CN109761815A - A kind of compound and preparation method based on resveratrol treatment the nervous system disease - Google Patents
A kind of compound and preparation method based on resveratrol treatment the nervous system disease Download PDFInfo
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- CN109761815A CN109761815A CN201910140613.8A CN201910140613A CN109761815A CN 109761815 A CN109761815 A CN 109761815A CN 201910140613 A CN201910140613 A CN 201910140613A CN 109761815 A CN109761815 A CN 109761815A
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Abstract
The invention belongs to hydroxy compounds technical fields, a kind of compound and preparation method thereof based on resveratrol treatment the nervous system disease is disclosed, the compound based on resveratrol treatment the nervous system disease is compound and its pharmaceutically acceptable salt with Formulas I structure.It is reacted using intermediate II and generates intermediate III；Intermediate III and intermediate IV add water quenching reaction, are extracted by room temperature reaction, wash, and purify finally obtained compound.Resveratrol belongs to polyphenol compound, has a variety of pharmacological activity, including antitumor, reduces platelet aggregation, prevents and treats atherosclerosis, cardiovascular and cerebrovascular disease etc..
Description
Technical field
The invention belongs to hydroxy compounds technical fields, more particularly to a kind of resveratrol that is based on to treat the nervous system disease
Compound and preparation method.
Background technique
Currently, the prior art commonly used in the trade is such that
Epidemiological study discovery, a large amount of intake fruits and vegetables can also reduce the risk of Ischemic Stroke.Early stage closes
Heart disease and cancer are focused primarily upon in the wholesome research of polyphenol.In recent years, whether can pass through blood brain about polyphenol
Barrier action is to brain and plays prevention effect to neurodegenerative disease and gets growing concern for.Initial research result is aobvious
Show, polyphenol compound has the function of improving aging nerve cell function, and can improve the inflammation caused by chronic alcoholism
Disease and oxidative damage.
Tea extraction main component is catechin, flavonols and procyanidine.Catechin mainly divides 4 kinds: epi-nutgall
Catechin and gallate (epigallocatechin-3-gallate, EGCG), epigallocatechin
(epigallocatechin, EGC), epicatechin (epicatechin, EC) and L-Epicatechin gallate
(epicatechin-3-gallate, ECG).Catechin has radicals scavenging, metal-chelating and anti-inflammatory activity, has an effect on
The signal path of cell death, growth and survival.Epidemiological study report, if people drink more than 5 cups of green tea daily, soldier
Middle disease incidence is lower.(middle cerebral arteryocclusion, MCAO) mould is occluded in preparation intraluminal middle cerebral artery occlusion in rats
7d, which takes orally green tea 100mg/kg or 300mg/kg, after type h and ischemic can improve the memory disorders of rat in water maze laboratory；Subtract
Small infarct；Improve malonaldehyde (malondialdehyde, MDA), glutathione (glutathione, GSH) and superoxides
Mutase (superoxide dismutase, SOD) activity；Same Hong etc. gives big for 3 weeks before preparing MCAO models in rats
The green-tea extract of mouse oral 0.5%, the results showed that green-tea extract reduces eicosanoid concentration, the level of hydrogen peroxide, rouge
Matter Peroxidation Product, 8-OhdG is formed and apoptosis cell.In vitro cell experiment shows that green tea can reduce glycosyloxy
Deprive the cell expansion and transmembrane potential difference of (oxygen and glucose deprivation, OGD) induction.It is continuous in rat
21d prepares MCAO ischaemic model after taking orally catechin 20mg/kg, as a result, it has been found that infarct size, falling tone can be obviously reduced
INOS, glial fibrillary acidic protein (glial fibrillary acidic protein, GFAP) and nuclear transcription factor-kappa B
The expression of (nuclear factor kappalight-chain-enhancer of activated B cells, NF- κ B),
Improve neurological deficit, protects nerve cell to anti-oxidation stress.3d and arteria carotis communis occlusion after rat MCAO
(common carotid arteryo c clus ion, CCAO) preceding 1d and rear 2d intraperitoneal injection EGCG 50mg/k g is showed
Mitochondria energy and citrate synthase activity are saved out.EGCG 50mg/k g is injected intraperitoneally immediately after preparing mouse MCAO model
It can reduce the active shape of infarct size, falling tone matrix metalloproteinase (matr i xmetallopeptidase 9, MMP9)
Formula and gelatinase activity.
EGb761 is the full standard items of ginkgo biloba p.e, which mainly contains two big compositions: in flavonoid glycoside and terpene
Ester.In vivo and in vitro studies have shown that EGb761 and its constituent show neuroprotection work in different ischemic model
With, and it is related to number of mechanisms.Rat is permanent and temporary cerebral ischemia model in, EGb761 show neuroprotection and
Promote neuron regeneration effect, reduces the damage of cognitive function.Preceding 10~14d, intraperitoneal injection silver are prepared in mouse MCAO model
Apricot leaf extract 10mg/kg shows to alleviate the death of hippocampus CA1 delayed neuronal, improves the neurobehavioral of test group of animals
Learn scoring；30min subcutaneous injection ginkalide A (50mg/kg) and ginkolide B (100mg/kg), are significantly reduced before preparing
Brain infarction area.These processing significantly inhibit the reduction of the area the CA1 COX-3mRNA as caused by ischemic, and mitochondria is prompted to take part in
Its protection mechanism.NV-31 is as a kind of ginkgolide derivatives, the 60min and after being successfully prepared before preparing mouse MCAO model
Intraperitoneal injection 10mg/kg and 20mg/kg is given immediately is significantly reduced infarct size.Same gerbil jird transient global cerebral ischemia mould
Oral Egb761 (37.5~150mg/kg) 15d before type preparation, the result similar with mouse and be in dose dependent as the result is shown,
Its mechanism of action may be anti-lipid peroxidation and nitric oxide production formation.
Turmeric, the rhizome powder of medicinal plant turmeric, its yellow derive from curcumin (1,7- bis- [4- hydroxyl -3- first
Phenyl] -1,6- heptadiene -3,5- diketone).One of most significant feature of curcumin be can Scavenger of ROS and nitrogen from
By base, inhibits the activation of NF- κ B and exogenous metabolism detoxification enzyme activity can be promoted, such as glutathione transferase and reduced coenzyme
The activity of II (nicotinamide adenine dinucleotidephosphate-oxidase, NADPH).Since these are anti-
Oxidation characteristic, curcumin can be used as the potential drug for the treatment of cerebral ischemia.Rat CCAO model is successfully prepared the rear abdominal cavity 30min
Curcumin 200mg/k g is injected, infarct size and edema volume, and the activity by reducing xanthine oxidase, rouge can be reduced
Matter peroxidating and the generation of superoxide radical and weaken damage caused by ischemia-reperfusion.And mouse intracranial hemotoncus
Intraperitoneal injection curcumin 150mg/kg can equally change after (intracerebral hemorrhage, ICH) model is successfully prepared
Kind mouse brain bleeding lesions and reduction brain tissue oedema；Alleviate neurological deficit.Turmeric, as food flavor and colorant
It is widely used, specific neuroprotection is also observed in rodent ischemia model, have exploitation at health care product
And the potentiality of nerve protection medicine.
Ischemic Stroke due to the cause of disease, the course of disease, obstructive position, degree of ischemia and combination system disease difference and cause to face
Bed variability is very big, so that clinical research needs more sample size to avoid the influence of Confounding Factor, and these variables exist
Available strict control in animal model.Experimental cerebral ischemia model is already used to simulation mankind's stroke, it is lacked in understanding
The pathomechanism of hemorrhagic cerebral injury plays an important role in terms of developing new therapeutic strategy.The therapeutic strategy of Ischemic Stroke
Two main aspects: thrombolysis and neuroprotection can be divided into.Currently, rt-PA (recombinant
Tissueplasminogen activator, rt-PA) it is unique acute ischemia for obtaining Food and Drug Adminstration of the US's approval
The therapeutic agent of property stroke, efficiency of thrombolysis are confirmed in Experimental animal model first.Although in animal model, perhaps
Drug shows neuroprotection, but then fails to show same effect into clinical Study on Transformation from animal, may
It is related that the application difference of the state or drug of authentic representative disease with animal and patient is unable to animal model.
Currently, stages alzheimer's disease (AD) is the most wide neurodegenerative disease of global implication.With social senilization's degree
Continuous intensification, stages alzheimer's disease patient populations rise rapidly.It is estimated that the whole world has more than 40,000,000 patients at present, and this
100,000,000 will likely be risen to when number is to the year two thousand fifty.Since the disease course of disease is very long, many patients need to receive additional nursing and day
The help often lived, it is estimated to exceed 1 trillion dollars in global bring financial burden at present.
" cerebral apoplexy " (cerebral stroke) is also known as " apoplexy ", " cerebrovascular accident " (cerebralvascular
Accident, CVA), it is a kind of acute cerebrovascular diseases.Wherein ischemic cerebrovascular disease accounts for 70%-80%, hemorrhagic cerebrovaseular
Disease accounts for 20%-30%.
Cerebral apoplexy is one of three big disease causes of the death in the world, rises to the first place of Proportional Death Rate in China, disability rate is
50%-75%, the death rate 25%；Chinese annual new cases are about 2,500,000, and dying of cerebrovascular disease is more than 1,500,000, is brought
Huge society and financial burden.
T-PA is uniquely to prove effective acute stages treated drug, but extreme early time window (3-4.5h) limits it extensively
Using；Collins et al. has counted 1026 kinds of neuroprotective agent results of study, has found that while that many cerebral apoplexy neuroprotective agents exist
Animal experiment stage shows good neuroprotection, but often finds that its curative effect does not comply with one's wishes in clinical test.
The new compound with neuroprotection of exploitation is had no at present, is used to prepare treatment cerebral apoplexy and other nerves
The drug of systemic disease.
In conclusion problem of the existing technology is:
(1) it has no the new compound with neuroprotection of exploitation, is used to prepare treatment cerebral apoplexy and other nerves
The drug of systemic disease.
(2) neuroprotective agent shows good neuroprotection in animal experiment stage, but past in clinical test
Toward discovery, its curative effect does not comply with one's wishes.
(3) the extreme early time window (3-4.5h) of t-PA limits its extensive use.
Summary of the invention
In view of the problems of the existing technology, the present invention provides a kind of based on resveratrol treatment the nervous system disease
Compound and preparation method.
The present invention is directed to develop the new compound with neuroprotection, it is used to prepare treatment cerebral apoplexy and other minds
Drug through systemic disease.
The invention is realized in this way a kind of compound based on resveratrol treatment the nervous system disease, for Formulas I
The compound and its pharmaceutically acceptable salt of structure.
Further, molecular formula I is resveratrol (R).
Further, with the compound and its pharmaceutically acceptable salt of Formulas I structure:
Further, with the compound and its pharmaceutically acceptable salt of Formulas I structure, preferred compound of formula I are as follows:
Further, pharmaceutically acceptable salt refers to: compound and inorganic acid, organic acid are at salt.
Another object of the present invention is to provide the preparation sides of the compound based on resveratrol treatment the nervous system disease
Method, specifically includes the following steps:
Step 1: intermediate III is generated using intermediate II reaction；
Step 2: intermediate III and intermediate IV add water quenching reaction, are extracted by room temperature reaction, wash, and purifying is most
Obtained compound eventually.
Another object of the present invention is to provide based on resveratrol treatment the nervous system disease compound preparation
The drug for treating the nervous system disease.
In conclusion advantages of the present invention and good effect are as follows:
Resveratrol belongs to polyphenol compound, also known as resvertrol, has a variety of pharmacological activity, including antitumor, drop
Low platelet aggregation, prevents and treats atherosclerosis, cardiovascular and cerebrovascular disease etc..Due to the particularity of resveratrol structure,
Absorption And Metabolism is poor in vivo for it, therefore during carrying out structural modification to resveratrol, its is fat-soluble for 1. increases, passes through
Introduce different carboxyl groups on the phenolic hydroxyl group of resveratrol and form ester bond, thus make compound more easily enter cell and
By blood-brain barrier, such as LX-1,3,7,8,10,11,12,13,14,15.2. considering different location halogen in the introducing of acyl group
The introducing of atom is to increase anti-tumor activity, such as LX-3, and 7,8,10,11, in view of the polyphenol design feature of resveratrol, consider
Substituent group is introduced to investigate phenolic hydroxyl group quantity for active influence.3. introducing methoxy group to investigate phenolic hydroxyl group quilt
For active influence after substitution.Such as LX-1,12.4. in view of nitrogen-atoms is on active influence, introduce isocyanate group from
And active variation is investigated, such as LX-12.
Resveratrol shows neuroprotection, uses target under many animals ischemia model and a variety of administration modes
Point multiplicity, definite effect.
Detailed description of the invention
Fig. 1 is the object preparation method of the chemical combination provided in an embodiment of the present invention based on resveratrol treatment the nervous system disease
Flow chart.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
The present invention is directed to develop the new compound with neuroprotection, it is used to prepare treatment cerebral apoplexy and other minds
Drug through systemic disease.
Compound provided in an embodiment of the present invention based on resveratrol treatment the nervous system disease is with Formulas I structure
Compound and its pharmaceutically acceptable salt.
Molecular formula I provided in an embodiment of the present invention is resveratrol (R).
Compound and its pharmaceutically acceptable salt provided in an embodiment of the present invention with Formulas I structure:
Compound and its pharmaceutically acceptable salt provided in an embodiment of the present invention with Formulas I structure, preferred Formulas I
Close object are as follows:
Pharmaceutically acceptable salt provided in an embodiment of the present invention refers to: compound and inorganic acid, organic acid are at salt.
The object preparation method of chemical combination provided in an embodiment of the present invention based on resveratrol treatment the nervous system disease, specifically
The following steps are included:
S101: intermediate III is generated using intermediate II reaction；
S102: intermediate III and intermediate IV add water quenching reaction, are extracted by room temperature reaction, wash, and purifying is final
Compound is made.
The treatment nerve of compound preparation provided in an embodiment of the present invention based on resveratrol treatment the nervous system disease
The drug of systemic disease.
Application principle of the invention is further described combined with specific embodiments below.
Embodiment 1；
The preparation of the compounds of this invention LX1:
Successively by 3g potassium carbonate, 100ml pears type bottle is added in 30ml DMF, and after ten minutes, 2g is added in 40 degrees Celsius of stirrings
S1 reacts 4h under 40 degrees Celsius, is cooled to room temperature, ice water is added into reaction flask, filters, washing, it is dry after white powder
Shape solid product LX-1128mg.
Application effect of the invention is described in detail below with reference to experiment.
Experiment 1；
One, materials and methods:
1, experimental material
(1) experimental animal experimental rat is SPF grades of Sprague Dawley rats, ties up tonneau China experimental animal purchased from Beijing
Technology Co., Ltd..Wherein pregnant 16-18 days rats are used for neuron culture.
(2) main agents and instrument
2, experimental method
(1) primary neuronal culture
(2) cellular damage of AAPH induction and cell viability detection:
(the 2- methyl-propyl miaow) dihydrochloride of 2,2- azo two (2,2'-Azobis (2-methylpropionamidine)
Dihydrochloride, AAPH) it is dissolved in DMEM and prepares 1mM；5mM；10mM；The solution of 20mM and 40mM, is added separately to mind
Through in member, while CCK-8 solution is added, in the absorbance using spectrophotometric determination 495nm wavelength after effect 4 hours, from
And cell viability is analyzed, observe influence of the AAPH to cell viability.
(3) protective effect of the noval chemical compound to neuron.
Primary cultured neurons first use the AAPH induced damage 4h of 40mM.Simultaneously the new of various concentration is added in replacement culture medium
Compound.For 24 hours, CCK-8 solution is added, in the extinction using spectrophotometric determination 495nm wavelength after effect 4 hours in protection
Degree, to analyze cell viability, judges the protective effect to neuron.
(4) Anti-G value of noval chemical compound
Primary cultured neurons first use the AAPH induced damage 4h of 40mM.Simultaneously the new of various concentration is added in replacement culture medium
Compound.Protection for 24 hours, be added anti-apoptotic detection reagent solution, later again under fluorescence microscope observing apoptosis cell quantity, point
Not Ji Lu 10 visuals field normal cell, apoptotic cell, and calculate its percentage.To judge that the anti-apoptotic of noval chemical compound is made
With.
(5) statistics and analysis
This experimental result uses SPSS15.0 for statistical analysis, and experimental data is indicated with mean ± standard deviation, compares between group
Relatively use variance analysis.P < 0.05 is statistically significant.
Protective effect of 1 the compounds of this invention of table to the AAPH neuron induced
Anti-G value of 2 the compounds of this invention of table to the AAPH neuron induced
3, result:
(1) AAPH can simulate cerebral apoplexy and prepare neure damage model
Primary cultured neurons expression neuron specific markers' object neurofilament protein (Neurofilament, NF) shows
The cell of culture is respectively neuron, and giving various concentration AAPH can cause to damage to neuron, and cell activity is dense with AAPH
The increase of degree and decline.Wherein 40mM AAPH can obvious Induction of neuronal damage.
(2) noval chemical compound can reduce neure damage
Addition acts on for 24 hours after 40mM AAPH induced neuronal injury.Neuronal cell viability is detected later.
The result shows that noval chemical compound can reverse neure damage caused by AAPH, as a result there is statistical significance.
Specific embodiment 2:
The studies have shown that of MCAO models in rats and CCA model is injected intravenously resveratrol before ischemic or after ischemic
30mg/kg can reduce infarct size, anti-lipid peroxidation reaction；Inhibit ganglioside in rat hippocampus and cerebral cortex
The reduction of rouge, phosphatide and cholesterol total amount enhances locomotor activity and Learning memory disorder；Reduce Hippocampal CA 1 original position end mark
Detection in notation (terminal deoxynucleotidyl transferasedUTP nick end labeling, TUNEL)
To positive neuronal cell quantity；Improve the expression of anti-apoptotic proteins Bcl-2；The expression of pro apoptotic protein Bax is reduced, line is improved
Plastochondria and blood-brain barrier function are abnormal.It is injected immediately in gerbil jird transient global cerebral ischemia model preparation process or after being successfully prepared
And resveratrol 30mg/kg is injected intraperitoneally after mould success for 24 hours, Death of hippocampus neurons reduces and the work of Deiter's cells
Change and reduces.And the 3d before prepared by mouse MCAO model, oral resveratrol 20mg/kg, is equally reduced significantly infarct daily
Area.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (7)
1. a kind of compound based on resveratrol treatment the nervous system disease, which is characterized in that described to be controlled based on resveratrol
The compound for treating the nervous system disease is compound and its pharmaceutically acceptable salt with Formulas I structure.
2. the compound as described in claim 1 based on resveratrol treatment the nervous system disease, which is characterized in that described point
Minor I is resveratrol (R).
3. the compound as described in claim 1 based on resveratrol treatment the nervous system disease, which is characterized in that the tool
There are the compound and its pharmaceutically acceptable salt of Formulas I structure:
4. the compound as described in claim 1 based on resveratrol treatment the nervous system disease, which is characterized in that the tool
There are the compound and its pharmaceutically acceptable salt of Formulas I structure, preferred compound of formula I are as follows:
5. the compound as described in claim 1 based on resveratrol treatment the nervous system disease, which is characterized in that the medicine
Acceptable salt refers on: compound and inorganic acid, organic acid are at salt.
6. a kind of preparation method of the compound based on resveratrol treatment the nervous system disease, which is characterized in that described to be based on
Resveratrol treats the preparation method of the compound of the nervous system disease, specifically includes the following steps:
Step 1: intermediate III is generated using intermediate II reaction；
Step 2: intermediate III and intermediate IV add water quenching reaction, are extracted by room temperature reaction, wash, and purify final system
Obtain compound.
7. a kind of drug of the treatment the nervous system disease of the compound preparation based on resveratrol treatment the nervous system disease.
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| CN102816090A (en) * | 2012-09-10 | 2012-12-12 | 四川大学 | Carbamate compounds, preparation method and application thereof |
| CN103012141A (en) * | 2012-12-17 | 2013-04-03 | 上海应用技术学院 | (E)-3-hydroxy-5-(hydroxystyryl)-2-phenyl chloroacetate compound and preparation method thereof |
| WO2018208709A1 (en) * | 2017-05-09 | 2018-11-15 | Warner Babcock Institute For Green Chemistry, Llc | Stilbene derivatives for the treatment of cns and other disorders |
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2019
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Patent Citations (5)
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|---|---|---|---|---|
| WO2009138437A1 (en) * | 2008-05-13 | 2009-11-19 | Genmedica Therapeutics Sl | Salicylate conjugates useful for treating metabolic disorders |
| CN102675100A (en) * | 2011-10-31 | 2012-09-19 | 牛婧 | Ester derivatives of resveratrol and medical applications |
| CN102816090A (en) * | 2012-09-10 | 2012-12-12 | 四川大学 | Carbamate compounds, preparation method and application thereof |
| CN103012141A (en) * | 2012-12-17 | 2013-04-03 | 上海应用技术学院 | (E)-3-hydroxy-5-(hydroxystyryl)-2-phenyl chloroacetate compound and preparation method thereof |
| WO2018208709A1 (en) * | 2017-05-09 | 2018-11-15 | Warner Babcock Institute For Green Chemistry, Llc | Stilbene derivatives for the treatment of cns and other disorders |
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| YANG, H ET AL.: "Synthesis and Anticoagulant Bioactivity of Heterocyclic Derivatives of Resveratrol", 《CHEMISTRY OF NATURAL COMPOUNDS》 * |
| 余婷婷 等: "白藜芦醇及其衍生物抗癫痫性脑损伤研究进展", 《第六届CAAE脑电图与神经电生理大会》 * |
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