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Substituted pyridino imidazole compound and application thereof in preparation of drugs for treating malignant tumor diseases

A pyridoimidazole, malignant tumor technology, applied in the field of medicine, can solve problems such as low overall survival rate, achieve the effects of inhibiting growth and metastasis, broad application prospects, and important theoretical significance

Active Publication Date: 2020-08-04
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the number of patients with advanced lung cancer is increasing year by year, and the overall survival rate is low

Method used

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  • Substituted pyridino imidazole compound and application thereof in preparation of drugs for treating malignant tumor diseases
  • Substituted pyridino imidazole compound and application thereof in preparation of drugs for treating malignant tumor diseases
  • Substituted pyridino imidazole compound and application thereof in preparation of drugs for treating malignant tumor diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1: Preparation of W2014

[0060]

[0061] Weigh compound 1, iron powder (3 equivalents) and ammonium chloride (4 equivalents) and dissolve them in 20ml of ethanol, heat at 80°C, cool to room temperature after the reaction is complete, filter the reaction solution through diatomaceous earth and rinse the silicon with an appropriate amount of ethyl acetate. alginate, the organic phase was dried with anhydrous sodium sulfate, and spin-dried to obtain a purple solid compound 2 with a yield of 78%. 1 H NMR (500MHz, CDCl 3 )δ6.85(d, J=7.8Hz, 1H), 6.60(d, J=7.8Hz, 1H), 4.45(s, 2H), 3.28(s, 2H).ESI-MS: 145.0[M+H ]+;

[0062] Weigh compound 3, p-hydroxybenzaldehyde (1.1 equivalents), and potassium carbonate (2 equivalents) and dissolve them in 40ml of acetonitrile, stir at room temperature overnight for reaction, filter after the reaction is complete, spin the organic phase to dry column chromatography and purify to obtain compound 4, the yield 90%, 1 H NMR (40...

Embodiment 2

[0065] Embodiment 2: Preparation of W2014R

[0066]

[0067] Weighed triphenylphosphine (1.8 equivalents) and dissolved it in 80 ml of tetrahydrofuran, under nitrogen protection, slowly added DIAD (1.8 equivalents) to the reaction under ice bath conditions, and after 20 minutes, kept ice bath conditions, successively added compound 6 (1 equivalent) and p-Hydroxybenzaldehyde (1 equivalent) were dissolved in 20 milliliters of tetrahydrofuran and added to the reaction respectively, stirred at room temperature, and the reaction was complete after 10 hours. The organic phase was spin-dried and concentrated, and the residue was purified by column chromatography to obtain compound 7 , with a yield of 44%, 1 H NMR (400MHz, CDCl 3 )δ9.84(s,1H),7.78–7.74(m,2H),7.39–7.36(m,4H),7.32–7.28(m,1H),6.99(d,J=8.7Hz,2H),5.44 (q, J=6.4Hz, 1H), 1.70 (d, J=6.4Hz, 3H).ESI-MS: 227.2[M+H]+;

[0068] Weigh intermediate compound 2 and compound 7 (1.1 equivalent) and dissolve in 10ml methanol, heat ...

Embodiment 3

[0070] Embodiment 3: Preparation of W2014S

[0071]

[0072] Weighed triphenylphosphine (1.8 equivalents) and dissolved it in 80 ml of tetrahydrofuran, under nitrogen protection, slowly added DIAD (1.8 equivalents) to the reaction under ice bath conditions, and after 20 minutes, maintained ice bath conditions, successively added compound 9 (1 equivalent) and p-Hydroxybenzaldehyde (1 equivalent) were dissolved in 20 milliliters of tetrahydrofuran and added to the reaction respectively, stirred at room temperature, and the reaction was complete after 10 hours. The organic phase was spin-dried and concentrated, and the residue was purified by column chromatography to obtain compound 10 , with a yield of 48%, 1 H NMR (400MHz, CDCl 3 )δ9.84(s,1H),7.79–7.74(m,2H),7.40–7.35(m,4H),7.32–7.28(m,1H),6.99(d,J=8.7Hz,2H),5.44 (q, J=6.4Hz, 1H), 1.70 (d, J=6.4Hz, 3H).ESI-MS: 227.2[M+H]+;

[0073] Weigh intermediate compound 2, compound 10 (1.1 equivalent) and dissolve in 10ml methanol, ...

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Abstract

The invention belongs to the field of medicines, and discloses a substituted pyridino imidazole compound as shown in the specification and an application thereof in preparation of a medicine for treating lung cancer. Cell level experiments prove that the compound can inhibit proliferation, migration, invasion and clone formation of lung cancer cells, induce apoptosis of the lung cancer cells and inhibit the phosphorylation level of STAT3; mouse in-vivo experiments show that the compound can inhibit growth and metastasis of lung cancer cells, specifically inhibit an STAT3 signal path, inhibit growth of lung cancer cell transplantation tumors and patient PDX tumors in an animal model, lay a foundation for subsequent new drug research and development, and have important theoretical significance and wide application prospects.

Description

technical field [0001] The present invention relates to the technical field of medicine, more specifically, to a substituted pyridoimidazole compound and its application in the preparation of medicines for treating malignant tumor diseases. [0002] technical background [0003] According to the results of global cancer statistics in 2018, lung cancer is still one of the malignant tumors with the fastest-growing morbidity and mortality worldwide and the greatest threat to human health and life. In 2018, regions with high incidence of lung cancer in the world are mainly distributed in North America and eastern Asia, among which China is one of the countries with the largest incidence of lung cancer. As of 2018, the incidence and mortality of lung cancer ranked first in the country. Among them, the incidence and mortality of lung cancer in men ranked first among all cancers, while the incidence of lung cancer in women ranked third, and the mortality rate was only Second only t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4545A61P35/00A61P35/02
CPCC07D471/04A61P35/00A61P35/02
Inventor 张小雷王元相刘培庆胡文浩郑琪瑶董辉
Owner SUN YAT SEN UNIV
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