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Substituted quinoline carboxamide compound and application thereof

A compound and hydrate technology, applied in the directions of active ingredients of heterocyclic compounds, organic chemistry, drug combination, etc., can solve the problem of uncontrolled cell proliferation, and achieve the effect of inhibiting angiogenesis, good effect, and inhibiting cell proliferation.

Active Publication Date: 2020-11-06
BEIJING WINSUNNY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, under certain conditions, these receptors are either mutated or overexpressed, causing uncontrolled cell proliferation, leading to tumor growth and ultimately cancer development

Method used

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  • Substituted quinoline carboxamide compound and application thereof
  • Substituted quinoline carboxamide compound and application thereof
  • Substituted quinoline carboxamide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Example 1: 4-(4-((2-(cyclopropylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)phenoxy)-7-methoxy Preparation of quinoline-6-carboxamide (compound 1)

[0122] (1) Preparation of intermediate 1:

[0123]

[0124]In a 50 mL flask was added 30 mL of DMSO, followed by 4-hydroxy-7-methoxyquinoline-6-carboxamide (2.2 g, 1 eq), 4-(Boc)aminophenol (2.3 g, 1.1 eq), four Butylammonium iodide (0.5eq) and cesium carbonate (3.6g, 1.1eq), the reaction solution was heated to 100°C, and reacted for 10h. Post-reaction treatment: the reaction liquid was cooled to room temperature, diluted with a large amount of water, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, then dried with anhydrous sodium sulfate, and rotary evaporated to obtain 2.2 g of intermediate 1.

[0125] MS m / z 310.1 (M+1) + ;

[0126] 1 H-NMR (400MHz, CDCl 3 ) δ: 8.68-8.64(m, 2H), 7.87-7.76(m, 2H), 6.60-6.56(m, 4H), 4.04(s, 3H).

[0127] (2) Preparation of intermediate 2:...

Embodiment 2-4

[0137] Example 2-4: 4-(4-((2-(cyclopropylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-fluorophenoxy) -7-methoxyquinoline-6-carboxamide (compound 2); 4-(4-((2-(cyclopropylamino)-3,4-dioxocyclobut-1-ene-1- base)amino)-3-(trifluoromethyl)phenoxy)-7-methoxyquinoline-6-carboxamide (compound 3); and 4-(4-((2-(cyclopropane (amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (compound a) preparation

[0138] Compounds 2, 3, and a were synthesized according to the operation similar to that of Example 1 (see Table 1).

[0139] Table 1 Structure and mass spectrum data of compounds 2, 3 and a

[0140] Example compound structural formula MS (ESI) M+H 2 2 Description: Description: C:\Program Files (x86)\gwssi\CPC client\cases\inventions\00a6d582-9f9b-4bc9-b061-c25ba57eeb68\new\100002\939081dest_path_image007.jpg

Embodiment 5

[0141] Example 5: N-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)phenyl)-N-cyclopropylcyclopropane-1,1-dicarboxy Preparation of acid amide (compound 4)

[0142] (1) Preparation of intermediate 3:

[0143]

[0144] To anhydrous THF (100 mL) was added 1,1-cyclopropyldicarboxylic acid (10.10 g, 70 mmol, 1.0 eq). Under nitrogen protection, triethylamine (7.03g, 70mmol, 1.0eq) was added dropwise and stirred at 0°C for 30min, followed by addition of thionyl chloride (8.26g, 70mmol, 1.0eq) and stirred at 0°C for 30min minute. Under nitrogen protection, a solution of intermediate 1 (23.7 g, 77 mmol, 1.1 eq) in anhydrous THF (50 mL) was added dropwise to the reaction solution, and stirred at 0° C. for 1.5 h. The reaction solution was diluted with ethyl acetate and extracted with 2N NaOH (pH>10). The aqueous phase was added dropwise with 2N HCl to adjust the pH to 1-2, and then extracted with ethyl acetate. The organic phase was dried and suspended to obtain 11.3 g of intermediat...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a substituted quinoline formamide compound and application thereof. The substituted quinoline carboxamide compound has excellent in-vitro inhibition activity to three kinases including FGFR-4, VEGFR-2 and PDGFR-beta, so the compound can be adopted as a small-molecular tyrosine kinase inhibitor, has the effects of cell proliferation inhibition and angiogenesis inhibition, shows good antitumor activity, and presents good effects on treatment of tumor diseases of mammals (including human beings).

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to substituted quinoline formamide compounds and applications thereof. Background technique [0002] Protein tyrosine kinases are a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues located on protein substrates, and can catalyze the phosphorylation of tyrosine residues in various substrate proteins. important role in proliferation and differentiation. Many growth factor receptor proteins act through tyrosine kinases and affect signaling through this process to regulate cell growth. For example, FGFR (Fibroblast Growth Factor Receptor, fibroblast growth factor receptor), VEGFR (Vascular Endothelial Growth Factor Receptor, vascular endothelial cell growth factor receptor) and PDGRF (Platelet-derived Growth Factor Receptor, platelet-derived cell growth factor receptor ). However, under certain conditions, these receptors are eit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48A61P35/00A61K31/47
CPCC07D215/48A61P35/00
Inventor 林国良唐春雷范为正
Owner BEIJING WINSUNNY PHARMA CO LTD
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