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Pyrimido 1,2,4-triazole LSD1 inhibitor, its preparation method and application

One – the technology of triazole and inhibitor, applied in the field of medicinal chemistry, can solve the problems of large toxic and side effects, weak targeting, and easy to produce drug resistance, and achieve the effect of high yield and feasible synthesis method

Active Publication Date: 2018-09-18
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Tumor is a serious threat to human diseases. Although there are many anti-tumor drugs on the market, there are still some shortcomings in these drugs, such as relatively large toxic side effects, weak targeting, and easy drug resistance.

Method used

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  • Pyrimido 1,2,4-triazole LSD1 inhibitor, its preparation method and application
  • Pyrimido 1,2,4-triazole LSD1 inhibitor, its preparation method and application
  • Pyrimido 1,2,4-triazole LSD1 inhibitor, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of compound 3a

[0029]

[0030] After adding 2-amino-5-mercapto-1,2,4-triazole (1g, 8.61mmoL) and sodium carbonate (1.37g, 12.92mmoL) into the reaction flask, add 20mL of acetone, slowly drop benzyl chloride (1.13mL, 9.47mmoL) was refluxed at 60°C, and the reaction was monitored by TLC. After the reaction was completed, suction filtration was performed directly, and the filtrate was subjected to column chromatography (dichloromethane:methanol=20:1) to obtain a pure product. Yield 67.57%, white solid. 1 H NMR (400MHz, DMSO-d 6 )δ7.41-7.18(m,5H),4.34(s,2H). 13 C NMR (100MHz, DMSO-d 6 )δ152.19,147.08,136.55,128.79,128.43,127.48,35.41.HRMS(ESI):m / z calcd for C 9 h 9 N 4 S(M-H) - ,205.0548; found, 205.0548.

[0031] Preparation of compound 4a

[0032]

[0033] Compound 3a (1 g, 4.85 mmoL) was added to the reaction flask, and after adding 20 mL of glacial acetic acid, ethyl acetoacetate (612.57 μL, 4.85 mmoL) was slowly added dropwise and heated t...

Embodiment 2

[0040] Example 2 Preparation of Compound 6b

[0041]

[0042] Compound 5a (150 mg, 515.87 μmoL) was added to the reaction flask, 2 mL of ethanol was added, excess ammonia water was added dropwise, the reaction was carried out at room temperature, and the progress of the reaction was monitored by TLC. After the reaction, a large amount of solid precipitated out. Suction filtration directly to obtain a filter cake. The filter cake was dried in an oven at 60 °C for 6 h to obtain pure compound 6b. yellow solid. Melting point: 196-201°C. Yield 89%.

[0043] 1 H NMR (400MHz, DMSO-d 6 )δ7.93(s,2H),7.55-7.43(m,2H),7.37-7.28(m,2H),7.24(dd,J=8.4,6.1Hz,1H),6.12(s,1H),4.49 (s,2H),2.37(s,3H). 13 C NMR (100MHz, DMSO-d 6 )δ164.29,162.84,155.87,147.50,138.07,128.92,128.38,127.16,90.25,34.36,24.37.HRMS(ESI):m / z calcd for C 13 h 12 N 5 S(M-H) - ,270.0813; found, 270.0821.

Embodiment 3

[0044] Example 3 Preparation of compound 6c

[0045]

[0046] Compound 5a (150 mg, 515.87 μmoL) was added to the reaction flask, 2 mL of ethanol was added, aniline (70.65 μL, 773.81 μmoL) was added dropwise, and the reaction was carried out at room temperature, and the progress of the reaction was monitored by TLC. After the reaction, a large amount of solid precipitated out. Suction filtration directly to obtain a filter cake. The filter cake was dried in an oven at 60 °C for 6 h to obtain pure compound 6c. white solid. Melting point: 189-192°C. Yield 89%. 1 HNMR (400MHz, CDCl 3 )δ7.71(s,1H),7.51-7.44(m,4H),7.36-7.27(m,5H),7.26-7.20(m,1H),6.30(s,1H),4.54(s,2H) ,2.51(s,3H). 13 C NMR (100MHz, CDCl 3 )δ166.54,164.77,155.92,144.35,137.57,135.76,130.02,129.11,128.53,127.36,126.92,123.82,89.01,35.80,25.41.HRMS(ESI):m / z calcd for C 19 h 16 N 5 S(M-H) - ,346.1126; found, 346.1135.

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a pyrimido1,2,4-triazole-based LSD1 inhibitor, a preparation method and applications thereof. According to the present invention, a pyrimido1,2,4-triazole compound and a LSD1 compound are combined to prepare a series of antitumor activity compounds; the synthesis method is feasible, and the yield is high; the structure general formula of the compounds is defined in the specification, wherein R is amino, hydroxyethylpiperazinyl, morpholinyl, piperazinyl, p-fluoroanilino, p-methylanilino, anilino and the like; and with the applications of the compounds in the antitumor drugs using histone lysine specific demethylase (LSD1) as the target, the good activity is provided, and the new approach is developed for the novel antitumor drug using the LSD1 as the target.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of pyrimido-1,2,4-triazole structural unit compounds, a preparation method and its preparation using histone lysine-specific demethylase (hereinafter referred to as LSD1 ) as the target of anti-tumor drugs. Background technique [0002] Tumor is a serious threat to human diseases. Although there are many anti-tumor drugs on the market, there are still some shortcomings in these drugs, such as relatively large toxic side effects, weak targeting, and easy drug resistance. Targeted drugs not only have good effects but also have much fewer side effects than conventional treatments, so their research and development has received more and more attention. [0003] Covalent modification is very important in epigenetics. Histone covalent modification includes histone phosphorylation, acetylation, ubiquitination, methylation, etc. The current research on acetylation a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04
Inventor 刘宏民王帅余斌赵丽杰郑甲信
Owner ZHENGZHOU UNIV