Pyridopyrimidinone derivatives for treatment of neurodegenerative disease

A neurodegenerative disease, pyridine technology, applied in the field of novel compounds, can solve the problem of marginal effectiveness

Inactive Publication Date: 2003-07-30
WARNER-LAMBERT CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Several drugs are available to treat the symptoms and physical consequences of these disorders, but most are only marginally effective

Method used

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  • Pyridopyrimidinone derivatives for treatment of neurodegenerative disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0589] 4-Ethylamino-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester

[0590]To a room temperature solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (10.00 g, 43.10 mmol) in 150 mL of THF was added triethylamine (18.5 mL, 133 mmol) followed by 9 mL of 70% ethylamine aqueous solution. The solution was stirred for 30 minutes, then concentrated in vacuo, partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford 9.32 g (90%) of ethyl 4-ethylamino-2-methylthio-pyrimidine-5-carboxylate as an oil.

[0591] Analytical calculated value C 10 h 15 N 3 o 2 S: C, 49.77; H, 6.27; N, 17.41.

[0592] Found values: C, 49.77; H, 6.24; N, 17.30.

Embodiment 2

[0594] (4-Ethylamino-2-methylthio-pyrimidin-5-yl)-methanol

[0595] A solution of ethyl 4-ethylamino-2-methylthio-pyrimidine-5-carboxylate (8.93 g, 37.1 mmol) in 100 mL THF was added dropwise to lithium aluminum hydride (2.30 g, 60.5 mmol) in 100 mL THF at room temperature in suspension. After 10 minutes, the reaction was carefully quenched with 4.5 mL of water, 4.5 mL of 15% NaOH and another 16 mL of water, and the mixture was stirred for 1.5 hours. The white precipitate was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and 1:1 hexane:ethyl acetate was added. The solid was collected to give 6.77 g (92%) of (4-ethylamino-2-methylthio-pyrimidin-5-yl)-methanol, mp 152-156°C.

[0596] Analytical calculated value C 8 h 13 N 3 OS: C, 48.22; H, 6.58; N, 21.09.

[0597] Found values: C, 48.14; H, 6.61; N, 20.85.

Embodiment 3

[0599] 4-Ethylamino-2-methylthio-pyrimidine-5-carbaldehyde

[0600] To a solution of (4-ethylamino-2-methylthio-pyrimidin-5-yl)-methanol (6.44 g, 32.4 mmol) in 600 mL of chloroform was added manganese oxide (21.0 g, 241 mmol). The suspension was stirred at room temperature for 2 hours and a further 5.5 g of manganese oxide were added. Stirring was continued for 4.5 hours. The mixture was filtered through celite, washing with chloroform. The filtrate was concentrated in vacuo to afford 6.25 g (97%) of 4-ethylamino-2-methylthio-pyrimidine-5-carbaldehyde, mp 58-61°C.

[0601] Analytical calculated value C 8 h 11 N 3 OS: C, 48.71; H, 5.62; N, 21.30.

[0602] Found values: C, 48.62; H, 5.60; N, 21.28.

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Abstract

This invention provides a method for treating neurodegenerative diseases in mammals comprising administering an effective amount of a cyclin-dependent kinase inhibitor. A preferred method uses cdk inhibitors of Formula (I) and Formula (II) where W is NH, S, SO, or SO2, R<1> includes phenyl and substituted phenyl, R<2> includes alkyl and cycloalkyl, R<3> includes alkyl and hydrogen, R<8> and R<9> include hydrogen and alkyl, and Z is carboxy.

Description

field of invention [0001] The present invention relates to methods of treating neurodegenerative diseases in mammals by administering compounds that inhibit cyclin-dependent kinases. The invention also provides novel compounds useful in this method. Background of the invention [0002] Neurodegenerative diseases are diseases characterized by breakdown in neuronal activity and dysfunction. Diseases that generally fall under the neurodegenerative category include Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Other diseases caused by functional degeneration of neurons are progressive supernuclear palsy (Progressive Supernuclear palsy, PSP) and Parkinson's disease-related pretemporal dementia (Pronto-temporal dementia, FTDP-17). [0003] Neurodegenerative diseases often accompany the aging process, becoming more prevalent around the world as the general population reaches about 60 years of age and above. Even though ne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/505A61K31/519A61K45/00C07D239/48A61P21/02A61P25/14A61P25/16A61P25/28A61P43/00C07D471/04C07D487/02
CPCC07D471/04A61P21/02A61P25/14A61P25/16A61P25/28A61P43/00A61K31/519
Inventor R·J·布斯A·查特吉T·C·马龙
Owner WARNER-LAMBERT CO
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