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Tricyclic protein kinase inhibitors

A benzene ring and aromatic ring technology, applied in the field of aromatic tricyclic compounds and their pharmaceutically acceptable salts, can solve the problem of no combination of substituents

Inactive Publication Date: 2005-12-07
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

3. US patent 5480883 discloses quinoline derivatives as protein tyrosine kinase inhibitors, but these derivatives do not have the unique combination of substituents that the compounds of the present invention have, including 3-cyano

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0786] 4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile

[0787]A suspension of 5.6 g (30 mmol) of 3-amino-2-naphthoic acid in 30 ml of N,N-dimethylformamide dimethyl acetal was refluxed for 6 hours. Removal of the solvent gave 7.06 g (86.4%) of methyl 3-{[(dimethylamino)methylene]amino}-2-naphthoate as a dark oily residue. To a solution of 20.8 ml (52 mmol) n-butyllithium (2.5M in hexane) in 18 ml tetrahydrofuran (THF) was added dropwise a solution of 5.97 ml (114 mmol) acetonitrile in 100 ml THF at -78°C. After the addition was complete, the suspension was stirred for 15 minutes. To this was added dropwise 7.02 g (26 mmol) of 3-{[(dimethylamino)methylene]amino}-2-naphthoate in 50 ml of THF. The resulting reaction mixture was stirred at -78°C for 1 hour. Then 7.8 g (130 mmol) of acetic acid were added dropwise. The reaction mixture was allowed to warm to room temperature and diluted with water. The precipitate was collected by filtration, washed with water and ethyl ace...

Embodiment 2

[0792] 4-Chlorobenzo[g]quinoline-3-carbonitrile

[0793] 3.5 g (16 mmol) of 4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 35 ml of phosphorus oxychloride and 22 drops of N,N-dimethylformamide (DMF) The reaction mixture was heated at 100-110°C for 5 hours. After cooling, the mixture was concentrated to dryness in vacuo to give a dark residue. The residue was partitioned between dichloromethane and ice-cold saturated aqueous sodium carbonate. The organic layer was washed with ice-cold brine and dried over sodium sulfate. The organic solution was passed through a short column of silica gel, eluting further with additional dichloromethane. Removal of solvent gave 1.89 g (49.5%) of product as a bright yellow solid, mp 253-255°C.

[0794] 1 H NMR (DMSO-d 6 ): δ7.77(m, 2H); 8.33(d, J=9.3, 1H); 8.39(d, J=9.5, 1H); 8.91(s, 1H); 9.08(s, 1H); 9.18(s , 1H). MS (ES, cationic mode): C 14 h 7 ClN 2 Calculated value of m / z: 238.68, measured value: 239.2 (M+H) + .

[0795] ...

Embodiment 3

[0798] 4-(4-Phenoxyanilino)benzo[g]quinoline-3-carbonitrile

[0799] 141.8mg (0.59mmol) 4-chlorobenzo [g] quinoline-3-carbonitrile, 111.1mg (0.60mmol) 4-phenoxyaniline and 57.8mg (0.50mmol) pyridine hydrochloride in 8ml 2- The reaction mixture in ethoxyethanol was heated at 110-120°C for 1 hour. After cooling, the mixture was diluted with water and made basic by adding 125.0 mg (1.18 mmol) of sodium carbonate. The precipitate was collected by filtration and washed with water. Drying in vacuo gave the crude product. The crude product was purified by chromatography eluting with a gradient of dichloromethane / methanol from 100:0 to 86:14 to afford 167.8 mg (73.4%) of pure product as a yellow solid, mp 250-251°C.

[0800] 1 H NMR (DMSO-d 6 ): δ7.05(s, 1H); 7.08(s, 1H); 7.14(m, 3H), 7.43(m, 4H); 7.66(m, 2H), 8.11(d, J=8.1, 1H); 8.19 (d, J = 7.8, 1H); 8.55 (d, 2H); 9.24 (s, 1H); 10.22 (bs, 1H). MS (ES, cationic mode): C 26 h 17 N 3 Calculated m / z of O: 387.44, found: 388.2 ...

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PUM

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Abstract

This invention provides compounds of formula (1) which are useful as inhibitors of protein tyrosine kinase and are antiproliferative agents.

Description

[0001] This application is a divisional application, its parent application number is 00819209.X, the filing date is December 29, 2000, and the invention name is "tricyclic protein kinase inhibitor". Background of the invention [0002] The present invention relates to a substituted aromatic tricyclic compound containing a nicotinyl nitrile ring and a pharmaceutically acceptable salt thereof. The compounds of the invention inhibit the action of certain protein kinases, thereby inhibiting the abnormal growth of particular cell types. Accordingly, the compounds of the present invention are useful in the treatment or inhibition of certain diseases caused by the dysregulation of these protein kinases. The compounds of the present invention are anticancer agents and are therefore useful in the treatment or inhibition of cancer in mammals. Furthermore, the compounds of the present invention are useful in the treatment and inhibition of polycystic kidney disease and colonic polyps. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/70A61K31/429A61K31/4355A61K31/4365A61K31/4375A61K31/473A61K31/4745A61K31/496A61K31/4985A61K31/5377A61P1/00A61P3/10A61P5/14A61P9/00A61P9/10A61P11/00A61P13/12A61P17/00A61P17/06A61P17/14A61P19/02A61P25/00A61P29/00A61P31/04A61P31/12A61P35/00A61P37/06A61P37/08A61P43/00C07C205/59C07C229/70C07D215/54C07D221/08C07D307/85C07D401/12C07D401/14C07D471/04C07D491/04C07D491/048C07D495/04C07D513/04
CPCC07D495/04C07D491/04C07D215/54C07D513/04C07D471/04A61P1/00A61P11/00A61P13/12A61P17/00A61P17/06A61P17/14A61P19/02A61P25/00A61P29/00A61P31/04A61P31/12A61P35/00A61P37/06A61P37/08A61P43/00A61P5/14A61P9/00A61P9/10A61P3/10
Inventor D·M·伯格M·D·杜蒂亚F·F·德莫林D·H·波舍利D·W·波维尔倪慧如A·维斯纳N·张叶菲B·吴
Owner WYETH LLC
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