2-aminoimidazopyridine derivatives and their preparation and application

A technology of azopyridines and imidazopyridines, applied in the field of 2-aminoimidazopyridine derivatives and their preparation, can solve the problems such as limited clinical efficacy

Active Publication Date: 2020-04-17
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 derivatives and their preparation and application
  • 2-aminoimidazopyridine derivatives and their preparation and application
  • 2-aminoimidazopyridine derivatives and their 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: Mix 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 was finished, the solid in the system was filtered with suction to obtain a red solid (3g), the product yield was 82%, m.p.: 157.7-158.6°C; 1 H NMR(500MHz,DMSO)δ10.06(s,1H),9.48(s,1H),8.53(d,J=8.5Hz,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 complete, water was added, extracted with di...

Embodiment 2

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

[0065] Referring to the method of Example 1, except that the 2-chloroacryloyl chloride in step 5 was replaced by 2-fluoroacryloyl chloride, after the reaction was completed, the crude product was concentrated to dryness under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM / MeOH=75:1 ) to obtain white solid 0.9g, yield 40%, m.p.:>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=8.1Hz,1H),7.26(d,J=7.4Hz,1H),7.19(d,J=8.1Hz,1H),6.99(d,J=9.0Hz,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] Referring to the method of Example 1, except that the 2-chloroacryloyl chloride in step 5 was replaced with 2-fluoroacryloyl chloride, after the reaction, concentrated to dryness under reduced pressure to obtain the crude product, which was purified by column chromatography (DCM / MeOH=75: 1) 1.0 g of white solid was obtained with a yield of 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 in particular 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 one or several EGFR family receptors are overexpressed or mutated in more than 60% of malignant tumors. Although in the past, EGFR inhibitors have been developed rapidly in the treatment of tumors, there is still a lot of research space, and the treatment resistance caused by the mutation of the target has brought new challenges to the research of targeted anti-tumor drugs. Challenges, irreversible inhibitors (including Afatinib, Dacomitinib, Neratinib, etc.) can be covalently bonded to EGFR tyrosine kinase, can resist the T790M mutation, and overcome the drug resistance caused by T790M. Among them, the first afatinib tablet developed by Boehring...

Claims

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Application Information

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Patent Type & Authority Patents(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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