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Bicyclic pyrazolone compound, and use method and applications thereof

A technology of compounds and nitrogen oxides, applied in the field of compounds that inhibit intercellular or intracellular signal response, human hyperproliferative diseases, and pharmaceutical compositions containing the compounds of the present invention, can solve problems such as poor prognosis

Active Publication Date: 2015-10-14
ZHONGSHAN INNOVATION BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Additionally, Met and Ron co-expression in ovarian, breast and bladder cancers predicts poorer prognosis

Method used

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  • Bicyclic pyrazolone compound, and use method and applications thereof
  • Bicyclic pyrazolone compound, and use method and applications thereof
  • Bicyclic pyrazolone compound, and use method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0335] Example 1N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo [1,2-b]pyrazole-3- Formamide

[0336]

[0337] Step 1) 4-Chloro-N'-phenylbutyric acid hydrazide

[0338] Will contain phenylhydrazine (16.0g, 148.0mmol) and 10% Na 2 CO 3A mixture of aqueous solution (250 mL) and dichloromethane (250 mL) was cooled to 0 °C, and 4-chlorobutyryl chloride (20.9 g, 148.0 mmol) was added thereto by syringe. The reaction solution was returned to room temperature, stirred overnight, and diluted with dichloromethane (150 mL). The organic phase was separated, and the resulting organic phase was washed successively with 2M hydrochloric acid (300 mL x 3), brine (150 mL), then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate / n-hexane (50 mL / 100 mL) to obtain the title compound (14.7 g, 47%) as a light-colored solid.

[0339] LC-MS(ESI,...

Embodiment 2

[0368] Example 2N-(4-((2-(cyclopropylcarboxamido)pyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-2,4,5,6-tetra Hydrogen-1H-pyrrolo[1,2-b] Pyrazole-3-carboxamide

[0369]

[0370] To the N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo [1,2-b]Pyrazole-3-carboxamide (150mg, 0.35mmol) and pyridine (1.4mL) in acetonitrile (2mL) were added cyclopropanoyl chloride (110mg, 1.05mmol) and DMAP (128.3mg, 1.05 mmol) in acetonitrile (1.4 mL). The reaction solution was heated and stirred at 60°C overnight, then cooled to room temperature, and diluted with dichloromethane / water (10 mL / 15 mL). The separated organic phase was washed with water (6 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate / petroleum ether (8 mL, v / v=1 / 3) to give the title compound (109 mg, 60%) as a pale solid.

[0371] LC-MS(ESI,pos,ion)m / z:496.3[M+H] + ;

[0372] Q-TOF(ESI,p...

Embodiment 3

[0375] Example 3N-(4-((2-acetylaminopyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrole And[1,2-b]pyrazole -3-Carboxamide

[0376]

[0377] To the N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo To a solution of [1,2-b]pyrazole-3-carboxamide (100 mg, 0.23 mmol) in acetic anhydride (2 mL) was added triethylamine (142 mg, 1.4 mmol). After the reaction solution was stirred overnight at 30°C, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (38 mg, 35%) as a light-colored solid.

[0378] LC-MS(ESI,pos,ion)m / z:470.2[M+H] + ;

[0379] Q-TOF(ESI,pos,ion)m / z:470.1827[M+H] + ;

[0380] 1 H NMR (600MHz, CDCl 3 )δ(ppm):10.22(s,1H),8.27(s,1H),8.08(d,J=5.8Hz,1H),7.86(s,1H),7.75(d,J=8.9Hz,2H) ,7.54(t,J=7.9Hz,2H),7.44(d,J=7.5Hz,2H),7.40(t,J=7.4Hz,1H),7.07(d,J=8.9Hz,2H),6.56 (dd, J=5.8Hz, 2.2Hz, 1H), 3.73(t, J=...

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Abstract

The invention provides a type of substituted bicyclic pyrazolone compounds which can be used for inhibiting the activities of receptor tyrosine kinases especially the activities of Axl, Mer, c-Met and Ron kinases. The invention also provides medicine compositions comprising the type of compounds, and applications of the compound and the medicine compositions in drug preparation. The medicines can be used for preventing and treating proliferative diseases or reducing the severity of the diseases.

Description

technical field [0001] The present invention relates to novel substituted bicyclic pyrazolone compounds and salts thereof useful in the treatment of hyperproliferative diseases such as cancers associated with mammals. In particular, the present invention relates to a class of compounds that inhibit intercellular or intracellular signal responses by inhibiting the activity of protein tyrosine kinases. The present invention also relates to a method of using the compound of the present invention to treat hyperproliferative diseases in mammals, especially human beings, and also relates to a pharmaceutical composition comprising the compound of the present invention. Background technique [0002] Protein kinases represent a large class of proteins that play a central role in the regulation of a variety of cellular processes. Protein kinase controls cell metabolism, cell division cycle, cell proliferation, cell apoptosis, differentiation and survival by regulating a series of sig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04C07D498/04A61K31/4439A61K31/5383A61P35/00A61P35/02A61P35/04A61P9/10A61P11/00
CPCC07D471/04C07D487/04C07D498/04
Inventor 习宁吴彦君
Owner ZHONGSHAN INNOVATION BIOPHARMACEUTICAL CO LTD
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