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A kind of 2-mercapto-5-cyanopyrimidine derivatives and its preparation method and application

A technology of derivatives and mercapto groups, which is applied in the field of 2-mercapto-5-cyanopyrimidine derivatives and their preparation, can solve the problems of low bioavailability, poor selectivity, easy to produce drug resistance, etc., and achieve good The effect of inhibiting activity

Active Publication Date: 2021-12-24
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Tumor is a disease that seriously endangers human health. Most of the anti-tumor drugs currently on the market have certain treatment limitations, such as easy drug resistance, large side effects, short half-life, low bioavailability, and poor selectivity. Therefore, it is very urgent to develop highly effective, low-toxic and selective drugs for the treatment of tumors.

Method used

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  • A kind of 2-mercapto-5-cyanopyrimidine derivatives and its preparation method and application
  • A kind of 2-mercapto-5-cyanopyrimidine derivatives and its preparation method and application
  • A kind of 2-mercapto-5-cyanopyrimidine derivatives and its preparation method and application

Examples

Experimental program
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preparation example Construction

[0042] The present invention provides a preparation method of 2-mercapto-5-cyanopyrimidine derivatives described in the above technical scheme, comprising the following steps:

[0043] Ethyl cyanoacetate, thiourea, R 3 -CHO, alkali reagent and solvent I are mixed, and the ring closure reaction is carried out to obtain the compound having the structure shown in formula II;

[0044] The compound having the structure shown in formula II, R 1 -R 4 Mix with solvent II, carry out substitution reaction I, obtain the compound with the structure shown in formula III; Said R 1 -R 4 Middle R 4 Including -Br or -Cl;

[0045] Mixing the compound having the structure shown in formula III, phosphorus oxychloride and solvent III, and performing substitution reaction II to obtain the compound having the structure shown in formula IV;

[0046] The compound having the structure shown in formula IV, R 2 -H is mixed with solvent IV to carry out substitution reaction III to obtain 2-mercapto...

Embodiment 1

[0073] Add ethyl cyanoacetate (20mmol) and potassium hydroxide (30mmol) into ethanol (AR, 50mL), stir and dissolve at 90°C, then add thiourea (30mmol) and 3,4,5-trimethoxy Benzaldehyde (30 mmol) was added to the reaction system, and the stirring was continued at 90°C for 10 h (TLC tracking and detection of the reaction progress); the obtained system was subjected to suction filtration and recrystallization to obtain a compound having the structure shown in formula II-1;

[0074] The compound (20mmol) having the structure shown in formula II-1 was mixed with acetonitrile (AR, 50mL), m-trifluoromethylbenzyl bromide (30mmol) was added dropwise to the resulting solution, and stirred at 60°C for 6h (TLC tracking detection reaction process); the acetonitrile in the gained system is evaporated, and the mixture of ethyl acetate and water (the volume ratio of ethyl acetate and water is 1:1) is used to extract the residue, and the gained organic phase is subjected to chromatographic colu...

Embodiment 2

[0081] According to the method in Example 1, the compound of the structure shown in formula I-2 is prepared, the only difference is that m-trifluoromethyl benzyl bromide is replaced by 4-methyl benzyl bromide, and 1-(2-dimethylamino Ethyl)-1H-5-mercaptotetrazole is replaced by 2-mercaptothiazole;

[0082] The compound with the structure shown in formula I-2 is a white solid with a melting point of 106-107°C and a yield of 56%;

[0083]

[0084] The analysis results are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.98(d, J=3.0Hz, 1H, Ar-H), 7.62(d, J=3.1Hz, 1H, Ar-H), 7.31(s, 2H, Ar-H, 7.10(s, 4H ,Ar-H),4.08(s,2H,-CH 2 -),3.93(d,J=5.6Hz,9H,-CH 3 ),2.32(s,3H,-CH 3 ).HR-MS(ESI),calcd.C 25 h 22 N 4 o 3 S 3 ,[M+H] + m / z: H Mass: 523.0932. Found: 523.0931.

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Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a 2-mercapto-5-cyanopyrimidine derivative and a preparation method and application thereof. The 2-mercapto-5-cyanopyrimidine derivatives provided by the present invention inhibit the DCN1-UBC12 protein-protein interaction by binding to the DCN1 protein. The results of the examples show that, compared with the compound DI-591, the 2-mercapto-5-cyanopyrimidine derivatives provided by the present invention have better inhibitory activity on DCN1-UBC12 protein-protein interaction.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a 2-mercapto-5-cyanopyrimidine derivative and a preparation method and application thereof. Background technique [0002] Tumor is a disease that seriously endangers human health. Most of the anti-tumor drugs currently on the market have certain treatment limitations, such as easy drug resistance, large side effects, short half-life, low bioavailability, and poor selectivity. Therefore, it is very urgent to develop highly effective, low-toxic and selective drugs for treating tumors. [0003] Ubiquitination regulates various life processes of cells by participating in protein post-translational modification. Studies have shown that abnormal ubiquitination process can lead to a variety of human diseases, such as Parkinson's disease, Alzheimer's disease, rectal cancer, breast cancer, etc. Neddylation modification, which is similar to ubiquitination modification, underg...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14C07D401/14C07D401/12C07D403/12C07D417/12C07D239/47A61P35/00
CPCA61P35/00C07D239/47C07D401/12C07D401/14C07D403/12C07D417/12C07D417/14
Inventor 刘宏民赵文马立英何张旭周文娟杨菲菲郑甲信
Owner ZHENGZHOU UNIV
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