CN103271903A - Novel medical use of icaritin and cycloicaritin as well as composition thereof - Google Patents
Novel medical use of icaritin and cycloicaritin as well as composition thereof Download PDFInfo
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Abstract
The invention discloses novel medical use of icaritin and cycloicaritin as well as composition thereof in preparation of a drug of an alpha-glucosidase inhibitor. The composition can be prepared from herba epimedii crude drugs which are matched according to a certain ratio after being respectively extracted to prepare, and also can be obtained in a chemical synthesis manner. The icaritin and the cycloicaritin can be respectively prepared into a hypoglycemic drug in a monomer form, and can be prepared into the hypoglycemic drug in a manner of the composition according to a certain ratio.
Description
Technical field
The present invention relates to 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one single component and two kinds of compositions application in preparation alpha-glucosidase inhibitor medicine that one-tenth is grouped into.The present invention also relates to the pharmaceutical preparation of this medicine, belong to medical technical field.
Background technology
Diabetes are one group of clinical syndromes that caused by the h and E factor interaction, absolute or relative deficiency and target tissue reduce insulin sensitivity because of insulin secretion in system, cause a series of metabolism disorders such as body sugar, fat, protein, power and water Xie Zhi, clinical is main common sign with the hyperglycemia.Prolonged illness can cause multisystem infringement, be in a bad way or stress the time acute metabolism disorder such as ketoacidosis etc. can take place.Alpha-glucosidase inhibitor is the activity by the competitive inhibition alpha-glucosidase, can block disaccharidase and be hydrolyzed to monosaccharide, delay the absorption of sugar, make blood glucose steadily also maintain certain level slowly, control postprandial hyperglycemia disease can also be improved carbohydrate tolerance simultaneously, prevention and treatment of obesity, the high triglyceride mass formed by blood stasis is used for the treatment of because of the disorderly disease that causes of carbohydrate.Experimentation shows that the chronic complicating diseases of acarbose treatment diabetes animal model is effective, reduces protein glycosylation by reducing post-prandial glycemia concentration, postpones or stop the development of kidney, retinal optic neuropathy generation and ischemic cardiomyopathy.
The main alpha-glucosidase inhibitor of bibliographical information has polysaccharide, alkaloid, glycoside, polypeptide, glucosides class, flavonoid, saponin and phenols etc.
3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one are Berberidaceae plant Herba Epimedii Epimedium brevicornum Maxim., arrow leaf Herba Epimedii Epimedium sagittatum(Sieb.et Zucc.) dry aerial parts of Maxim., pubescence Herba Epimedii Epimedium pubescens Maxim., Epimedium wushanense Epimedium wushanense T.S.Ying or Herba Epimedii Epimedium koreanum Nakai obtain icariin through extracting, obtain through different method for hydrolysis then.The flat patent of invention of Xie Juan (publication number: CN102093380A) report, the ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one have antioxidation, antibiotic, improve cardiovascular and cerebrovascular vessel, osteoporosis, antiinflammatory, enhance immunity and improve estrogen level; Dong Jing becomes patent of invention (publication number: report that CN101836976A) 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one has the effect that antineoplastic vascular generates; Dong Jing becomes patent of invention (publication number: report that CN101428015A) 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one has the effect for the treatment of endotoxemia; The just rich patent of invention of the Yin Dynasty (publication number: CN101284000A) report, 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one has the effect of the obesity of preventing and treating or fatty liver; Lou Yi praises patent of invention, and (publication number: CN1194701C) report, 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one or Desmethylicaritin 8-Prenylkaempferol have the application in the preparation estrogenic agents.
Find no before the present invention finishes and close 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and encircle 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one as alpha-glucosidase inhibitor, at the report of using aspect prevention and the treatment blood sugar lowering, do not find yet with 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one be the compositions formed of main component as alpha-glucosidase inhibitor, at the report of using aspect prevention and the treatment blood sugar lowering, the present invention is with a wide range of applications.
Summary of the invention
Main contribution of the present invention has provided 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and the ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one has the activity that suppresses alpha-glucosidase.3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one are for the preparation of the new purposes of preventing and treating the hyperglycemia medicine specifically.The inventor proves that through animal experiment 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one have the activity of remarkable inhibition alpha-glucosidase; Can delay the normal mouse post-prandial glycemia and raise, can delay the hyperglycemia mice post-prandial glycemia rising that alloxan is induced; Reduce the blood glucose of alloxan induced hyperglycemia mice.Do not see that before the present patent application 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one are as alpha-glucosidase inhibitor, at the application and the report that prevent and treat hypoglycemic drug.
Of the present invention another mainly contributed and is, had than single component 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and encircled 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one by 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and the compositions formed of ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one to have the activity of stronger inhibition alpha-glucosidase.Embody the synergism of two kinds of compositions, had stronger practicality.
The structural formula of 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one (Icaritin):
The structural formula of ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one (Cycloicaritin):
The inventor utilizes different method for hydrolysis to obtain icariside, 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one through extract icariin from Herba Epimedii, proves through activity test, and 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one have the activity of very strong inhibition alpha-glucosidase.And the inventor has determined to have stronger pharmacologically active by the compositions that 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one are formed through test of many times, obtains best ratio combination by test, has tangible technological innovation.
In order to realize above technical scheme, 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one can obtain by directly extract purification from Chinese medicine, also can obtain by chemosynthesis.The raw material of using in this test prepares by the following method:
Get the dry medical material of Herba Epimedii, add the 0.5-5% calcium oxide, decoct 1-3 time with 10-20 times of water gaging, each 1-3 hour, merge decoction liquor, filter, filtrate is condensed into every 1ml and contains the 1g medical material, and D101 macroporous resin column on the concentrated solution washes 5-8 times of column volume earlier with water, discard eluent, reuse 4-8 40-70% ethanol elution is doubly collected eluent, reclaims ethanol, drying under reduced pressure gets Herba Epimedii total flavones;
Get Herba Epimedii total flavones, add 30-60 and doubly measure back hydrolysis 3-6h in the acidic ethanol of 4-10%, place room temperature, add isopyknic water, stir, place, filter, must encircle the 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one crude product; Ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one crude product utilizes dissolve with methanol, separates with normal pressure ODS post, and mobile phase is acetonitrile-water (70:30), merges same composition, reclaims solvent, and crystallize filters, and obtains high-purity ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one (content is greater than 95%).
Getting Herba Epimedii total flavones puts in citric acid-sodium hydrogen phosphate buffer (PH=4.0) (W:V=2:1), add cellulase (W:V=5:1), beta-glucosidase (W:W=5:1), yeast (W:W=5:1), stirred 10-20 hour down at 40-50 ℃, carry out complex enzyme degradation, after reaction finishes, add the water of 2 times of volumes in the reactant liquor, stir, place, filter, get the 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one crude product; The 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one crude product utilizes dissolve with methanol, separates with normal pressure ODS post, and mobile phase is acetonitrile-water (70:30), merges same composition, reclaims solvent, and crystallize filters, and obtains high-purity 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one (content is greater than 95%).
Another object of the present invention provides the pharmaceutical preparation of 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one or ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and compositions.Mainly be oral formulations, mainly be selected from tablet, capsule, pill, granule, suspensoid, drop pill, any in the oral formulations.
The compositions that 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one single component and two kinds of one-tenth are grouped into can suppress alpha-glucosidase activity, have in the purposes in preparation prevention and treatment hyperglycemia medicine.These pharmacological actions are confirmed by following pharmacodynamics test example.
1, the compositions that is grouped into of 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one single component and two kinds of one-tenth is to the inhibitor effect of alpha-glucosidase
1.1 standard reaction system 67mmol/L pH is 6.8 kaliumphosphate buffer 150uL, 1mg/mL glutathione solution 50 μ L, 0.1mg/mL alpha-glucosaccharase enzymatic solution 100 μ L, 37 ℃ of insulation 10min, 20mmol/L PNPG solution 100ul adds 0.2mol/L Na behind 37 ℃ of reaction 20min
2CO
3Solution 400uL cessation reaction is measured 400nm place absorbance value.Sample is to the suppression ratio computing formula of enzymatic activity:
Suppression ratio (%)=(A contrast-A sample)/A contrast * 100%1.2 acarboses are got the original solution that acarbose after the grinding is mixed with 50mg/ml to the influence of alpha-glucosidase activity, and are diluted to 50.0,25.0 with this, 10.0,4.0,1.0,0.2, the 0.05mg/ml variable concentrations.The 100ul acarbose is joined in the enzyme reaction system, is incubated 10min with enzyme at 37 ℃ earlier,, add substrate reactions 20min again, use Na
2CO
3The solution cessation reaction is measured 400nm place absorbance value.
1.3 the compositions that 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth are grouped into influences 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of compositions dmso solutions that one-tenth is grouped into to alpha-glucosidase activity, be diluted to 1.0 with buffer then, 0.5,0.25,0.125,0.0625,0.03125,0.01mg/ml dimethyl sulfoxide is whole content ﹤ 1% in reaction system.The compositions that 100ul 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth are grouped into joins in the reaction system, measures compositions that 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth is grouped into to the inhibitory action of alpha-glucosidase.Experimental result sees Table 1.
Table 1 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of compositionss that one-tenth is grouped into
Inhibitory action to alpha-glucosidase
The result shows that acarbose has good dose-effect relationship to the inhibitory action of alpha-glucosidase activity.The compositions that single component 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth are grouped into is 1.0 in concentration, 0.5,0.25,0.125,0.0625,0.03125,0.01mg/ml under the condition, there is good dose-effect relationship in inhibitory action to alpha-glucosidase, and the compositions that single component 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth are grouped into is more than 5 times of positive drug acarbose to the inhibitory action of alpha-glucosidase activity, and alpha-glucosidase is shown very strong inhibitory action.3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one is stronger than the single component activity with the compositions of ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one composition simultaneously.
2, the compositions that is grouped into of 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth is tested the normal mouse carbohydrate tolerance
Get 110 of mices, 10 every group, be divided into 11 groups at random, press table 2 grouping.Negative control group filling normal saline, positive control are that acarbose is irritated stomach 50mg/kg, according to table 2 administration, and successive administration 7 days, fasting 8h before the last administration, administration is starch 5g/kg filling stomach after 1 hour, measures to 0.5h behind the starch, 1h, 2h, the blood glucose value of 3h.The blood sampling of eye socket venous sinus.Measure blood glucose value with the glucoseoxidase test paper method.The results are shown in Table 2.
Table 2,3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of compositionss that one-tenth is grouped into
To normal mouse carbohydrate tolerance experimental result
* compare * P＜0.01 with negative control group;
Illustrate that compositions that 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth are grouped into can suppress the normal mouse post-prandial glycemia and raise.Compositions is stronger than the single component activity.
3, the compositions that is grouped into of 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth the anti-sugar amount of hyperglycemia mice experiment that alloxan is induced
Get 110 of male mices, 10 every group, behind the fasting 14h, lumbar injection 2% alloxan 30mg/kg normal saline solution, behind the injection 72h, the blood sampling of eye socket venous sinus.Get the preceding fasting 10h of blood, measure fasting glucose, measure blood glucose value with the glucoseoxidase test paper method.Blood glucose is higher than the diabetic mice that is of 11.1mmol/l.Model divides into groups according to table 3.Model control group is irritated normal saline, and positive control is to irritate stomach acarbose 50mg/kg, according to table 3 administration, and successive administration 10 days, fasting 6h before the last administration, administration is starch 5g/kg filling stomach after 1 hour, measures to 0.5h behind the starch, 1h, the blood glucose value of 2h.The results are shown in Table 3.
Table 3,3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of compositionss that one-tenth is grouped into
To hyperglycemia mice carbohydrate tolerance experimental result
* compare * P＜0.05 with model control group; * P＜0.01
Illustrate that compositions that 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth are grouped into can delay the hyperglycemia mice post-prandial glycemia that alloxan induces and raise.The activity of compositions is stronger than the activity of single component.
4, the compositions that is grouped into of 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth hyperglycemia mouse blood sugar value experiment that alloxan is induced
Get 110 of male mices, 10 every group, behind the fasting 14h, lumbar injection 2% alloxan 30mg/kg normal saline solution, behind the injection 72h, the blood sampling of eye socket venous sinus.Get the preceding fasting 10h of blood, measure fasting glucose, measure blood glucose value with the glucoseoxidase test paper method.Blood glucose is higher than the diabetic mice that is of 11.1mmol/l.Model divides into groups according to table 4.Model control group is irritated normal saline, and positive control is to irritate stomach acarbose 50mg/kg, according to table 4 administration, and successive administration 10 days, fasting 10h after the last administration, the blood sampling of eye socket venous sinus, centrifuging and taking serum is pressed the determination of glucose oxidase blood sugar level, the results are shown in Table 4.
Table 4,3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of compositionss that one-tenth is grouped into
The hyperglycemia mouse blood sugar value experimental result that alloxan is induced
* compare * P＜0.05, * * P＜0.01 with model control group;
Illustrate that the high, medium and low dosage group of combination that 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth are grouped into all can significantly reduce the blood glucose of alloxan induced hyperglycemia mice, and the activity of compositions is stronger than 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one activity.
5, the compositions that is grouped into of 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth is to normal mouse blood sugar, serum insulin, glucagon, hepatic glycogen, muscle glycogen influence
Get 100 of mices, according to table 5 grouping, 10 every group, administration, every day 1 time, continuous 14 days, 2h after the last administration, the eye socket vein is got blood, use determination of glucose oxidase blood glucose, with serum measured by radioimmunoassay insulin, glucagon, and get liver, diaphram with anthrone method mensuration hepatic glycogen, the muscle glycogen improved, the results are shown in Table 5.
Table 5 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of compositionss that one-tenth is grouped into
Normal mouse blood sugar, serum insulin, glucagon, hepatic glycogen, muscle glycogen are influenced the result
* compare * P＜0.01 with negative control group
Illustrate that the combination that 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and two kinds of one-tenth are grouped into can reduce normal mouse blood glucose, promote insulin secretion, reduce glucagon content, increase hepatic glycogen, muscle glycogen content.Wherein high dose group has the difference of significance, and compositions is stronger than the single component activity.
Embodiment
The present invention executes example by following experiment to be achieved (confirmation), but is not limited only to this example.
The preparation method of example 1 Herba Epimedii total flavones
Get the dry medical material 5kg of Herba Epimedii, add 2% calcium oxide, decoct 2 times with 15 times of water gagings, each 2 hours, merge decoction liquor, filter, filtrate is condensed into 5000ml, and D101 macroporous resin column on the concentrated solution washes 5 times of column volumes earlier with water, discard eluent, 60% ethanol elution that reuse is 6 times is collected eluent, reclaims ethanol, drying under reduced pressure gets Herba Epimedii total flavones.
The preparation method of example 2 ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-ones
Get Herba Epimedii total flavones 100g, back hydrolysis 4h in the ethanol of adding 4000ml 5% sulphuric acid places room temperature, adds the water of 4000ml, stirs, and places, and filters, and must encircle the 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one crude product; Ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one crude product utilizes dissolve with methanol, separates with normal pressure ODS post, and mobile phase is acetonitrile-water (70:30), merges same composition, reclaims solvent, and crystallize filters, and obtains high-purity ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one (content is 97.4%).
The preparation method of example 3 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-ones
Getting Herba Epimedii total flavones 100g puts in 50ml citric acid-sodium hydrogen phosphate buffer (PH=4.0), add cellulase 20ml, beta-glucosidase 20g, yeast 20g, stirred 16 hours down at 45 ℃, after reaction finishes, add the water of 100ml in the reactant liquor, stir, place, filter, get the 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one crude product; The 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one crude product utilizes dissolve with methanol, separates with normal pressure ODS post, and mobile phase is acetonitrile-water (70:30), merges same composition, reclaims solvent, and crystallize filters, and obtains high-purity 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one (content is 98.2%).
Claims (6)
1. 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one, the application of ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one in preparation alpha-glucosidase inhibitor medicine.
2. the application of compositions in preparation alpha-glucosidase inhibitor medicine of 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one and ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one composition.
3. according to the described compositions of claim 2, it is characterized in that: by weight percentage: 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one accounts for 30-90%, and the ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one accounts for 10-50%.
4. pharmaceutical composition according to claim 3, it is characterized in that: by weight percentage: 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one accounts for 70%, and the ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one accounts for 30%.
5. it is characterized in that according to claim 1,2 described purposes: the application in the medicine of preparation alpha-glucosidase inhibitor refers to contain the 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one of effective therapeutic dose and compositions and one or more the pharmaceutically acceptable pharmaceutical excipients that the ring 3,5,7-trihydroxy-2-(4-methoxy-phenyl)-8-(3-methyl-but-2-enyl)-chromen-4-one uses or forms separately separately.
6. described pharmaceutical preparation is characterized in that according to claim 5: said oral formulations is selected from any in the middle of the tablet, capsule, soft capsule, granule, pill, suspensoid, drop pill, oral liquid.
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| CN110699263A (en) * | 2019-10-29 | 2020-01-17 | 浙江工业大学 | Aspergillus niger YH-6 and application thereof in improving content of icaritin in epimedium |
| CN112451515A (en) * | 2020-12-04 | 2021-03-09 | 中国科学院广州生物医药与健康研究院 | Human glucagon-like peptide-1receptor activator and application thereof |
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