4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazine derivatives as inhibitors of beta-secretase (BACE)

An alkyl, drug technology, applied to 4-amino-6-phenyl-6 as a beta-secretase (BACE) inhibitor, can solve problems such as low efficiency and reduced in vitro Aβ production

Active Publication Date: 2016-02-10
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

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  • 4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazine derivatives as inhibitors of beta-secretase (BACE)
  • 4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazine derivatives as inhibitors of beta-secretase (BACE)
  • 4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazine derivatives as inhibitors of beta-secretase (BACE)

Examples

Experimental program
Comparison scheme
Effect test

example E1

[0321]N-{3-[(6R)-4-amino-6-methyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6-yl]- 4-fluorophenyl}-5-fluoropyridine-2-carboxamide (compound 1)

[0322]

[0323] 1M aqueous HCl (0.29 mL, 0.3 mmol) was added to intermediate compound I-7 (75 mg, 0.3 mmol) in MeOH (1.5 mL) at room temperature. Then 5-fluoro-2-picolinic acid (41 mg, 0.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.4 mmol) were added. The mixture was stirred at room temperature for 3 h. Add Na 2 CO 3 a saturated solution of and the mixture was extracted with DCM. The organic layer was separated, washed with brine, dried (MgSO 4 ), filtered and evaporated the solvent in vacuo. The crude product was purified by flash column chromatography (silica; 7M ammonia in MeOH in DCM, 0 / 100 to 10 / 90). The desired fractions were collected and the solvent was evaporated in vacuo to yield compound 1 (79 mg, 71%) as a white solid.

example E2

[0325] N-{3-[(6R)-4-amino-6-methyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6-yl]- 4-fluorophenyl}-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide (compound 5)

[0326]

[0327] 4-Chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (0.083 g, 0.423 mmol) was added to DMTMM (0.117 g, 0.423 mmol) in MeOH (2 mL). After the mixture was stirred for 5 min, a solution of Intermediate I-12 (0.1 g, 0.384 mmol) in MeOH (2 mL) was added at 0 °C, and the mixture was stirred for 24 h. The solvent was evaporated in vacuo. The residue was then suspended in DCM and washed with saturated Na 2 CO 3 aqueous solution for processing. The organic layer was separated and dried (MgSO 4 ), filtered and evaporated the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; 7M ammonia in MeOH / DCM, 0 / 100 to 5 / 95). The desired fractions were collected and concentrated in vacuo. The product was passed through preparative HPLC (RP, C18XBridge30x1005um...

example E3

[0329] N-{3-[(6R)-4-amino-6-methyl-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6-yl]- 4,5-Difluorophenyl}-5-fluoropyridine-2-carboxamide (Compound 8)

[0330]

[0331] 5M HCl solution in 2-propanol (0.11 mL, 0.54 mmol) was added to Intermediate I-21 (150 mg, 0.54 mmol) in MeOH (4 mL) at room temperature. Then 5-fluoro-2-picolinic acid (76 mg, 0.54 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol) were added. The mixture was stirred at room temperature for 3 h. Add saturated Na 2 CO 3 aqueous solution and the mixture was extracted with DCM. The organic layer was separated, washed with brine, dried (MgSO 4 ), filtered and evaporated the solvent in vacuo. The crude product was purified by flash column chromatography (silica; 7M ammonia in MeOH in DCM, 0 / 100 to 5 / 95). The desired fractions were collected and the solvent was evaporated in vacuo to provide a solid which was suspended in DIPE, filtered and dried (vacuum oven, 50 °C) to y...

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PUM

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Abstract

The present invention relates to novel 6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin- 6-yl 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 6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6-yl derivatives as inhibitors of β-secretase, which also Known as β-site amyloid cleavage enzyme, BACE, especially 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 d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P25/28
CPCA61P1/04A61P3/00A61P3/10A61P7/02A61P9/00A61P9/10A61P9/12A61P17/00A61P19/02A61P21/00A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P35/00A61P37/06A61P43/00C07D487/04A61K31/4985
Inventor D.奧伊里奇H.J.M.吉森
Owner JANSSEN PHARMA NV
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