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Quinoline compound and preparation method thereof, medicament combination containing compound and application of compound

A technology of compounds and quinolines, applied in the fields of quinoline compounds, their preparation, pharmaceutical compositions containing the compounds, and uses of the compounds, capable of solving problems such as limited structures

Inactive Publication Date: 2013-09-11
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many inhibitors developed for this signaling pathway, the structure is still very limited.

Method used

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  • Quinoline compound and preparation method thereof, medicament combination containing compound and application of compound
  • Quinoline compound and preparation method thereof, medicament combination containing compound and application of compound
  • Quinoline compound and preparation method thereof, medicament combination containing compound and application of compound

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0166] Preparation of Example 1 Intermediate [3-(4-methylpiperazin-1-yl)-7-trifluoromethyl-5-hydroxyquinoline]

[0167]

[0168] Preparation of 7-trifluoromethyl-5-nitroquinoline: 3-nitro 5-aminobenzotrifluoride (7.5g), glycerol (12.3g), and arsenic pentoxide (6.8g) were added to the reaction flask After stirring until the mixture is uniform, slowly add concentrated sulfuric acid (8g), first react at 130°C for one hour, then raise the temperature to 180°C for four hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then adjusted to be alkaline with 4mol / L sodium hydroxide solution, the solid is filtered out, the solid is dissolved in ethanol, decolorized by activated carbon, the solvent is evaporated, and 7- Trifluoromethyl-5-nitroquinoline (1.7 g, 15%). 1 H-NMR (300MHz, CDCl 3 ): δ9.14(dd, 1H, J1=1.5Hz, J2=4.2Hz), 9.03(d, 1H, J=9.0Hz), 8.71(s, 1H), 8.54(d, 1H, J=1.5Hz ), 7.77 (dd, 1H, J1=9.0Hz, J2=4.2Hz).

[0169] The prepar...

preparation Embodiment 2

[0173] Preparation Example 2 Preparation of Compound IA-1:

[0174] The compound 3-(4-methylpiperazin-1-yl)-7-trifluoromethyl-5-hydroxyquinoline (16.0mg, 0.05mmol) was dissolved in THF (1ml), and Cs was added under ice-cooling 2 CO 3 (25.0mg, 0.078mmol), after stirring for 10min, m-nitrobenzyl bromide (11.6mg, 0.054mmol) was added to the reaction solution under nitrogen protection, the temperature was slowly raised to room temperature, stirred for two hours, concentrated and separated by column chromatography The target compound IA-1 (20.0 mg, 0.045 mmol) was purified with a yield of 90%.

[0175]

[0176] IA-1: 1 H-NMR (300MHz, CDCl 3 ): δ8.87(d, 1H, J=2.7Hz), 8.47(s, 1H), 8.25(d, 1H, J=9.3Hz), 7.93(s, 1H), 7.81(d, 1H, J= 7.5Hz), 7.73(d, 1H, J=2.4Hz), 7.63(t, 1H, J1=7.8Hz, J2=8.1Hz), 6.98(s, 1H), 5.37(s, 2H), 3.41(t , 4H, J1=4.8Hz, J2=5.1Hz), 2.64(t, 4H, J1=5.1Hz, J2=4.8Hz), 2.38(s, 3H).

preparation Embodiment 3

[0177] Preparation Example 3 Preparation of Compound IA-2:

[0178] Preparation of intermediate 3-(4-methylpiperazin-1-yl)-5-hydroxyquinoline:

[0179]

[0180] In addition to using 5-nitroquinoline instead of 7-trifluoromethyl-5-nitroquinoline, using the same method as in Preparation Example 1 to synthesize 3-(4-methylpiperazin-1-yl)-7- The same steps as trifluoromethyl-5-hydroxyquinoline synthesized 3-(4-methylpiperazin-1-yl)-5-hydroxyquinoline.

[0181] Preparation of compound IA-2:

[0182] The compound 3-(4-methylpiperazin-1-yl)-5-hydroxyquinoline (30.0mg, 0.123mmol) was dissolved in THF (1ml), and Cs was added under ice-cooling 2 CO 3(60.3mg, 0.185mmol), after stirring for 10min, m-fluorobenzyl bromide (25.5mg, 0.136mmol) was added to the reaction solution under nitrogen protection, the temperature was slowly raised to room temperature, stirred for two hours, concentrated and purified by column chromatography The target compound IA-2 (37.9 mg, 0.108 mmol) was obta...

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Abstract

Disclosed are disubstituted or trisubstituted quinoline compounds represented by the following general formula (I) or their pharmaceutically acceptable salts or solvates, which are used as c-Met inhibitors, their preparation methods, pharmaceutical compositions containing the same and uses of these compounds for preparing medicaments for preventing or treating diseases relating to cell abnormal proliferation and morphological variation associated with hepatocyte growth factor (HGFR) in organism, diseases relating to hyperkinesia and diseases relating to angiogenesis or metastasis, especially medicaments for treating or preventing tumor growth and metastasis.

Description

technical field [0001] The present invention relates to a class of quinoline compounds used as c-Met inhibitors and their pharmaceutically acceptable salts or pharmaceutically acceptable solvates, their preparation methods, pharmaceutical compositions containing the compounds, and these compounds In preparation for the prevention or treatment of diseases related to abnormal cell proliferation, morphological changes and hyperkinetic function related to the hepatocyte growth factor receptor (HGFR) in vivo, as well as diseases related to angiogenesis or cancer metastasis Use of medicines, especially medicines for treating or preventing tumor growth and metastasis. Background technique [0002] Hepatocyte growth factor (hepatocyte growth factor, HGF), also known as scatter factor (SF), is the endogenous ligand of c-Met, a family of tyrosine kinase receptors. Proto-oncogene Met and HGF / SF are co-expressed in breast cancer, colon cancer, gastric cancer, prostate cancer and other ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/38C07D405/04C07D409/04C07D401/12A61K31/635A61K31/496A61P35/00A61P35/04
CPCC07D409/04A61K31/496C07D405/04C07D215/38A61K31/4709A61P35/00A61P35/04
Inventor 张翱耿美玉王元相艾菁刘振凯
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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