Inositol and trehalose derivatives and pharmaceutical compositions for treating neurodegenerative diseases comprising the same

a technology which is applied in the field of inositol and trehalose derivatives, can solve the problems of inability to cure the disease, inositol is known to have difficulty in passing through the blood-brain barrier (bbb), and the agent cannot cure the disease, so as to improve the permeability of the bbb

Inactive Publication Date: 2011-09-15
POSTECH ACAD IND FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]Accordingly, it is the object of the present invention to provide inositol derivatives, trehalose derivatives, and monosaccharide derivatives, which have improved BBB permeability.

Problems solved by technology

Such aggregated peptides induce cell damage and apoptosis, resulting in neurodegenerative diseases.
The presently available methods of symptomatic therapy include the use of acetylcholinesterase inhibitors and NMDA acceptor antagonists, but such agents do not cure the disease.
However, inositol is known to have difficulty in passing through the blood-brain barrier (BBB), and the amount thereof transferred to the nervous system of the brain is insignificantly small (L. M. Lewin et al., Biochem.
No therapeutically effective agent for Huntington's disease has been developed.
However, it is also known that trehalose cannot pass through the BBB to reach the brain (www.huntingtonproject.org / portals / 0 / trehalose).

Method used

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  • Inositol and trehalose derivatives and pharmaceutical compositions for treating neurodegenerative diseases comprising the same
  • Inositol and trehalose derivatives and pharmaceutical compositions for treating neurodegenerative diseases comprising the same
  • Inositol and trehalose derivatives and pharmaceutical compositions for treating neurodegenerative diseases comprising the same

Examples

Experimental program
Comparison scheme
Effect test

example

Preparative Example 1

Preparation of Scyllo-Inositol Having Carbobenzoxy (Cbz)-Protected Linker

Introduction of Acetonide Protecting Group

[0074]

[0075]1-O-Bz-2,3,4,5,6-pentahydroxyl-scyllo-inositol (Korean Patent No. 578732; 9.96 g, 35.05 mmol) was dissolved in N,N-dimethylformamide (110 ml), and para-toluene sulfonic acid (3.33 g) was added dropwise thereto to obtain a mixture. 2-Methoxypropene (33.5 ml) was added to the mixture and the mixture was stirred at room temperature for 16 hours.

[0076]After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the extract was washed several times with saturated aqueous NaHCO3 and water. The organic layer thus obtained was dried over Na2SO4, concentrated under a reduced pressure, and then purified by column chromatography (ethyl acetate:hexane=1:2) to obtain the title compound having two isopropylidene groups introduced to the backbone thereof, as a white foamy solid (6.03 g).

[0077]1H NMR (CDCl3): δ 1.44-...

example 1

Preparation of Scyllo-Inositol Derivative Having Ten Guanidine Groups

[0135] Introduction of Side Chain to scyllo-Inositol by Acylation

[0136]The compound having five OH groups obtained in Preparative Example (34 mg, 0.079 mmol), a branched linker having two guanidine groups (Korean Patent No. 699279; 464 mg, 0.636 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (151 mg, 0.79 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (2 ml), and stirred at room temperature for two days.

[0137]After the completion of the reaction, the reaction mixture was washed several times with water and aqueous NaHCO3. The organic layer thus obtained was dried over Na2SO4, concentrated under a reduced pressure, and then purified by column chromatography (dichloromethane:methanol=10:1) to obtain the title compound having five acyl side chains, as a sticky solid (228 mg).

[0138]1H NMR (CDCl3): δ 1.25-1.69 (m, 236H), 2.16-2.25 (m, 12H), 2.30-2.46 (m, 30H), 3.14 (m,...

example 2

Preparation of Scyllo-Inositol Derivative Having Five Guanidine Groups

[0148] Introduction of Side Chain to scyllo-Inositol by Acylation

[0149]The compound having five OH groups obtained in Preparative Example (85.8 mg, 0.2 mmol), a linear linker having a single guanidine group (600 mg, 1.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (383.42 mg, 2 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide (2 ml) and stirred at room temperature for two days.

[0150]After the completion of the reaction, the reaction mixture was washed several times with water and aqueous NaHCO3. The organic layer thus obtained was dried over Na2SO4, concentrated under a reduced pressure, and then purified by column chromatography (dichloromethane:methanol=10:1) to obtain the title compound having five acyl side chains, as a sticky solid (402 mg).

[0151]1H NMR (CDCl3, 500 MHz): δ 1.28-1.38 (m, 12H), 1.47-1.62 (m, 114H), 2.22-2.42 (m, 12H), 3.18-3.21 (m, 2H), 3.37-3...

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Abstract

The invented inositol and trehalose derivatives, prepared by introducing multiple units of the guanidine group to the backbone molecules, show excellent blood-brain barrier permeability, and accordingly, it can be easily transported to the brain tissues and utilized for the treatment of neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.

Description

FIELD OF THE INVENTION[0001]The present invention relates to inositol and trehalose derivatives having excellent blood-brain barrier permeability, which are prepared by introducing several guanidine groups to the backbone of inositol and trehalose, and to pharmaceutical compositions for treating neurodegenerative diseases comprising the same.BACKGROUND OF THE INVENTION[0002]Approximately 25 million people worldwide are currently suffering from Alzheimer's disease, and that number is expected to double every five years. Studies of the brain tissue of Alzheimer's disease patients have revealed the presence of aggregated peptides, particularly senile plaques and neurofibrillary tangles, which have been reported to be formed from mutated beta-amyloids and Tau peptides (M. Goedert, M. G Spillantini, Science, 314: 777-784 (2006)). Such aggregated peptides induce cell damage and apoptosis, resulting in neurodegenerative diseases. The presently available methods of symptomatic therapy inclu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H15/02C07C279/12
CPCC07C279/12C07C279/14C07H3/04C07H15/04C07C2101/14A61P25/00A61P25/14A61P25/28A61K31/155A61K31/351C07C279/08C07H3/02
Inventor CHUNG, SUNG-KEELEE, WOO SIRLKIM, BORAMIM, JUNGKYUNGHOSH, SUBHASH C.
Owner POSTECH ACAD IND FOUND
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