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APP with the A673T substitution (positioning the two C-terminal amino acids to the β-secretase cleavage site) was less efficiently cleaved by β-secretase, resulting in approximately 40% reduction in Aβ production in vitro
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[0498] 5-Methoxypyrazine-2-carboxylic acid (141 mg, 0.92 mmol) was added to a stirred solution of DMTMM (60% purity, 461 mg, 1 mmol) in MeOH (14 mL). After 5 min, intermediate compound I-15 (216 mg, 0.83 mmol) in MeOH (2 mL) was added at 0 °C. The mixture was stirred at room temperature for 16 h. use Na 2 CO 3 The mixture was treated with a saturated solution of DCM and extracted with DCM. The organic phase was separated and dried (MgSO 4 ), filtered and evaporated the solvent in vacuo. By flash column chromatography (silica; DCM-MeOH (10:1 (25% NH 3 ), v / v) in DCM, 0 / 100 to 40 / 60) the crude product was purified. The desired fractions were collected and the solvent was evaporated in vacuo. Dilute the solid with Et 2 O was triturated and filtered to yield final compound 1 (181 mg, 54%) as a solid.
[0502] Intermediate compound I-13 (269mg, 0.83mmol), pyrimidine-5-boronic acid (113mg, 0.9mmol) and 1M Na 2 CO 3 A solution of aqueous solution (1.67 mL, 1.67 mmol) in 1,4-dioxane (8 mL) was degassed with nitrogen for 5 min. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (34 mg, 0.04 mmol) was added. The mixture was stirred at 100 °C for 4 h. Water and DCM were added. The organic phase was separated and dried (MgSO 4 ), filtered and evaporated the solvent in vacuo. By flash column chromatography (silica; DCM-MeOH (10:1 (25% NH 3 ), v / v) in DCM, 0 / 100 to 80 / 20) the crude product was purified. The desired fractions were collected and the solvent was evaporated in vacuo. This product was triturated with DIPE to yield final compound 2 (41 mg, 15%) as a light brown solid.
[0506] at 5°C, in N 2 Trifluoroacetic anhydride (14 μL, 0.1 mmol) and triethylamine (14 μL, 0.1 mmol) were added to a solution of Intermediate 1-21 (21 mg, 0.049 mmol) in DCM (4 mL) at atm in a closed vessel. solution. The reaction mixture was stirred at room temperature for 48 hours, then cooled to 5 °C, and additional trifluoroacetic anhydride (40 μL, 0.288 mmol) and triethylamine (40 μL, 0.286 mmol) were added. The reaction mixture was stirred overnight at room temperature. The mixture was saturated with Na 2 CO 3 Aqueous work-up and extraction with DCM. The organic phase was separated and dried (MgSO 4 ), filtered and evaporated the solvent in vacuo. The crude product was dissolved in acetonitrile (5 mL) and washed with 25% NH 3 Aqueous solution (0.5 mL) was worked up. The reaction mixture was concentrated in ...
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Abstract
The present invention relates to novel 5,6-dihydroimidazo[1,5-a]pyrazinyl derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, in particular BACE1 and / or BACE2 (wherein BACE1, is also known as Asp2, or memapsin2 and BACE2 is also known as Asp1, Memapsin 1 or DRAP). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, dementia associated with beta-amyloid, age-related macular degeneration, type 2 diabetes and other metabolic disorders.
Description
field of invention [0001] The present invention relates to novel 5,6-dihydroimidazo[1,5-a]pyrazinyl derivatives as inhibitors of β-secretase, also known as β-site amyloid lyase , BACE, in particular BACE1 and / or BACE2 (wherein BACE1 is also known as Asp2 or aspartic protease 2, and BACE2 is also known as Asp1, aspartic protease 1 or DRAP). The present invention also relates to pharmaceutical compositions comprising such compounds, to processes for the preparation of such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, These disorders are eg Alzheimer's disease (AD), mild cognitive impairment, aging, dementia, dementia with Lewy bodies, Down syndrome, stroke-related dementia, Parkinson's disease-related dementia, Alzheimer's disease Silent dementia, beta-amyloid-related dementia. In addition to Alzheimer's disease, Down syndrome and related disorders, BACE inhibiti...
Claims
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