure of the 2,4-diaminopyrimidine is represented by the following formula (I) in which R is amino or methyl. The 2,4-diaminopyrimidine containing the dihydropyran thiazole can inhibit cyclin-dependent kinases (CDKs), particularly CDK2, and has a remarkable control effect on the proliferation of cervical, colon and liver tumor cells.

Description

technical field [0001] The present invention relates to nitrogen-containing heterocyclic compounds, in particular to 2,4-diaminopyrimidine containing dihydropyranothiazole. The compound inhibits cyclin-dependent kinases (CDKs). Background technique [0002] In recent years, tumors have surpassed cardiovascular diseases and become the world's leading cause of death. Studies have found that the occurrence and development of malignant tumors are related to the dysfunction of cell cycle regulation. Therefore, regulating or blocking cell cycle is an important way to treat tumors. [0003] CDKs have become a hot spot in the research and development of new anticancer drugs. There are 21 CDK subtypes (CDK1–21) discovered so far, and CDKs of different subtypes all contain a conserved catalytic center consisting of about 300 amino acids. In different phases of the cell cycle, the accumulation of different cyclins binds to the corresponding CDKs and becomes activated. According to ...

Claims

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Application Information

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IPC IPC(8): C07D513/04A61K31/506A61P35/00
CPCA61P35/00C07D513/04
Inventor 赵培亮刁鹏程
Owner SOUTHERN MEDICAL UNIVERSITY
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