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New compounds 834

a new type of compound and compound technology, applied in the field of new compounds 834, can solve the problems of increasing the prevalence of alzheimer's disease in this population, increasing the difficulty of drug preparation, etc., and achieve the effect of improving potency and beneficial properties

Inactive Publication Date: 2008-11-20
ASTRAZENECA AB +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]The compounds of the present invention show beneficial properties compared to the potential inhibitors known in the art, e.g. improved potency.

Problems solved by technology

The likelihood of developing Alzheimer's disease increases with age, and as the aging population of the developed world increases, this disease becomes a greater and greater problem.
This is thought to be due to the extra copy of the APP gene found in these patients, which leads to overexpression of APP and therefore to increased levels of APPβ causing the high prevalence of Alzheimer's disease seen in this population.

Method used

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  • New compounds 834
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Examples

Experimental program
Comparison scheme
Effect test

example 1

3-(3-Bromobenzoyl)pyridine-2-carbonitrile

[0245]

[0246]A suspension of highly active zinc (Rieke zinc) in THF (100 mg / mL, 12.7 mL, 19.4 mmol) was added via a syringe to a solution of 3-bromo-2-cyanopyridine (1.189 g, 6.497 mmol) in anhydrous THF (20 mL) under an atmosphere of argon. The mixture was stirred for four h at room temperature and then at 50° C. for 15 min. The remaining zinc powder was allowed to settle at the bottom of the flask overnight at −20° C. The top solution was transferred to another flask and cooled to −20° C. To this was added a 1 M solution of copper cyanide di(lithium bromide) complex in THF (6.82 mL) and the resulting mixture was stirred for 5 min at −20° C. and for 35 min at 0° C. and then cooled to −30° C. prior to the addition of 3-bromobenzoyl chloride (1.78 g, 8.12 mmol). The mixture was stirred for 6 h during which time the temperature went from −30° C. to 0° C. The reaction was quenched by the addition of saturated ammonium chloride solution and ethyl ...

example 2

N-[(1E)-(3-Bromophenyl)(2-cyanopyridin-3-yl)methylenel-2-methylpropane-2-sulfinamide

[0247]

[0248]Titanium(IV)ethoxide (1 M solution in THF, 18.7 mL) was added to a solution of 3-(3-bromobenzoyl)pyridine-2-carbonitrile (2.680 g, 9.334 mmol) and tert-butylsulfinamide (1.244 g, 10.27 mmol) in anhydrous THF (10mL) under an atmosphere of argon. The mixture was heated at 50° C. for 70 h. After cooling to room temperature the mixture was diluted with methanol (20 mL) and 100 drops of water was added. The resulting mixture was allowed to stand for about 1 h and then filtered through a pad of sodium sulfate. The filter cake was taken up in saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The mixture was stirred over night, the phases were separated and the aqueous phase was extracted with dichloromethane. The extracts were combined with the filtrate from above, dried over sodium sulfate and evaporated. Purification by column chromatography using a gradient of increasi...

example 3

5-(3-Bromophenyl)-5-(4-methoxyphenyl)-5H-pyrrolo[3,4-blpyridin-7-amine

[0249]

[0250]Butyllithium (2.5 M in hexanes, 0.947 mL) was added dropwise to a solution of 4-bromoanisole (483 mg, 2.58 mmol) in anhydrous THF at −78° C. under an atmosphere of argon. The mixture was stirred at that temperature for 30 min and then a solution of N-[(1E)-(3-bromophenyl)(2-cyanopyridin-3-yl)methylene]-2-methypropane-2-sulfinamide (Example 2, 840 mg, 2.15 mmol) in THF (10 mL) was added dropwise. Stirring was continued for 3 h at −78° C., and then for 1 h at −25° C. The reaction was quenched by the addition of water, the mixture was diluted with ethyl acetate and washed with water, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (20 mL) and to this was added 2 M hydrochloric acid in diethyl ether (2.5 mL). The mixture was stirred at room temperature for 22 h and then concentrated. The residue was partitioned between dichloromethane and saturated aqueous sodium hydrog...

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PUM

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Abstract

This invention relates to novel compounds having the structural formula I below:and to their pharmaceutically acceptable salt, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. provisional Ser. No. 60 / 948,007 filed Jul. 5, 2007, and to U.S. provisional Ser. No. 60 / 938,005 filed May 15, 2007, each of which is incorporated herein by reference in its entirety.[0002]The present invention relates to novel compounds, their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and / or prevention of Aβ-related pathologies such as Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI (“mild cognitive impairment”), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senil...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/506C07D471/04C12N9/99A61P25/16A61P25/28A61K31/437
CPCC07D471/04A61P25/00A61P25/16A61P25/28A61P43/00A61P9/00A61P9/10A61K31/437
Inventor CHESSARI, GIANNICONGREVE, MILES STUARTHOLENZ, JORGMURRAY, CHRISTOPHERPATEL, SAHILRAKOS, LASZLOROTTICCI, DIDIER
Owner ASTRAZENECA AB
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