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Quinoline compound, and preparation method, intermediate, medicinal composition and application thereof

A technology of quinolines and compounds, applied in the field of quinolines

Active Publication Date: 2014-10-22
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there is currently no selective C-Met inhibitor drug on the market, many compounds have been developed that have C-Met inhibitory activity and can improve diseases caused by abnormal C-Met. Such compounds include Johnson&Johnson's JNJ- 38877605, AMG-458 from Amgen, E-7050 from Eisai and PF-04217903 from Pfizer

Method used

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  • Quinoline compound, and preparation method, intermediate, medicinal composition and application thereof
  • Quinoline compound, and preparation method, intermediate, medicinal composition and application thereof
  • Quinoline compound, and preparation method, intermediate, medicinal composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0596] Example 1: 6-((6-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyrazine-1)-methylene)-quinoline (compound 1-1)

[0597]

[0598] Step 1 Preparation of 6-Bromo-N 2 -(quinoline-6-methylene)pyrazine-2,3-diamine

[0599] 3,5-Dibromopyrazin-2-amine (6.1 g, 24 mmol), 6-quinoline methyleneamine (3.8 g, 24 mmol) and N,N-diisopropylethylamine (DIPEA) (8.6 mL, 48mmol) was added into NMP (20mL), and reacted overnight at 130°C under the protection of argon. The reaction solution was evaporated to remove DIPEA, the residue was poured into water (100mL), extracted with dichloromethane (30mL×3), the organic phase was washed with water, washed with saturated brine, dried and subjected to flash column chromatography to obtain 4.7g of a brown product, yield: 59%. LC-MS (ESI): [M+H] + =330; 1 H-NMR (δppm, DMSO-d 6 ,400MHz): 8.85(dd,J 1 =4.2Hz,J 2 =1.6Hz,1H), 8.33(d,J=8.3Hz,1H), 7.99(d,J=8.7Hz,1H), 7.87(s,1H), 7.73(dd,J 1 =8.7Hz,J 2 =1.9Hz,1H), 7.50(dd,J 1 =8.3Hz,J 2 =4.2Hz, ...

Embodiment 2～ Embodiment 18

[0605] According to the same method as in Example 1, different boric acids or boric acid esters were used to prepare the compounds of Examples 2 to 18, and the specific experimental data are shown in Table 1.

[0606] Table 1 Experimental data table of compound 1-2~compound 1-18

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

Embodiment 19

[0613] Example 19: 6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyrazin-1-yl)ethyl)quinone Phenyl (compounds 1-19)

[0614]

[0615] Step 1 Preparation of 6-Bromo-N 2 -(1-(6-quinolyl)ethyl)pyrazine-2,3-diamine

[0616] With reference to the method of Example 1 step 1, 1-(quinolin-6-yl)ethylamine is substituted for 6-quinoline methyleneamine to obtain 6-bromo-N 2 -(1-(6-Quinolinyl)ethyl)pyrazine-2,3-diamine, dark brown solid, yield 68%. LC-MS (ESI): [M+H] + =344; 1 H-NMR (δppm, DMSO-d 6 ,400MHz): 8.85(dd,J 1 =4.2Hz,J 2 =1.7Hz,1H), 8.34(dd,J 1 =8.4Hz,J 2 =0.9Hz,1H), 7.99(d,J=8.7Hz,1H), 7.89(d,J=1.7Hz,1H), 7.79(dd,J 1 =8.7Hz,J 2 =2.0Hz,1H), 7.50(dd,J 1 =8.3Hz,J 2 =4.2Hz,1H), 7.16(s,1H), 7.01(d,J=7.1Hz,1H), 6.35(s,2H), 5.77(d,J=3.3Hz,1H), 5.26(q,J =6.9Hz,1H), 3.36(s,1H), 3.29(dd,J 1 =8.8Hz,J 2 =5.3Hz,1H), 2.53-2.46(m,1H), 2.17(t,J=8.1Hz,1H), 1.95-1.82(m,1H), 1.58(d,J=6.9Hz,3H).

[0617]Step 2 Preparation of 6-(1-(6-bromo-1H-imidazo[4,5-b]pyrazin-1-yl)eth...

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Abstract

The invention discloses a quinoline compound, and a preparation method, an intermediate, a medicinal composition and an application thereof / The invention provides a quinoline compound represented by formula 1 shown in the specification, and its pharmaceutically acceptable salts, solvates, metabolites, metabolism precursors or medicinal precursors. The quinoline compound has a good inhibition effect on tyrosine kinases C-Met, and can be used for preparing medicines for prevention, treatment or adjuvant treatment of many C-Met expression or activity related diseases, especially tumor diseases.

Description

technical field [0001] The present invention relates to quinoline compounds, their preparation methods, intermediates, pharmaceutical compositions and applications. Background technique [0002] C-Met is a protein product encoded by the C-Met proto-oncogene. It is a hepatocyte growth factor receptor with tyrosine kinase activity. It is related to various oncogene products and regulatory proteins and participates in cell information transduction, cell Regulation of cytoskeletal rearrangements is an important factor in cell proliferation, differentiation and motility. At present, it is believed that C-Met is closely related to the occurrence and metastasis of various cancers. Studies have shown that many tumor patients have C-Met overexpression and gene amplification during the occurrence and metastasis of their tumors. The relationship between the activation of C-Met and carcinogenesis is mainly manifested in: [0003] 1. Activation mechanism dependent on hepatocyte growth ...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/4985A61K31/506A61K31/53A61P35/00A61P35/02C07D401/12C07D215/12C07D401/04
CPCC07D215/12C07D215/18C07D401/04C07D401/12C07D487/04C07D519/00
Inventor 余建鑫郭利军赵菲郝宇李萍徐磊夏广新范艺沈竞康
Owner SHANGAI PHARMA GRP CO LTD
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