CN114213480B - Glycoside compound, pharmaceutical composition, preparation method and application - Google Patents

Glycoside compound, pharmaceutical composition, preparation method and application Download PDF

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CN114213480B
CN114213480B CN202111611492.4A CN202111611492A CN114213480B CN 114213480 B CN114213480 B CN 114213480B CN 202111611492 A CN202111611492 A CN 202111611492A CN 114213480 B CN114213480 B CN 114213480B
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pharmaceutical composition
column chromatography
methanol
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CN114213480A (en
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张维库
续洁琨
赫军
张佳
李雅楠
郭林波
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China Japan Friendship Hospital
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    • C—CHEMISTRY; METALLURGY
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    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
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Abstract

The invention provides a novel glycoside compound, a pharmaceutical composition, a preparation method and application, and relates to the technical field of medicines. The novel glycoside compound has a parent nucleus structure of a formula I. The invention separates a class of glycoside compounds with the parent nucleus structure from euphorbia chamaejasme (Euphorbia fischeriana Steud.) and discovers that the class of compounds has obvious inhibition effect on alpha-glucosidase, can be used for preparing medicines for treating diabetes related diseases, and has wide application prospect.
Figure DDA0003435593250000011

Description

Glycoside compound, pharmaceutical composition, preparation method and application
Technical Field
The invention relates to the technical field of medicines, in particular to a novel glycoside compound, a pharmaceutical composition, a preparation method and application.
Background
Along with the increasing changes of people's life and working modes, the incidence of diabetes appears to rise year by year. The continued development of the course of diabetes may cause a series of complications, which in turn affect the quality of life of the patient and increase the economic burden on the patient and the country. Accordingly, the development of drugs having a preventive or therapeutic effect on diabetes has been receiving increasing attention.
Euphorbia radix (Euphorbia fischeriana Steud.) is a perennial herb of Euphorbia genus of Euphorbiaceae family, and research on this plant has been focused on terpenoid compounds and antitumor activity. For example, patent CN104622865A discloses the use of ingenioids for the preparation of antitumor drugs, patent CN103623033a discloses ingenioids active substances for inhibiting cancer and/or tumor cell growth and their use, which all show an important role of active extracts of ingenioids for anticancer or antitumor (e.g. promoting tumor cell death).
There are few or no studies and reports concerning the role of glycoside compounds or Euphorbiaceae plant extracts in diabetes.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide novel glycoside compounds, a pharmaceutical composition, a preparation method and application thereof, so as to enrich the types of related drugs for diabetes in the prior art and provide a novel treatment way for diabetes and related diseases thereof.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
in one embodiment, the present invention provides a novel class of glycoside compounds having a parent core structure of formula (I):
Figure SMS_1
wherein R is 1 And R is 2 Each is independently selected from any one of hydrogen, an ester group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a galloyl group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, an isopropylamino group, a diisopropylamino group, a saturated hydrocarbon group, an unsaturated hydrocarbon group, a substituted aromatic ring, an unsubstituted aromatic ring, an oligosaccharide, a polysaccharide, a metal ion, an organic acid ester group, a nitro group, or a halogen.
The invention searches high-efficiency low-toxicity bioactive components from Euphorbia fischeriana, and extracts a class of glycoside compounds from the plant, wherein the class of compounds has remarkable alpha-glucosidase inhibition activity.
In one embodiment, among the glycoside compounds,
R 1 is that
Figure SMS_2
R 2 Is->
Figure SMS_3
This compound was named Euphorbiacetophenone E.
The molecular structural formula of the compound Euphorbiacetophenone E is as follows:
Figure SMS_4
in one embodiment, among the glycoside compounds,
R 1 is that
Figure SMS_5
R 2 Is->
Figure SMS_6
This compound was designated 1,2, 3-tri-O-ballonyl-beta-D-glucopyranose.
The molecular structural formula of the compound 1,2, 3-tri-O-galloyl-beta-D-glucopyranose is as follows:
Figure SMS_7
in another aspect, the present invention provides a pharmaceutical composition comprising the novel glycoside compounds described above.
In one embodiment, the pharmaceutical composition comprises a combination drug; preferably, the combination comprises one or more of the following: insulin, tolbutamide, chlorpropamide, glibenclamide, glipizide gliclazide, glimepiride, glibenclamide, gliquidone, metformin, gliclazide, glimepiride, glibenclamide metformin hydrochloride, phenformin, pioglitazone hydrochloride, rosiglitazone maleate, troglitazone, ciglitazone, englitazone alogliptin, alogliptin benzoate, saxagliptin, sitagliptin phosphate, vildagliptin, linagliptin, sugar-100, acarbose, voglibose, miglitol, repaglinide, nateglinide, mitiglinide, exenatide, liraglutide, pralidoxime Lin Lantai, pralanin acetate;
more preferably, the insulin comprises one or more of zinc insulin aspartyl, zinc insulin globin, or zinc insulin protamine.
In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient; "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent, and includes various excipients and diluents. In general, carriers are not essential active ingredients and are not overly toxic after administration. Pharmaceutically acceptable carriers in the compositions can include liquids such as water, saline, glycerol, and ethanol. In some cases, the excipient includes fillers, binders, lubricants, disintegrants, cosolvents, surfactants, and the like. Suitable carriers and or excipients are well known to those of ordinary skill in the art and may be selected in accordance with the circumstances. The pharmaceutically active ingredients of the present invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to form a suitable administration form or dosage form for use as a human or veterinary drug.
In the present invention, the dosage form of the pharmaceutical composition includes any one of tablets, capsules, granules, oral liquid, syrup, paste, electuary, dripping pills or pellets. For example, tablets include, but are not limited to, conventional tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets; capsules include, but are not limited to, hard capsules, soft capsules, enteric capsules; injections include, but are not limited to, water injections, powder injections, and infusion solutions. The medicament of the invention can also be prepared into other dosage forms common in the field, for example, solutions including but not limited to true solutions and colloidal solutions; emulsions include, but are not limited to, o/w, w/o and multiple emulsions; semi-solid dosage forms include, but are not limited to, ointments, gels, pastes, and the like; suspensions, powders, suppositories, films, patches, aerosol (powder) sprays and the like.
In one embodiment, the pharmaceutical composition comprises an effective amount of the glycoside compound; for example, in the pharmaceutical composition, the glycoside compound is present in an amount of 0.01 to 95% by weight, including but not limited to 0.01, 0.1, 0.2, 0.5, 1, 1.5, 2,3, 4, 5, 6, 7, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, and 95%.
In a preferred embodiment, the weight ratio of the glycoside compound in the unit dosage form of the pharmaceutical composition is 0.01 to 50mg, including but not limited to 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50mg; more preferably, the weight ratio is 0.01 to 10mg.
In another aspect, the invention provides a method of preparing the glycoside compound isolated from Euphorbia radix (Euphorbia fischeriana Steud);
further, drying and crushing the root of the Euphorbia championii, extracting with a solvent, collecting an extracting solution, and concentrating to obtain a concentrated solution; extracting the concentrated solution with an organic solvent to obtain an extract; subjecting the extract to silica gel column chromatography, and subjecting the eluted first objective fraction to reversed-phase silica gel column chromatography; subjecting the second objective fraction obtained by reversed phase silica gel column chromatography to sephadex column chromatography, and purifying by reversed phase or normal phase preparative liquid chromatography to obtain the compound.
In one embodiment, the preparation method specifically comprises:
(a) Drying radix Euphorbiae Fischerianae, pulverizing, extracting with extraction solvent, mixing extractive solutions, filtering, and concentrating under reduced pressure to obtain concentrated solution;
(b) Extracting the concentrated solution by using an organic solvent, and combining organic phases to obtain an extract;
(c) Performing silica gel column chromatography on the extract, performing gradient elution by using an eluent to obtain a first target fraction, and performing reversed-phase silica gel column chromatography elution to obtain a second target fraction; subjecting the second target fraction to sephadex column chromatography and eluting;
(d) Purification by reverse phase or normal phase preparative liquid chromatography gives the compound.
In one embodiment, in step (a), the extraction solvent is 8 to 15 times, preferably 10 times, the mass of the Euphorbia lathyris root material; preferably, the extraction is a reflux extraction;
further, the reflux extraction time is 1-3 hours, the temperature is 65-85 ℃, and the times of reflux extraction are 2-4 times; more preferably, the extraction solvent is selected from one or more of water, methanol or ethanol; most preferably, the extraction solvent is 60% -95% ethanol;
in the step (b), after dispersing with water, extracting for 2-5 times by using an organic solvent; preferably, the organic solvent comprises one or more of dichloromethane, chloroform, ethylene, ethyl acetate, propyl acetate and petroleum ether, preferably ethyl acetate, propyl acetate; preferably, the dosage of the organic solvent is 1.5-2 times of the volume of the concentrated solution;
in step (c), the gradient elution eluent comprises any one of chloroform-methanol, petroleum ether-acetone, petroleum ether-ethyl acetate, cyclohexane-acetone or cyclohexane-ethyl acetate; preferably petroleum ether-ethyl acetate, cyclohexane-ethyl acetate; the eluent of the reverse phase silica gel column chromatography is selected from any one of ethanol-water or methanol-water; the eluent of the sephadex column chromatography is selected from any one of methanol, chloroform-methanol, dichloromethane-methanol and petroleum ether-chloroform-methanol, preferably methanol and dichloromethane-methanol; preferably, the Sephadex LH-20, sephadex G-10, G-15, G-25, G-50, G-75, G-100, G-150 and G-200, preferably Sephadex LH-20;
in step (d), the chromatographic column in the chromatographic purification treatment is selected from any one of C4, C8, C6 or C18; among them, C18 is preferable; the mobile phase is selected from any one of methanol-water or acetonitrile-water.
In a specific embodiment, the process for the preparation of compound Euphorbiacetophenone E and 1,2,3-tri-O-galloyl- β -D-glucopyranose comprises the steps of:
step 1: collecting radix Euphorbiae Fischerianae, drying, pulverizing, reflux extracting with solvent for several times, mixing extractive solutions, filtering, and concentrating under reduced pressure to obtain concentrated solution;
step 2: extracting the concentrated solution obtained in the step S10 for a plurality of times by using an organic solvent, combining organic phases, and recovering the solvent to obtain an extract III;
step 3: performing silica gel column chromatography on the extract III, performing gradient elution by using an eluent, and combining to sequentially obtain a fraction A, a fraction B, a fraction C, a fraction D and a fraction E after detection by using a silica gel thin layer plate;
subjecting fraction D to reverse phase silica gel column chromatography, and obtaining (6 fractions D1-D6) fraction D1, fraction D2, fraction D3, fraction D4, fraction D5 and fraction D6 by silica gel thin layer plate detection; subjecting the fraction D3 to sephadex column chromatography;
step 4: purification by reverse phase or normal phase preparative liquid chromatography, respectively, gives the compounds Euphorbiacetophenone E and 1,2, 3-tri-O-ballonyl-beta-D-glucopyranoside.
In another aspect, the invention provides application of the glycoside compound or the pharmaceutical composition containing the glycoside compound in preparing medicaments for preventing or treating diabetes and complications thereof.
The invention provides application of the glycoside compound in preparing an alpha-glucosidase inhibitor hypoglycemic pharmaceutical preparation (such as an alpha-glucosidase inhibitor).
The invention takes the glycoside compounds as raw materials, and the results of the screening test of alpha-glucosidase inhibitory activity show that the activity of Euphorbiacetophenone E and 1,2, 3-tri-O-galloyl-beta-D-glucopyranose for inhibiting alpha-glucosidase is superior to that of acarbose (IC) 50 = 286.23 ±0.86 μm). Wherein, the compound 1,2, 3-tri-O-galloyl-beta-D-glucopyranose has the most remarkable inhibitory activity and IC 50 The value was 15.48.+ -. 0.19. Mu.M. The compound is found to be an alpha-glucosidase mixed inhibitor by enzyme inhibition kinetics test of 1,2, 3-tri-O-galloyl-beta-D-glucopyranose.
The beneficial effects are that: the invention provides a glycoside compound, which is proved by an alpha-glucosidase inhibitory activity screening test and an inhibitory kinetics test to have obvious inhibitory effect on alpha-glucosidase and can be applied as a medicament for treating diabetes. Can also be used for preparing health food or functional food for reducing blood sugar.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the inhibition of alpha-glucosidase activity by 1,2, 3-tri-O-ballonyl-beta-D-glucopyranose of the invention;
FIG. 2 is a graph showing the inhibition kinetics of the α -glucosidase activity by 1,2, 3-tri-O-ballonyl- β -D-glucopyranose of the invention;
FIG. 3 is a Michaelis-Menten plot (Mi Haili s-Mantut plot, also known as Mies plot) of 1,2, 3-tri-O-ballonyl-beta-D-glucopyranose versus alpha-glucosidase activity of the invention;
FIG. 4 is a Lineweaver-Burk plot (i.e., double reciprocal plot) of 1,2, 3-tri-O-ballonyl-beta-D-glucopyranoside versus alpha-glucosidase activity of the invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
EXAMPLE 1 preparation of glycoside Euphorbiacetophenone E and 1,2, 3-tri-O-galloyl-beta-D-glucopyranose
Step S1: collecting radix Euphorbiae Fischerianae, drying, pulverizing, reflux extracting with 8-15 times of solvent for 1-3 hr, repeating for 2-4 times, mixing extractive solutions, filtering, and concentrating under reduced pressure to obtain concentrated solution; the extraction temperature is 65-85 ℃;
the extraction solvent is selected from water, methanol, ethanol or their mixture, preferably 60-95% ethanol; (in this example, 10 times of 80% ethanol solvent was added, and the reflux extraction was repeated 3 times for 2 hours).
Step S2: extracting the concentrated solution with organic solvent for 2-5 times, mixing organic phases, and recovering organic solvent to obtain extract III; the extraction temperature is 65 ℃ to the boiling point temperature of the extraction solvent;
the organic extraction solvent can be dichloromethane, chloroform, cyclohexane, ethyl acetate, propyl acetate and petroleum ether, preferably ethyl acetate and propyl acetate; (in this example, the concentrate was extracted 4 times with an organic solvent, which was ethyl acetate).
Step S3: subjecting the extract III to silica gel column chromatography, gradient eluting with organic reagent, detecting with silica gel thin layer plate, and mixing into 5 fractions (A-E); then selecting D to carry out reversed-phase silica gel column chromatography, and identifying 6 fractions (D1-D6) through a silica gel thin layer plate; carrying out sephadex column chromatography on the D3;
the silica gel column chromatography eluent is petroleum ether-ethyl acetate, petroleum ether-acetone, cyclohexane-ethyl acetate, cyclohexane-acetone, chloroform-methanol, preferably petroleum ether-ethyl acetate, cyclohexane-ethyl acetate; the eluent of reverse phase silica gel column chromatography can be ethanol-water or methanol-water; the Sephadex LH-20, sephadex G-10, G-15, G-25, G-50, G-75, G-100, G-150 and G-200 can be selected as the material for Sephadex column chromatography; the eluent used in the Sephadex column chromatography can be methanol, chloroform-methanol, dichloromethane-methanol, petroleum ether-chloroform-methanol, preferably methanol, dichloromethane-methanol (in this embodiment, the eluent used in the silica gel column chromatography is petroleum ether-ethyl acetate, the eluent used in the reversed-phase silica gel column chromatography is ethanol-water, the material used in the Sephadex column chromatography is Sephadex LH-20, and the eluent used in the Sephadex column chromatography is methanol).
Step S4: purifying by reverse phase preparative liquid chromatography to obtain compound Euphorbiacetophenone E and 1,2, 3-tri-O-galloyl-beta-D-glucopyranose;
the reversed phase preparation liquid chromatographic column can select C4, C6, C8 or C18, preferably C18; the mobile phase may be methanol-water or acetonitrile-water (in this example, a C18 liquid chromatography column is selected, and the mobile phase is methanol-water).
Example 2
The other points are the same as in example 1, except that:
step S1: in this example, 8 times of 50% ethanol solvent was added, and the reflux extraction was repeated 2 times for 1 hour.
Step S2: in this example, the concentrate was extracted 2 times with an organic solvent, which was propyl acetate.
Step S3: in this embodiment, the silica gel column chromatography eluent is petroleum ether-acetone, the reverse phase silica gel column chromatography eluent is methanol-water, the Sephadex G-10 is used as the material of Sephadex column chromatography, and the eluent is dichloromethane-methanol.
Step S4: in this example, a C4 liquid chromatography column was selected, and acetonitrile-water was selected as the mobile phase.
Example 3
The other points are the same as in example 1, except that:
step S1: in this example, 15 times of 95% ethanol solvent was added, and the reflux extraction was repeated 4 times for 3 hours.
Step S2: in this example, the concentrate was extracted 5 times with an organic solvent, which was propyl acetate.
Step S3: in this example, the silica gel column chromatography eluent is cyclohexane-ethyl acetate, the reverse phase silica gel column chromatography eluent is methanol-water, the Sephadex G-10 is used as the material of Sephadex column chromatography, and the petroleum ether-chloroform-methanol is used as the eluent.
Step S4: in this example, a C6 liquid chromatography column was selected, and acetonitrile-water was selected as the mobile phase.
It should be noted that, examples 2 to 3 of the present invention and other preparation methods not shown in the present invention are similar to those of example 1 of the present invention; the glycoside compounds Euphorbiacetophenone E and 1,2, 3-tri-O-galloyl-beta-D-glucopyranose of the present invention can be prepared under the parameters defined by the preparation method of the present invention.
Example 4
The molecular structural formula of the compound Euphorbiacetophenone E is as follows:
Figure SMS_8
euphorbiacetophenone E the physical properties are white amorphous powders; the nuclear magnetic data are as follows:
UV(MeOH)λ max 215,280nm；IR(KBr)ν max 3396,1715,1619cm –1 ；HR-ESI-MS:m/z 647.1254[M-H] - (cal.647.1254)； 1 H NMR(500MHz,DMSO-d 6 ):δ H 5.72(1H,d,J＝8.0Hz,H-1),5.18(1H,dd,J＝9.8,8.0Hz,H-2),5.42(1H,t,J＝9.5Hz,H-3),3.65(1H,t,J＝9.5Hz,H-4),3.81(1H,overlap,H-5),3.42(1H,dd,J＝12.0,3.0Hz,H-6α),3.33(1H,dd,J＝12.0,6.5Hz,H-6β),6.89(1H,s,H-2’),6.89(1H,s,H-6’),6.83(1H,s,H-2”),6.83(1H,s,H-6”),6.17(1H,d,J＝2.3Hz,H-3”’),6.10(1H,d,J＝2.3Hz,H-5”’),2.53(3H,s,H-8”’),3.80(3H,s,OCH 3 )； 13 C NMR(125MHz,DMSO-d 6 ):δ c 96.7(C-1),73.3(C-2),74.9(C-3),67.7(C-4),77.1(C-5),60.4(C-6),119.1(C-1’),108.8(C-2’),145.5(C-3’),138.6(C-4’),145.5(C-5’),108.8(C-6’),165.1(C-7’),118.5(C-1”),108.8(C-2”),145.5(C-3”),139.0(C-4”),145.5(C-5”),108.8(C-6”),164.7(C-7”),106.9(C-1”’),162.7(C-2”’),92.0(C-3”),162.7(C-4”’),96.2(C-5”’),165.2(C-6”’),203.2(C-7”’),32.9(C-8”’),56.2(OCH 3 )。
example 5
The molecular structural formula of the compound 1,2, 3-tri-O-galloyl-beta-D-glucopyranose is as follows:
Figure SMS_9
/>
the physical properties of 1,2, 3-tri-O-galloyl-beta-D-glucopyranose are pale amorphous powders; the nuclear magnetic data are as follows:
UV(MeOH)λ max 215,280nm；HR-ESI-MS:m/z 635.0889[M-H] - (cal.635.0890)； 1 H NMR(500MHz,DMSO-d 6 ):δ H 6.05(1H,d,J＝8.3Hz,H-1),5.41(1H,dd,J＝9.9,8.2Hz,H-2),5.55(1H,t,J＝9.5Hz,H-3),3.73-3.97(4H,m,H-4,H-5,H-6),7.03(1H,s,H-2’),7.02(1H,s,H-6’),7.03(1H,s,H-2”),7.02(1H,s,H-6”)； 13 C NMR(125MHz,DMSO-d 6 ):δ c 93.9(C-1),72.4(C-2),76.8(C-3),69.3(C-4),79.1(C-5),61.9(C-6),119.9(C-1’),110.0(C-2’),146.4(C-3’),146.6(C-4’),146.4(C-5’),110.4(C-6’),166.4(C-7’),120.5(C-1”),110.0(C-2”),146.4(C-3”),146.4(C-4”),146.4(C-5”),110.4(C-6”),167.2(C-7”),121.1(C-1”’),110.4(C-2”’),146.6(C-3”),146.6(C-4”’),146.6(C-5”’),110.6(C-6”’),167.8(C-7”’)。
example 6
The embodiment provides a tablet taking Euphorbiacetophenone E as a raw material medicine, which comprises the following components:
Figure SMS_10
Figure SMS_11
making into 100 pieces.
Mixing Euphorbiacetophenone E with hydroxypropyl methylcellulose, pulvis Talci, lactose, and magnesium stearate, adding absolute ethanol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and tabletting.
Example 7
The embodiment provides a tablet taking 1,2, 3-tri-O-galloyl-beta-D-glucopyranose as a raw material drug, which comprises the following components:
1,2,3-tri-O-galloyl-β-D-glucopyranose 24.0mg
hydroxypropyl methylcellulose 16g
Talc powder 0.3g
Lactose and lactose 0.2g
Magnesium stearate 0.2g
Absolute ethyl alcohol 0.1mL
Making into 100 pieces.
Mixing 1,2, 3-tri-O-galloyl-beta-D-glucopyranose with hydroxypropyl methylcellulose, talcum powder, lactose and magnesium stearate, adding absolute ethanol to prepare soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and tabletting.
Example 8
The embodiment provides a capsule taking a compound Euphorbiacetophenone E as a raw material drug, which comprises the following components:
Figure SMS_12
Figure SMS_13
making into 100 granules.
Mixing Euphorbiacetophenone E with starch, microcrystalline cellulose and sodium metabisulfite, adding absolute ethanol, making into soft mass, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and making into capsule.
Example 9
The embodiment provides a capsule taking a compound of 1,2, 3-tri-O-galloyl-beta-D-glucopyranose as a raw material drug, which comprises the following components:
1,2,3-tri-O-galloyl-β-D-glucopyranose 19.0mg
microcrystalline cellulose 0.2g
Starch 5.0g
Sodium metabisulfite 0.2g
Magnesium stearate 0.2g
Absolute ethyl alcohol 0.1mL
Making into 100 granules.
Mixing 1,2, 3-tri-O-galloyl-beta-D-glucopyranose with starch, microcrystalline cellulose and sodium metabisulfite, adding absolute ethanol to obtain soft mass, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and making into capsule.
Example 10
The embodiment provides a granule taking a compound Euphorbiacetophenone E as a raw material drug, which comprises the following components:
Figure SMS_14
Figure SMS_15
making into 100 bags.
Mixing Euphorbiacetophenone E with starch and sodium bisulphite, adding absolute ethanol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and bagging.
Example 11
The embodiment discloses a granule taking a compound 1,2, 3-tri-O-galloyl-beta-D-glucopyranose as a raw material drug, which comprises the following components:
1,2,3-tri-O-galloyl-β-D-glucopyranose 34.0mg
starch 5g
Sodium metabisulfite 0.2g
Magnesium stearate 0.2g
Absolute ethyl alcohol 0.1mL
Making into 100 bags.
Mixing 1,2, 3-tri-O-galloyl-beta-D-glucopyranose with starch and sodium bisulphite, adding absolute ethanol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and bagging.
Example 12
The embodiment discloses an oral liquid taking a compound Euphorbiacetophenone E as a raw material drug, which comprises the following components:
Figure SMS_16
Figure SMS_17
100 pieces of the Chinese herbal medicine are prepared. Mixing the above components, preparing into oral liquid by conventional method, and packaging.
Example 13
The embodiment provides an oral liquid taking a compound 1,2, 3-tri-O-galloyl-beta-D-glucopyranose as a raw material drug, which comprises the following components:
1,2,3-tri-O-galloyl-β-D-glucopyranose 24.0mg
sucrose 2.0g
Sodium bisulfite 0.2g
P-hydroxybenzoic acid methyl ester 0.2g
Sodium bicarbonate 0.1mL
Water for injection 1000mL
100 pieces of the Chinese herbal medicine are prepared. Mixing the above components, preparing into oral liquid by conventional method, and packaging.
Example 14
The embodiment provides an injection taking a compound Euphorbiacetophenone E as a raw material drug, which comprises the following components:
Euphorbiacetophenone E 45.0mg
vitamin C 0.2g
Sodium chloride 6.0g
Sodium bicarbonate 0.1mL
Water for injection 1000mL
100 pieces of the Chinese herbal medicine are prepared. After the components are evenly mixed, 100 pieces can be obtained by adopting the conventional preparation method of injection.
Example 15
The embodiment discloses an injection taking a compound 1,2, 3-tri-O-galloyl-beta-D-glucopyranose as a raw material drug, which comprises the following components:
1,2,3-tri-O-galloyl-β-D-glucopyranose 44.0mg
vitamin C 0.2g
Sodium chloride 5.0g
Sodium bicarbonate 0.1mL
Water for injection 1000mL
100 pieces of the Chinese herbal medicine are prepared. After the components are evenly mixed, 100 pieces can be obtained by adopting the conventional preparation method of injection.
Example 16
The embodiment provides a tablet taking a compound Euphorbiacetophenone E and acarbose as raw material medicines, which comprises the following components:
Euphorbiacetophenone E 20.0mg
acarbose candy 5g
Hydroxypropyl methylcellulose 18g
Talc powder 0.4g
Lactose and lactose 0.2g
Magnesium stearate 0.2g
Absolute ethyl alcohol 0.1mL
Making into 100 pieces. Mixing Euphorbiacetophenone E with acarbose, hydroxypropyl methylcellulose, pulvis Talci, lactose, and magnesium stearate, adding anhydrous ethanol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and tabletting.
Example 17
The embodiment discloses a tablet taking a compound of 1,2, 3-tri-O-galloyl-beta-D-glucopyranose and acarbose as raw materials, which comprises the following components:
Figure SMS_18
Figure SMS_19
making into 100 pieces.
Mixing 1,2, 3-tri-O-galloyl-beta-D-glucopyranose, acarbose, hydroxypropyl methylcellulose, talcum powder, lactose and magnesium stearate, adding absolute ethyl alcohol to prepare soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and tabletting.
Example 18
The embodiment provides a capsule taking a compound Euphorbiacetophenone E and voglibose as raw material medicines, which comprises the following components:
Euphorbiacetophenone E 18.0mg
voglibose 2.0g
Microcrystalline cellulose 0.2g
Starch 6.0g
Sodium metabisulfite 0.2g
Magnesium stearate 0.2g
Absolute ethyl alcohol 0.1mL
Making into 100 granules.
Mixing Euphorbiacetophenone E with voglibose, starch, microcrystalline cellulose, and sodium metabisulfite, adding absolute ethanol, making into soft mass, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and making into capsule.
Example 19
The embodiment provides a capsule taking the compounds 1,2, 3-tri-O-galloyl-beta-D-glucopyranose and voglibose as raw material medicines, which comprises the following components:
1,2,3-tri-O-galloyl-β-D-glucopyranose 17.0mg
voglibose 2.0g
Microcrystalline cellulose 0.2g
Starch 5.0g
Sodium metabisulfite 0.2g
Magnesium stearate 0.2g
Absolute ethyl alcohol 0.1mL
Making into 100 granules.
Mixing 1,2, 3-tri-O-galloyl-beta-D-glucopyranose, voglibose, starch, microcrystalline cellulose and sodium metabisulfite, adding absolute ethanol to obtain soft material, sieving with 24 mesh sieve, granulating, drying, adding magnesium stearate, mixing, and making into capsule.
Example 20
The embodiment discloses an injection taking a compound Euphorbiacetophenone E and insulin as raw material medicaments, which comprises the following components:
Euphorbiacetophenone E 40.0mg
insulin 2.0g
Vitamin C 0.2g
Sodium chloride 6.0g
Sodium bicarbonate 0.1mL
Water for injection 1000mL
100 pieces of the Chinese herbal medicine are prepared. After the components are evenly mixed, 100 pieces can be obtained by adopting the conventional preparation method of injection.
Example 21
The embodiment discloses an injection taking a compound of 1,2, 3-tri-O-galloyl-beta-D-glucopyranose and insulin as raw materials, which comprises the following components:
1,2,3-tri-O-galloyl-β-D-glucopyranose 39.0mg
insulin 2.0g
Vitamin C 0.2g
Sodium chloride 5.0g
Sodium bicarbonate 0.1mL
Water for injection 1000mL
100 pieces of the Chinese herbal medicine are prepared. After the components are evenly mixed, 100 pieces can be obtained by adopting the conventional preparation method of injection.
The pharmaceutical preparations prepared in examples 6 to 21 all have obvious inhibition effect on alpha-glucosidase and can be applied as a medicament for treating diabetes.
In order to better understand the essence of the present invention, the novel application of the above glycoside compounds in the pharmaceutical field will be described below in conjunction with pharmacological tests and results.
Test example 1
This test example provides an alpha-glucosidase inhibitory activity assay of the compounds Euphorbiacetophenone E, 1,2, 3-tri-O-galloyl-beta-D-glucopyranoside and the known compounds 3,5-dihydroxy-2,4-dimethyl-1-O- (6' -O-galloyl-1-beta-D-glucopyranoside) -benzophenone, salaciacochinoside A, 3,4, 6-tri-O-galloyl-beta-D-glucopyranoside and 1-O-gallocy-6-O- (3-methoxy) cam-beta-D-glucopyranoside.
(1) Experimental materials and instruments
Alpha-glucosidase (from yeast), 4-nitrobenzene-alpha-D-glucopyranoside (p-NPG), acarbose all purchased from shanghai source leaf biotechnology limited; PBS (beijing solibao technologies limited); reagent anhydrous Na 2 CO 3 Is analytically pure.
Carbon dioxide cell incubator (us Thermo Fisher Scientific company); full wavelength microplate reader (us Thermo Fisher Scientific company); pipettes (Eppendorf, germany).
(2) Experimental method
The experiments were divided into a blank group, a blank control group, a sample blank group and a sample group. Experiments are carried out in 96-well plates, 20 mu L of sample or positive drug acarbose with different concentrations is added into each well of a sample group and a sample blank group, 3 parallel compound wells are arranged in each group, 100 mu L of PBS buffer solution is respectively added into each group, 120 mu L of PBS buffer solution is added into a blank control group and a sample blank group, and 140 mu L of PBS buffer solution is added into a blank group; adding 20 μL of alpha-glucosidase phosphate buffer solution (0.25U/mL) into the sample group and the blank group, incubating at 37 ℃ for 15min, taking out, adding 20 μL of 2.5mmol/Lp-NPG solution, fully mixing, incubating at 37 ℃ for 15min, and adding 40 μL of Na at 0.2mol/L after the completion 2 CO 3 The solution was quenched. The absorbance was measured at 405nm according to the following formula:
inhibition ratio (%) = [ (OD control-OD control blank) - (OD sample-OD sample blank) ]/(OD control-OD control blank) ×100% >
The inhibition of α -glucosidase by each sample was calculated. Using acarbose as positive control to obtain corresponding IC 50 Values.
(3) The results are shown in Table 1:
screening of alpha-glucosidase inhibitory Activity of Compounds of Table 1.Euphorbiacetophenone E, 1,2, 3-tri-O-galloyl-beta-D-glucopyranose and the like
Figure SMS_20
The results in Table 1 show that the glycoside compounds Euphorbiacetophenone E and 1,2, 3-tri-O-galloyl-beta-D-glucopyranose have good inhibition effect on alpha-glucosidase, the inhibition activity is superior to that of Acarbose which is a positive drug and other known compounds, the inhibition effect is arranged from big to small and is 1,2, 3-tri-O-galloyl-beta-D-glucopyranose > Euphorbiacetophenone E > 3,4, 6-tri-O-galloyl-beta-D-glucopyranose > 3,5-dihydroxy-2,4-dimethyl-1-O- (6' -O-galloyl-1-beta-D-glucopyranose) -benzophenol > Acarose > 1-O-galloy-6-O- (3-methoxy-beta-D-glucopyranose > 35. Alpha. The compounds are more active than the natural glycoside compounds in the invention, and can be used as the natural products for treating diabetes.
Test example 2
The test example discloses an alpha-glucosidase inhibition kinetic test of a compound of 1,2, 3-tri-O-galloyl-beta-D-glucopyranose.
(1) Experimental materials and instruments
Alpha-glucosidase (from yeast), 4-nitrobenzene-alpha-D-glucopyranoside (p-NPG), acarbose all purchased from shanghai source leaf biotechnology limited; PBS (beijing solibao technologies limited); the reagent anhydrous Na2CO3 is analytically pure.
Carbon dioxide cell incubator (us Thermo Fisher Scientific company); full wavelength microplate reader (us Thermo Fisher Scientific company); pipettes (Eppendorf, germany).
(2) Determination of the binding mode of alpha-glucosidase
According to the method of test 1, initial rates of reaction of different concentrations of 1,2, 3-tri-O-galloyl-beta-D-glucopyranose (0,12.5,25,50 mu mol/L) and alpha-glucosidase are respectively 0.125, 0.25, 0.5 and 1.0U/mL, the final concentration of the substrate p-NPG is 2.5mmol/L, three parallel holes are formed in each concentration, the enzyme concentration E (U/mL) is taken as an abscissa, the initial rate v (delta OD/min) of reaction is taken as an ordinate, and the characteristic of the graph is utilized to infer the enzyme binding mode.
(3) Determination of type of alpha-glucosidase inhibition
According to the method of test 1, the initial speed of the reaction between 1,2, 3-tri-O-galloyl-beta-D-glucopyranose (0,12.5,25,50 mu mol/L) and the substrate p-NPG with the concentration of 0.625, 1.25, 2.5 and 5mmol/L is measured respectively, the alpha-glucosidase concentration is added to be 0.25U/mL, three parallel holes are made for each concentration, statistical drawing is carried out according to Michaelis-Menten and Lineweaver-Burk equations, and the inhibition dynamics curve is drawn to determine the inhibition type.
(4) Statistical analysis
Data were processed using GraphPad Prism 6.02 software and all experimental results were measured 3 times and expressed as mean ± standard deviation (x ± SD).
(5) Results
As shown in FIGS. 1 and 2, the compound 1,2, 3-tri-O-galloyl-beta-D-glucopyranose is an alpha-glucosidase inhibitor with good inhibitory activity, and is a reversible inhibitor by non-covalent bond with enzyme to lose or reduce activity
As can be seen from FIGS. 3 and 4, the inhibition pattern of the compounds 1,2, 3-tri-O-galloyl-beta-D-glucopyranose and alpha-glucosidase is a mixed inhibition, V with increasing substrate concentration max Reduction, K m The increase, i.e. the compound not only competes with the substrate for binding to the enzyme active site, but also binds to the free enzyme or enzyme-substrate complex, thereby reducing or losing the enzyme activity.
In conclusion, the glycoside compound has the inhibition activity superior to that of acarbose which is a first-line drug for reducing blood glucose, and can be used as a drug for treating diabetes.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (9)

1. A glycoside compound characterized by having a parent nucleus structure of formula (I):
Figure QLYQS_1
wherein,,
R 1 is that
Figure QLYQS_2
R2 is->
Figure QLYQS_3
2. A pharmaceutical composition comprising the glycoside compound according to claim 1.
3. The pharmaceutical composition of claim 2, comprising a combination drug comprising one or more of the following: insulin, tolbutamide, chlorpropamide, glibenclamide, glipizide gliclazide, glimepiride, glibenclamide, gliquidone, metformin, gliclazide, glimepiride, glibenclamide metformin hydrochloride, phenformin, pioglitazone hydrochloride, rosiglitazone maleate, troglitazone, ciglitazone, englitazone Algliptin, alogliptin benzoate, saxagliptin, sitagliptin phosphate, vildagliptin, linagliptin, sugar-100, acarbose, voglibose, miglitol, repaglinide, nateglinide, mitiglinide, exenatide, liraglutide, pralidoxime Lin Lantai, pralanin acetate.
4. A pharmaceutical composition according to claim 3, wherein the insulin is selected from one or more of zinc insulin hypo-protamine, zinc insulin globin or zinc insulin protamine.
5. A pharmaceutical composition according to claim 2 or 3, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient; the dosage form of the pharmaceutical composition is selected from any one of tablets, capsules, granules, oral liquid, syrup, paste, electuary, dripping pills or pellets.
6. The method for preparing the glycoside compound according to claim 1, wherein the glycoside compound is isolated from euphorbia lathyris;
the method comprises the following steps:
(a) Drying radix Euphorbiae Fischerianae, pulverizing, extracting with extraction solvent, mixing extractive solutions, filtering, and concentrating under reduced pressure to obtain concentrated solution;
(b) Extracting the concentrated solution by using an organic solvent, and combining organic phases to obtain an extract;
(c) Performing silica gel column chromatography on the extract, performing gradient elution by using an eluent to obtain a first target fraction, and performing reversed-phase silica gel column chromatography elution to obtain a second target fraction; subjecting the second target fraction to sephadex column chromatography and eluting;
(d) Purification by reverse phase or normal phase preparative liquid chromatography gives the compound.
7. The preparation method according to claim 6, wherein in the step (a), the mass of the extraction solvent is 8-15 times of the mass of the euphorbia lathyris root raw material, the extraction is reflux extraction, the time of the reflux extraction is 1-3 hours, the temperature is 65-85 ℃, the times of the reflux extraction is 2-4 times, and the extraction solvent is 60% -95% ethanol;
in the step (b), after dispersing with water, ethyl acetate is used for extraction for 2 to 5 times, and the dosage of the ethyl acetate is 1.5 to 2 times of the volume of the concentrated solution;
in step (c), the gradient elution eluent is selected from any one of petroleum ether-ethyl acetate and cyclohexane-ethyl acetate; the eluent of the reverse phase silica gel column chromatography is selected from any one of ethanol-water or methanol-water; the eluent of the Sephadex column chromatography is selected from any one of methanol and dichloromethane-methanol, and the Sephadex type is Sephadex LH-20;
in the step (d), the chromatographic column in the chromatographic purification treatment is a C18 reversed phase chromatographic column; the mobile phase is selected from any one of methanol-water or acetonitrile-water.
8. Use of a glycoside compound according to claim 1 or a pharmaceutical composition according to any one of claims 3 to 6 for the preparation of a medicament for the prevention or treatment of diabetes and complications thereof.
9. The use of a glycoside compound or pharmaceutical composition according to claim 8 for the preparation of a medicament for the prophylaxis or treatment of diabetes and complications thereof, characterized by the use of an α -glucosidase inhibitor hypoglycemic agent.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106065023A (en) * 2015-04-23 2016-11-02 中国医学科学院药物研究所 Hydrolysable tannin compounds, its medical composition and its use

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