Inhibitor with pyrimido-triazole-tetrazole-thione LSD1 (lysine specific demethylase 1), preparation method of inhibitor and application

A technology of mercaptotetrazolium and triazole, applied to medical preparations containing active ingredients, pharmaceutical formulas, organic active ingredients, etc.

Active Publication Date: 2017-08-11
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 and triazole-mercaptotetrazolium compounds with the anti-tumor effect based on the LSD1 target, so this study has very important value

Method used

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  • Inhibitor with pyrimido-triazole-tetrazole-thione LSD1 (lysine specific demethylase 1), preparation method of inhibitor and application
  • Inhibitor with pyrimido-triazole-tetrazole-thione LSD1 (lysine specific demethylase 1), preparation method of inhibitor and application
  • Inhibitor with pyrimido-triazole-tetrazole-thione LSD1 (lysine specific demethylase 1), preparation method of inhibitor and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Compound 8 of Example 1, R 1 =Propyl-S-, R 3 = Preparation of Me-

[0054] (1) Compound 2 (R 1 = Preparation of Propyl-S-)

[0055] 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%.

[0056] (2) Compound 3 (R 1 = Preparation of Propyl-S-)

[0057] 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%.

[0058] (3) Compound 4 (R 1 = Preparation of Propyl-S-)

[0059] Compound 3b (12.4g, 1eq) was dissolved in 50ml of phosphorus oxy...

Embodiment 2

[0068] Example 2 Compound 9, R 1 =Propyl-S-, R 3 = Preparation of Me-

[0069] Furfurylamine replaces ethanolamine, adopts the same method of embodiment 7 to prepare 9. 1 HNMR (400MHz, CDCl 3 ,ppm):δ7.36-7.37(d,J=1.2Hz,1H),6.50-6.51(d,J=3.2Hz,1H),6.35-6.36(m,1H),5.74(s,2H), 4.13(s,3H),2.91-2.94(t,J=7.4Hz,2H),1.62-1.67(m,2H),0.99-1.03(t,J=7.4Hz,3H). 13 CNMR (100MHz, CDCl 3 , ppm): δ171.46, 158.02, 149.18, 146.81, 145.05, 143.51, 131.09, 110.81, 110.48, 43.43, 34.82, 33.54, 22.14, 13.37. Yield 66%.

Embodiment 3

[0070] Example 3 Compound 10, R 1 =Propyl-S-, R 3 = Preparation of Me-

[0071] Thiphenethylamine replaces ethanolamine, adopts the same method of embodiment 7 to prepare 10. 1 HNMR (400MHz, CDCl 3 ,ppm): δ7.13-7.14(m,1H),6.87-6.89(m,1H),6.75-6.76(d,J=3.2Hz,1H),4.83-4.86(t,J=7.2Hz,2H ),4.14(s,3H),3.55-3.59(t,J=7.2Hz,2H),2.87-2.91(t,J=7.2Hz,2H),1.58-1.65(m,2H),0.99-1.02( t,J=7.2Hz,3H). 13 CNMR (100MHz, CDCl 3 , ppm): δ171.18, 157.92, 149.45, 145.08, 138.36, 131.06, 127.16, 126.08, 124.68, 48.37, 34.83, 33.50, 29.59, 22.17, 13.40. Yield 72%.

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a compound with pyrimido-triazole-tetrazole-thione structures, a preparation method of the compound and an application of the compound to preparation of anti-tumor medicines by taking lysine specific demethylase 1 (hereinafter referred to as LSD1) as a target. The general formula of the compound is as shown in the specification. In-vitro LSD1 inhibitory activity tests show that the compound has obvious inhibiting and killing functions on various tumor cells by inhibiting activity of the LSD1, can serve as a further developed lead and is applied to preparation of anti-tumor medicines.

Description

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

Claims

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Application Information

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Patent Type & Authority Applications(China)
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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