Oxazine derivative

A compound and solvate technology, applied in the field of oxazine derivatives, can solve the problem of no hint of drug activity

Inactive Publication Date: 2012-12-19
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although non-patent literature 1 describes a compound similar to the structure of the present invention, it does not suggest any medicinal activity

Method used

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  • Oxazine derivative
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0702] The synthesis of embodiment 1 compound (I-12) and (I-13)

[0703] [chemical formula 78]

[0704]

[0705] first step

[0706] To a solution of compound 1 (1.20 g) in acetone (70 ml)-water (40 ml) was added a solution of benzoyl isothiocyanate (0.82 g) in acetone (10 ml) at 0°C, and stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography to obtain Compound 2 (1.35 g).

[0707] 1 H-NMR (CDCl 3 )δ: 1.69 (1H, t, J=4.7Hz), 2.14 (3H, s), 2.21-2.31 (1H, m), 2.73-2.83 (1H, m), 3.78-3.98 (2H, m), 7.15 (1H, dd, J=11.1, 9.1Hz), 7.48-7.55(2H, m), 7.60-7.67(1H, m), 7.85(2H, d, 7.2Hz), 8.14-8.20(1H, m), 8.30-8.34 (1H, m), 8.81 (1H, s), 11.56 (1H, s).

[0708] second step

[0709] Add methyl iodide (0.30ml) and diisopropylethylamine (0.84ml) to the acetonitrile (5ml) solution of compound 2 (1.26g) obtained in the first step, stir at room temperature for 32 hours, Stir for 2 hours. W...

Embodiment 2

[0717] Example 2 Synthesis of Compounds (I-14) and (I-15)

[0718]

[0719] first step

[0720] Benzoyl isocyanate (854 µl) was added to a tetrahydrofuran (10 ml) solution of compound (4) (1.1 g) obtained by the method described in Reference Example described later at 0°C, followed by stirring at room temperature for 30 minutes. Next, N-bromosuccinimide (675 mg) was added, followed by stirring at room temperature for 30 minutes. Ethyl acetate was added, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain compound (5) (2.4 g) as a crude product.

[0721] second step

[0722] Sodium tert-butoxide was added to a solution of compound (5) (2.4 g) obtained in the first step in tetrahydrofuran (12 ml) and dimethyl sulfide (12 ml), followed by stirring at room temperature for 2 hours. The reaction solution was poured into 1mol / L hydrochloric acid and extracted with ethyl acetate. The organic la...

Embodiment 3

[0740] The synthesis of embodiment 3 compound (I-54)

[0741]

[0742]

[0743] first step

[0744] Under a nitrogen atmosphere, compound (9) (3.00 g) prepared by the method described in WO2009 / 151098 was dissolved in tetrahydrofuran (30 ml), and cooled with a dry ice acetone bath. 2-Methallylmagnesium chloride (0.5 mol / L THF solution, 85.0 ml) was added dropwise at -78°C, followed by stirring at -78°C for 2 hours. Saturated ammonium chloride aqueous solution and water were added to the reaction liquid, extracted with ethyl acetate, washed with water and saturated brine in this order. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography to obtain compound (11) (2.49 g).

[0745] 1 H-NMR (CDCl 3 )δ: 1.26(s, 9H), 1.38(s, 3H), 1.86(s, 3H), 2.84(ABq, J=13.4Hz, 2H), 4.21(s, 1H), 4.81(s, 1H), 4.92(d, J=1.5Hz, 1H), 7.05(dd, J=11.7, 8.7Hz, 1H),...

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PUM

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Abstract

Disclosed is a compound or the like which serves as a prophylactic or therapeutic agent for diseases induced by the production, secretion and / or deposition of amyloid beta protein. Specifically disclosed is a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt. In the formula, R1, R2a, R2b, R3, R4a, R4b, ring A and broken line are as defined in the description.

Description

technical field [0001] The present invention relates to a compound having an activity of inhibiting amyloid β production and useful as a therapeutic or preventive agent for diseases induced by the production, secretion and / or deposition of amyloid β. Background technique [0002] In the brains of patients with Alzheimer's disease, it is widely recognized that there are insoluble spots (senile plaques) in which a polypeptide consisting of approximately 40 amino acids called β-amyloid accumulates outside nerve cells. It is believed that the senile plaques lead to the death of nerve cells, leading to the onset of Alzheimer's disease. As a drug for Alzheimer's disease, β-amyloid decomposition promoters, β-amyloid vaccines, etc. are being developed. be studied. [0003] Secretase is an enzyme that cleaves a protein called β-amyloid precursor protein (APP) in cells to generate β-amyloid. The enzyme that controls the N-terminal production of β-amyloid is called β-secretase (beta-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/06A61K31/535A61K31/5355A61K31/5365A61P25/16A61P25/28A61P27/02A61P43/00C07D265/08C07D413/12C07D413/14C07D498/04
CPCC07D413/14C07D498/04C07D265/08C07D413/12C07D265/06A61P25/00A61P25/16A61P25/28A61P27/02A61P43/00A61K31/535A61K31/5355
Inventor 桝井盛泰堀章洋
Owner SHIONOGI & CO LTD
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