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40H-GTS-21 compounds, preparation method and application thereof

A 4OH-GTS-21, 1.4OH-GTS-21 technology, applied in the field of compound drugs, can solve the problems of limited application and low blood-brain barrier

Inactive Publication Date: 2011-11-23
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This shows that although 4OH-GTS-21 has a strong partial agonistic activity on human α7 receptors, its ability to penetrate the blood-brain barrier (BBB) ​​is extremely low (J.Pharm.Pharmacol.1996, 48, 136-146; J .Neurochem.1993, 60, 793-803.), thus limiting its clinical application

Method used

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  • 40H-GTS-21 compounds, preparation method and application thereof
  • 40H-GTS-21 compounds, preparation method and application thereof
  • 40H-GTS-21 compounds, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1, preparing the 4OH-GTS-21 compound shown in the general formula, where R1 = difluoromethoxy, R3 = H, and X = O, the compound is named Q4. The preparation method is as follows:

[0033]

[0034] Synthesis of Intermediate 2:

[0035] In 500mL eggplant-shaped bottle, add 2,4-dihydroxybenzaldehyde (10g, 72.4mmol), K 2 CO 3 (12g, 86.9mmol), acetone (200mL) and a catalytic amount of tetrabutylammonium iodide (2.6g, 7.2mmol), added benzyl bromide (8.64mL, 72.4mmol) at room temperature, heated to reflux for 2h, followed by TLC process, remove potassium carbonate by filtration after the reaction, concentrate under reduced pressure, dilute the residue with dichloromethane (600ml), wash with water (100ml×2), combine the organic phases and dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Compound 2 (13.4g, 64.8%) was obtained by analysis. 1 H NMR (CDCl 3 , 600MHz) δ=11.48(s, 1H, OH), 9.72(s, 1H, CHO, 7.45-7.41(m, 5H, ...

Embodiment 2

[0043] Example 2, preparation of the following general formula 4OH-GTS-21 compound, wherein R1 = methoxy, X = O, R3 includes 1,2-trans-D-glucopyranosyl, 1,2-trans- D-xylopyranosyl, 1,2-trans-D-galactopyranosyl:

[0044]

[0045] Synthesis of intermediates 12-14:

[0046] Dissolve 0.41 mmol of compound 9 (or 10, or 11) and compound 8 (100 mg, 0.34 mmol) in CHCl 3 (10mL) and H 2 In the mixed solvent of O (10mL), add K 2 CO 3 (117.3mg, 0.85mmol) and tetrabutylammonium bromide (10.9mg, 0.03mmol) were stirred at 50°C for 5h. TLC detects the reaction progress, after the reaction finishes, add cold water (10mL) to dilute, with CHCl 3 (3×50mL) extraction, the combined organic phases were washed successively with 5% NaOH (2×50mL) and saturated brine (2×50mL), anhydrous NaOH 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (chloroform:methanol=80:1) to obtain the corresponding compound 12 ...

Embodiment 3

[0055] Example 3, preparation of 4OH-GTS-21 compounds represented by the general formula, wherein R1 = methoxy, R3 = 1,2-trans-D-glucopyranosyl, X includes OCH 2 CO(CH 2 ) 3 , OCH 2 CO(CH 2 ) 2 When O:

[0056]

[0057] Synthesis of intermediate 16

[0058] Compound 15 (5.0 g, 12.8 mmol) was weighed and dissolved in 40 mL of tetrahydrofuran, 2 mL of benzylamine was added and stirred at room temperature. After the reaction was detected by TLC, it was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluting with ethyl acetate:petroleum ether=1:4, to obtain 3.14 g of red liquid, with a yield of 64%.

[0059] Synthesis of Intermediate 17

[0060] Dissolve 16 (2.2 g, 5.7 mmol) in 30 mL of dry CH 2 Cl 20.43mL 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) was added dropwise under ice-cooling, then 4.6mL trichloroacetonitrile was slowly added, and stirred at room temperature for 2h. The end of the reaction was dete...

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PUM

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Abstract

The invention, belonging to the field of drug compound, relates to 40H-GTS-21 compounds of formula (I), a preparation method and applications of the compounds, wherein, R1, R2 and X in the formula (I) are as defined in the description. The 40H-GTS-21 compounds are prepared by using 40H-GTS-21 as a matrix and introducing different glycosyl units in the position of hydroxyl groups of benzene ring. Experiments prove that the compounds disclosed in the invention has obvious stimulation to the excitatory synapse in hippocampal CA1 region, can improve the capability of permeating blood brain barrier (BBB), the bioavailability and the target activity of the drug molecules, and can be further used for preparing anti-Alzheimer drugs.

Description

technical field [0001] The invention belongs to the field of compound drugs, and relates to 4OH-GTS-21 compounds, their preparation methods, and their application in pharmacy. Background technique [0002] Learning and memory are advanced functions of the brain. More and more studies have shown that central acetylcholine (ACh) is an important neurotransmitter involved in learning and memory, and nicotinic receptors (nAChR) play a role in cognitive function activities. played an important role. The hippocampus is an important brain area for learning and memory. The hippocampus belongs to the limbic system. The hippocampus-limbic system is rich in cholinergic fibers, choline-sensitive cells and receptors, which are closely related to learning and memory. In recent years, the connection between Alzheimer's disease (AD) and the neurobiochemical and morphological structure of the hippocampus has become a research hotspot in the prevention and treatment of AD. The prior art disc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/26C07H13/06C07D401/04A61K31/706A61K31/444A61P25/28
Inventor 李英霞张伟丁宁肖华玲
Owner FUDAN UNIV
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