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Quinoline and quinazoline derivatives and drugs containing the same

a technology of quinazoline and quinoline, which is applied in the direction of biocide, cardiovascular disorder, drug composition, etc., can solve the problems of hematopoietic failure and intestinal tract movement failure, pharmaceutical compounds with potent angiostenosis inhibitory activity that have not yet been developed, and achieve low side effects.

Inactive Publication Date: 2006-09-21
KIRIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] Another object of the present invention is to provide compounds that can be used in the treatment of diseases mediated by the autophosphorylation of PDGF receptors and have a low level of side effects attributable to c-kit autophosphorylation inhibitory activity.

Problems solved by technology

Vascular restenosis, which is observed in a frequency of about 30% within 3 to 6 months after the operation of PTCA, however, has become a serious problem associated with long-term prognosis and medical economy.
Further, SCF is a growth factor involved in the upstream of hematopoietic system and the movement of intestinal tracts, and substances that inhibit receptors of SCF possibly induce hematopoietic failure and intestinal tract movement failure.
Although various restenosis inhibitors have been developed up to now, any pharmaceutical compound having potent angiostenosis inhibitory activity has not yet been developed.

Method used

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  • Quinoline and quinazoline derivatives and drugs containing the same
  • Quinoline and quinazoline derivatives and drugs containing the same
  • Quinoline and quinazoline derivatives and drugs containing the same

Examples

Experimental program
Comparison scheme
Effect test

production example 1

4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline

[0220] Sodium hydride (60 wt %, 0.20 g) was added to dimethyl sulfoxide (15 ml), and the mixture was stirred at room temperature for 10 min. 4-Amino-3-nitrophenol (0.77 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinazoline (1.12 g) was added thereto, and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a 1 N aqueous sodium hydroxide solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give the title compound (1.10 g, yield 64%).

[0221]1H-NMR (CDCl3-d1, 400 MHz): δ 4.07 (s, 3H), 4.08 (s, 3H), 6.10-6.15 (m, 2H), 6.92 (d, J=9.0 Hz, 1H), 7.34 (s, 1H), 7.35 (...

production example 2

4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline

[0223] 4-Chloro-6,7-dimethoxyquinazoline (10.23 g) and 2-fluoro-4-nitrophenol (14.37 g) were suspended in monochlorobenzene (100 ml), and the suspension was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure, and the residue was washed with toluene, was filtered, and was dried. The crystal thus obtained was then suspended in an aqueous sodium hydroxide solution, and the suspension was filtered, followed by drying to give 4-(3-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (14.2 g, yield 90%). 4-(2-Fluoro-4-nitrophenoxy)-6,7-dimethoxy-quinoline (4.57 g) was dissolved in ethyl acetate / N,N-dimethylformamide / triethylamine (100 ml / 100 ml / 20 ml) to prepare a solution. Palladium hydroxide (1.2 g) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. After filtration through Celite, the solvent was removed by distillation under the reduced ...

production example 3

3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline

[0226] Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 20 min. 4-Amino-3-chlorophenol hydrochloride (1.61 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by suction filtration to give the title compound (0.80 g, yield 60%).

[0227]1H-NMR (CDCl3-d1, 400 MHz): δ 4.06 (s, 3H), 4.07 (s, 3H), 6.36 (d, J=5.4 Hz, 1H), 6.65 (dd, J=8.5 Hz, J=2.9 Hz, 1H), 6.76 (...

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Abstract

There are provided compounds which can be used in the treatment of diseases mediated by the autophosphorylation of a PDGF receptor, specifically, compounds which can inhibit neointima formation hypertrophy. The compounds are those represented by formula (I) or pharmacologically acceptable salts or solvates thereof: wherein R1 and R2 represent hydrogen, alkyl or the like; R3, R4, R5, and R6 represent hydrogen, halogen, alkyl, alkoxy or the like; R11 and R12 represent hydrogen, alkyl, alkylcarbonyl or the like; and A represents any one of formulae (i) to (x), provided that compounds wherein R3, R4, R5 and R6 represent hydrogen and A represents group (v) wherein u is 0 (zero) and R19 represents phenyl optionally substituted by halogen, alkyl, or alkoxy are excluded.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates to quinoline derivatives and quinazoline derivatives and more particularly to quinoline derivatives and quinazoline derivatives that can be used in the treatment of diseases associated with the autophosphorylation of a PDGF receptor and particularly can inhibit angiostenosis. [0003] 2. Background Art [0004] PTCA (percutaneous transluminal coronary angioplasty) is widely adopted as therapy useful for ischemic heart diseases resulting from coronary stenosis. Vascular restenosis, which is observed in a frequency of about 30% within 3 to 6 months after the operation of PTCA, however, has become a serious problem associated with long-term prognosis and medical economy. The restenosis is considered attributable to the fact that vascular smooth muscular cells or fibroblasts of the vascular outer membrane are activated, for example, by platelet activation caused by the tear of vascular tunica i...

Claims

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Application Information

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IPC IPC(8): A61K31/517C07D403/02A61K31/47A61K31/4709A61K31/496A61K31/505A61K31/5377A61P9/10A61P43/00C07D215/22C07D215/233C07D233/88C07D401/12C07D403/12C07D405/12C07D409/12C07D521/00
CPCA61K31/47A61K31/4709A61K31/496A61K31/505A61K31/517A61K31/5377C07D215/233C07D231/12C07D233/56C07D233/88C07D249/08C07D401/12C07D403/12C07D405/12C07D409/12A61P43/00A61P9/10
Inventor SAKAI, TERUYUKISENGA, TERUFUMIFURUTA, TAKAYUKIMIWA, ATSUSHI
Owner KIRIN PHARMA
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