CN103951721B - The application in treatment lipid metabolism disorder of the Quercetin-O-glycosides derivative - Google Patents
The application in treatment lipid metabolism disorder of the Quercetin-O-glycosides derivative Download PDFInfo
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Abstract
The present invention relates to pharmaceutical synthesis and area of pharmacology, be specifically related to the preparation method of a class Quercetin O glycosides derivatives and the application in treatment lipid metabolism disorder thereof.The compound of described derivative such as Formulas I, including the salt of compound of formula I and the optical isomer of compound of formula I and racemic modification.The technical problem to be solved in the present invention is to design and synthesize a class Quercetin O glycosides derivatives, is found by external, internal pharmacology activity research, and Quercetin O glycosides derivatives all can play the effect of lipopenicillinase in testing in vivo and in vitro.Additionally present invention also offers a kind of pharmaceutical composition treating lipid metabolism disorder.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a class Quercetin-O-glycosides derivative at treatment disorders of lipid metabolism
Application in 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
Increasingly rise.Lipid metabolism disorder (lipid metabolism disorders) refers to
The energetic supersession relevant disease of principal character, including fatty liver, obesity, atherosclerotic and hyperlipoprotememia etc..Facing
On bed, lipid metabolism disorder be mainly characterized by lipid (lipid) and metabolite matter thereof in blood and hetero-organization organ thereof
With the exception of amount, the accumulation of triglycerides and cholesterol, liver lobular inflammation and glutamic-pyruvic transaminase (alanine can be shown
Transaminase, ALT) increase of content and the change of Adipocyte Factor secretory volume.Sending out of lipid metabolism disorder
Interpretation of the cause, onset and process of an illness system is complicated, and treatment is relatively difficult at present.
Quercetin-O-glycosides compounds is widely distributed in various water fruits and vegetables and Chinese herbal medicine, and it is at safflower, mattress
Rich content in old, witloof, mango.In recent years, domestic and international lot of documents report finds, witloof has the most hypoglycemic, fall
Blood fat (Xinjiang traditional Chinese medicine, 2006,24:80-83).
Summary of the invention
We have discovered that a class Quercetin-O-glycosides compound in witloof is the main pharmacodynamics of its performance effect for reducing fat
Composition, on this basis, we use the method for chemistry to synthesize a class Quercetin-O-glycosides derivative, and it is carried out inside and outside
Pharmacological Activity Screening, study its play effect for reducing fat mechanism, the treatment for lipid metabolism disorder has important
It is worth.
Present invention Quercetin is Material synthesis one class Quercetin-O-glycosides derivative, and its pharmacology and chemical research show
Derivative and the pharmaceutical composition thereof of the present invention have potential using value in treatment lipid metabolism disorder.
The Quercetin of the present invention-O-glycosides derivative (I) structural formula is as follows:
Wherein R1Represent hydrogen atom, monosaccharide groups, glucuronic acid or galacturonic acid；
R2Represent hydrogen atom, monosaccharide groups, glucuronic acid or galacturonic acid；
R3Represent hydrogen atom, methyl, methanol-based, ethyl, ethanol base, acetate or benzyl；
R4Represent hydrogen atom, methyl, methanol-based, ethyl, ethanol base, acetate or benzyl；
And R1、R2、R3、R4Different times table hydrogen atom.
The wherein preferred glucose of the monose in monosaccharide groups, galactolipin, rhamnose, wood sugar, arabinose or fructose.
Most preferably compound is as follows:
It is same that the pharmaceutically acceptable salt of the compounds of this invention, solvate or polymorph have same the compounds of this invention
The pharmacologically active of sample.
The invention also discloses a kind of pharmaceutical composition, wherein contain the compound (I) of the present invention or it pharmaceutically can connect
The salt, solvate or the polymorph that are subject to and pharmaceutically acceptable carrier.Described composition can be prepared as multiple pharmacy neck
The conventional formulation in territory, such as tablet, granule, injection, dripping pill, capsule, aerosol, suppository, plaster etc., oral administration or through quiet
Arteries and veins, muscle, subcutaneous or with other injection system are injected, and direct oral cavity, rectum, vagina, skin absorption or via intranasal application suck, with
Containing the pharmaceutical dosage forms of active component, give with pharmaceutically acceptable dosage form.According to described disease and to be treated
Patient and method of administration, composition can be given with different dosage.The compound of the present invention, it is also possible to be used for treating it
The disease that he is relevant with disorders of lipid metabolism.
Dosage used by the compound clinic of the present invention is 0.01mg～1000mg/ days, it is possible to according to weight or the agent of the state of an illness
The difference of type deviates this scope.
The compound of the present invention can be prepared by following method:
Pharmacodynamics test and the result of of the present invention part of compounds be presented herein below:
One, the Quercetin-O-glycosides derivative regulating and controlling effect to liver cell triglycerides (TG) metabolism
After rat hepatocytes normally cultivates 24h (6 orifice plate), with the foundation of FFA inducing hepatocyte hyperlipidemia model, give afterwards
After medium culture 24h containing different types of Quercetin-O-glycosides derivative (20 μMs), remove nutrient solution, wash 2 with PBS
Secondary, every hole adds 100 μ L lysates afterwards, scrapes cell, places 20min, 12000rpm/min on ice and be centrifuged 10min, take supernatant,
Press the operation of TG, TC kit specification respectively, measure the content of TG, TC respectively.
Experimental result is shown in Table 1, table 2:
Table 1 Quercetin of the present invention-O-glycosides derivative (20 μMs) is to triglycerides in Rat Primary Hepatocytes (TG) content
Impact
Compare with model group:*p<0.05,**p<0.01
Table 2 Quercetin of the present invention-O-glycosides derivative (20 μMs) is to cholesterol in Rat Primary Hepatocytes (TC) content
Impact
Compare with blank group:###p<0.001；Compare with model group:*p<0.05,**P < 0.01,***p<0.001
From table 1, the result of table 2, the Quercetin of the above present invention-O-glycosides derivative all can reduce triglycerides
(TG), the cholesterol (TC) deposition in primary rat hepatocyte.Wherein compound 2 (Quercetin-3-O-β-D-Glucose glycosides),
The effect of compound 4 (Quercetin-3-O-β-D-Glucose aldehydic acid glycosides) is the most notable.
Two, Quercetin of the present invention-O-glycosides derivative (Quercetin, Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-
O-β-D-Glucose aldehydic acid glycosides) high lipid food is fed the pharmacodynamic study of lipid metabolism in rats disorder model caused
Take healthy male rat 30, weight 200 ± 20g/ only, sub-cage rearing, freely drink water, room temperature 20 DEG C-25 DEG C, light
According to 12 hours/day.After normal diet feeds one week, except normal rats 6 is fed with normal diet, remaining is fed with high lipid food
(2% cholesterol, 10% lard and 88% basal feed).After 4 weeks, feed and divide at random by serum TC level with the rat of high lipid food
It is 4 groups, often group 6.Test and be 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 fat
Feed+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.Feeding while feed, every morning gavage respectively gives relative medicine, normal group and model group and gives equivalent
0.5%CMC-Na solution.Adjust dosage by body weight weekly, be administered 4 weeks.
The sight to ordinary circumstances such as the animal state of mind, diet, activity, stool colour and proterties is noted in feeding process
Examine, and weigh weekly the weight of animals, check and feed high lipid food and the impact on animal bodies situation of the medicine gavage.
Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides is to liver tissues of rats structure shadow
The investigation rung: collecting sample is grouped and is administered, after last is administered, fasting (can't help water) 16h, puts to death rat, wins rapidly
Liver, cleans with physiological saline, puts in 10% formaldehyde and solidifies, carries out pathological section HE dyeing.
Pathological section HE dyes:
Rat is put to death, and takes out liver, removes miscellaneous tissue, removes blood with the rinsing of pre-cold saline, and filter paper blots, and immerses
In 10% formalin fixing, embed through dehydration, waxdip, cut into slices, open up sheet, affixed, bake sheet after dye.By to HE's
Adsorbing, absorb, acidic cell core is dyed blueness by alkalescence haematoxylin, and alkalescence endochylema is dyed redness by acid Yihong, and result makes born of the same parents
Core is blueness, and endochylema takes on a red color.
Oil red O stain investigation Hepaticlipid deposition conditions:
Taking fresh rat liver organization a little, freezing microtome section after OTC embedding, slice thickness is 8-10 μm, attaches
On slide；By frozen section with after oil red O dye liquor dyeing 10-15min, after 60% isopropanol short rinse, flowing water is washed
5min；Haematoxylin redyes 30s, acid alcohol acidifying；Flowing water rinses 5min；After blotting with filter paper, 50% glycerine mounting, take pictures under mirror
Observe.
The mensuration of serum Biochemical Indexes:
After last is administered, fasting (can't help water) 16h, weighs in, puts to death rat, take out liver, use normal saline flushing
Blood blots with filter paper.Liver is weighed and calculates liver index, liver index=liver weight/body weight.Take blood through femoral artery, put
After room temperature 2h, 3500r/min is centrifuged 15min, and upper strata clear liquid, by being taken serum, is sub-packed in-70 DEG C of Refrigerator stores.Press
Method described in agent box specification, measures TC, TG, LDL-C and HDL-C content.Zymetology end-point method is used to measure TC and TG content,
Chemical Inhibition Method measures LDL-C and HDL-C content.
PPAR-α, HMGR and ABCA1 albumen in Western Blot mensuration liver:
The preparation of protein sample: take the liver of each treated animal, extracts total protein in tissue.
BCA protein quantification: take 1.2mL protein standard preparation liquid and join in a tubulin standard (30mg BSA), fully
The protein standard solution of 25mg/mL it is configured to after dissolving.Take appropriate 25mg/mL protein standard, be diluted to PBS final concentration of
0.5mg/mL.According to sample size, add 1 volume BCA reagent B (50:1) by 50 volume BCA reagent A and prepare appropriate BCA working solution,
Fully mixing.Standard items are added in the standard sample wells 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 dilutions to 20 μ l.Each hole adds 200 μ l BCA work
Liquid, places 20-30min for 37 DEG C.Note: can also room temperature place 2 hours, or 60 DEG C are placed 30 minutes.BCA method measures protein concentration
Time, color can constantly be deepened in prolongation over time.And chromogenic reaction can be accelerated because temperature raises.If concentration is relatively low,
It is suitable for hatching at higher temperature, or proper extension incubation time.Measuring A562, the wavelength between 540-595nm also can accept.Root
The protein concentration of sample is calculated according to calibration curve.
Protein sample and 5 × standard SDS-PAGE loading buffer mixing make SDS-PAGE loading buffer
Final concentration of 1 ×, be then placed in boiling water bath and boil 5min, protein sample is put in-20 DEG C and saves backup.
Western Blot process: perfusion separation gel: prepare 10% separation gel, mixing, implantation glass groove, then adds on glue
One layer of water fluid-tight；Perfusion concentrates glue: after glue to be separated polymerization, pour out covering water layer, adds 4% concentration glue, is inserted by comb dense
In contracting glue；Loading: install electrophoretic apparatus, adds electrophoretic buffer.Applied sample amount is the sample volume containing 30 μ g albumen；Electrophoresis: even
After connecting electrophoretic apparatus, to concentrate glue 80V about 30 minutes, arriving Voltage Cortrol after separation gel until bromophenol blue is 120V, about 60
Minute.Electrophoresis is stopped, according to Marker band cutting gel when bromophenol blue 1cm bottom separation gel；Transferring film: cutting size is closed
Suitable nitrocellulose filter (NC film), lays according to filter paper-gel-NC film-filter paper order, drives bubble away, connect transferring film dress
Putting, 10V transferring film (adjusts according to molecular weight of albumen, within 1 minute, calculate by every 1kD transferring film), after transferring film terminates, takes out NC film；Close:
2.5%BSA room temperature is closed 1 hour；Hatch one to resist: an anti-TBST is diluted to suitable concentration, reaction plate adds 1mL mono-and resists
Dilution, is attached to counter for NC film face down in an anti-dilution, 4 DEG C of overnight incubation；Wash film: room temperature shaker TBST washs 10 points
Clock, totally 3 times；Hatch two to resist: two anti-TBST are diluted to suitable concentration, reaction plate add the anti-dilution of 1mL bis-, by NC film
Face down is counter to be attached in two anti-dilutions, incubated at room 1 hour；Wash film: room temperature shaker TBST washs 10 minutes, totally 3 times；Aobvious
Look: Fresh ECL luminescent solution.The mixing of ECL luminescent solution A liquid+B liquid equal-volume (is not prepared) under high light, after 1 minute, by film
Protein powder is fully contacted with this mixed liquor down, is transferred on another preservative film by film, removes most raffinate after reacting 5 minutes；Gel
Graphical analysis: put in gel imaging instrument by the film after above-mentioned colour developing, utilizes full automatic gel imaging analysis instrument to expose and carries out
Analyze.
Experimental result
1, rat liver tissue is tied by Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides
The impact of structure
Experimental result is as it is shown in figure 1, compared with normal group, model group liver rope arrangement disorder, in liver cell, appearance is significantly
Cavity, partially visible cell infiltration.Simvastatin and Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-grape
Glycuronide all can obviously improve above-mentioned pathological condition.
2, Hepaticlipid is sunk by Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides
Long-pending impact
Experimental result is as in figure 2 it is shown, compared with normal group, be full of the red fat differed in size and drip in model group endochylema, aobvious
Show that high lipid food is fed and can cause the accumulation that in liver, fat drips.Simvastatin and Quercetin-3-O-β-D-Glucose glycosides, quercitrin
Element-3-O-β-D-Glucose aldehydic acid glycosides administration group is compared with model group, and endochylema lactones drips content and significantly reduces, and Quercetin-3-
Improvement degree relatively Quercetin-3-O-β-D-Glucose glycosides group that Hepaticlipid is deposited by O-β-D-Glucose aldehydic acid glycosides group is
Excellent.
3, Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides are to rat body weight and serum
The impact of biochemical indicator
Table 3 shows, model group body weight, liver index, cholesterol (TC), triglycerides (TG) and LDL-C
(LDL-C) all there is pole significant difference (p < 0.01) compared with normal group.Simvastatin and Bezafibrate can substantially reduce rat
TC, TG and LDL-C content in serum, raise HDL-C content, compare with model group have significant difference (p < 0.05 or p <
0.01).Quercetin (25mg/kg), Quercetin-3-O-β-D-Glucose glycosides (25mg/kg), Quercetin-3-O-β-D-Glucose
Aldehydic acid glycosides (25mg/kg) all TC, TG and LDL-C can contain in reduction rat body weight, liver index and serum to a certain extent
Amount, raises HDL-C content, and part has significant difference (p < 0.05 or p < 0.01) compared with model group, but identical administration
Under concentration conditions, the pharmacological action Quercetin to be less than-3-O-β-D-Glucose glycosides of Quercetin, Quercetin-3-O-β-D-grape
The pharmacological action of glycuronide.Experimental result is pointed out, Simvastatin and Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-
β-D-Glucose aldehydic acid glycosides all can be obviously improved high lipid food to a certain extent, and to feed the obesity that causes disorderly with lipid-metabolism
Disorderly.
Table 3 Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides is to rat body weight and blood
The impact (n=6) of clear biochemical indicator
Compare with blank group,*p<0.05,**p<0.01；Compare with model group,#p<0.05,##p<0.01
4, Quercetin (1), Quercetin-3-O-β-D-Glucose glycosides (2), Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4)
Expression on rat liver PPAR-α affects
PPAR-α is the major target class of Bezafibrate triglyceride reducing.Experimental result as shown in Figure 3, with blank group
Comparing hyperlipidemia model group PPAR-alpha expression to lower, display high lipid food is fed and Triglyceride Metabolism in Patients approach in liver can be caused disorderly
And produce seviparous accumulation.Bezafibrate and Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid
Glycosides administration group is compared with model group, and PPAR-alpha expression significantly activates；And Quercetin administration group is compared with model group, the table of PPAR-α
Reach and have no notable activation.Prompting Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides are to pass through
Act on PPAR-α and play the effect of triglyceride reducing.
5, Quercetin (1), Quercetin-3-O-β-D-Glucose glycosides (2), Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4)
On rat liver HMGR and the impact of ABCA1 protein expression
HMGR is the rate-limiting enzyme of hepatic cholesterol synthesis, and ABCA1 is the important albumen of row outside mediation hepatic cholesterol.By attached
Fig. 4 understands, and compares with control group, Quercetin-3-O-β-D-Glucose glycosides (2), Quercetin-3-O-β-D-Glucose aldehydic acid glycosides
(4) can significantly raise the rising of rat liver ABCA1 expressing quantity, significantly lower rat liver HMGR albumen
The decline (P < 0.01) of expression, but Quercetin (1) can not significantly raise the rising of rat liver ABCA1 expressing quantity.
Experimental result is pointed out, and Quercetin-3-O-β-D-Glucose glycosides (2), Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (4) can be direct
Regulate and control the synthesis of hepatocellular cholesterol and outer row；Quercetin (1) can not the outer row of direct regulation and control liver cell cholesterol.
Accompanying drawing explanation
Fig. 1 is that Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides are to rat liver group
The Fig. 2 that affects knitting structure is that Quercetin-3-O-β-D-Glucose glycosides, Quercetin-3-O-β-D-Glucose aldehydic acid glycosides are to rats'liver
The Fig. 3 that affects of dirty lipidosis is Quercetin (1), Quercetin-3-O-β-D-Glucose glycosides (2), Quercetin-3-O-β-D-grape
The expression of rat liver PPAR-α is affected by glycuronide (4)
Fig. 4 is Quercetin (1), Quercetin-3-O-β-D-Glucose glycosides (2), Quercetin-3-O-β-D-Glucose aldehydic acid glycosides
(4) on rat liver HMGR and the impact of ABCA1 protein expression
Detailed description of the invention
Embodiment 1
The synthesis of Quercetin-3-O-β-D-Glucose glycosides (compound 2)
By Quercetin 50g (150mmol), diphenyl dichloromethane 50mL (256mmol), diethylene glycol dimethyl ether 100mL throw
Enter in the single port flask of 200mL, be heated to reflux 10 minutes.Decompression boils off solvent and obtains yellow slurry, pure through silica gel column chromatography
Changing, obtain faint yellow solid (35.67g, 46.32%), the compound 23.3g (50mmol) upper step prepared is with potassium carbonate 13.8g
(100mmol) successively (100mL) it is dissolved in tetrahydrofuran solution, to being slowly added thereto to acetyl bromide-α-D-grape under stirring
Sugar 19.85g (50mmol), the temperature of control reactant liquor, at 0-5 DEG C, continues stirring reaction 8 hours under this temperature conditions.Reaction
Liquid dichloromethane 40mL dilutes, and filters and removes remaining potassium carbonate, and by filtrate waterside, organic layer anhydrous sodium sulfate is dried,
Through silica gel chromatography, obtain solid 11.84g, yield 32.17%.The compound 11.84g (15mmol) upper step prepared is molten
In oxolane 100mL, add 10%Pd/C10.65g, normal pressure hydrogenolysis, after room temperature reaction 24h, filter and remove 10%Pd/C.
Decompression is removed solvent and is obtained syrup thing, through silica gel chromatography, obtains faint yellow syrup thing.It is added thereto to sodium methoxide solution
15mL, reacts 3 hours under room temperature condition, separates (chloroform: methyl alcohol=5:1) through polyamide column chromatography, obtains faint yellow solid
(3.01,45.6%), mp214～217 DEG C.
1H-NMR(400MHz,DMSO-d6): δ 3.30 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
The synthesis of 3', 4'-dihydroxymethyl Quercetin-3-O-β-D-Glucose glycosides (compound 3)
First two steps reaction with embodiment 1, the faint yellow syrup thing (6.18g, 10mmol) that will obtain, bromine methyl alcohol (1.09g,
10mmol), potassium carbonate (1.38g, 10mmol) is successively dissolved in 50ml tetrahydrofuran solution, and it is little that fire-bar adds lower back flow reaction 7
Time, after through silica gel chromatography, obtain faint yellow solid, be added thereto to sodium methoxide solution 15mL, under room temperature condition react 3
Hour, separate (chloroform: methyl alcohol=7:1) through polyamide column chromatography, obtain faint yellow solid (3.23g, 67.2%), mp231～235
℃。
1H-NMR(400MHz,DMSO-d6): δ 3.34 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
The synthesis of Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (compound 4)
Acetyl bromide-alpha-D-glucose used by second step reaction, with embodiment 1, is changed to acetyl bromide-α-D-by preparation process
Glucuronic acid methyl ester, reaction yield is 46.7%, mp245～248 DEG C.
1H-NMR(400MHz,DMSO-d6): δ 3.30 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
The synthesis of 3', 4'-dihydroxymethyl Quercetin-3-O-β-D-Glucose aldehydic acid glycosides (compound 5)
Acetyl bromide-alpha-D-glucose used by second step reaction, with embodiment 2, is changed to acetyl bromide-α-D-by preparation process
Glucuronic acid methyl ester, reaction yield is 50.2%, mp224～227 DEG C.
1H-NMR(400MHz,DMSO-d6): δ 3.34 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
The synthesis of Quercetin-7-O-β-D-Glucose glycosides (compound 6)
Preparation process with embodiment 1, Quercetin is carried out glycosylated during, utilize 3 and 7 hydroxyls of compound
Acid difference, by control reaction temperature between 10 DEG C-15 DEG C, successfully obtains at 7 hydroxyl generation glycosylation reactions
Product Quercetin-7-O-β-D-Glucose glycosides (6), reaction yield is 34.7%, mp202～206 DEG C.
1H-NMR(400MHz,DMSO-d6): δ 3.27 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
The synthesis of Quercetin-7-O-β-D-Glucose aldehydic acid glycosides (compound 7)
Preparation process with embodiment 3, Quercetin is carried out glycosylated during, utilize 3 and 7 hydroxyls of compound
Acid difference, by control reaction temperature between 14 DEG C-20 DEG C, successfully obtains at 7 hydroxyl generation glycosylation reactions
Product Quercetin-7-O-β-D-Glucose aldehydic acid glycosides (7), reaction yield is 46.2%, mp213～215 DEG C.
1H-NMR(400MHz,DMSO-d6): δ 3.19 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
The synthesis of Quercetin-3-O-β-D-galactoside (compound 8)
Preparation method with embodiment 1, acetyl bromide-alpha-D-glucose is changed to acetyl bromide-α-D-galactolipin quercitrin
Element-3-O-β-D-galactoside (8), yield is 49.1%, mp234～237 DEG C.
1H-NMR(400MHz,DMSO-d6): δ 3.23 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
The synthesis of Quercetin-3-O-β-D-galacturonic acid glycosides (compound 9)
Acetyl bromide-alpha-D-glucose aldehydic acid methyl esters, with embodiment 3, is changed to acetyl bromide-α-D-galacturonic by preparation method
Acid methyl esters, Quercetin-3-O-β-D-galacturonic acid glycosides (9), yield is 41.9%, mp219～223 DEG C.
1H-NMR(400MHz,DMSO-d6): δ 3.21 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 (5)
1. a treatment or the pharmaceutical composition of prevention lipid metabolism disorder disease, it is characterised in that containing following chemical formula
Represented compound 3, compound 5 or its pharmaceutically acceptable salt:
2. pharmaceutical composition as claimed in claim 1, containing pharmaceutically acceptable carrier.
3. following compound 3, compound 5 or its pharmaceutically acceptable salt represented by chemical formula is at preparation treatment or prevention fat
Purposes in the medicine of matter metabolic disorder disease:
4. purposes as claimed in claim 3, wherein lipid metabolism disorder disease is pionemia, NASH or dynamic
Pulse atherosclerosis.
5. any one or its pharmaceutically acceptable salt of following compound 3 represented by chemical formula, compound 5:
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| PCT/CN2015/073814 WO2015169121A1 (en) | 2014-05-05 | 2015-03-06 | Use of quercetin-o-glycoside derivatives in treating lipid metabolism disorders |
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| CN106031732A (en) * | 2015-03-12 | 2016-10-19 | 南京瑞菁医药科技有限责任公司 | Uses of quercetin glucoside compounds in treatment of hepatic fibrosis |
| CN104788518A (en) * | 2015-05-04 | 2015-07-22 | 中国药科大学 | Preparation method for quercetin-3-O-beta-D-glucoside and use of quercetin-3-O-beta-D-glucoside in lipid regulation |
| CN106243173B (en) * | 2016-07-14 | 2020-10-30 | 塔里木大学 | Method for extracting, separating and purifying blood fat reducing active compound quercetin-3-O-beta-D-galactoside from southern Xinjiang jun jujubes |
| JP2022511400A (en) * | 2018-10-02 | 2022-01-31 | ヤンセン ファーマシューティカ エヌ．ベー． | Pharmaceutical composition containing hydroxyethyl quercetin glucuronide |
| US11304968B2 (en) | 2018-11-16 | 2022-04-19 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide |
| US10639294B2 (en) * | 2018-10-02 | 2020-05-05 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide metabolite |
| CN111961097B (en) * | 2020-08-12 | 2023-01-24 | 青岛海合生物科技有限公司 | Capsaicin derivative, preparation method thereof and application thereof in preparation of cardiovascular disease drugs |
| CN111925405B (en) * | 2020-08-20 | 2023-03-28 | 湖南省人民医院 | Methylisopyrazine A ring glycosylation derivative and preparation method and application thereof |
| CN116693585B (en) * | 2023-06-08 | 2024-06-21 | 大洲新燕(厦门)生物科技有限公司 | Method for preparing quercetin-7-O-beta-D-glucoside from dried orange peel and application thereof |
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| CN1185246C (en) * | 2003-06-26 | 2005-01-19 | 中山大学 | Method for extracting quercetin-7-0-rhamnoside |
| CN1978452A (en) * | 2005-12-01 | 2007-06-13 | 新疆医科大学 | New process for preparing isoquercitrin |
| CN1817876A (en) * | 2006-03-20 | 2006-08-16 | 中国农业科学院作物科学研究所 | Method for preparing quercetol and iso-quercitrin from melin |
| CN100402543C (en) * | 2006-04-30 | 2008-07-16 | 重庆大学 | Preparation method of hyperin and hypericin of Hypericum perforatum |
| GB0618168D0 (en) * | 2006-09-15 | 2006-10-25 | Babraham Inst | Compounds |
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| US20150190369A1 (en) * | 2012-07-03 | 2015-07-09 | Majambu Mbikay | Quercetin-3-glucoside and uses thereof |
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| JPH09143070A (en) * | 1995-09-22 | 1997-06-03 | Nippon Flour Mills Co Ltd | Inhibitory agent for lipase and lowering agent for triglyceride in blood |
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