3-cyan-6-aminoquinoline derivatives, preparation method thereof and application thereof in medicines

An alkyl and aryl technology, applied in 3-cyano-6-aminoquinoline derivatives, its preparation and its application in medicine, can solve the problems of increased cell division rate and genome instability

Active Publication Date: 2011-08-10
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mutations can make c-Kit have a continuously activated tyrosine kinase activity, thereby increasing the rate of cell division, leading to genome instability, and inducing carcinogenesis

Method used

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  • 3-cyan-6-aminoquinoline derivatives, preparation method thereof and application thereof in medicines
  • 3-cyan-6-aminoquinoline derivatives, preparation method thereof and application thereof in medicines
  • 3-cyan-6-aminoquinoline derivatives, preparation method thereof and application thereof in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] (E)-4-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-but-2-enoic acid {4-[3-chloro-4-(pyridin-2-yl Methoxy)-aniline Base-3-cyano-7-ethoxy-quinolin-6-yl}-amide

[0137]

[0138] (E)-4-Bromo-but-2-enoic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-anilino]-3-cyano-7-ethoxy -Quinolin-6-yl}-amide 1a (396mg, 0.70mmol, prepared by the known method "Journal of Medicinal Chemistry, 2000, 43(17), 3244-3256"), sodium iodide (315mg, 2.10mmol ) and N, N-diisopropylethylamine (0.6mL, 3.50mmol) were dissolved in 5mL N, N-dimethylformamide, and 2-oxa-6-aza-spiro[3.3]heptane was added Oxalate 1b (264 mg, 1.4 mmol, prepared by the known method "Organic Letters, 2008, 10(16), 3525-3526") was reacted with stirring for 12 hours. Pour the reaction solution into 50 mL of ice water, extract with dichloromethane (75 mL×3), combine the organic phases, wash with saturated brine (40 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure on silica gel The r...

Embodiment 2

[0142] (E)-4-((3aR, 6aS)-5-hydroxy-hexahydro-cyclopenta[c]pyrrol-2-yl)-but-2-enoic acid {4-[3-chloro-4-( Pyridin-2-yl Methoxy)-anilino]-3-cyano-7-ethoxy-quinolin-6-yl}-amide

[0143]

[0144] first step

[0145] (3aR,6aS)-tert-butyl 5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylate

[0146]Dissolve (3aR, 6aS)-5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylate tert-butyl ester 2a (500 mg, 2.22 mmol, prepared according to existing document WO2008089636) in 100 mL methanol , cooled to 0° C. in an ice bath, slowly added sodium borohydride (168 mg, 4.44 mmol), and stirred for 30 minutes. 1 mL of water was added, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine (25 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Crude product (3aR, 6aS)-tert-butyl 5-hydroxy-hexahydro-cyclopenta[c]py...

Embodiment 3

[0156] (3aR, 6aS, E)-3-Hydroxy-2-hydroxymethyl-2-methyl-propionic acid 2-(3-{4-[3-chloro-4-(pyridin-2-ylmethoxy) -aniline Base]-3-cyano-7-ethoxy-quinolin-6-ylcarbamoyl}-allyl)-octahydro-cyclopenta[c]pyrrol-5-yl ester

[0157]

[0158] first step

[0159] 2,2,5-Trimethyl-[1,3]dioxane-5-carboxylic acid

[0160] 3-Hydroxy-2-hydroxymethyl-2-methyl-propionic acid 3a (10.01g, 0.075mol, purchased from Shaoyuan Chemical Technology Co., Ltd.), 2,2-dimethoxy-propane (11mL, 0.09 mol) and p-toluenesulfonic acid monohydrate (1.40 g, 0.075 mol) were dissolved in 100 mL of acetone, and stirred for 12 hours. Concentrate under reduced pressure, dissolve the residue in 100 mL of dichloromethane, wash with water (50 mL×2) and saturated brine (50 mL×2) successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2, 2, 5 - Trimethyl-[1,3]dioxane-5-carboxylic acid 3b (3.9 g, white solid), yield: 30.0%.

[0161] MS m / z(ESI): 173.1[...

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Abstract

The invention relates to 3-cyan-6-aminoquinoline derivatives, a preparation method thereof and application thereof in medicines, in particular to new 3-cyan-6-aminoquinoline derivatives shown as a general formula (I) and medicinal salts thereof, and use thereof as a therapeutical agent, particularly a protein kinase inhibitor, wherein the definition of each substituent group in the general formula (I) is shown as the description. The formula (I) is shown in the description.

Description

technical field [0001] The present invention relates to a novel 3-cyano-6-aminoquinoline derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a protein kinase inhibitor. Background technique [0002] As a basic regulatory mechanism of cells, signal transduction transmits various extracellular signals to the inside of cells, so that cells can make corresponding biological responses and realize processes such as proliferation, differentiation, and apoptosis. Most signal transduction is achieved by reversible phosphorylation of proteins involving specific protein kinases and phosphatases. [0003] Protein kinases (PKs) can be divided into two classes: protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). PTKs can phosphorylate tyrosine residues on proteins, and STKs can phosphorylate serine and threonine residues. Tyrosine kinases can be further divided into receptor t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107C07D401/14C07D487/04C07D471/08C07D401/12A61K31/4709A61K31/4985A61P35/00
Inventor 邓炳初李心李相勤王斌朱哲
Owner JIANGSU HENGRUI MEDICINE CO LTD
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