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Styryl sulfone compounds, their preparation and their use as neuroprotective agents

A compound and alkyl technology, applied in the field of E-3, can solve the problems of not easily permeating the blood-brain barrier and fast metabolism

Active Publication Date: 2017-11-21
HUAXIASHENGSHENG PHARMA BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In view of the shortcomings of caffeic acid phenethyl ester that is not easy to pass through the blood-brain barrier and has a fast metabolism in the body, we modified its structure to make the new compound easier to pass through the blood-brain barrier and have stronger stability, thereby improving neuroprotective activity

Method used

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  • Styryl sulfone compounds, their preparation and their use as neuroprotective agents
  • Styryl sulfone compounds, their preparation and their use as neuroprotective agents
  • Styryl sulfone compounds, their preparation and their use as neuroprotective agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: Preparation of E-2-(3,4-dihydroxy)styrylbenzyl sulfone (3a)

[0059] Step 1, the preparation of 2-benzylthioacetic acid (1a)

[0060]

[0061] Thioglycolic acid (0.69ml, 10mmol) was dissolved in a reaction flask filled with 15ml of methanol, NaOH (0.8g, 20mmol) in methanol (10ml) was added dropwise, followed by benzyl bromide (1.19ml, 10mmol) dropwise, Stir at room temperature for 6 hours, TLC detected that the reaction was complete, spin the solvent under reduced pressure, add a small amount of water, neutralize with 1N hydrochloric acid to pH 7, extract with ethyl acetate, wash the combined ester layer with saturated brine, and dry over anhydrous sodium sulfate. Separation and purification by silica gel column (petroleum ether / ethyl acetate elution) gave white solid 1a, 1.7 g, yield 93.4%, m.p.62-63°C.

[0062] 1 H NMR (400MHz, DMSO-d 6 )δ=12.61(s, 1H, COOH), 7.24-7.35(m, 5H, ArH), 3.81(s, 2H, SCH 2 COOH), 3.12(s, 2H, ArCH 2 S).

[0063] Step 2,...

Embodiment 2

[0073] Example 2: Preparation of E-2-(3,4-diacetoxy) styrylbenzyl sulfone (4a)

[0074]

[0075] Compound E-2-(3,4-dihydroxy)styrylbenzyl sulfone (0.19g, 0.66mmol) was dissolved in acetic anhydride (10ml), anhydrous pyridine (0.11ml, 1.34mmol) was added, and the reaction was stirred After 5 minutes, TLC detected that the reaction was complete, poured the reaction solution into ice water and stirred, extracted with ethyl acetate, washed the ester layer with saturated brine, dried over anhydrous sodium sulfate, separated and purified with silica gel column (petroleum ether / ethyl acetate elution) A white cotton-like solid 4a was obtained, 220mg, 89.8% yield, m.p.163-164°C.

[0076] 1 H NMR (400MHz, CDCl 3 ) δ=7.24-7.41 (m, 9H, ArH, ArCH=CHSO 2 ), 6.66 (d, J=15.2Hz, 1H, ArCH=CHSO 2 ), 4.32 (s, 2H, ArCH 2 SO 2 ), 2.33 (s, 3H, p-ArOCOCH 3 ), 2.32 (s, 3H, m-ArOCOCH 3 ).

[0077] 13 C NMR (100MHz, CDCl 3 )δ=167.98, 167.88, 144.36, 143.66, 142.52, 130.93, 129.04, 128.97, ...

Embodiment 3

[0079] Example 3: Preparation of E-2-(3,4-dihydroxy)styryl-4-chlorobenzyl sulfone (3b)

[0080] Step 1, the preparation of 2-(4-chloro)benzylthioacetic acid (1b)

[0081]

[0082] Using the synthesis method of compound 1a above, 4-chlorobenzyl bromide was used as a reactant to obtain white solid 1d with a yield of 85.5%, m.p.51-52°C.

[0083] Step 2, the preparation of 2-(4-chloro)benzylsulfonylacetic acid (2b)

[0084]

[0085] Using the synthesis method of compound 2a above, 2-(4-chloro)benzylthioacetic acid was used as a reactant to obtain white solid 2d with a yield of 82.1%, m.p.144-145°C.

[0086] Step 3: Preparation of E-2-(3,4-dihydroxy)styryl-4-chlorobenzyl sulfone (3b)

[0087]

[0088] Using the synthesis method of compound 3a above, 2-(4-chloro)benzylsulfonylacetic acid was used as a reactant to obtain white solid 3b with a yield of 71.1%, m.p.166-167°C.

[0089] 1 H NMR (400MHz, DMSO-d 6 )δ=9.75(s, 1H, p-ArOH), 9.23(s, 1H, m-ArOH), 6.76-7.45(m, 9H, A...

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Abstract

This application involves taking caffeic acid phenethyl ester (CAPE) extracted from natural propolis and having neuroprotective activity as a precursor, and designing a class of sulfone groups instead of ester groups according to the theory of bioelectronic isosterism and hydrogen bonding. The new molecule, its structure is shown in general formula I, and the definition of each group in the formula is as described in the claims. At the same time, it also involves the evaluation of the compound's antioxidant capacity in vitro, the evaluation of neuroprotective activity at the cellular level, and the evaluation of the ability to penetrate the blood-brain barrier. The activity evaluation results showed that the synthesized new compound had enhanced neuroprotective activity and could pass through the blood-brain barrier more easily, thus becoming a new type of neuroprotective agent for treating neurodegenerative diseases.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a new type of E-3,4-disubstituted E-3,4-disubstituted compound obtained by structural modification from natural propolis extracted from natural propolis and having neuroprotective activity as a raw material. Styrene sulfone compounds, processes for their preparation and use as medicines. Background technique [0002] Neurodegenerative diseases are a class of chronic, progressive neurological diseases. Such diseases mainly include Alzheimer's disease, Parkinson's disease, Huntington's chorea, different types of spinocerebellar ataxia, dentate nucleus rubrum pallidus subthalamic nucleus atrophy and amyotrophic lateral sclerosis, etc. In recent years, the number of neurodegenerative diseases has been increasing. For example, the prevalence of Alzheimer's disease in my country is 2% to 5%, and the annual new incidence is 1%. Studies hav...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C317/18C07C315/04C07C317/44A61K31/10A61K31/277A61P25/00A61P25/02A61P25/08A61P25/16A61P25/28A61P25/14A61P9/10
Inventor 吕新安刘俊义周受辛
Owner HUAXIASHENGSHENG PHARMA BEIJING CO LTD
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