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Quinoline as well as pharmaceutical composition and use thereof

A derivative, quinoline technology, applied in the field of quinoline derivatives, can solve problems such as poor prognosis and achieve excellent therapeutic effects

Active Publication Date: 2010-02-03
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, it has been reported that in breast cancer, oral cancer, lung cancer, etc., once EGF receptor and HER2 appear together, it will lead to poor prognosis [Clin. Cancer Res. 19995, 4164-4174]

Method used

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  • Quinoline as well as pharmaceutical composition and use thereof
  • Quinoline as well as pharmaceutical composition and use thereof
  • Quinoline as well as pharmaceutical composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example 1

[0192]

[0193] Make 1,1-dimethyl-2-propyl acetate (2-methyl-3-butyn-2-yl acetate) (51.5g, 408.2mmol), copper (I) chloride (2.02g , 20.4mmol), triethylamine (56.6mL, 408.2mmol) and 1-methylpiperazine (54.3mL, 489.9mmol) in THF (480mL) were reacted under reflux for 2 hours. The reaction solution was concentrated, tert-butyl methyl ether (200 mL) was added to the residue, and the product was extracted with dilute hydrochloric acid. While stirring the extract under ice cooling, 6N aqueous sodium hydroxide solution was added until the aqueous layer became basic, and extracted with dichloromethane (500 mL×1, 150 mL×3). The extract was washed with 14% ammonia water and then with saturated brine, then dried and concentrated. The resulting dark brown solid was purified by sublimation (60°C / 5-6 Torr) to obtain the title compound as colorless crystals (49.07 g, 72%).

[0194]

[0195] 4a: 1 H NMR (CDCl 3 ) δppm: 1.40(s, 6H), 2.28(s, 1H), 2.28(s, 3H), 2.49(t, 4H), 2.69(t, 4H). ...

Synthetic example 2

[0196]

[0197] 1) Dissolve 96.5mmol of 4,7-dichloro-6-nitro-3-cyanoquinoline and 14.05g (96.5mmol) of 3-chloro-4-fluoroaniline in 900ml of 2-propanol, nitrogen Reflux for 3.5h under protection. TLC (ethyl acetate:n-hexane=1:1) showed no starting point. Stir at room temperature overnight, filter and wash with 2-propanol to obtain 36.5 g of 4-(3-chloro-4-fluoroanilino)-7-chloro-6-nitro-3-cyanoquinoline.

[0198] 2) In 4-(3-chloro-4-fluoroanilino)-7-chloro-6-nitro-3-cyanoquinoline (40.1mmol), 1-(1,1-dimethyl-2- Propyl)-4-methylpiperazine (4a) (10.0g, 60.1mmol), copper (I) iodide (380mg) and tetrakis (triphenylphosphine) palladium (1.39g) in DMF solution (70mL) After blowing nitrogen gas at 50°C for 15 minutes, triethylamine (13.9 mL, 100.0 mmol) was added, and stirred at an oil bath temperature of 140°C for 50 minutes. After standing to cool, the reaction solution was concentrated, and aqueous sodium bicarbonate solution (300 mL) was added. The resultant was extracted with...

Synthetic example 3

[0204]

[0205] 1) 2-cyano-3-ethoxy ethyl acrylate In a 2000ml three-necked reaction flask equipped with a fractionating column, add 280ml (2.5mol) of ethyl cyanoacetate and 833ml (5.0mol) of triethyl orthoformate , 27.8ml of acetic anhydride was reacted at 120°C for 3h, the distillate was recovered by distillation, 187ml of absolute ethanol was added after cooling, crystallized by cooling, the crude product was filtered, recrystallized with absolute ethanol after drying, and 312.2g of light yellow crystals were obtained. was 88.0%.

[0206] 2) 4-Hydroxy-6-nitro-7-bromo-3-cyanoquinoline

[0207] 0.324 mol of 3-bromo-4-nitroaniline (Mieczyslaw Makosza and Maciej Bialecki, JOrg Chem, 1998, 63, 4878-4888) and 77.2 g (0.456 mol) of 2-cyano-3-ethoxyacrylic acid ethyl The ester was dissolved in 210ml of toluene and refluxed for 16h. Cool in an ice bath, filter, and wash with ether to obtain 94.2 g of solid. The obtained solid (37.5 g, 0.123 mol) was added to a 5 L three-necked ...

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PUM

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Abstract

The invention relates to a quinoline shown in the general formula (I) or a salt accepted in pharmacy, hydrate or solvate, an optical active body or racemate or diastereoisomer mixture thereof, having excellent proteinkinase suppressive activity of tyrosine specificity. The quinoline and the pharmaceutical composition are effective for treating / preventing various cancers, diseases based on arteriosclerosis or chronic eczema.

Description

technical field [0001] The present invention relates to a novel quinoline derivative. More specifically, the present invention relates to quinoline derivatives having tyrosine-specific protein kinase (hereinafter referred to as tyrosine kinase) inhibitory activity. In addition, the present invention relates to a pharmaceutical composition containing the quinoline derivative and a pharmaceutically acceptable carrier, a tyrosine kinase inhibitor containing the quinoline derivative, and an anticancer agent, for diseases and interventions based on arteriosclerosis A therapeutic and / or preventive drug for diseases caused by hyperactivation of tyrosine kinases such as ringworm. Background technique [0002] In cancer chemotherapy, drugs that inhibit DNA synthesis or directly inhibit cell division are often used. However, these drugs currently act as cytotoxicity, and although they are effective against rapidly dividing cancer cells, in many cases, their cytotoxicity is not limit...

Claims

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Application Information

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IPC IPC(8): C07D215/54C07D401/06C07D405/06A61K31/4706A61K31/496A61K31/5377A61K31/4709A61K31/55A61K31/541A61K31/551A61P35/00A61P9/10A61P17/00
Inventor 易崇勤赵鸿莲
Owner NEW FOUNDER HLDG DEV LLC
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