CN103951721A - Application of quercetin-O-glucoside derivative to treatment of lipid metabolism disorders - Google Patents

Application of quercetin-O-glucoside derivative to treatment of lipid metabolism disorders Download PDF

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CN103951721A
CN103951721A CN201410186813.4A CN201410186813A CN103951721A CN 103951721 A CN103951721 A CN 103951721A CN 201410186813 A CN201410186813 A CN 201410186813A CN 103951721 A CN103951721 A CN 103951721A
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quercetin
glycosides
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glucose
lipid metabolism
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CN103951721B (en
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尚靖
李妤
金�雨
吕金鹏
王路路
张志超
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Nanjing Ruijing Medical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention relates to the field of drug synthesis and pharmacology and in particular relates to a preparation method of a quercetin-O-glucoside derivative and an application of the quercetin-O-glucoside derivative to treatment of lipid metabolism disorders. The derivative is a compound in a formula I in the specification and comprises salt, optical isomers and racemes of the compound in the formula I. The invention aims to design and synthesize the quercetin-O-glucoside derivative. Through in vitro and in vivo pharmacological activity study, the quercetin-O-glucoside derivative can play a role in reducing the lipid in the in vivo and in vitro experiments. Besides, the invention also provides a drug composition for treating lipid metabolism disorders.

Description

The application of Quercetin-O-glycosides derivative in treatment lipid metabolism disorders disease
Technical field
The present invention relates to field of medicaments, be specifically related to the application of class Quercetin-O-glycosides derivative in treatment lipid metabolism disorders disease.
Background technology
Along with the development of economic level, the change of national life mode, the incidence of the disease of a series of disorders of lipid metabolism rises increasingly.Lipid metabolism disorders disease (lipid metabolism disorders) refers to take the energy metabolism relative disease that body abnormalities of sugar/lipid metabolism is principal character, comprises fatty liver, obesity, atherosclerosis and hyperlipoproteinemia etc.Clinically, the principal character of lipid metabolism disorders disease is the abnormal of lipid (lipid) and meta-bolites quality and quantity thereof in blood and hetero-organization organ thereof, can show accumulating of triglyceride level and cholesterol, the increase of liver leaflet inflammation and gpt (alanine transaminase, ALT) content and the change of Adipocyte Factor secretory volume.The pathogenesis of lipid metabolism disorders disease is complicated, and treatment is more difficult at present.
Quercetin-O-glycosides compounds is widely distributed in various fruit, vegetables and herbal medicine, and it is rich content in Stigma Croci, oriental wormwood, witloof, mango.In recent years, both at home and abroad lot of documents report is found, witloof have significantly hypoglycemic, reducing blood lipid (Xinjiang Chinese materia medica, 2006,24:80-83).
Summary of the invention
We study the main pharmacodynamics composition that class Quercetin-O-glycosides compound of finding in witloof is its performance effect for reducing fat, on this basis, we use chemical method to synthesize class Quercetin-O-glycosides derivative, it is carried out to the Pharmacological Activity Screening of inside and outside, the mechanism of studying its performance effect for reducing fat, has important value for the treatment of lipid metabolism disorders disease.
The present invention's Quercetin is the synthetic class Quercetin-O-glycosides derivative of raw material, and its pharmacology and chemical research show that derivative of the present invention and pharmaceutical composition thereof have potential using value in treatment lipid metabolism disorders disease.
Quercetin-O-glycosides derivative of the present invention (I) structural formula is as follows:
R wherein 1represent hydrogen atom, monosaccharide groups, glucuronic acid or galacturonic acid;
R 2represent hydrogen atom, monosaccharide groups, glucuronic acid or galacturonic acid;
R 3represent hydrogen atom, methyl, methanol-based, ethyl, ethanol based, acetoxyl or benzyl;
R 4represent hydrogen atom, methyl, methanol-based, ethyl, ethanol based, acetoxyl or benzyl;
And R 1, R 2, R 3, R 4different times table hydrogen atom.
The wherein preferred glucose of the monose in monosaccharide groups, semi-lactosi, rhamnosyl, wood sugar, pectinose or fructose.
Most preferred compound is as follows:
The pharmacy acceptable salt of the compounds of this invention, solvate or polymorphic form have the same pharmacologically active of same the compounds of this invention.
The invention also discloses a kind of pharmaceutical composition, wherein contain compound of the present invention (I) or its pharmacy acceptable salt, solvate or polymorphic form and pharmaceutically acceptable carrier.Described composition can be prepared into the conventional formulation of multiple pharmaceutical field, as tablet, granule, injection, dripping pill, capsule, aerosol, suppository, plaster etc., oral administration or through vein, muscle, subcutaneous or with other injection system injection, direct oral cavity, rectum, vagina, skin absorb or via intranasal application sucks, to contain the pharmaceutical dosage forms of activeconstituents, with pharmaceutically acceptable dosage form, give.According to described disease, and patient to be treated and route of administration, can give composition with different dosage.Compound of the present invention, also can be used for the treatment of other diseases relevant with lipid metabolism disorders.
The clinical dosage used of compound of the present invention is 0.01mg～1000mg/ days, also can depart from this scope according to the difference of the weight of the state of an illness or formulation.
Compound of the present invention can be prepared by following method:
Pharmacodynamics test and the result of part of compounds of the present invention below:
One, the regulating and controlling effect of Quercetin-O-glycosides derivative to liver cell triglyceride level (TG) metabolism
Rat hepatocytes is normally cultivated (6 orifice plate) after 24h, with the foundation of FFA inducing hepatocyte hyperlipidemia model, contain afterwards after the culture medium culturing 24h of different types of Quercetin-O-glycosides derivative (20 μ M), remove nutrient solution, with PBS, wash 2 times, every hole adds 100 μ L lysates afterwards, scrapes cell, places 20min on ice, the centrifugal 10min of 12000rpm/min, get supernatant, press respectively TG, the operation of TC test kit specification sheets, measure respectively the content of TG, TC.
Experimental result in Table 1, table 2:
The impact of table 1 Quercetin-O-glycosides of the present invention derivative (20 μ M) on triglyceride level in Rat Primary Hepatocytes (TG) content
With model group comparison: *p<0.05, *p<0.01
The impact of table 2 Quercetin-O-glycosides of the present invention derivative (20 μ M) on cholesterol in Rat Primary Hepatocytes (TC) content
With the comparison of blank group: ###p<0.001; With model group comparison: *p<0.05, *p<0.01, * *p<0.001
From the result of table 1, table 2, above Quercetin-O-glycosides derivative of the present invention all can reduce triglyceride level (TG), the deposition of cholesterol (TC) in primary rat hepatocyte.Wherein the effect of compound 2 (Quercetin-3-O-β-D-Glucose glycosides), compound 4 (Quercetin-3-O-β-D-Glucose aldehydic acid glycosides) is comparatively remarkable.
Two, Quercetin-O-glycosides derivative of the present invention (Quercetin, Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides) is fed the pharmacodynamic study of the disorderly model of lipid metabolism in rats causing to high lipid food
Get 30 of healthy male rats, only, sub-cage rearing, freely drinks water weight 200 ± 20g/, 20 ℃-25 ℃ of room temperatures, illumination 12 hours/day.Normal diet was fed after one week, except 6 of normal rats, fed with normal diet, and all the other are fed with high lipid food (2% cholesterol, 10% lard and 88% basal feed).After 4 weeks, the rat feeding with high lipid food is divided into 4 groups at random by serum TC level, 6 every group.Experiment is grouped as follows 1. normal group: normal diet+0.5%CMC-Na; 2. hyperlipidemia model group: high lipid food+0.5%CMC-Na; 3. Simvastatin group (10mg/kg): high lipid food+Simvastatin 10mg/kg; 4. bezafibrate group (10mg/kg): high lipid food+bezafibrate 10mg/kg; 5. Quercetin-3-O-β-D-Glucose glycosides group (25mg/kg): high lipid food+Quercetin-3-O-β-D-Glucose glycosides 25mg/kg; 6. Quercetin-3-O-β-D-Glucose aldehydic acid glycosides group (25mg/kg): high lipid food+Quercetin-3-O-β-D-Glucose aldehydic acid glycosides 25mg/kg; 7. Quercetin (25mg/kg): high lipid food+Quercetin 25mg/kg.When feeding with feed, every morning respectively gavage give relative medicine, normal group and model group give the 0.5%CMC-Na solution of equivalent.By body weight, adjust dosage, administration 4 weeks weekly.
In feeding process, note the observation to generalized cases such as the animal mental status, diet, activity, stool colour and proterties, and weigh weekly the weight of animals, check feed high lipid food and the impact of medicine gavage on animal bodies situation.
Quercetin-3-O-β-D-Glucose glycosides, the investigation of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides to liver tissues of rats structure influence: collecting sample divides into groups and administration, after last administration, fasting (can't help water) 16h, put to death rat, win rapidly liver, with physiological saline, clean, put into 10% formaldehyde and solidify, carry out pathological section HE dyeing.
Pathological section HE dyeing:
Rat is put to death, and takes out liver, except impurity elimination tissue, with pre-cold saline rinsing, removes blood, and filter paper blots, and immerses in 10% formaldehyde solution and fixes, and after dehydration, waxdip embedding, section, exhibition sheet, affixed, roasting sheet, dyes.By to the absorption of HE, absorption, acid nucleus is dyed blueness by alkaline Hematorylin, and alkaline endochylema is dyed redness by acid Yihong, and result makes karyon be blue, and endochylema takes on a red color.
Oil red O stain is investigated Hepaticlipid deposition situation:
Get fresh rat liver organization a little, freezing microtome section after OTC embedding, slice thickness is 8-10 μ m, attaches on slide glass; By frozen section, with after oil red O dye liquor dyeing 10-15min, with after the quick rinsing of 60% Virahol, flowing water is washed 5min; Hematorylin is redyed 30s, sour alcohol acidifying; Flowing water rinses 5min; After blotting with filter paper, 50% glycerine mounting, the observation of taking pictures under mirror.
The mensuration of serum Biochemical Indexes:
After last administration, fasting (can't help water) 16h, weighs in, and puts to death rat, takes out liver, with normal saline flushing blood, with filter paper, blots.Liver is weighed and is calculated liver index, liver index=liver weight/body weight.Through femoral artery, get blood, be placed in after room temperature 2h, the centrifugal 15min of 3500r/min, upper strata clear liquid, by being got serum, is sub-packed in-70 ℃ of Refrigerator stores.By method described in agent box specification sheets, measure TC, TG, LDL-C and HDL-C content.Adopt zymetology end-point method to measure TC and TG content, Chemical Inhibition Method is measured LDL-C and HDL-C content.
Western Blot measures PPAR-α, HMGR and ABCA1 albumen in liver:
The preparation of protein sample: get the liver of each treated animal, extract total protein in tissue.
BCA protein quantification: get 1.2mL protein standard preparation liquid and join in a tubulin standard (30mg BSA), be mixed with the protein standard solution of 25mg/mL after fully dissolving.Get appropriate 25mg/mL protein standard, with PBS, being diluted to final concentration is 0.5mg/mL.Quantity, adds 1 volume BCA reagent B (50:1) by 50 volume BCA reagent A and prepares appropriate BCA working fluid per sample, fully mixes.Standard substance are added in the standard substance hole of 96 orifice plates by 0,1,2,4,8,12,16,20 μ l, add PBS and supply 20 μ l.Add proper volume sample in the sample well of 96 orifice plates, add standard substance diluent to 20 μ l.Each hole adds 200 μ l BCA working fluids, places 20-30min for 37 ℃.Note: also can room temperature place 2 hours, or 60 ℃ are placed 30 minutes.When BCA method is measured protein concentration, color can constantly be deepened along with the prolongation of time.And color reaction can raise and accelerate by Yin Wendu.If concentration is lower, be adapted at comparatively high temps and hatch, or proper extension incubation time.Measure A562, the wavelength between 540-595nm also can be accepted.According to typical curve, calculate the protein concentration of sample.
Protein sample mix with 5 * standard SDS-PAGE loading buffer make the final concentration of SDS-PAGE loading buffer be 1 *, be then placed in boiling water bath and boil 5min, protein sample is put in-20 ℃ and saves backup.
Western Blot process: perfusion separation gel: preparation 10% separation gel, mix, implantation glass groove, then adds the fluid-tight of one deck water on glue; The concentrated glue of perfusion: after glue polymerization to be separated, incline and covering water layer, add 4% concentrated glue, comb is inserted in concentrated glue; Loading: electrophoresis apparatus is installed, is added electrophoretic buffer.Applied sample amount is the sample volume containing 30 μ g albumen; Electrophoresis: connect after electrophoresis apparatus, to concentrate glue 80V approximately 30 minutes, voltage is adjusted into 120V, approximately 60 minutes after tetrabromophenol sulfonphthalein arrives separation gel.Until tetrabromophenol sulfonphthalein, stop electrophoresis during apart from separation gel bottom 1cm, according to Marker band cutting gel; Transferring film: the sizeable nitrocellulose filter of cutting (NC film), according to filter paper-gel-NC film-filter paper, sequentially lay, drive bubble away, connect membrane-transferring device, 10V transferring film (according to molecular weight of albumen adjustment, calculating for 1 minute by every 1kD transferring film), after transferring film finishes, take out NC film; Sealing: 2.5%BSA room temperature sealing 1 hour; Hatch primary antibodie: primary antibodie is diluted to suitable concentration with TBST, on Sptting plate, adds 1mL primary antibodie diluent, be attached in primary antibodie diluent 4 ℃ of overnight incubation by NC film face down is counter; Wash film: room temperature shaking table TBST washing 10 minutes, totally 3 times; Hatch two anti-: anti-ly with TBST, be diluted to suitable concentration by two, on Sptting plate, add the anti-diluent of 1mL bis-, be attached in two anti-diluents incubated at room 1 hour by NC film face down is counter; Wash film: room temperature shaking table TBST washing 10 minutes, totally 3 times; Colour developing: fresh preparation ECL luminescent solution.ECL luminescent solution A liquid+B liquid equal-volume mixes (under high light, not preparing), after 1 minute, the membranin mixed solution therewith that faces down is fully contacted, and reacts and after 5 minutes, film is transferred on another preservative film, removes most raffinate; Gel image analysis: the film after above-mentioned colour developing is put into gel imaging instrument, utilize full automatic gel imaging analysis instrument expose and analyze.
Experimental result
1, Quercetin-3-O-β-D-Glucose glycosides, the impact of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides on rat liver weave construction
Experimental result as shown in Figure 1, is compared with normal group, and obvious cavity appears in model group liver rope arrangement disorder in liver cell, and local visible inflammatory cell infiltrates.Simvastatin and Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides all can obviously improve above-mentioned pathological condition.
2, Quercetin-3-O-β-D-Glucose glycosides, the impact of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides on Hepaticlipid deposition
Experimental result as shown in Figure 2, is compared with normal group, is full of the red fat differing in size and drips in model group endochylema, shows that high lipid food nursing can cause accumulating that in liver, fat drips.Simvastatin is compared with model group with Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides administration group, endochylema lactones drips content obviously to be reduced, and Quercetin-3-O-β-D-Glucose aldehydic acid glycosides group is excellent to the improvement degree of Hepaticlipid deposition compared with Quercetin-3-O-β-D-Glucose glycosides group.
3, Quercetin-3-O-β-D-Glucose glycosides, the impact of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides on rat body weight and Biochemical Indices In Serum
Table 3 demonstration, model group body weight, liver index, cholesterol (TC), triglyceride level (TG) and low density lipoprotein cholesterol (LDL-C) are compared with normal group all utmost point significant difference (p<0.01).Simvastatin and bezafibrate can obviously reduce TC in rat blood serum, TG and LDL-C content, and rising HDL-C content relatively has significant difference (p<0.05 or p<0.01) with model group.Quercetin (25mg/kg), Quercetin-3-O-β-D-Glucose glycosides (25mg/kg), Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (25mg/kg) all can be to a certain extent reduction rat body weight, TC in liver index and serum, TG and LDL-C content, rising HDL-C content, part is compared with model group has significant difference (p<0.05 or p<0.01), but under identical administration concentration condition, the pharmacological action of Quercetin will be lower than Quercetin-3-O-β-D-Glucose glycosides, the pharmacological action of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides.Experimental result prompting, Simvastatin and Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides all can obviously improve to a certain extent high lipid food and feed obesity and the lipid metabolism disorders causing.
Table 3 Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides are on the impact of rat body weight and Biochemical Indices In Serum (n=6)
With the comparison of blank group, *p<0.05, *p<0.01; With model group comparison, #p<0.05, ##p<0.01
4, Quercetin (1), Quercetin-3-O-β-D-Glucose glycosides (2), the expression impact of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4) on rat liver PPAR-α
PPAR-α is the main target spot of bezafibrate triglyceride reducing.Experimental result as shown in Figure 3, is compared hyperlipidemia model group PPAR-alpha expression and is lowered with blank group, show that high lipid food is fed can cause in liver that Triglyceride Metabolism in Patients approach is disorderly and produce seviparous accumulating.Bezafibrate is compared with model group with Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides administration group, and PPAR-alpha expression significantly activates; And Quercetin administration group is compared with model group, the expression of PPAR-α has no remarkable activation.Prompting Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides are the effects of triglyceride reducing of bringing into play by acting on PPAR-α.
5, Quercetin (1), Quercetin-3-O-β-D-Glucose glycosides (2), the impact of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4) on rat liver HMGR and ABCA1 protein expression
HMGR is the rate-limiting enzyme of liver cholesterol biosynthesis, and ABCA1 is the important albumen of mediation liver cholesterol efflux.From accompanying drawing 4, with control group comparison, Quercetin-3-O-β-D-Glucose glycosides (2), Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4) can extremely significantly raise the rising of rat liver ABCA1 expressing quantity, further extremely significantly lower the decline (P<0.01) of rat liver HMGR expressing quantity, but Quercetin (1) can not significantly raise the rising of rat liver ABCA1 expressing quantity.Experimental result prompting, the synthetic and outer row that Quercetin-3-O-β-D-Glucose glycosides (2), Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4) can the hepatocellular cholesterol of direct regulation and control; Quercetin (1) can not direct regulation and control liver cell cholesterol outer row.
Accompanying drawing explanation
Fig. 1 is that Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides are that Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides are Quercetin (1), Quercetin-3-O-β-D-Glucose glycosides (2), the expression impact of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4) on rat liver PPAR-α on the Fig. 3 that affects of Hepaticlipid deposition on the Fig. 2 that affects of rat liver weave construction
Fig. 4 is Quercetin (1), Quercetin-3-O-β-D-Glucose glycosides (2), the impact of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4) on rat liver HMGR and ABCA1 protein expression
Embodiment
Embodiment 1
Synthesizing of Quercetin-3-O-β-D-Glucose glycosides (compound 2)
By Quercetin 50g (150mmol), diphenyl dichloromethane 50mL (256mmol), diethylene glycol dimethyl ether 100mL drops in the single port flask of 200mL, reflux 10 minutes.Pressure reducing and steaming solvent obtains yellow soup compound, through silica gel chromatography, obtain faint yellow solid (35.67g, 46.32%), the compound 23.3g (50mmol) that upper step is made is successively dissolved in (100mL) in tetrahydrofuran solution with salt of wormwood 13.8g (100mmol), under stirring, to slowly adding wherein acetyl bromide-alpha-D-glucose 19.85g (50mmol), control the temperature of reaction solution at 0-5 ℃, under this temperature condition, continue stirring reaction 8 hours.Methylene dichloride 40mL dilution for reaction solution, filters and removes remaining salt of wormwood, and by filtrate waterside, organic layer anhydrous sodium sulfate drying, through silica gel chromatography, obtains solid 11.84g, yield 32.17%.The compound 11.84g (15mmol) that upper step is made is dissolved in tetrahydrofuran (THF) 100mL, adds 10%Pd/C10.65g, and normal pressure hydrogenolysis, after room temperature reaction 24h, is filtered and removed 10%Pd/C.Decompression is removed solvent and is obtained syrup thing, through silica gel chromatography, obtains faint yellow syrup thing.Add wherein sodium methoxide solution 15mL, under room temperature condition, react 3 hours, through the separated (chloroform: methyl alcohol=5:1), obtain faint yellow solid (3.01,45.6%), mp214～217 ℃ of polyamide column chromatography.
1H-NMR(400MHz,DMSO-d 6)：δ3.30–3.60(m,6H),5.15(d,J＝7.6Hz,1H),6.10(d,J＝1.6Hz,1H),6.30(d,J＝2.0Hz,1H),6.71(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),7.61(d,J＝2.0Hz,1H).ESI-MS(m/z):Calcd.464.1；found:463.2[M-H] -.
Embodiment 2
3', 4'-dihydroxymethyl Quercetin-3-O-β-D-Glucose glycosides (compound 3) synthetic
First two steps reaction is with embodiment 1, by the faint yellow syrup thing (6.18g obtaining, 10mmol), bromine methyl alcohol (1.09g, 10mmol), salt of wormwood (1.38g, 10mmol) is successively dissolved in 50ml tetrahydrofuran solution, and heater strip adds lower back flow reaction 7 hours, afterwards through silica gel chromatography, obtain faint yellow solid, add wherein sodium methoxide solution 15mL, under room temperature condition, react 3 hours, through the separated (chloroform: methyl alcohol=7:1) of polyamide column chromatography, obtain faint yellow solid (3.23g, 67.2%), mp231～235 ℃.
1H-NMR(400MHz,DMSO-d 6)：δ3.34–3.67(m,6H),4.27-4.31(m,4H),5.25(d,J＝7.6Hz,1H),6.16(d,J＝1.6Hz,1H),6.38(d,J＝2.0Hz,1H),6.54(s,2H),6.56(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,2.0Hz,1H),7.75(d,J＝2.0Hz,1H).MS(m/z):525.3[M+H] +.
Embodiment 3
Synthesizing of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (compound 4)
Preparation process is with embodiment 1, and acetyl bromide-alpha-D-glucose that second step is reacted used is changed to acetyl bromide-alpha-D-glucose aldehydic acid methyl esters, and reaction yield is 46.7%, mp245～248 ℃.
1H-NMR(400MHz,DMSO-d 6)：δ3.30–3.60(m,6H),5.15(d,J＝7.6Hz,1H),6.10(d,J＝1.6Hz,1H),6.30(d,J＝2.0Hz,1H),6.71(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),8.27(d,J＝2.4Hz,1H).MS(m/z):479.1[M+H] +.
Embodiment 4
3', 4'-dihydroxymethyl Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (compound 5) synthetic
Preparation process is with embodiment 2, and acetyl bromide-alpha-D-glucose that second step is reacted used is changed to acetyl bromide-alpha-D-glucose aldehydic acid methyl esters, and reaction yield is 50.2%, mp224～227 ℃.
1H-NMR(400MHz,DMSO-d 6)：δ3.34–3.67(m,6H),4.27-4.31(m,4H),5.25(d,J＝7.6Hz,1H),6.16(d,J＝1.6Hz,1H),6.38(d,J＝2.0Hz,1H),6.54(s,2H),6.56(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,2.0Hz,1H),8.35(d,J＝3.2Hz,1H).MS(m/z):540.3[M+H] +.
Embodiment 5
Synthesizing of Quercetin-7-O-β-D-Glucose glycosides (compound 6)
Preparation process is with embodiment 1, Quercetin is being carried out in glycosylated process, utilize the difference of 3 and 7 hydroxyl acidity of compound, by controlling temperature of reaction between 10 ℃-15 ℃, successfully obtain the product Quercetin-7-O-β-D-Glucose glycosides (6) at 7 hydroxyl generation glycosylation reactions, reaction yield is 34.7%, mp202～206 ℃.
1H-NMR(400MHz,DMSO-d 6)：δ3.27–3.54(m,6H),5.05(d,J＝7.6Hz,1H),6.17(d,J＝1.6Hz,1H),6.19(d,J＝2.0Hz,1H),6.74(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),7.61(d,J＝2.0Hz,1H).MS(m/z):465.2[M+H] +.
Embodiment 6
Synthesizing of Quercetin-7-O-β-D-Glucose aldehydic acid glycosides (compound 7)
Preparation process is with embodiment 3, Quercetin is being carried out in glycosylated process, utilize the difference of 3 and 7 hydroxyl acidity of compound, by controlling temperature of reaction between 14 ℃-20 ℃, successfully obtain the product Quercetin-7-O-β-D-Glucose aldehydic acid glycosides (7) at 7 hydroxyl generation glycosylation reactions, reaction yield is 46.2%, mp213～215 ℃.
1H-NMR(400MHz,DMSO-d 6)：δ3.19–3.34(m,6H),5.25(d,J＝7.6Hz,1H),5.76(d,J＝1.6Hz,1H),6.01(d,J＝2.0Hz,1H),6.28(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),8.27(d,J＝2.4Hz,1H).MS(m/z):479.1[M+H] +.
Embodiment 7
Synthesizing of Quercetin-3-O-β-D-galactoside (compound 8)
Preparation method, with embodiment 1, is changed to acetyl bromide-α-D-semi-lactosi by acetyl bromide-alpha-D-glucose and gets final product to obtain Quercetin-3-O-β-D-galactoside (8), and yield is 49.1%, mp234～237 ℃.
1H-NMR(400MHz,DMSO-d 6)：δ3.23–3.43(m,6H),5.35(d,J＝7.6Hz,1H),6.10(d,J＝1.6Hz,1H),6.30(d,J＝2.0Hz,1H),6.87(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),7.61(d,J＝2.0Hz,1H).MS(m/z):465.2[M+H] +.
Embodiment 8
Synthesizing of Quercetin-3-O-β-D-galacturonic acid glycosides (compound 9)
Preparation method, with embodiment 3, is changed to acetyl bromide-α-D-galacturonic acid methyl esters by acetyl bromide-alpha-D-glucose aldehydic acid methyl esters, gets final product to obtain Quercetin-3-O-β-D-galacturonic acid glycosides (9), and yield is 41.9%, mp219～223 ℃.
1H-NMR(400MHz,DMSO-d 6)：δ3.21–3.52(m,6H),5.15(d,J＝7.6Hz,1H),6.19(d,J＝1.6Hz,1H),6.30(d,J＝2.0Hz,1H),6.56(d,J＝8.4Hz,1H),7.56(dd,J＝8.4,2.0Hz,1H),8.27(d,J＝2.4Hz,1H).MS(m/z):479.1[M+H] +。

Claims (6)

1. the compound shown in general formula (I) or its pharmacy acceptable salt, solvate or polymorphic form:
R wherein 1represent hydrogen atom, monosaccharide groups, glucuronic acid or galacturonic acid;
R 2represent hydrogen atom, monosaccharide groups, glucuronic acid or galacturonic acid;
R 3represent hydrogen atom, methyl, methanol-based, ethyl, ethanol based, acetoxyl or benzyl;
R 4represent hydrogen atom, methyl, methanol-based, ethyl, ethanol based, acetoxyl or benzyl;
And R 1, R 2, R 3, R 4different times table hydrogen atom.
2. the compound of claim 1 or its pharmacy acceptable salt, solvate or polymorphic form, wherein monose is glucose, semi-lactosi, rhamnosyl, wood sugar, pectinose or fructose.
3. the compound of claim 1 or its pharmacy acceptable salt, solvate or polymorphic form are following structural compounds:
4. a pharmaceutical composition, wherein contain claim 1 compound or its pharmacy acceptable salt, solvate or polymorphic form and pharmaceutically acceptable carrier.
Claim 1,2 or 3 compound or its pharmacy acceptable salt, solvate or polymorphic form for the preparation of the purposes of the medicine for the treatment of or prevention lipid metabolism disorders disease.
6. the purposes of claim 5, wherein lipid metabolism disorders disease is lipidemia, non-alcoholic fatty liver disease or atherosclerosis.
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