Quinoxalinone-containing 4-phenoxy pyridine compound and application thereof

A technology of phenoxypyridine and quinoxalinone, applied in the field of medicine, can solve the problems of low oral bioavailability, unsatisfactory clinical treatment effect and pharmacokinetic parameters, and large toxic and side effects

Inactive Publication Date: 2020-06-19
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are mainly the following problems in the research of c-Met inhibitors: high toxicity and side effects in clinical application, unsatisfactory clinical treatment effect and pharmacokinetic parameters, low oral bioavailability, etc.

Method used

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  • Quinoxalinone-containing 4-phenoxy pyridine compound and application thereof
  • Quinoxalinone-containing 4-phenoxy pyridine compound and application thereof
  • Quinoxalinone-containing 4-phenoxy pyridine compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] The preparation of embodiment 1 compound 1

[0056]

[0057] Step 1: the preparation of intermediate N-(4-chloropyridin-2-yl) cyclopropyl formamide

[0058]

[0059] 8.80g of 2-amino4-chloropyridine and 20.80g of triethylamine were dissolved in 80mL of dichloromethane, and 30mL of dichloromethane solution containing 9.30g of cyclopropylformyl chloride was added dropwise to the solution under ice-bath conditions. Warm up to room temperature after the addition is complete. Stirred for 12h, after the completion of the reaction, the mixture was washed with 20% K 2 CO 3 solution and saturated brine were washed 3 times respectively, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to obtain a crude product, which was separated by column chromatography to obtain a white solid N-(4-chloropyridin-2-yl) Cyclopropylformamide. 1 H NMR (600MHz, CDCl 3 )δ8.79(s,1H),8.31(s,1H),8.16(d,J=5.4Hz,1H),7.03(d...

Embodiment 2

[0081] The preparation of embodiment 2 compound 2

[0082]

[0083] 5.97 g of 4-fluoroaniline was used to replace 5.00 g of aniline in Step 4 of Example 1, and according to the preparation scheme of Example 1, Example 2 (compound 2) was finally obtained. 1 H NMR (600MHz, CDCl 3 )δ11.91(s,1H),8.32(d,J=7.0Hz,1H),8.19–8.08(m,2H),7.98(dd,J=12.1,2.3Hz,1H),7.79(s,1H ),7.63–7.56(m,1H),7.55–7.49(m,1H),7.45–7.33(m,5H),7.15(t,J=8.6Hz,1H),6.80(d,J=8.3Hz, 1H),6.60(dd,J=5.7,2.2Hz,1H),1.52–1.47(m,1H),0.90–0.81(m,4H); MS(ESI)m / z(%):554.1[M+ H] + ,576.1[M+Na] + .

Embodiment 3

[0084] The preparation of embodiment 3 compound 3

[0085]

[0086] 6.85 g of 4-chloroaniline was used to replace 5.00 g of aniline in Step 4 of Example 1, and according to the preparation scheme of Example 1, Example 3 (compound 3) was finally obtained. 1 H NMR (600MHz, CDCl 3 )δ11.88(s,1H),8.30(t,J=7.2Hz,1H),8.25(s,1H),8.11(d,J=5.8Hz,1H),7.97(dd,J=12.1,2.3 Hz,1H),7.79(d,J=1.6Hz,1H),7.69(d,J=8.6Hz,2H),7.61–7.56(m,1H),7.55–7.49(m,1H),7.40(d ,J=8.8Hz,1H),7.32(d,J=8.6Hz,2H),7.20–7.13(m,1H),6.81(d,J=8.4Hz,1H),6.60(dd,J=5.8, 2.3Hz,1H),1.54–1.47(m,1H),1.09–1.03(m,2H),0.89–0.83(m,2H); MS(ESI)m / z(%):569.3[M] + ,592.1[M+Na] + .

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Abstract

The invention belongs to the field of medicine, and particularly relates to a quinoxalinone-containing 4-phenoxy pyridine compound and application thereof, wherein the quinoxalinone-containing 4-phenoxy pyridine compound has a structure represented by a general formula (I). The invention also relates to a compound represented by the general formula (I), wherein the compound has a strong c-Met kinase inhibition effect. The invention also provides application of the quinoxalinone-containing 4-phenoxy pyridine compound and the pharmaceutically acceptable salt thereof in preparation of drugs for treating and / or preventing diseases caused by abnormal high expression of c-Met kinase, especially application in preparation of drugs for treating and / or preventing cancers.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to quinoxalinone-containing 4-phenoxypyridine compounds and pharmaceutically acceptable salts thereof, their preparation methods and pharmaceutical compositions containing the compounds. The present invention also relates to the use of such compounds and pharmaceutically acceptable salts thereof in the preparation of medicines for the treatment of diseases caused by abnormally high expression of c-Met kinase, especially in the preparation of treatments and / or prevention of cancers such as colon cancer and lung cancer. Uses in medicine. Background technique [0002] c-Met is a protein encoded by the proto-oncogene c-Met. Hepatocyte growth factor (HGF) activates the HGF / c-Met signaling pathway after binding to c-Met, thereby exerting its biological effects (such as: embryonic development, tissue damage, etc.) repair, etc.); abnormal expression of c-Met is closely related to tumor ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/497A61P35/00
CPCC07D401/12A61P35/00
Inventor 刘举陈烨丁实史建涛宫益林李春艳朱翔龙赵雯雯王震
Owner LIAONING UNIVERSITY
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