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Pyrimidotriazole-containing LSD1 inhibitor, preparation method and application

A technology of triazole and inhibitor, applied in the field of medicinal chemistry

Inactive Publication Date: 2017-07-07
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 new compounds combining pyrimidine and triazole structures with the anti-tumor effect based on the LSD1 target, so such research is of great value

Method used

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  • Pyrimidotriazole-containing LSD1 inhibitor, preparation method and application
  • Pyrimidotriazole-containing LSD1 inhibitor, preparation method and application
  • Pyrimidotriazole-containing LSD1 inhibitor, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Compound 8 of Example 1, R 1 =propyl-S-, preparation of

[0052] (1) Compound 2 (R 1 = the preparation of propyl-S-)

[0053] Barbituric acid (3g, 1eq) and triethylamine (2.9ml, 1eq) were added to 30ml of methanol, under reflux, bromopropane (1.8ml, 1eq) was slowly added dropwise, and reflux was continued for 1 hour after the addition , cooled, and suction filtered to obtain 3.7g of pink solid compound 2b with a yield of 97%.

[0054] (2) Compound 3 (R 1 = the preparation of propyl-S-)

[0055] Under ice bath, carefully dissolve 3ml of fuming nitric acid in 6ml of acetic acid, then add 2.9g of compound 2b in batches, after the addition, continue to stir for 2 hours, then add the reaction solution to 18ml of ice water, filter with suction, After washing with water, a dark red powder compound 3b was obtained with a yield of 77.5%.

[0056] (3) Compound 4 (R 1 = the preparation of propyl-S-)

[0057] Compound 3b (12.4g, 1eq) was dissolved in 50ml of phosphorus ox...

Embodiment 2

[0066] Example 2 Compound 9, R 1 =propyl-S-, preparation of

[0067] The hydroxyethylamine of methanesulfonyl chloride protection replaces ethanolamine, adopts the same method of embodiment 7 to prepare 9. 1 HNMR (400MHz, CDCl 3 ,ppm): δ8.12-8.14(d,J=8.0Hz,1H),7.97-7.99(d,J=7.6Hz,1H),7.55-7.59(m,1H),7.49-7.53(m,1H ), 4.95-4.97(t, J=5.2Hz, 2H), 4.79-4.81(t, J=5.2Hz, 2H), 3.00(s, 3H), 1.57-1.62(m, 2H), 0.85-0.89( t,J=7.4Hz,3H). 13 CNMR (100MHz, CDCl 3 , ppm): δ171.34, 160.36, 154.99, 152.17, 149.24, 137.33, 131.06, 126.62, 126.08, 123.47, 121.31, 65.21, 46.06, 37.95, 33.50, 22.17, 13.26. Yield 70%.

Embodiment 3

[0068] Example 3 Compound 10, R 1 =propyl-S-, preparation of

[0069] The hydroxyethylamine of benzoyl protection replaces ethanolamine, adopts the same method of embodiment 7 to prepare 10. 1 HNMR (400MHz, CDCl 3 ,ppm): δ8.11-8.13(d,J=8.0Hz,1H),7.96-7.98(d,J=7.6Hz,1H),7.91-7.94(m,2H),7.54-7.58(m,2H ),7.48-7.52(m,1H),7.40-7.44(m,2H),5.02-5.05(t,J=5.2Hz,2H),4.83-4.85(t,J=5.2Hz,2H),2.87- 2.90(t,J=7.2Hz,2H),1.50-1.59(m,2H),0.83-0.86(t,J=7.4Hz,3H). 13 CNMR (100MHz, CDCl 3 ,ppm):δ171.04,166.04,160.02,155.33,152.08,149.33,137.23,133.37,131.01,129.75,129.20,128.50,126.57,125.99,123.40,121.26,62.34,46.12,33.32,22.12,13.27.。 Yield 63%.

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a class of pyrimidotriazole compounds, a preparation method thereof and the use of lysine-specific demethylase (hereinafter referred to as LSD1) as a target in the preparation of antitumor drugs Applications. The general formula of the compound of the present invention is shown in I. The LSD1 enzyme inhibitory activity experiment in vitro proves 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 drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to pyrimidotriazole compounds, their preparation methods and their use in antitumor drugs targeting histone lysine specific demethylase (hereinafter referred to as LSD1) application. 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 mechanism of histone modification. histone modification. Before 2004, histone methylati...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCC07D487/04
Inventor 刘宏民李中华郑一超张婷索凤至耿鹏飞
Owner ZHENGZHOU UNIV
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