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Triazolo-azepine derivatives

A triazolo and azabicyclic technology, applied in the field of triazolo-aza* derivatives, can solve the problem of selectivity reduction

Active Publication Date: 2020-07-14
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] An alternative to treatment is modulation of γ-secretase activity, which results in a selective reduction of Aβ42 production

Method used

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  • Triazolo-azepine derivatives
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  • Triazolo-azepine derivatives

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0134] 1.1) generally

[0135] · Analytical method:

[0136] a) HPLC (method LCMS_fast gradient)

[0137] - Column: Agilent Zorbax Eclipse Plus C18, Fast Resolution HT, 2.1x30 mm, 1.8 μm, part number 959731-902

[0138] - Solvent A: Water 0.01% Formic Acid; Solvent B: Acetonitrile (MeCN)

[0139] -gradient:

[0140] time [min] Flow rate [ml / min] ％A ％B initial 0.8 97 3 0.2 1.0 97 3 1.7 1.0 3 97 2.0 1.0 3 97 2.1 1.0 97 3

[0141] · abbreviation:

[0142] The following abbreviations are used in the experimental section:

[0143] tBuONa=sodium tert-butoxide;

[0144] DMF = dimethylformamide;

[0145] EtOAc = ethyl acetate;

[0146] EtOH = ethanol;

[0147] Et 3 N=triethylamine;

[0148] LDA = lithium diisopropylamide;

[0149] MeOH=methanol;

[0150] Me 2 SO = dimethyl sulfoxide;

[0151] RT = room temperature, 20-25°C;

[0152] TFA = trifluoroacetic acid;

[0153] THF = tetrahydrofuran;

[0154] TBME = ...

Embodiment 1 and 2

[0203] (9R)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo [3.2.1] Oct-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine -2-amine

[0204] with

[0205] (9S)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo [3.2.1] Oct-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine -2-amine

[0206]

[0207] Using intermediate (3.1)(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-amine with compound 2-bromo- 9-(3-Chloro-5-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine The general procedure of the Buchwald coupling between (2), followed by chiral HPLC separation of the enantiomers, prepared 13 mg of (9R)-9-(3-chloro-5-fluoro-phenyl)-N- [(1S,5R,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl]-6,7,8,9-tetra Hydrogen-5H-[1,2,4]triazolo[1,5-a]azepine -2-Amine as a white solid (MS(ES+) m / z: 482.2[(M+H) + ]), and 13 mg of (9S)-9-(3-chloro-5-fluoro-pheny...

Embodiment 3 and 4

[0209] (9R)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methoxypyridazin-4-yl)-3-aza Bicyclo[3.2.1]oct-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine -2-amine

[0210] with

[0211] (9S)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methoxypyridazin-4-yl)-3-aza Bicyclo[3.2.1]oct-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine -2-amine

[0212]

[0213] Using intermediate (3.2)(1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]oct-8-amine with compound 2- Bromo-9-(3-chloro-5-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine The general procedure of the Buchwald coupling between (2), followed by chiral HPLC separation of the enantiomers, prepared 33 mg of (9R)-9-(3-chloro-5-fluoro-phenyl)-N- [(1S,5R,8S)-3-(6-Methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl]-6,7,8,9 -Tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine -2-Amine as a white solid (MS(ES+) m / z: 498.3[(M+H) + ]), and 32 mg of (9S)-9-(3-chloro-5-fluoro-phenyl...

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Abstract

The present invention relates to a compound of formula (I) wherein Ar is (II) or (III); R is CH3or OCH3; or a pharmaceutically acceptable acid addition salt or a corresponding enantiomer thereof. Thecompounds are modulators of gamma-secretase (A[BETA)42) and may be useful for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome.

Description

[0001] field of invention [0002] The present invention relates to pyrimidine derivatives useful as gamma-secretase modulators, their preparation, pharmaceutical compositions comprising said compounds and their use as medicaments for the treatment of brain cells associated with beta-amyloid Deposition-related diseases in the brain, such as Alzheimer's disease, cerebral amyloid angiopathy, Dutch type hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D ), multi-infarct dementia, dementia pugilistica and Down syndrome. Background technique [0003] Alzheimer's disease (AD) is the most common cause of senile dementia. Pathologically, AD is characterized by the deposition of amyloid in extracellular plaques and intracellular neurofibrillary tangles in the brain. Amyloid plaques are mainly composed of amyloid peptides (Aβ peptides), which are derived from β-amyloid precursor protein (APP) through a series of proteolytic cleavage steps. Several forms of APP have b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/55A61P25/28
CPCC07D487/04A61P25/28C07D519/00
Inventor 哈萨内·拉特尼
Owner F HOFFMANN LA ROCHE & CO AG
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