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Imidazo[1,2-a]pyridine compound, and preparation method and applications thereof

An imidazo compound technology, which is applied in the field of imidazo[1,2-a]pyridine compounds and their synthesis, can solve problems such as unsatisfactory cell activity, and achieves the effect of inhibiting tumor cell proliferation and tumor growth, and significantly inhibiting tumor effects. Effect

Inactive Publication Date: 2017-03-15
EAST CHINA NORMAL UNIV
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AI Technical Summary

Problems solved by technology

The cell activity of these inhibitors is very unsatisfactory, and there are no reports of inhibitors with in vivo tumor suppression effects

Method used

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  • Imidazo[1,2-a]pyridine compound, and preparation method and applications thereof
  • Imidazo[1,2-a]pyridine compound, and preparation method and applications thereof
  • Imidazo[1,2-a]pyridine compound, and preparation method and applications thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1: Synthesis of imidazo[1,2-a]pyridine compound 16

[0066]

[0067] synthetic route:

[0068]

[0069] After dissolving 2-amino-4-hydroxypyridine (4.4g, 40.0mmol) in 200mL EtOH, chloroacetaldehyde (16.5mL, 100mmol) was added, and stirred and refluxed overnight. The reaction solution was concentrated, and column chromatography gave 6-imidazo[1,2-a]pyridin-7-ol as a white solid with a yield of 88%. 1 H NMR (400MHz, MeOD) δ8.56(d, J=8.2Hz, 1H), 7.93(d, J=1.7Hz, 1H), 7.74(d, J=1.9Hz, 1H), 7.05-7.01(m ,2H).

[0070] The imidazo[1,2-a]pyridin-7-ol (218mg, 1.63mmol), N-Boc-4-hydroxypiperidine (654mg, 3.25mmol) and Ph 3 P (1.71g, 6.52mmol) was dissolved in THF (30mL), then DBAD (748mg, 3.25mmol) dissolved in THF (10mL) was dropped into the reaction solution at 0°C, after the reaction was complete at room temperature, water was added to quench the reaction , vacuum spin-dry column chromatography to obtain the product 7 (250mg, 48%). 1 H NMR (400MHz, CDCl ...

Embodiment 2

[0080] Embodiment 2: Synthesis of imidazo[1,2-a]pyridine compound 21

[0081]

[0082] Dissolve methyl 4-bromo-2-hydroxybenzoate (4.6g) in isopropanol (20mL), then add ammonia water (40mL), react at 50°C for 5h and spin dry to obtain the crude product 4-bromo-2-hydroxy Benzamide was used directly in the next reaction.

[0083] 4-Bromo-2-hydroxybenzamide (8.64g, 40.0mmol) was dissolved in DMF (80mL), then 2-(trifluoromethyl)benzyl bromide (11.5g, 1.2eq) and K 2 CO 3 (6.08g, 1.1eq), then reacted at 50°C for 6h. After the reaction is complete, add EA (500mL) to dilute, wash with water (2250mL), wash with saturated brine (150mL), Na 2 SO 4 After drying, it was concentrated and spin-dried, and column chromatography EA:PE=1:10 gave compound 18c (12.4g, 82.9%). 1 H NMR (400MHz, CDCl 3 )δ8.09(d, J=8.4Hz, 1H), 7.77(d, J=7.8Hz, 1H), 7.62(t, J=6.1Hz, 2H), 7.53(dt, J=8.3, 4.2Hz, 1H),7.40(s,1H),7.31–7.23(m,1H),7.18(d,J=1.2Hz,1H),5.97(s,1H),5.37(s,2H).

[0084] Compound 18c (2.9g...

Embodiment 3

[0087] Embodiment 3: 20d synthesis of imidazo[1,2-a]pyridine compound

[0088]

[0089] Iodide 10 (71.4mg, 0.20mmol) and boronate 19d (106mg, 0.30mmol, 1.5eq) were dissolved in DMF / H 2 After O (10 / 1, 2.2mL), add K 2 CO 3 (55.3mg, 0.40mmol 2.0eq) and Pd(PPh 3 ) 4 (23.1mg, 0.02mmol 0.10eq), and then reacted at 80°C for 12h. After suction filtration with diatomaceous earth, the filtrate was spin-dried, and purified by column chromatography (2-10% MeOH / DCM) to obtain compound 20d (75mg, 78%). 1 H NMR(400MHz,DMSO)δ8.35(s,1H),7.94(d,J=7.6Hz,1H),7.79(s,1H),7.66(s,1H),7.59(s,1H),7.53 (d,J=6.5Hz,2H),7.48–7.32(m,4H),7.31–7.19(m,2H),6.74(s,1H),5.40(s,2H),4.85(s,1H), 3.28–3.06(m,4H),2.85(s,3H),2.30–1.87(m,4H).HRMS(ESI)m / z calcd for C 27 h 29 N 4 o 3 (M+H) + 457.2240,found 457.2222.

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Abstract

The invention discloses an imidazo[1,2-a]pyridine compound, and a preparation method and applications thereof. The imidazo[1,2-a]pyridine compound can inhibit the activity of NEK2 kinases as an NEK2 micro-molecular inhibitor with a novel structure. The invention also discloses effects of the imidazo[1,2-a]pyridine compound in inhibition of proliferation of tumor cells and inhibition of growth of the tumor cells in animal bodies through inducing cell cycle stopping and apoptosis.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis and chemical engineering, and specifically relates to an imidazo[1,2-a]pyridine compound and its synthesis method and application. As a NEK2 inhibitor, the imidazo[1,2-a]pyridine compound can be Inhibits the proliferation of tumor cells by inducing cell cycle arrest and apoptosis, and has good antitumor activity both in vivo and in vitro. Background technique [0002] The World Health Organization and its affiliated Cancer Research Institute (IARC) released a research report in 2012, stating that about 14 million new cancer cases were diagnosed worldwide. Half of the world's new cancer cases occur in Asia, most of which occur in China [http: / / china.caixin.com / 2014-02-08 / 100636253.html? cx_from=news.baidu.com]. According to the report, 20 years later, the number of new cancer cases worldwide will increase to 22 million each year. At the same time, the number of cancer deaths wil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00
CPCC07D471/04
Inventor 胡文浩席建备雷锐锐朱孟丽马明亮肖国兰章雄文方艳芬李宏宇
Owner EAST CHINA NORMAL UNIV
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