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2-morpholino-4-pyrimidone compound

A compound and alkyl technology, applied in the field of 2-morpholino-4-pyrimidinone compounds, can solve the problems of insufficient use as medicines and the like

Inactive Publication Date: 2007-09-12
MITSUBISHI TANABE PHARMA CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds are not yet sufficient to be used as drugs in terms of pharmacokinetics etc.

Method used

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  • 2-morpholino-4-pyrimidone compound
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  • 2-morpholino-4-pyrimidone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0529] N-(4-((2S)-4-(1-methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl)-morpholine-2 -yl) phenyl) acetamide (compound number 39)

[0530] 2-Bromo-(1S)-1-(4-bromophenyl)ethanol

[0531] The borane-THF complex (1.0 M solution in THF, 270 mL, 270 mmol) was added to (S)-CBS ((S)-2-methanol) at -30 °C over 15 minutes base-CBS-oxazoboridine, 50 ml, 1.0 M toluene solution) solution and stirred for 15 minutes. 4-Bromophenacyl bromide (75.0 g, 270 mmol) in dichloromethane (350 mL) was then added dropwise over 70 minutes while maintaining the temperature at -32 to -28°C. After stirring for 1 hour, the resulting solution was warmed to room temperature, and methanol (10 mL) was added slowly, followed by dropwise addition of 0.5M hydrochloric acid (300 mL) over 10 minutes. After stirring for 40 minutes, the resulting solution was filtered and the filtrate was extracted with dichloromethane. The combined organic layers were washed with 0.5M hydrochloric acid, 0.1M aqueous sodium...

Embodiment 2

[0552]N-(4-((2S)-4-(1,6-dihydro-1-methyl-6-oxo-4,4'-bipyrimidin-2-yl)-morpholin-2-yl) -Phenyl)acetamide (compound number 40)

[0553] N-(4-((2S)-morpholin-2-yl)phenyl)acetamide (5.78 g, 26.2 mmol), 2-chloro-1,6-dihydro-1-methyl-6- A solution of oxo-4,4'-bipyrimidine (4.00 g, 18 mmol) and triethylamine (6.00 g, 60 mmol) in THF (100 mL) was stirred at 95°C for 1 hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol, 10:1) to obtain N-(4-((2S)-4-(1,6-dihydro-1- Methyl-6-oxo-4,4'-bipyrimidin-2-yl)-morpholin-2-yl)-phenyl)acetamide (5.7 g, 30%).

Embodiment 3

[0555] (S)-2-(2-(4-(N-cyclohexyl-N-methylamino)phenyl)morpholin-4-yl)-3-methyl-6-(4-pyridyl)-pyrimidine -4-one (Compound No. 10)

[0556] (2S)-2-(4-(cyclohexylamino)phenyl)-4-((1R)-1-phenylethyl)morpholine

[0557] Add (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (7.62 g, 22.0 mmol), palladium acetate (198 mg, 0.88 millimol), 2-(di-tert-butylphosphine)biphenyl (525 mg, 1.76 mmol) and sodium tert-butoxide (2.96 g, 30.8 mmol) in toluene (40 ml) suspension was added cyclohexylamine ( 3.78 mL, 33.0 mmol). After heating at 90°C for 2.5 hours, the resulting suspension was passed through a column of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: 5%-25% ethyl acetate in hexanes) to give (S)-2-(4-(cyclo Hexylamino)phenyl)-4-((R)-1-phenethyl)morpholine (6.95 g, 87%).

[0558] (2S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)-4-((1R)-1-phenylethyl)morpholine

[0559] Add (S)-2-(4-(cyclohexylami...

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PUM

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Abstract

A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof: wherein X represents CH or N; C07D 413 / 04 C07D 413 / 14 A61K 31 / 5377 A61P 25 / 28 0 119 17 2005 / 9 / 9 101035781 2007 / 9 / 12 000000000 Mitsubishi Pharma Corp. Japan Watanabe Kazutoshi Uehara Fumiaki Hiki Shinsuke Kohara Toshiyuki Fukunaga Kenji Yokoshima Satoshi dingye beng zhangtian shu 11112 The MEdical and Hygienical Patent Agency of Beijing City No.59 Beiwei Road, Xuanwu District of Beijing 100050 Japan 2004 / 9 / 9 296926 / 2004 2007 / 3 / 9 PCT / JP2005 / 017080 2005 / 9 / 9 WO2006 / 028290 2006 / 3 / 16 English

Description

technical field [0001] The present invention relates to compounds useful as active ingredients of medicaments for the prevention and / or treatment of diseases mainly caused by abnormal activity of tau protein kinase 1, such as neurodegenerative diseases (eg Alzheimer's disease). Background technique [0002] Alzheimer's disease is progressive senile dementia in which marked atrophy of the cerebral cortex due to degeneration of nerve cells and decrease in the number of nerve cells is observed. Pathologically, numerous senile plaques and neurofibrillary tangles were observed in the brain. As the population ages, the number of patients increases, and the disease also poses serious social problems. Although many theories have been put forward, the cause of the disease has not been elucidated. It is desirable to determine the etiology earlier. [0003] It is known that the degree of expression of two characteristic pathological changes of Alzheimer's disease is closely related ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D413/14A61K31/5377A61P25/28
CPCC07D413/14A61P17/14A61P25/00A61P25/02A61P25/16A61P25/18A61P25/24A61P25/28A61P27/02A61P27/06A61P3/04A61P35/00A61P35/02A61P43/00A61P5/48A61P9/00A61P9/10A61P3/10A61K31/5377
Inventor 渡边和俊上原史朗比企绅介小原利行福永谦二横岛聪
Owner MITSUBISHI TANABE PHARMA CORP
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