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Sulfoximine-substituted pyrimidines as CDK-and/or VEGF inhibitors, their production and use as pharmaceutical agents

A compound and alkyl technology, which is applied in the field of drugs for the treatment of various diseases, can solve the problems of limited clinical application such as carbodehydratase inhibition and side effects

Inactive Publication Date: 2006-11-22
BAYER IP GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The clinical utility of CDK inhibitors containing phenylsulfamoyl groups is limited by the possible inhibition of carbodehydratases and the resulting side effects

Method used

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  • Sulfoximine-substituted pyrimidines as CDK-and/or VEGF inhibitors, their production and use as pharmaceutical agents
  • Sulfoximine-substituted pyrimidines as CDK-and/or VEGF inhibitors, their production and use as pharmaceutical agents
  • Sulfoximine-substituted pyrimidines as CDK-and/or VEGF inhibitors, their production and use as pharmaceutical agents

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Experimental program
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Effect test

Embodiment 1

[0175]

[0176] Substituent Q, R 1 , R 2 , R 3 , R 4 , R 5 and m are the same as defined in the general formula (I).

Embodiment 10

[0178] Preparation of (RS)-S-[4-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S -Methylaminosulfoxide

[0179]

[0180] Method A

[0181] 40 mg (0.23 mmol) of (RS)-S-(4-aminophenyl)-S-methylaminosulfoxide and 62 mg (0.23 mmol) of (R)-2-[(5-bromo -2-chloropyrimidin-4-yl)amino]propan-1-ol with 0.5 ml of 1-butyl-3-methyl-imidazolium tetrafluoroborate (review article on ionic liquids: a) T.Welton, Chem.Rev.1999,99,2071; b) H.Zhao, Aldrichimica Acta2002,35,75; c) M.J.Earle, K.R.Seddon, ACS Symposium Series 2002,819,10) mixed, and at room temperature Stir for 10 minutes. The reaction mixture was heated to 60°C and stirred at this temperature for a further 3 hours. Mix with 0.08 ml of 4M hydrochloric acid solution in dioxane and stir at 60° C. for 60 hours. After cooling, the reaction mixture was mixed with 10 ml of ethyl acetate and stirred for 10 minutes. The organic solvent was decanted off, and the residue was dissolved in 10 ml methanol. ...

Embodiment 11

[0196] Preparation of (RS)-S-[3-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S -Methyl-N-nitroaminosulfoxide

[0197]

[0198] A solution of 37mg (0.17mmol) of (RS)-S-(3-aminophenyl)-S-methyl-N-nitroaminosulfoxide in 3ml of acetonitrile was mixed with 91mg (0.34mmol) of (R)- 2-[(5-Bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol and 0.06 ml of 4M hydrochloric acid solution in dioxane were mixed and stirred overnight at reflux. A further 0.05 ml of 4M hydrochloric acid solution in dioxane was added and refluxed for a further 6 hours. After TLC monitoring, it was mixed with 92 mg (0.34 mmol) of (R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol and refluxed overnight. After cooling, the reaction was made basic with saturated sodium bicarbonate solution, then extracted with ethyl acetate. The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated by evaporation. The residue obtained is purified by chromatography (DC...

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Abstract

The present invention relates to pyrimidine derivatives of formula (I), which are useful as inhibitors of cyclin-dependent kinases and VEGF receptor tyrosine kinases. The present invention also relates to a method for preparing the derivative and its use as a medicine for treating various diseases.

Description

technical field [0001] The invention relates to a pyrimidine derivative substituted by aminosulfoxide (sulfoximine), its preparation method and its use as a medicine for treating various diseases. Background technique [0002] Cyclin-dependent kinases (CDKs) are a class of enzymes that play an important role in regulating the cell cycle, and thus can be particularly advantageous targets for the development of small inhibitory molecules. Selective inhibitors of CDKs are useful in the treatment of cancer or other diseases resulting from disorders of cell proliferation. [0003] Receptor tyrosine kinases and their ligands, which specifically regulate endothelial cell function, play a decisive role in physiological and pathological angiogenesis. The vascular endothelial growth factor (VEGF) / VEGF receptor system is of particular importance here. In pathological conditions accompanied by increased neovascularization, such as neoplastic diseases, an increased expression of angiog...

Claims

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Application Information

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IPC IPC(8): C07D239/48A61K31/506A61K31/513C07D239/46
CPCC07D239/47C07D239/48A61P1/04A61P1/16A61P13/12A61P15/00A61P17/00A61P17/06A61P17/12A61P17/14A61P19/02A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/00A61P31/12A61P31/14A61P31/18A61P31/22A61P33/00A61P35/00A61P35/02A61P35/04A61P37/00A61P37/06A61P43/00A61P9/00A61P9/10C07D239/46A61K31/505
Inventor 乌尔里希·吕金马丁·克吕格尔罗尔夫·乔特莱特格哈德·西迈斯特
Owner BAYER IP GMBH
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