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Spiroaminodihydrothiazine derivatives

An amino and group technology, applied in the field of spiroamino dihydrothiazine derivatives and their pharmaceutical applications, can solve the problem that basic drug therapy has not yet been developed and the like

Inactive Publication Date: 2014-04-09
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, only symptom-improving agents represented by acetylcholinesterase inhibitors are used for symptomatic treatment of Alzheimer's disease, and basic drug therapy to inhibit the progression of the disease has not yet been developed

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0261] Synthesis of 8-Fluorochroman-4-one (Compound 1-3)

[0262] [Formula 8]

[0263]

[0264] (1) Synthesis of 3-(2-fluorophenoxy)propionic acid (compound 1-2)

[0265] (1-1) A solution of 2-fluorophenol (compound 1-1, 3.0g) in N,N-dimethylformamide (7.0ml) was added to sodium hydride (3.22 g) in a 50% solution in N,N-dimethylformamide (100ml). After stirring at the same temperature for 30 minutes, a solution of 3-bromo-propionic acid (4.91 g) in N,N-dimethylformamide (8.0 ml) was added. The mixture was returned to room temperature and stirred at the same temperature for 24 hours. The reaction was terminated by adjusting the pH to 1-2 with 1N hydrochloric acid (100ml). The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized by adding a 20% ethyl acetate-hexane mixed solvent to o...

preparation example 2

[0276] Synthesis of 2,3,5',6'-tetrahydrospiro[benzopyran-4,4'-[1,3]thiazin]-2'-amine (compound 1)

[0277] [Formula 9]

[0278]

[0279] (1) Synthesis of 4-vinyl-chroman-4-ol (compound 2-2)

[0280] Zinc chloride (461 mg) was added to vinylmagnesium chloride (1.48 M solution in tetrahydrofuran; 29.7 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was cooled to 0°C, followed by dropwise addition of a solution (20.0 ml) of compound 2-1 (5.00 g) in tetrahydrofuran. The reaction solution was stirred at the same temperature for 5 hours. After confirming the disappearance of the starting material, ammonium chloride solution was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chroma...

preparation example 3

[0289] Synthesis of N-(2'-amino(6-nitro-2,3,5',6'-tetrahydrospiro[benzopyran-4,4'-[1,3]thiazin]-6-yl ) Trifluoroacetamide (Compound 2)

[0290] [Formula 10]

[0291]

[0292] (1) Synthesis of 2,2,2-trifluoro-N-(4-oxochroman-6-yl)acetamide (compound 3-3)

[0293] Compound 3-1 (1.0 g) was dissolved in acetone (50 ml). Tin chloride dihydrate (3.66 g) was added and the mixture was heated at reflux overnight. After confirming that the reaction was complete, the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure, and aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The aqueous layer was back extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The obtained product (464 mg) was dissolved in dichloromet...

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PUM

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Abstract

A compound represented by the general formula (I): or a pharmaceutically acceptable salt thereof, has an Abeta production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Abeta and typified by Alzheimer-type dementia.

Description

technical field [0001] The present invention relates to spiroaminodihydrothiazine derivatives and their pharmaceutical application. More specifically, the present invention relates to spiroaminodihydrothiazine derivatives having an inhibitory effect on the production of amyloid-β (hereinafter referred to as Aβ) protein or cleavage of β-site amyloid-β precursor protein Enzyme 1 (hereinafter referred to as BACE1) inhibition and effective treatment of neurodegenerative diseases caused by Aβ protein, especially Alzheimer's type dementia, Down's syndrome, etc.; Derivatives as active ingredients in pharmaceutical compositions. Background technique [0002] Alzheimer's disease is a disease characterized by neuronal degeneration and loss, senile plaque formation, and neurofibrillary degeneration. Currently, only symptom-improving agents represented by acetylcholinesterase inhibitors are used for symptomatic treatment of Alzheimer's disease, and basic drug therapy to inhibit the pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/10A61K31/547A61P25/28
CPCC07D513/10A61P25/28
Inventor 元木贵史金子敏彦山本昇A·卡恩
Owner EISIA R&D MANAGEMENT CO LTD
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