A class of 2-aryl-4-(1h-pyrazol-3-yl)pyridine-like LSD1/HDAC dual-target inhibitors

A technology of pyridines and aryls, applied in the field of medicinal chemistry, to achieve the effects of favorable promotion and application, strong inhibitory activity, and good in vitro antitumor activity

Active Publication Date: 2022-05-03
XINXIANG MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In order to discover new LSD1 / HDAC dual-target inhibitors, explore the synthesis of a class of 2-aryl-4-(1H-pyrazol-3-yl)pyridine compounds, verify their LSD1, HDAC dual-target inhibitory activity and in vitro Anti-tumor activity is the starting point of this application, and there are no reports on the synthesis, LSD1 / HDAC inhibitory activity and anti-tumor activity of this type of compound

Method used

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  • A class of 2-aryl-4-(1h-pyrazol-3-yl)pyridine-like LSD1/HDAC dual-target inhibitors
  • A class of 2-aryl-4-(1h-pyrazol-3-yl)pyridine-like LSD1/HDAC dual-target inhibitors
  • A class of 2-aryl-4-(1h-pyrazol-3-yl)pyridine-like LSD1/HDAC dual-target inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Synthesis of 2-bromo-4-(1H pyrazol-3-yl)pyridine (3)

[0024]

[0025] Add compound 2-bromo-4-iodopyridine (1212.1mg, 6.0mmol), toluene (20mL), ethanol (25mL), H 2 O (7.5mL), K 2 CO 3 (1.68g, 11.1mmol), Pd(PPh 3 ) 4(694.0mg, 0.6mmol) and pyrazole-3-boronic acid (1451.9mg, 7.2mmol), stirred and reacted at 92°C for 4 hours under nitrogen protection. After the reaction, the reaction system was cooled to room temperature, and then added to the reaction system Extract with water and ethyl acetate, combine the ethyl acetate layers, wash with water and saturated NaCl aqueous solution respectively, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the concentrate by silica gel column chromatography (petroleum ether: acetone = 5:1) to obtain compound 3a (850.4mg), white solid, yield: 65.5%, Mp: 140-141℃. 1 H NMR (400MHz, DMSO-d 6 )δ13.36(s,1H),8.39(d,1H,J=5.2Hz),8.03(d,1H,J=1.6Hz),7.88(s,1H),7.8...

Embodiment 2

[0026] Example 2 Synthesis of methyl 4-((3-(2-bromo-pyridin-4-yl)-1H-pyrazol-1-yl)methyl)benzoate (4)

[0027] Add compound 3 (1244.4mg, 6.0mmol), methyl 4-bromomethylbenzoate (1451.9mg, 7.2mmol) and cesium carbonate (2932.2mg, 9.0mmol) in a 50ml two-necked flask, add DMF (8mL), Stir the reaction at room temperature under nitrogen protection for 5 h. Then add water and ethyl acetate to the reaction system for extraction, combine the ethyl acetate layers, wash with water and saturated NaCl aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separation and purification by silica gel column chromatography (petroleum ether: acetone = 2:1) gave compound 4 (1755.4 mg), a white solid, yield: 78.6%, Mp: 127-128°C. 1 H NMR (400MHz, CDCl 3 )δ8.36 (d, 1H, J = 5.2Hz), 8.03 (d, 2H, J = 8.0Hz), 7.90 (d, 1H, J = 1.2Hz), 7.64 (dd, 1H, J 1 =1.6Hz,J 1 =5.2Hz),7.47(d,1H,J=2.4Hz),7.29(d,2H,J=8.4Hz),6.69(d,1H,J=2.4Hz),5.43(s,2H),3....

Embodiment 3

[0028] Example 3 Synthesis of 4-((3-(2-(4-methylphenyl)pyridin-4-yl)-1H-pyrazol-1-yl)methyl)benzoate (5a)

[0029]

[0030] In a 50 ml two-neck round bottom flask, add compound 4 (521.1 mg, 1.4 mmol), toluene (5 mL), ethanol (5 mL), H 2 O (1.3mL), K 2 CO 3 (359.3mg, 2.6mmol), Pd(PPh 3 ) 4 (162.0mg, 0.14mmol) and 4-methylphenylboronic acid (231.1mg, 1.7mmol), under nitrogen protection, stirred at 92°C for 4 hours. After the reaction, the reaction system was cooled to room temperature, extracted with water and ethyl acetate , the ethyl acetate layers were combined, washed with water and a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered with suction, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1), to obtain compound 5a (483.7mg), yield: 90.1%, white solid, Mp: 92-93°C. 1 H NMR (400MHz, CDCl 3 )δ8.68(dd,1H,J 1 =0.8Hz,J 2 =...

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Abstract

The invention relates to a class of 2-aryl-4-(1H-pyrazole-3-yl)pyridine LSD1 / HDAC dual-target inhibitors, its preparation method and its application in the preparation of antitumor drugs, belonging to medicinal chemistry technology field. The compound has the following general formula: wherein, R 1 CH is preferred 3 、OCH 3 and H; R 2 F and H are preferred. The compounds of the present invention have strong inhibitory activity on both LSD1 and HDAC, and the IC on HDAC1 50 The value is less than 5 nM, significantly better than the positive drug SAHA. It shows good in vitro anti-tumor activity against human acute myeloid leukemia THP‑1 cell line, which is better than the positive drug SAHA, which provides a basis for the development of LSD1 / HDAC dual-target inhibitor drugs and can be used as a candidate for further development Or lead compounds are used to develop anti-tumor therapeutic drugs.

Description

technical field [0001] The invention specifically relates to a class of 2-aryl-4-(1H-pyrazol-3-yl)pyridine LSD1 / HDAC dual-target inhibitors, its preparation method and its application in the preparation of antitumor drugs, belonging to medicinal chemistry technology field. Background technique [0002] The dysregulation of epigenetic modification is closely related to the occurrence, development and poor prognosis of tumors. The development of anticancer drugs targeting epigenetic regulatory proteins has aroused great interest and has made great progress. [0003] Histone lysine-specific demethylase 1 (LSD1), also known as KDM1A, CPRF, BHC110 and AOF2, was discovered by Shi Yang's team at Harvard University in 2004. LSD1 is a flavin adenine dinucleotide-dependent amino oxidase whose main function is to specifically remove monomethylation and dimethylation on histone H3K4. LSD1 represses the transcription of genes by removing the methylation marks of H3K4me1 / 2, thereby regu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61P35/02
CPCC07D401/04A61P35/02
Inventor 段迎超关圆圆张少杰于童靳林峰
Owner XINXIANG MEDICAL UNIV
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