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Saccharide Dendritic Cluster Compounds as Inhibitors of Bace-1

a dendritic cluster and bace-1 technology, applied in the field of dendritic compounds, can solve the problems of difficult synthesis of long linear heparan sulfate mimics, and difficulty in synthesis, and achieve the effect of reducing the amount of a1-40

Inactive Publication Date: 2017-06-01
VICTORIA LINK LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a new version of compounds that can cluster together and enhance their interactions, using multiple copies of a specific fragment. These compounds also showed activity in a brain slice assay, which can help with drug discovery. Using brain slices instead of animals can save time and money, and also make it easier to control the environment and study the effects of different compounds. Overall, this patent aims to improve the effectiveness and efficiency of drug discovery.

Problems solved by technology

However, the anti-coagulant properties of heparin need to be attenuated if it is to be used for other pharmaceutical applications otherwise possible side effects, such as internal bleeding and impaired blood clotting, can be problematic.
However, long linear heparan sulfate mimics can be complex and expensive to synthesise.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compounds

Example 1.1

Synthesis of tetra-succinimidyl ester

[0165]

[0166]Preparation of 1′

[0167]Tetranitrile precursor (Ref.1, Hukkämaki, J.; Pakkanen, T. T. Journal of Molecular Catalysis A: Chemical 2001, 174, 205-211) is prepared via Michael-type addition of acrylonitrile to pentaerythritol. Acidic hydrolysis of tetranitrile (Ref. 2, Newcombe, G. R.; Mishra, A; Moorfield, C. N. J. Org. Chem. 2002, 67, 3957-3960) furnishes the tetraacid. Tetraacid (1.0 g, 2.35 mmol) is dissolved in dry DMF (15 mL). N-Hydroxysuccinimide (1.62 g, 14.14 mmol) and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC, 2.71 g, 14.14 mmol) are added to the reaction mixture at room temperature and stirring continued for 24 hrs. The mixture is diluted with DCM and washed with water, then with diluted HCl and water, dried over magnesium sulfate and concentrated. The residue is purified by flash chromatography on silica gel eluting with EtOAc followed by EtOAc:MeOH, 19:1→9:1→7:1→4:1 to g...

example 1.2

Synthesis of di-succinimidyl ester

[0183]

[0184]Preparation of 14′

[0185]3,6,9-Trioxaundecanedioic acid (500 mg, 2.25 mmol) is dissolved in dry DMF (10 mL). N-Hydroxysuccinimide (785 mg, 6.75 mmol, 3 eq.), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC, 1.32 g, 6.75 mmol, 3 eq.) and N,N-diisopropylethylamine (2.38 mL, 13.5 mmol) followed by benzyl 8-aminooctanate (1.68 g, 6.75 mmol, 3 eq.) are added to the reaction mixture at room temperature and stirring continued for 4 hrs. The mixture is diluted with DCM and washed with water, then with diluted HCl and water, dried over magnesium sulfate and concentrated. The residue is dissolved in hot EtOAc, the crystals are filtered off and discharged. The mother liquor is concentrated and the residue is purified by flash chromatography on silica gel eluting with Chloroform:EtOAc:MeOH, 5:2:0.3 to afford the di-benzyl ester (10, 1.1 g, 1.61 mmol, 71%). 13C-NMR (125 MHz, CDCl3) δ 173.4, 169.9, 136.1, 128.4, 128.3, 128.1, 127.8, 12...

example 1.3

Synthesis of Dendritic Cluster Compounds

[0190]Preparation of 6e (Scheme 8)

[0191]Thioglycoside donor (WO 2012 / 121617) (1 g, 2.2 mmol) and Cbz-protected hexa-amino alcohol (Chipowsky, S.; Lee, Y. C. Carb. Res., 1973, 31, 339-346) (1 g, 4.3 mmol, 2.0 eq) are dissolved in anhydrous dichloromethane (20 mL) and cooled to −15° C. and powdered molecular sieves (4 Å) are added. After 10 min N-iodosuccinimide (836 mg, 3.7 mmol, 1.7 eq) and silver trifluoromethanesulfonate (281 mg, 1 mmol, 0.5 eq) are added. The reaction mixture is allowed to warm up to room temperature over 1 h. The mixture is diluted with ethyl acetate and filtered through celite. The filtrate is washed with a 1:1 mixture of saturated aq. sodium bicarbonate and aq. thiosulfate (30%), washed with saturated aq. sodium chloride, dried over magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (EtOAc:petroleum ether, 1:2) to furnish the glycoside 6e as a syrup (1.35 g, 2.0 mmol, 93%), TLC (EtOA...

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Abstract

The invention relates to dendritic compounds, the use of these compounds as pharmaceuticals, pharmaceutical compositions containing the compounds, processes for preparing the compounds, and methods of treating diseases or conditions in which it is desirable to inhibit β-secretase.

Description

TECHNICAL FIELD[0001]This invention relates generally to dendritic compounds, the use of these compounds as pharmaceuticals, pharmaceutical compositions containing the compounds, processes for preparing the compounds, and methods of treating diseases or conditions in which it is desirable to inhibit β-secretase.BACKGROUND[0002]As populations age neurodegenerative disorders, such as Alzheimer's disease, become more prevalent. Alzheimer's disease is a common form of dementia, and is progressive and irreversible. The pathogenesis of the disease is thought to involve cerebral deposits of aggregated amyloid β-peptide. The first (and rate-limiting) step in the generation of amyloid β-peptide is cleavage of amyloid precursor protein by β-secretase (β-site amyloid precursor protein cleaving enzyme-1, β-secretase-1, hereinafter “BACE-1”). This makes BACE-1 an attractive target for new Alzheimer's therapies.[0003]Heparan sulfate (HS) and its highly sulfated analogue heparin have been shown to...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H15/08C07H15/04
CPCC07H15/08C07H15/04A61P25/00A61P25/28A61P43/00
Inventor TYLER, PETER CHARLESZUBKOVA, OLGA VLADIMIROVNATURNBULL, JEREMY E.
Owner VICTORIA LINK LTD
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