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Dihydropyrazolopyrimidinone derivative

A compound, hydrogen atom technology, used in the field of medicine

Active Publication Date: 2009-05-13
บันยิว ฟาร์มาซูติคัล โค แอลทีดี
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no specific disclosure or suggestion for the Weel kinase inhibitory effect of this compound and the compound of the present invention in these documents

Method used

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  • Dihydropyrazolopyrimidinone derivative
  • Dihydropyrazolopyrimidinone derivative
  • Dihydropyrazolopyrimidinone derivative

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0567] Preparation of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0568] 1) 1-allylhydrazine carboxylic acid = tert-butyl ester

[0569] To a solution of 280 g of phthalic anhydride in 3 L of toluene was added 250 g of hydrazinecarboxylic acid = t-butyl ester. The reaction mixture was heated to reflux under a Dean-Stark trap for 3 hours. After cooling to room temperature, the resulting solid was collected by filtration to obtain 516 g of a crude product of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)carbamate=tert-butyl ester.

[0570] 520 g of potassium carbonate, 43.3 g of benzyltriethylammonium chloride, and 250 mL of allyl bromide were sequentially added to a solution of the above compound in 3.5 L of acetonitrile, and stirred at room temperature for 18 hours. 1.5 L of water was added to the reaction solution, and the acetonitrile layer was separated and concentrated. 1 L of water was added to the residue and the aqueous layer, followed by extra...

preparation example 2

[0578] Preparation of 2-(2-chlorophenyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0579] 1) Preparation of ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate

[0580] To 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester 9.4g, 2-chlorophenylhydrazine hydrochloride 8.3g tetrahydrofuran 300mL solution was added N,N-diisopropylethyl Base amine 16.2mL, heated to reflux for 18 hours. After the solvent was concentrated under reduced pressure, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate was obtained as a crude yellow oil.

[0581] 2) Preparation of 2-(2-chlorophenyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0582] To a solution of 13.8 g of the compound obtained...

preparation example 3

[0587] Preparation of 2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0588] 1) Preparation of ethyl 4-hydrazino-2-(methylthio)pyrimidine-5-carboxylate

[0589] Add 15.0 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate dissolved in 200 mL of ethanol to a solution obtained by dissolving 9.71 g of hydrazine monohydrate in 200 mL of ethanol and cooling to 0°C to obtain The solution was stirred for 1 hour. The precipitated solid was collected by filtration, washed with distilled water, and dried to obtain 9.66 g of the title compound as a white solid.

[0590] 1 H-NMR (400MHz, CD 3 OD)δ: 8.56(1H, s), 4.36(2H, q, J=7.2Hz), 2.62(3H, s), 1.39(3H, t, J=7.2Hz).

[0591] ESI-MS measured: m / z[M+H]+229

[0592] 2) Preparation of ethyl 4-[2-(1-methylethylene)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate

[0593] 9.66 g of the above compound was dissolved in 300 mL of acetone, and stirred at 70° C. for 12 hours. After cooling the reaction so...

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Abstract

The invention relates to compounds of a general formula (I): wherein Ar<1>is an optionally-substituted aryl or heteroaromatic group; R<1 >is an optionally-substituted lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R<2>is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R<3>is a hydrogen atom or a lower alkyl group; R<4>is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a group of -N(R<1k>)R<1m>; T and U are a nitrogen atom or a methine group, etc. The compounds of the invention have excellent Weel kinase-inhibitory effect and are therefore useful in the field of medicines, especially treatment of various cancers.

Description

technical field [0001] The invention is used in the field of medicine. More specifically, the dihydropyrazolopyrimidinone derivatives of the present invention are useful as kinase inhibitors, especially Weel kinase inhibitors, in the field of various cancer treatments. Background technique [0002] Cells have a checkpoint mechanism that temporarily stops the cell cycle when DNA is damaged and repairs it [Cell Proliferation, vol. 33, pp. 261-274]. In about half of human cancers, the function of the G1 checkpoint is lost due to the mutation or defect of the cancer suppressor gene p53. However, the G2 checkpoint function still remains in such cancer cells, and it is considered to be one of the important reasons for reducing the sensitivity to DNA-acting anticancer agents or radiation. [0003] Weel kinases are tyrosine kinases associated with the G2 checkpoint of the cell cycle. Weel inactivates Cdc2 by phosphorylating tyrosine 15 of Cdc2 (Cdk1) associated with the transitio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61K31/5377A61K31/54A61K31/551A61P35/00A61P43/00C07D487/04
CPCC07D487/04A61K31/4162A61K31/519A61P35/00A61P35/02A61P43/00
Inventor 坂本俊浩角南聪山本冬树新山健治番场诚高桥启治古山英知后藤康裕相良武大槻幸惠西端俊秀吉住隆平井洋
Owner บันยิว ฟาร์มาซูติคัล โค แอลทีดี
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