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Novel fused aminodihydrothiazine derivative

A compound, alkyl technology, applied in the field of fused aminodihydrothiazine derivatives, can solve problems such as no fundamental treatment has been developed

Inactive Publication Date: 2011-08-31
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, Alzheimer's type dementia is treated only with symptomatic treatment using symptom-improving agents typified by acetylcholinesterase inhibitors, and no fundamental treatment for suppressing the progression of the disease has been developed yet.

Method used

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  • Novel fused aminodihydrothiazine derivative
  • Novel fused aminodihydrothiazine derivative
  • Novel fused aminodihydrothiazine derivative

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0614] (-)-[(4aR ＊ ,8aS ＊ )-8a-(5-amino-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1- Synthesis of tert-butyl azinaphthalen-2-yl]carbamate

[0615] [Formula 26]

[0616]

[0617] (1) Synthesis of 3-butenyloxyglyoxaldoxime

[0618] Hydroxylamine sulfate (20.5g), sodium acetate (12.8g) and water (20ml) were added to 3-butenyloxyacetaldehyde (17.8g; J.Chem.Soc., Perkin Trans.1, 1999, 3143-3155) in ethanol (200ml) solution. The mixture was stirred overnight at room temperature, then water was added. Excess ethanol was evaporated under reduced pressure and the resulting residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (6.20 g).

[0619] 1 H-NMR (400MHz, CDCl 3 )δ (ppm): 2.36 (m, 2H), 3.53 (dt, J = 6.6, 8.4Hz, 2H), 4.10 (d, J = 5....

preparation Embodiment 2

[0648] Synthesis of 5-fluoromethoxypyrazine-2-carboxylic acid

[0649] [Formula 27]

[0650]

[0651] (1) Synthesis of Methyl 5-Fluoromethoxypyrazine-2-carboxylate

[0652] Toluene-4-sulfonic acid fluoromethyl ester (Journal of Labeled Compounds & Radiopharmaceuticals, 46(6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to 5-hydroxypyrazine-2-carboxylic acid methyl ester (130mg) in N,N-dimethylformamide (2.0mL). The reaction solution was stirred at 70°C for 5 hours and 30 minutes, then cooled to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg).

[0653] 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 4.03 (s, 3H), 6.14 (d, J=51.2Hz, 2H), 8.42 (d, J=1.2Hz, 1H), 8.94 (d, J=1.2Hz, 1H).

[0654] (2) Synthesis of 5-fluoromethoxypyrazine-2-carboxy...

preparation Embodiment 3

[0658] Synthesis of 5-cyanopyridine-2-carboxylic acid

[0659] [Formula 28]

[0660]

[0661] (1) Synthesis of methyl 5-cyanopyridine-2-carboxylate

[0662] A mixture of methyl 5-bromopyridine-2-carboxylate (2.8 g) and copper cyanide (3.6 g) in NMP (30 ml) was heated at 170° C. for 1.5 hours with stirring. Water was added to the reaction solution at room temperature and insolubles were removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (920 mg).

[0663] 1 H-NMR (400MHz, CDCl 3 )δ(ppm): 4.06(s, 3H), 8.16(dd, J=2.0, 8.0Hz, 1H), 8.27(d, J=8.0Hz, 1H), 9.01(d, J=2.0Hz, 1H) .

[0664] (2) Synthesis of 5-cyanopyridine-2-carboxylic acid

[0665] A solution of the compound (9...

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Abstract

A compound represented by general formula (I), a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt has an Abeta production inhibitory activity or BACE 1 inhibitory activity, and is thus useful as an agent for treating neurodegenerative diseases caused by Abeta as typified by Alzheimer's disease. In the formula, ring A represents a C6-14 aryl group or the like; L represents -NRLCO- (wherein RL represents a hydrogen atom or the like) or the like; ring B represents a C6-14 aryl group or the like; X represents a C1-3 alkylene group or the like; Y represents a C1-3 alkylene group or the like; Z represents an oxygen atom or the like; R<1> and R<2> each independently represents a hydrogen atom or the like; and R<3>, R<4>, R<5> and R<6> each independently represents a hydrogen atom, a halogen atom or the like.

Description

technical field [0001] The present invention relates to fused aminodihydrothiazine derivatives and their medical use. More specifically, the present invention relates to amyloid-β (hereinafter referred to as Aβ) protein production inhibitory effect or β-site amyloid-β precursor protein cleaving enzyme 1 (hereinafter referred to as BACE1 or β-secretase) inhibitory effect. Fused aminodihydrothiazide derivatives, which are useful for the treatment of neurodegenerative diseases caused by Aβ protein, especially Alzheimer's type dementia, Down's syndrome, etc., and relate to fused aminodihydrothiazide A pharmaceutical composition in which an oxazine derivative is used as an active ingredient. Background technique [0002] Alzheimer's disease is a disease characterized by degeneration and loss of nerve cells and the formation of senile plaques and neurofibrillary tangles. Currently, Alzheimer's type dementia is treated only with symptomatic treatment using a symptom-improving age...

Claims

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Application Information

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IPC IPC(8): C07D513/04A61K31/542A61P25/00A61P25/28A61P43/00
CPCC07D513/04A61P25/00A61P25/28A61P43/00A61K31/542
Inventor 元木贵史武田邦稔北阳一高石守铃木裕一石田祐
Owner EISIA R&D MANAGEMENT CO LTD
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