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A 4,6-dimethyl-oxazolo[5,4-d]pyrimidine-5,7(4h,6h)-dione derivative acting on the FGF receptor

A dimethyl, 4-d technology, applied in the field of medicinal chemistry, can solve the problem of unutilized ATP pocket space

Active Publication Date: 2016-02-03
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

(4) FGFR can also mediate broad-spectrum antitumor drug resistance, and the resistance of tumor cells to chemotherapy drugs and the limited efficacy of chemotherapy in the treatment of metastatic tumors are the two most important clinical challenges
We collected the crystal structures of FGFR-1 tyrosine kinases that have been reported so far. Through computer simulation analysis, we found that the current FGFR-1 inhibitors all have large conjugated structures, and the ATP binding site in the inhibitory active region is only A small part of the FGFR-1 protein pocket is located on the left side of the entire pocket cavity, while there is a large unused space on the right side of the ATP pocket

Method used

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  • A 4,6-dimethyl-oxazolo[5,4-d]pyrimidine-5,7(4h,6h)-dione derivative acting on the FGF receptor
  • A 4,6-dimethyl-oxazolo[5,4-d]pyrimidine-5,7(4h,6h)-dione derivative acting on the FGF receptor
  • A 4,6-dimethyl-oxazolo[5,4-d]pyrimidine-5,7(4h,6h)-dione derivative acting on the FGF receptor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The synthesis of embodiment 1 compound

[0042] 1.1 Synthetic routes of compounds

[0043] Concrete synthetic route is as follows:

[0044]

[0045] i:NaNO 2 ,CH 3 COOH:H 2 O=1:1; ii:Na 2 S 2 o 4 ,NH 4 OH; iii: R-CHO,CH 3 CH 2 OH; iv: SOCl 2

[0046] 1.2 Synthesis steps

[0047] 1.2.11, Preparation of 3-dimethyl-5-nitrosopyrimidine-2,4,6(1H,3H,5H)-trione (2)

[0048] Add 5g of 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (1) into a mixture of 140ml of acetic acid and water (acetic acid:water=1:1), at 75°C Heating at low temperature for 30min until the reaction mixture is homogeneous, lowering the temperature to 50°C, adding NaNO in batches 2 4.0g, after the addition, cooled to room temperature, and stirred for 1h to obtain a precipitate, filtered, washed with water, suction filtered, and dried to obtain 1,3-dimethyl-5-nitrosopyrimidine-2,4,6( 1H, 3H, 5H)-trione (2), yield: 90%.

[0049] 1.2.2 Preparation of 1,3-dimethyl-5-aminopyrimidine-2,4,6(1H,3H,...

Embodiment 2

[0064] Example 2 compound antitumor activity

[0065] MTT is a yellow compound that accepts hydrogen ions. It can act on the respiratory chain in the mitochondria of living cells. The succinate dehydrogenase in the mitochondria of living cells reduces it to produce a water-insoluble blue-purple crystalline formazan. And deposited in cells, and dead cells do not have this function. DMSO can dissolve formazan in cells, and use an enzyme-linked immunosorbent assay to measure its light absorption value at a specific wavelength. Within a certain range of cell numbers, the amount of formazan formed is proportional to the number of cells, so it can indirectly reflect the number of living cells. quantity.

[0066] 2.1 Experimental process

[0067] 2.1.1 Cell culture

[0068] A549 cells, B16F10 cells, and H460 cells were incubated at 37°C in 5% CO 2 Under these conditions, the cells were respectively subcultured with RPMI1640 medium containing 10% fetal bovine serum, and the cells ...

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Abstract

The invention discloses a 4,6-dimethyl-oxazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione derivative acting on a fibroblast growth factor (FGF) receptor. A target compound is prepared by implementing nitrosation on 1,3-dimethyl pyrimidine-2,4,6(1H,3H,5H)-trione which serves as a starting material through NaNO2, reducing the material through Na2S2O4, implementing a Schiff alkali reaction with aromatic aldehyde, and finally cyclizing through SOCl2. The 4,6-dimethyl-oxazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione derivative disclosed by the invention has a certain inhibiting function on experimental cells and shows a certain antitumor activity. For an H460 cell, IC50 values of compounds N5a, N5g and N5k are less than that of a positive control drug; for a B16F10 cell, IC50 values of compounds N5f, N5h and N5i are less than IC50 value of the positive control drug; for an A549 cell, IC50 value of the positive control is relatively high, and IC50 values of compounds N5f, N5g, N5h and N5l are less than IC50 value of the positive control drug.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a derivative of 4,6-dimethyl-oxazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione acting on FGF receptors things. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. The mortality rate caused by malignant tumor is second only to cardiovascular and cerebrovascular diseases. At present, although there are many kinds of treatment methods, chemotherapy is still the main method. Although traditional antitumor drugs have strong effects, they lack selectivity and have relatively high toxicity and side effects, which limit their clinical application. Therefore, people have always hoped to develop drugs based on the transmission mechanism of tumor signals. [0003] Protein kinases are phosphotransferases that play key roles in regulating metabolism, gene expression, cell growth, cell division, and cell differ...

Claims

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Application Information

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IPC IPC(8): C07D498/04A61P35/00
CPCC07D498/04
Inventor 叶发青郭平谢自新刘剑敏王跃武宋晓琴陈梁芳
Owner WENZHOU MEDICAL UNIV
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