2-aminoimidazopyridine derivative as well as preparation and application

A technology of imidazopyridines and azolopyridines, which is applied in the field of 2-aminoimidazopyridine derivatives and their preparation, and can solve the problems of limited clinical curative effect

Active Publication Date: 2017-11-24
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, such inhibitors can not only inhibit drug resistance caused by T790M, but also effectively inhibit sensitive EGFR mutations, and the clinical efficacy is limited.

Method used

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  • 2-aminoimidazopyridine derivative as well as preparation and application
  • 2-aminoimidazopyridine derivative as well as preparation and application
  • 2-aminoimidazopyridine derivative as well as preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: N-(3-(5-chloro-2-((4-(4-methylpiperazine)phenyl)amino)-3H-[4,5-b]imidazopyridine)phenyl) Acrylamide;

[0057]

[0058] Step 1: Combine 2,6-dichloro-3-nitropyridine (1.92g, 10mmol) with tert-butyl (3-aminophenyl) carbamate (2.08g, 10mmol) and potassium carbonate (1.38g, 10mmol) Dissolve in ethanol (25ml) and react overnight. After the reaction is completed, the solid in the system is suction filtered to obtain a red solid (3g), the product yield is 82%, m.p.: 157.7-158.6°C; 1 H NMR (500MHz, DMSO) δ 10.06 (s, 1H), 9.48 (s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.27-7.24 (m, 3H) ,7.00(d,J=8.5Hz,1H),1.48(s,9H).HRMS(ESI):m / z calcd for(C 16 H 17 ClN 4 O 4 +H) + :365.1011; found:365.1015.

[0059] Step 2: Dissolve the product obtained in Step 2 (3g, 8.25mmol), sodium borohydride (1.32g, 33mmol) and nickel chloride (3.9g, 16.5mmol) in dichloromethane (20mL) and cool to 0°C React at -2°C for 1 hour. After the reaction was completed, water was added, extracted wi...

Embodiment 2

[0064] Example 2: N-(3-(5-chloro-2-((4-(4-methylpiperazine)phenyl)amino)-3H-[4,5-b]imidazopyridine)phenyl) -2-Methylacrylamide

[0065] Refer to the method in Example 1, except that the 2-chloroacryloyl chloride in step 5 was replaced with 2-fluoroacryloyl chloride. After the reaction, the product was concentrated under reduced pressure to dryness to obtain the crude product, which was purified by column chromatography (DCM / MeOH=75:1 ) Obtain 0.9g of white solid, yield 40%, mp:> 200℃, 1 H NMR(500MHz,DMSO)δ7.95(d,J=8.2Hz,1H),7.92(s,1H),7.75(d,J=8.1Hz,1H),7.66(d,J=8.6Hz,2H ), 7.59 (t, J = 8.1 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 9.0 Hz, 2H), 5.85(s,1H),5.56(s,1H),3.47(m,4H),3.14(m,4H),2.80(s,3H),1.96(s,3H).HRMS(ESI): m / z calcd for(C 27 H 28 ClN 7 O+H) + :502.2117; found:502.2115.

Embodiment 3

[0066] Example 3: N-(3-(5-chloro-2-((4-(4-methylpiperazine)phenyl)amino)-3H-[4,5-b]imidazopyridine)phenyl) -2-Fluoroacrylamide

[0067] Refer to the method of Example 1, except that the 2-chloroacryloyl chloride in step 5 was replaced with 2-fluoroacryloyl chloride. After the reaction, the product was concentrated under reduced pressure to dryness to obtain the crude product, which was purified by column chromatography (DCM / MeOH=75: 1) 1.0 g of white solid is obtained, and the yield is 46%. m.p.:> 200℃, 1 H NMR(500MHz, CDCl 3 )δ8.57(s,1H),7.92(s,1H),7.71-7.67(m,2H),7.54(t,J=8.1Hz,1H),7.49(d,J=8.8Hz,2H), 7.29(d,J=7.8Hz,1H), 7.12(d,J=8.2Hz,1H), 6.92(d,J=8.8Hz,2H), 6.47(s,1H), 5.79(dd,J=47.2 ,3.3Hz,1H),5.24(dd,J=15.0,3.3Hz,1H),3.21-3.17(m,4H),2.61(m,4H),2.37(s,3H).HRMS(ESI): m / z calcd for(C 26 H 25 ClFN 7 O+H) + :506.1866; found:506.1865.

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Abstract

The invention provides a 2-aminoimidazopyridine derivative shown as a formula I, a formula II, a formula III or a formula IV and further provides a preparation method and application of the 2-aminoimidazopyridine derivative. An experiment shows that the 2-aminoimidazopyridine derivative has a remarkable proliferation inhibition effect on tumor cells (including an over-expressed wild type EGFR (Epidermal Growth Factor Receptor) human epidermal carcinoma cell line A431 and a Gefitinib drug-resisting human lung adenocarcinoma cell line H1975) related to the activity of EGFR tyrosine kinase in the aspect of a cell level, especially has a relatively good inhibition effect on the drug-resisting cell line H1975, has relatively weak inhibition activity on a low-expression EGFR human colon cancer cell line SW620 and can be applied to preparation of corresponding anti-tumor cell medicines. A general formula is shown in the description.

Description

Technical field [0001] The invention belongs to the field of pharmacy, and specifically relates to a 2-aminoimidazopyridine derivative and a preparation method and application thereof. Background technique [0002] Epidermal growth factor receptor (EGFR) has ligand-induced tyrosine protein kinase activity. Studies have shown that more than 60% of malignancies have overexpression or mutation of one or several EGFR family receptors. Although in the past time, EGFR inhibitors have been rapidly developed in tumor treatment, there is still a lot of research space. The treatment resistance caused by target mutations has proposed new research on targeted antitumor drugs. The challenge is that irreversible inhibitors (including Afatinib, Dacomitinib, Neratinib, etc.) can covalently bind to EGFR tyrosine kinase, which can resist the T790M mutation and overcome the resistance caused by T790M. Among them, the first afatinib tablet developed by Boehringer Ingelheim was marketed under the t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00
CPCC07D471/04Y02P20/55
Inventor 陈文腾刘星雨邵加安陈恩俞永平
Owner ZHEJIANG UNIV
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