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3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors

A group, cycloalkyl technology applied to 3-cyanoquinoline, 3-cyano-1,6-naphthalene and 3-cyano-1,7-diazine as protein kinase inhibitors In the field of azanaphthalenes, problems such as undisclosed 3-cyano groups can be solved

Inactive Publication Date: 2008-12-03
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

WO 9802437 and WO 9935146 patent applications further describe 5- or 6-membered heteroaryl groups having an anilino group at carbon-4 and 1 or more optional substitutions at carbon-5 to carbon-8 as kinase inhibitors or phenyl ring substituted ring systems including quinoline compounds, 1,6-naphthyridine and 1,7-naphthyridine compounds, but does not disclose the 3-cyano group of the present invention

Method used

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  • 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
  • 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
  • 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors

Examples

Experimental program
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Effect test

reference example 1

[0976] 6-Bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile

[0977] A solution of 5-bromoanthranilic acid (21.6g, 100mmol) and dimethylformamide dimethyl acetal (50ml) in dimethylformamide (150ml) was heated at 155-160°C for 8 hours, then cooled to room temperature. Volatiles were removed under vacuum to yield 28.5 g of the intermediate amidine.

[0978] Lithium diisopropylamide (LDA) was produced from isopropylamine (9.84ml, 70.2mmol) and 2.5M n-butyllithium (29.5ml, 70.2mmol) in tetrahydrofuran (150ml) at -78°C. Acetonitrile (3.67ml, 70.2mmol) was added and the resulting white suspension was stirred at -78°C for 1 hour. A solution of 10 g of the above-mentioned amidine in 100 ml of tetrahydrofuran was added and stirring was continued for 1 hour at -78°C and then for 1 hour at room temperature. Acetic acid (15ml) was added to quench the reaction. Volatiles were removed under vacuum and water was added to the residue. Ammonium hydroxide was added to basify the aqueous sol...

reference example 2

[0984] 6-Bromo-4-chloro-3-quinolinecarbonitrile

[0985]A mixture of 6-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile (1.3 g, 4.86 mmol) and 8 ml of phosphorus oxychloride was heated at reflux for 30 minutes. The resulting dark brown solution was cooled to room temperature and 10 ml of hexane was added. The resulting solid was collected by filtration, washed with hexane, water and hexane to give 1.05 g of 6-bromo-4-chloro-3-quinolinecarbonitrile as a tan solid.

[0986] 1 H NMR (DMSO-d 6 )δ8.12(d, J=9Hz, 1H), 8.19(dd, J=9, 2Hz, 1H), 8.45(d, J=2Hz, 1H), 9.23(s, 1H); MS(ES)m / z 267.1, 269.0(M+1).

[0987] Elemental Analysis: C 9 h 4 BrClN 2 :

[0988] Calculated: C, 44.90; H, 1.51; N, 10.47.

[0989] Found values: C, 44.53; H, 1.63; N, 10.27.

reference example 3

[0991] 6-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

[0992] A mixture of 2,4-dichloro-5-methoxyaniline (prepared as described in WO 8501939-A1) (730 mg, 3.77 mmol) and sodium hydride (180 mg 60% oil dispersion, 4.5 mmol) in 30 ml THF Heat at reflux for 1 hour. The mixture was cooled, 6-bromo-4-chloro-3-quinolinecarbonitrile (600mg, 2.24mmol) was added, and the resulting mixture was heated under reflux for 50 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained solid was purified by flash chromatography, and 3:1-1:1 hexane: ethyl acetate was used for gradient elution to obtain 530 mg (yield 53%) of 6-bromo-4-(2,4-di Chloro-5-methoxyanilino)-3-quinolinenitrile, melting point (mp) 232-234°C.

[0993] 1 H NMR (DMSO-d 6 / trifluoroac...

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Abstract

Compounds of structure formula (I) or a pharmaceutically salt thereof are useful as antineoplastic agents and in the treatment of osteoporosis and polycystic kidney disease.

Description

field of invention [0001] The present invention relates to compounds containing 3-cyanoquinoline, 3-cyano-1,6-naphthyridine and 3-cyano-1,7-naphthyridine and pharmaceutically acceptable salts thereof. The compounds of the present invention inhibit the activity of protein kinases required for cell growth and differentiation. The compounds of the present invention are therefore useful in the treatment of certain diseases which are attributable to the activity of these protein kinases. The compounds of the present invention are anticancer agents and are useful in the treatment of cancer in mammals. In addition, the compounds of the present invention are useful in the treatment of polycystic kidney disease in mammals. The compounds of the present invention are also useful in the treatment of osteoporosis. The present invention also relates to the production method of the compound, its use for treating cancer, polycystic kidney disease and osteoporosis, and the pharmaceutical pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/54C07D409/04C07D401/04C07D401/06C07D405/04C07D405/14C07D409/14C07D401/12C07D401/10C07D401/14C07D405/12C07D471/04A61K31/4706A61K31/4709A61P35/00C07D221/00A61K31/496A61K31/5377A61K31/541A61P1/00A61P1/02A61P1/16A61P1/18A61P9/00A61P11/00A61P11/04A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P19/02A61P19/10A61P29/00A61P31/00A61P31/12A61P37/04A61P37/06A61P43/00C07D413/10C07D413/14C07D417/06
CPCC07D401/14C07D401/12C07D471/04C07D409/04C07D405/14C07D401/06C07D405/12C07D215/54C07D405/04C07D409/14C07D401/10C07D401/04A61P1/00A61P1/02A61P1/16A61P1/18A61P11/00A61P11/04A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P19/02A61P19/10A61P29/00A61P31/00A61P31/12A61P35/00A61P37/04A61P37/06A61P43/00A61P9/00
Inventor D·H·波舍利王亚农F·C·波舍利D·M·伯格张南D·W·波维尔叶菲A·亚马施塔F·F·德莫林吴碧琪倪慧如E·G·奥弗贝克-克卢姆佩尔斯A·维斯纳
Owner WYETH LLC
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