Benzodiazepinone beta -amyloid inhibitors: arylacetamidoalanyl derivatives

a technology of arylacetamidoalanyl and benzodiazepine, which is applied in the direction of biocide, peptide/protein ingredient, peptide/protein ingredient, etc., can solve the problems of increased alzheimer's disease cost, increased risk of adverse effects, so as to achieve effective anti-amyloid

Inactive Publication Date: 2002-02-21
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0052] Therefore, the compounds of Formula I or pharmaceutical compositions thereof are useful in the treatment of disorders associated with the aberrant extracellular deposition of amyloid, and (as formulated) will be effective to alter one or more clinical indicia of disease activity in a patient in need thereof.

Problems solved by technology

The cost of Alzheimer's Disease is enormous (in the U.S., greater than $100 billion annually) and includes the suffering of the patients, the suffering of families, and the lost productivity of patients and caregivers.
There is currently no effective treatment.
.beta.-AP and related fragments have been shown to be toxic for PC-12 cell lines and primary cultures of neurons, as well as causing neuronal degeneration with accompanying amnesia in rodents.
Currently, however, it is unclear which classes of proteinases or inhibitors thereof that would be effective in treating AD.

Method used

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  • Benzodiazepinone beta -amyloid inhibitors: arylacetamidoalanyl derivatives
  • Benzodiazepinone beta -amyloid inhibitors: arylacetamidoalanyl derivatives
  • Benzodiazepinone beta -amyloid inhibitors: arylacetamidoalanyl derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

1-Methyl-2-(1-methylethyl)hydrazine (VII)

[0064] a) To the stirred solution of N-methyl hydrazine (25.00 g, 543.47 mmol ) in THF (600 ml) at -10.degree. C. was added di-tert-butyl dicarbonate (124.5 g, 167 mmol). The resulting mixture was stirred for 1 h and diluted with ethyl acetate (400 ml), further washed with water (1 L), brine (600 ml) and dried over magnesium sulfate. Filtration and concentration in vacuo produced 70 g of crude 1-methylhydrazinecarboxylic acid, 1,1 -dimethylethyl ester.

[0065] b) To the solution of above compound (70 g, 479.45 mmol) in ether (1 L) was added acetone (46.34 mL), 3 mL of acetic acid and 500 mg of sodium acetate. The solution was stirred further for an hour and was then concentrated. The resulting residue was diluted with ethyl acetate (800 mL) and washed with water (700 mL), brine (700 mL), dried over magnesium sulfate, filtrated and concentrated to afford 80 g of 2-propanone, methyl-(1,1-dimethylethoxycarbonyl)hydrazone.

[0066] c) To lithium alumi...

example 2

2,3,4,5-Tetrahydro-3-methyl-2-(1-methylethyl)-1 H-2,3-benzodiazepin-1,4-di-one (VIA)

[0068] To the solution of homophthalic anhydride (6.80 g, 41.9 mmol) in 70 mL of glacial acetic acid was added 1-methyl-2-(1-methylethyl)hydrazine, dihydrochloride (6.75 g, 41.9 mmol) in 35 mL of pyridine (Rosen, et al., J. Heterocyclic Chem., 1969, 6, 9-12). The solution was refluxed for 12 h, cooled, diluted with water (300 mL), and extracted with chloroform (3.times.400 mL). The chloroform extract was washed with 10% hydrochloric acid (600 mL) and 5% sodium bicarbonate (600 mL) , dried over magnesium sulfate and concentrated to dryness. The mixture was purified by silica gel chromatography (hexane / ethyl acetate, 3 / 1) to afford 2,3,4,5-tetrahydro-3-methyl-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-di-one (5 g, 51%).

example 3

5-(R,S)-Azido-2,3,4,5-tetrahydro-3-methyl-2-(1-methylethyl)-1 H-2,3-benzodiazepin-1,4-dione (VA)

[0069] Potassium bis(trimethylsilyl)amide (6.54 g, 32.8 mmol) was added to a -78.degree. C. solution of above compound (3.8 g, 16.3 mmol) in THF (200 mL) followed by the addition of trisyl azide (5.49 g, 17.7 mmol) solution in THF (5 mL) at -78.degree. C. via cannula after 5 minutes (Evans, et al., J. Amer. Chem. Soc. 1990, 112, 4011-4030; Butcher, et al., Tetrahedron Lett., 1996, 37 (37), 6685-6688). The reaction mixture was further stirred for another 5 min at -78.degree. C., and 4.5 mL of glacial acetic acid was added and the reaction mixture was warmed to 30.degree. C. over a period of 2 h. Aqueous sodium bicarbonate (200 mL) was added and the mixture was extracted with dichloromethane (3.times.300 mL). The organic layer was washed with brine (600 mL) dried over magnesium sulfate and concentrated. The resulting solid was purified on silica gel column to afford 5-azido-2,3,4,5-tetrahyd...

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Abstract

There is provided a series of arylacetamidoalanyl derivatives of benzodiazepinones of Formula I wherein R1 through R7 and n are defined herein, which are inhibitors of beta-amyloid peptide (beta-AP) production and are useful in the treatment of Alzheimer's Disease and other conditions characterized by aberrant extract cellular deposition of amyloid.

Description

[0001] This non-provisional application claims priority from provisional application U.S. Ser. No. 60 / 216,391 filed Jul. 6, 2000.[0002] This invention provides novel benzodiazepinone compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with arylacetamidoalanyl derivatives of 2,3-benzodiazepin-4-ones. These compounds uniquely inhibit .beta.-amyloid peptide (.beta.-AP) production, thereby acting to prevent the accumulation of amyloid protein deposits in the brain. More particularly, the present invention relates to the treatment of Alzheimer's Disease (AD).[0003] Alzheimer's Disease is a progressive, neurodegenerative disorder characterized by memory impairment and cognitive dysfunction. AD is characterized pathologically by the accumulation of senile (neuritic) plaques, neurofibrillary tangles, amyloid deposition in neural tissues and vessels, synaptic loss, and neuronal death. It is the mos...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00C07K5/06C07K5/065C07K5/08C07K5/087
CPCA61K38/00C07K5/06078C07K5/06191C07K5/0812C07K5/0827
Inventor CHATURVEDULA, PRASAD V.YEOLA, SURESHVIG, SHIKHA
Owner BRISTOL MYERS SQUIBB CO
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