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2-aminopyridine derivative containing 2-pyridone ring side chain, preparation and application

A technology of aminopyridine and pyridone rings, applied in the field of 2-aminopyridine derivatives, can solve the problems of drug resistance and affecting the binding affinity of ALK tyrosine kinase

Inactive Publication Date: 2016-11-09
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, ALK inhibitors have been rapidly developed in the treatment of tumors. However, for early marketed drugs such as Crizotinib developed by Pfizer, patients who are initially effective in treatment will develop drug resistance within 6-12 months, and the results show that the drug resistance of patients is large. Partly due to site mutations on ALK that affect the binding affinity of the drug molecule to the ALK tyrosine kinase

Method used

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  • 2-aminopyridine derivative containing 2-pyridone ring side chain, preparation and application
  • 2-aminopyridine derivative containing 2-pyridone ring side chain, preparation and application
  • 2-aminopyridine derivative containing 2-pyridone ring side chain, preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: 6-amino-[3,4'-bipyridine]-2'(1'H)-one (compound 1):

[0083]

[0084] step:

[0085] 5-Bromo-2-aminopyridine (10.0 mmol) was dissolved in 20 mL of anhydrous dioxane with pinacol diboronate (11.0 mmol) and potassium acetate (15.0 mmol), and then Pd(dppf)Cl was added 2 (0.5mmol), replaced with nitrogen, heated at 80°C for 8h, monitored the reaction by LC-MS until the disappearance of the raw material. After the reaction is naturally cooled, without separation, directly add cesium carbonate (15.0mmol) and Pd(dppf)Cl to the reaction system 2 (0.5mmol) and 4-bromopyridin-2(1H)-one (11.0mmol), then add 0.5mL water, and stir overnight at 110°C. After the reaction was completed, the reaction system was filtered with diatomaceous earth, the filtrate was spin-dried, and then extracted with DCM. Combine the organic phases, then anhydrous Na 2 SO 4 Drying, filtration, rotary evaporation, the crude product was separated by silica gel column chromatography (DCM:MeO...

Embodiment 2

[0086] Example 2: 6-Amino-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one

[0087] Referring to the method of Example 1, only the raw material 4-bromopyridin-2(1H)-one was replaced with 4-bromo-1-methyl-2(1H)-one, after the reaction was completed, the crude product was obtained by concentrating under reduced pressure to dryness , purified by column chromatography (DCM / MeOH=10:1) to obtain a yellow solid with a yield of 68%.

[0088] m.p.233-236°C; 1 H NMR (500MHz, DMSO) δ8.32(d, J=2.3Hz, 1H), 7.74(dd, J=8.7, 2.6Hz, 1H), 7.66(d, J=7.1Hz, 1H), 6.55(d ,J=1.9Hz,1H),6.52(dd,J=7.1,2.1Hz,1H),6.50–6.45(m,1H),6.36(s,2H),3.39(s,3H); HRMS(ESI) :m / z calcd for C 11 h 11 N 3 O[M+H] + :202.0975,Found:202.0976.m.p.>250℃;

Embodiment 3

[0089] Example 3: 6-Amino-1'-benzyl-[3,4'-bipyridine]-2'(1'H)-one

[0090] Referring to the method of Example 1, only the raw material 4-bromopyridin-2(1H)-one was replaced with 1-benzyl-4-bromo-2(1H)-one, and after the reaction was completed, it was concentrated to dryness under reduced pressure to obtain the crude product , purified by column chromatography (DCM / MeOH=10:1) to give a white solid with a yield of 60%.

[0091] m.p.207-209°C; 1 H NMR (500MHz, DMSO) δ8.33 (s, 1H), 7.75 (dd, J = 10.2, 4.5Hz, 2H), 7.38–7.20 (m, 5H), 6.65–6.54 (m, 2H), 6.48 ( d,J=8.7Hz,1H),6.38(s,2H),5.08(s,2H); HRMS(ESI):m / z calcd for C 17 h 15 N 3 O[M+H] + :278.1288,Found:278.1288.

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Abstract

The invention provides a 2-aminopyridine derivative containing a 2-pyridone ring side chain or an enantiomer of the 2-aminopyridine derivative. The target compound is obtained mainly by taking 2-aminopyridine as a parent nucleus to be coupled with a 4-bromo-2-pyridone ring. Experiments prove that the 2-aminopyridine derivative has a significant proliferation inhibition effect on tumor cells Karpas 299 (NPM-ALK positive cell lines) related to the ALK tyrosine kinase activity, NCI-H2228 (EML4-ALK positive cell lines), SKN-BE2 (ALK gene amplification cell lines) and SH-SY5Y (ALK F1174 mutant cell lines) and can be prepared into corresponding anti-tumor-cell drugs. The 2-aminopyridine derivative has a general structural formula I (please see the formula in the description).

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a 2-aminopyridine derivative containing a 2-pyridone ring side chain, as well as a preparation method and application. Background technique [0002] Anaplastic lymphoma kinase (ALK), namely anaplastic lymphoma kinase, is a receptor tyrosine kinase belonging to the insulin receptor superfamily. In 1994, Morris and Shiota discovered ALK in the form of an activated fusion oncogene (NPM-ALK) from anaplastic large cell lymphoma (ALCL), and subsequent continuous research in various cancers A variety of fusion forms of ALK have been found in , including non-small cell lung cancer, inflammatory myofibroblastic tumor, diffuse large B-cell lymphoma, etc. The complete ALK gene has the characteristics of a typical receptor tyrosine kinase, including an extracellular domain, a hydrophobic transmembrane domain and an intracellular kinase domain. ALK is closely related to cell growth, prol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73C07D213/82A61P35/00
CPCC07D213/73C07D213/82
Inventor 郭晓陈文腾张璨刘星雨舒可邵加安俞永平
Owner ZHEJIANG UNIV
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