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Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, preparation method and application

A technology of pyrimidine derivatives and structural units, applied in the field of medicinal chemistry

Active Publication Date: 2016-03-16
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few reports on the combination of pyrimidine compounds and the anti-tumor effect based on the LSD1 target, so this study has very important value

Method used

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  • Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, preparation method and application
  • Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, preparation method and application
  • Pyrimidine derivatives containing semicarbazide and terminal alkyne structural units, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1 general formula( II ), R 2 =Derivatives of Phenyl( II-1 ) preparation

[0076] Add ethyl cyanoacetate (2.3g, 20mmol) and sodium hydroxide (1.2g, 30mmol) into the ethanol solution, under reflux conditions, react for a period of time, then add thiourea (2.3g, 30mmol) and benzaldehyde (3.2 g, 30mmol) was added to the reaction system, the reaction was stirred, followed by TLC detection. After the reaction, filter with suction and recrystallize to obtain the pure product. Yield 92%, yellow solid.

Embodiment 2

[0077] Example 2 general formula( III ), R 1 =Cl,R 2 =Derivatives of Phenyl( III-1 ) preparation

[0078] Add propyne bromide (3.6g, 30mmol) dropwise into a solution of II-1 (2.7g, 10mmol) in 1,4-dioxane, and heat and stir at 60°C for reaction. Monitor the reaction process with TLC until the reaction is complete; without separation, directly add phosphorus oxychloride (4.6g, 30mmol) dropwise to the reaction system. Filtration to obtain a solid, the pure compound III-1 solid was obtained by column chromatography. Yield 64%, pale yellow solid. Melting point: 131-132 o c. 1 HNMR (400MHz, CDCl 3 ,δ,ppm)δ8.20–8.07(m,2H,Ar-H),7.70–7.52(m,3H,Ar-H),4.01(d, J =2.6Hz,2H,-CH 2 -),2.28(t, J =2.6Hz,1H,≡C-H). 13 CNMR (100MHz, CDCl 3 ,δ,ppm):δ174.02,168.73,163.95,134.07,132.72,129.35,129.02,114.43,101.42,78.17,71.63,20.36.HR-MS(ESI):Calcd.C 14 h 9 ClN 3 S,[M+H] + m / z:286.0206,found:286.0202.

Embodiment 3

[0079] Example 3 general formula( III ), R 1 =Cl,R 2 =Derivatives of 4-Chlorophenyl ( III-2 ) preparation

[0080] Take the same method as in Example 1 to prepare II-2 , R 2 =4-Chlorophenyl; take the same method as in Example 2 to prepare III-2 , R 1 =Cl,R 2 =4-Chlorophenyl; Mp:79–80°C. 1 HNMR (400MHz, CDCl 3 ,δ,ppm)δ8.17–8.01(m,2H,Ar-H),7.63–7.47(m,2H,Ar-H),4.00(d, J =2.6Hz,2H,-CH 2 -),2.28(t, J =2.6Hz,1H,≡C-H). 13 CNMR (100MHz, CDCl 3 ,δ,ppm):δ174.20,167.41,164.04,139.39,132.39,130.69,129.40,114.27,101.19,78.07,71.66,20.40.HR-MS(ESI):Calcd.C 14 h 8 Cl 2 N 3 S,[M+H] + m / z:319.9816,found:319.9818.

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a class of pyrimidine compounds containing semicarbazide and terminal alkyne structural units, their preparation method and the preparation of anti- Application in tumor medicine. The invention uses a three-component one-pot method to construct pyrimidine active fragments, and then prepares target compounds through substitution, chlorination and amination reactions. The general formula of the compound of the present invention is shown in I. I. In vitro anti-tumor activity experiments and LSD1 enzyme inhibitory activity experiments prove that this type of compound has obvious inhibitory and killing effects on a variety of tumor cells by inhibiting the activity of LSD1, and can be used as a lead compound for further development and applied to the preparation of anti-tumor drug.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of pyrimidine compounds containing semicarbazide and terminal alkyne structural units, their preparation methods and their preparation using histone lysine specific demethylase (hereinafter referred to as LSD1) as Application of targeted anticancer drugs. Background technique [0002] Tumor is a disease that seriously endangers human health and is difficult to overcome. There are many anti-tumor drugs that have been marketed, but there are still some problems in these drugs, such as high toxicity, weak targeting, and easy drug resistance. Therefore, the research and development of new anticancer drugs is particularly important. [0003] Histone covalent modification is an important epigenetic mode, including histone acetylation, methylation, phosphorylation, and ubiquitination, among which acetylation and methylation are more frequently studied for the mecha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/38C07D239/47C07D409/04A61K31/505A61K31/506A61P35/00
CPCC07D239/38C07D239/47C07D409/04
Inventor 刘宏民马立英王博庞露苹王志茹张淼户彪郑甲信马玉培张笑丹
Owner ZHENGZHOU UNIV
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