CN115010598A - Compound Villanovane VI, pharmaceutical composition thereof, preparation method and application thereof - Google Patents
Compound Villanovane VI, pharmaceutical composition thereof, preparation method and application thereof Download PDFInfo
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- CN115010598A CN115010598A CN202210376380.3A CN202210376380A CN115010598A CN 115010598 A CN115010598 A CN 115010598A CN 202210376380 A CN202210376380 A CN 202210376380A CN 115010598 A CN115010598 A CN 115010598A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
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- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 6
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- DNJVYWXIDISQRD-UHFFFAOYSA-N Cafestol Natural products C1CC2(CC3(CO)O)CC3CCC2C2(C)C1C(C=CO1)=C1CC2 DNJVYWXIDISQRD-UHFFFAOYSA-N 0.000 description 3
- JEKMKNDURXDJAD-UHFFFAOYSA-N Kahweol Natural products C1CC2(CC3(CO)O)CC3CCC2C2(C)C1C(C=CO1)=C1C=C2 JEKMKNDURXDJAD-UHFFFAOYSA-N 0.000 description 3
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- IVZWRQBQDVHDNG-UHFFFAOYSA-N (-)-Kauran; alpha-Dihydrokauren Natural products C1CC2C3(C)CCCC(C)(C)C3CCC22CC(C)C1C2 IVZWRQBQDVHDNG-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- UYNPPIDGSVPVSW-UHFFFAOYSA-N ent-kaurane Natural products CC1(O)CC23CCC4C(CCCC4(C)C(=O)O)C2C=CC1C3 UYNPPIDGSVPVSW-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
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- LVTHXRLARFLXNR-UHFFFAOYSA-M potassium;1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound [K+].[O-]S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F LVTHXRLARFLXNR-UHFFFAOYSA-M 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- General Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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Abstract
The invention provides an antipodal-coastal twinborn anthane coffee diterpene (compound Villanovane VI), a pharmaceutical composition thereof, a preparation method thereof and application thereof in preparing medicaments and foods. Belongs to the technical field of medicines and foods. The novel compound Villanovane VI pairα-glucosidase inhibitory activity IC 50 (mu.M) is 9.2 +/-1.73, and the compound Villanovane VI pairαFirst line clinical glucosidase inhibitory ActivityαThe glucosidase inhibitory drug, Acarbose, is stronger. Can be used as medicine for treating diabetes related diseases. Can be used as health product for lowering blood sugar. The preparation method has the advantages of easily available raw materials, easy operation and high yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines and foods, and particularly relates to an antipodal-coastal twinborn peanut type coffee diterpene (compound Villanovane VI), a pharmaceutical composition thereof, a preparation method thereof, and application thereof in preparation of medicines and foods.
Background
Coffee diterpenes belong to ent-kaurane diterpenes and are a very important secondary metabolite in coffee, two main components are cafestol and kahweol, and because coffee diterpene substances exist in coffee in a non-negligible manner, a great deal of research is carried out all the time, including novel coffee diterpene structures and active functions. At present, the coffee diterpenoid compounds have deeper research on the antitumor activity, and have the activities of resisting bacteria, resisting viruses and the like besides the antitumor activity.
The present inventors have been exploring deeply the novel structure and activity of coffee diterpene, and have found that the compounds of coffee diterpene and the like have been published 13 C NMR is carried out, and a coffee diterpene database is established; then writing data matching grammar (DATAanalyyte software) by Python to carry out crude extraction 13 C NMR is compared with a database, main diterpene compounds in the crude extract are quickly analyzed, the crude extract is selectively purified, and new active diterpene compounds are quickly discovered, separated and identified. With this technology, more than 80 new coffee diterpenoids were found from Yunnan coffee, including oxidized diterpenes, rearranged diterpenes, furan diterpenes, lactam diterpenes, lactone diterpenes, Δ 4,18 diterpenes, degraded diterpenes, veranorwa diterpenes, and etianane diterpenes. The qiuhuang research team recently discovered ten novel enantiomeric kaurane diterpene derivatives from roasted beans of Yunnan coffee. Four of them showed moderate inhibition of alpha-glucosidase, and the two diterpenes Cafestol and Kahweol, the highest in coffee, were found to be active on alpha-glucosidaseGlycosidases do not show inhibitory effects, but are of great interest: the coffee diterpene main component showed moderate alpha-glucosidase inhibitory activity against dehydration products Dehydrocafestol and Dehydrokahweol of Cafestol and Kahweol. This phenomenon indicates that the double bond between C-15 and C-16 is advantageous for exerting the alpha-glucosidase inhibitory activity. The possible mechanism of the activity of the diterpene derivatives is intensively studied by molecular docking experiments.
To date, no report on the novel compound Villanovane VI, nor on its activity and use, has been found in the prior art.
The invention content is as follows:
the invention aims to provide a novel enantiomer-coastal twinborn peanut type coffee diterpene, a pharmaceutical composition and a preparation method thereof, and application of the novel enantiomer-coastal twinborn peanut type coffee diterpene in preparation of medicines and foods.
The invention applies the analysis technology of a coffee diterpene NMR characteristic database to separate and identify 60 compounds in the boiled beans of the Yunnan coffee cultivar S288, wherein the compounds comprise 2 types of diterpene new skeletons and 32 new compounds. Alpha-glucosidase inhibition activity experiments are carried out on the separated coffee diterpene, and the results show that: the novel compound Villanovane VI shows a medium inhibitory activity which is obviously superior to that of acarbose. The novel compound Villanovane VI belongs to an enantiomorph-coastal twin arachidine diterpenoid, and the invention also discusses the alpha-glucosidase inhibitory activity of part of the diterpenoids separated and identified by molecular docking in a configuration relationship.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
a compound Villanovane VI of the formula,
the invention also provides a preparation method of the compound Villanovane VI, which comprises the following steps: crushing roasted Yunnan coffee beans, heating and refluxing the roasted Yunnan coffee beans by using 3-5 times of methanol for twice, wherein the extraction time is 10 hours and 3 hours respectively, combining extracting solutions, recovering a solvent under reduced pressure to obtain a concentrated extract MeOHE, dispersing the extract in a water phase, and sequentially extracting by using petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE respectively; performing flow part segmentation on AcOEtE extractum by using a normal phase silica gel column, using petroleum ether/ethyl acetate as a mobile phase and chloroform/methanol as a mobile phase, wherein the petroleum ether/ethyl acetate is in a volume ratio of 15:1, 10:1, 2:1, 1:1 and 1:4, and the chloroform/methanol is in a volume ratio of 50:1, 20:1, 10:1, 2:1, 1:1 and 0:1, so as to obtain eight groups of segments Fr.A → Fr.H; and (3) carrying out flow fraction segmentation on the Fr.B part by using a C18 reverse phase chromatographic column and water/methanol of 70:30 → 0:100, and combining the same parts to obtain 9 parts Fr.B-1 → Fr.B-9, wherein the Fr.B-6 part is treated by using a normal phase silica gel column chromatography and petroleum ether/ethyl acetate 4:1 → 0:1 to respectively obtain 6 parts Fr.B-6-1 → Fr.B-6-6, the Fr.B-6-4 is subjected to reverse phase silica gel column chromatography and acetonitrile/water 45:55 purification to obtain a monomer compound Villanovane VI.
The invention also provides application of the compound Villanovane VI in preparing a medicament for treating diabetes.
The application of a compound Villanovane VI in preparing hypoglycemic drugs.
Use of compound Villanovane vi in the preparation of a food product.
In addition, the invention also provides a pharmaceutical composition containing the compound Villanovane VI and a pharmaceutically acceptable carrier.
The preparation method of the pharmaceutical composition comprises the following steps: crushing roasted Yunnan coffee beans, heating and refluxing the roasted Yunnan coffee beans by using 3-5 times of methanol for twice, wherein the extraction time is 10 hours and 3 hours respectively, combining extracting solutions, recovering a solvent under reduced pressure to obtain a concentrated extract MeOHE, dispersing the extract in a water phase, and sequentially extracting by using petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE respectively; performing flow part segmentation on AcOEtE extractum by using a normal phase silica gel column, using petroleum ether/ethyl acetate as a mobile phase and chloroform/methanol as a mobile phase, wherein the petroleum ether/ethyl acetate is in a volume ratio of 15:1, 10:1, 2:1, 1:1 and 1:4, and the chloroform/methanol is in a volume ratio of 50:1, 20:1, 10:1, 2:1, 1:1 and 0:1, so as to obtain eight groups of segments Fr.A → Fr.H; performing fractional division on the Fr.B part by using a C18 reverse phase chromatographic column and water/methanol with a ratio of 70:30 → 0:100, combining the same parts to obtain 9 parts Fr.B-1 → Fr.B-9, wherein the Fr.B-6 part is processed by using a normal phase silica gel column chromatography and petroleum ether/ethyl acetate 4:1 → 0:1 to respectively obtain 6 parts Fr.B-6-1 → Fr.B-6-6, the Fr.B-6-4 part is subjected to reverse phase silica gel column chromatography and acetonitrile/water 45:55 purification to obtain a monomer compound Villanovane VI, and then adding a medicinal carrier.
The application of the pharmaceutical composition in preparing medicines for treating diabetes is provided.
The application of the medicine composition in preparing hypoglycemic medicine.
Application of the pharmaceutical composition in preparing food.
When the compound of the present invention is used as a medicament, it may be used as it is or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90%, of the compound of the invention, the remainder being pharmaceutically acceptable, non-toxic and inert pharmaceutically acceptable carriers and/or excipients for humans and animals.
The pharmaceutically acceptable carrier or excipient is one or more of solid, semi-solid and liquid diluents, fillers and pharmaceutical adjuvants. The pharmaceutical composition of the present invention is used in the form of a dose per unit body weight. The medicine of the invention can be administrated in various forms (liquid preparation, solid preparation, injection, external preparation, spray and compound preparation).
Compared with the prior art, the invention has the following advantages:
1. the invention provides a new compound Villanovane VI, which fills the blank of the prior art.
2. The invention provides a method for preparing a novel compound Villanovane VI, which has the advantages of easily obtained raw materials, easy operation and high yield and is suitable for industrial production.
3. The invention provides a pharmaceutical composition with a novel compound Villanovane VI as an active ingredient, and provides a novel medicament with better medicinal effect for a novel anti-tumor medicament.
4. The novel compound Villanovane VI of the invention has alpha-glucosidase inhibition activity IC 50 The (mu M) is 9.2 +/-1.73, and the alpha-glucosidase inhibitory activity of the compound Villanovane VI is stronger than that of a first-line clinical alpha-glucosidase inhibitory drug, Acarbose.
5. The novel compound Villanovane VI can be used as a medicine for treating diabetes-related diseases. Can be used as a health product for reducing blood glucose.
Description of the drawings:
FIG. 1A flow chart of the preparation process of Villanovane VI;
FIG. 2 results of molecular docking of Villanovane VI with alpha-glucosidase protein;
FIG. 3 is a schematic diagram of the chemical structure of the compound Villanovane VI.
The specific implementation mode is as follows:
the following description will further explain the substance of the present invention by using the embodiments of the present invention with reference to the accompanying drawings, but the present invention is not intended to be limited thereto.
Example 1
Preparation of an ent-coastal gemini caffeoditerpene (compound Villanovane VI):
the method comprises the steps of taking a certain amount of Yunnan coffee S288 roasted beans, crushing the roasted beans, then heating and refluxing the crushed roasted beans by 3-5 times of methanol for twice extraction, wherein the extraction time is 10 hours and 3 hours respectively, combining extracting solutions, recovering a solvent under reduced pressure to obtain a concentrated extract MeOHE (yield is 20% -25%), dispersing the extract in a water phase, and sequentially extracting by petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE (yield is 6% -8%).
And (3) performing flow portion segmentation on the AcOEtE extract by using a normal phase silica gel column and using petroleum ether/ethyl acetate as a mobile phase (15:1, 10:1, 2:1, 1:4, v/v) and chloroform/methanol as a mobile phase (50:1, 20:1, 10:1, 2:1, 1:1, 0:1, v/v) to obtain eight groups of segments (Fr.A → Fr.H). Fraction fractionation of Fr.B (yield 0.2% -0.3%) with water/methanol (70:30 → 0:100, v/v) using a C18 reverse phase column and the same fractions were combined to give 9 fractions (Fr.B-1 → Fr.B-9). Wherein Fr.B-6 fraction (yield 0.1% -0.15%) is treated with normal phase silica gel column chromatography (petroleum ether/ethyl acetate, 4:1 → 0:1, v/v) to obtain 6 fractions (Fr.B-6-1 → Fr.B-6-6), respectively. And Fr.B-6-4 is purified by reverse phase silica gel column chromatography (acetonitrile/water, 45:55) to obtain a monomer compound Villanovane VI (the yield is 0.02-0.04 percent).
The preparation process flow of the compound Villanovane VI is as follows: according to the experimental summary, the preparation process flow of the target active molecule Villanovane VI is summarized in figure 1. Structural characterization of a target active molecule Villanovane VI:
1) chemical structure of compound vilannovane vi:
2) structural characterization of compound Villanovane VI.
Villanovane vi: white amorphous powder. [ alpha ] to] 28 D 96.54(c 0.26,MeOH)；UV(MeOH)λmax(logε):243.0(4.01),196.0(4.02)；HRESIMS m/z 339.1931[M+Na] + Giving the formula C 20 H 28 O 3 (calculated value: C) 20 H 28 O 3 Na + ,339.1931)；。
1 H NMR(CH 3 OD,600MHz,J in Hz)δ H :1.50(1H,m,H-1a),1.56(1H,m,H-1b),1.54(1H,m,H-2a),1.93(1H,m,H-2b),1.09(1H,m,H-3a),2.21(1H,m,H-3b),2.11(1H,d,J＝10.2Hz,H-5),6.11(1H,d,J＝10.2Hz,,H-6),5.88(1H,dd,d,J＝3,10.2Hz,H-7),1.33(1H,m,H-11a),1.85(1H,m,H-11b),1.66(2H,m,H-12),2.39(1H,m,H-13),1.58(1H,m,H-14a),1.76(1H,m,H-14b),5.17(1H,brs,H-15),2.63(1H,m,H-16),3.50(2H,d,J＝8.4Hz,H-17),1.30(3H,s,H-18),0.83(3H,s,H-20),xx(1H,s,COOH)。
13 C NMR(CH 3 OD,150MHz)δ C :32.2(CH 2 ,C-1),20.5(CH 2 ,C-2),38.7(CH 2 ,C-3),44.5(C,C-4),52.2(CH,C-5),128.4(CH,C-6),126.7(CH,C-7),144.7(C,C-8),53.8(C,C-9),39.1(C,C-10),32.9(CH 2 ,C-11),24.2(CH 2 ,C-12),35.9(CH,C-13),36.6(CH 2 ,C-14),123.2(CH,C-15),47.9(CH,C-16),64.4(CH 2 ,C-17),30.0(CH 3 ,C-18),181.2(C,C-19),17.5(CH 3 ,C-20).
Example 2
Test of the alpha-glucosidase inhibitory activity of compound Villanovane vi with control:
1) principle of experiment
Alpha-glucosidase can catalyze alpha-1, 4-glycosidic bond hydrolysis, and hydrolyze oligosaccharides such as maltose, sucrose and the like in the small intestine. Inhibiting the activity of alpha-glucosidase, slowing the generation and absorption of glucose, reducing the peak value of postprandial blood sugar, and regulating the blood sugar level. Alpha-glucosidase inhibitors have become a research hotspot in pharmaceutical chemistry in recent years. 4-Nitrophenyl-alpha-D-glucopyranoside (PNPG) is a specific substrate for alpha-glucosidase, PNPG can be hydrolyzed by alpha-glucosidase to produce p-nitrophenol (yellow), and the product has characteristic absorption at 405 nm. The alpha-glucosidase inhibitory activity of the compound can be determined by comparing the production amount of p-nitrophenol in the system before and after the compound Villanovane VI is added. Acarbose (Acarbose) was selected as a positive control in the experiment.
2) Experimental method
i) Solution preparation
a) Phosphate buffered saline PBS (pH 6.86) Mixed phosphate powder was added to a 500mL volumetric flask, and CO-free solution was added 2 Distilled water is added to the scale, dissolved and shaken evenly, and then stored at 4 ℃ for standby.
b) Substrate solution PNPG (2.5mM) 37.6mg of PNPG was weighed out precisely, and the volume was adjusted to 50mL with the above PBS, dissolved, shaken well, and stored at 4 ℃ for future use.
c) 2.3mg (26U/mg) of glucosidase powder was precisely weighed out and dissolved in the above PBS to 10U/mL, and the solution was dispensed into 10U/mL tubes and stored at-20 ℃ until use. Each time diluted 10-fold with PBS.
d)Na 2 CO 3 Solution (0.2M) anhydrous Na was weighed 2 CO 3 2.12g of the powder was put in a 100mL volumetric flask, and the volume was adjusted to 100mL by the above-mentioned PPBS, dissolved and shaken well, and then stored at 4 ℃ for later use.
e) The sample solution is a monomer compound mother solution with the preparation concentration of 20 mu mol/mL, and the positive medicine mother solution with the preparation concentration of 20 mu mol/mL. The mother liquor was diluted to the corresponding fold when assayed.
ii) determination of alpha-glucosidase inhibitory Activity
Sample group, in 96-well plate, 40. mu.L PBS buffer solution, 10. mu.L sample solution, 10. mu.L alpha-grape were added in sequencePre-incubating glycosidase solution at 37 deg.C for 10min, adding 50 μ L PNPG solution, incubating at 37 deg.C for 60min, and adding 80 μ L Na 2 CO 3 And (3) solution.
Background group, 50. mu.L PBS buffer solution and 10. mu.L sample solution were sequentially added to a 96-well plate, pre-incubated at 37 ℃ for 10min, then 40. mu.L PNPG solution was added, incubated at 37 ℃ for 60min, and finally 80. mu.L Na was added 2 CO 3 And (3) solution.
The control group comprises adding 40 μ L PBS buffer solution and 10 μ L acarbose solution into 96-well plate, pre-incubating at 37 deg.C for 10min, adding 40 μ L PNPG solution, incubating at 37 deg.C for 60min, and adding 80 μ L Na 2 CO 3 And (3) solution.
Each group of experiments is carried out in parallel for three times, the absorbance at 405nm is detected in a microplate reader, and the enzyme inhibition rate of the sample is calculated according to the following formula, wherein the inhibition rate of alpha-glucosidase is equal to (OD) Background -OD Sample (I) )/OD Background ×100％。
As a result:
IC of compound Villanovane VI on alpha-glucosidase inhibitory activity 50
Villanovane Ⅵ IC 50 (μM)9.2±1.73
Same experiment in Acarbose IC 50 (μM)60.71±16.45
The experimental results show that: the compound Villanovane VI has stronger inhibiting activity to alpha-glucosidase than first-line clinical alpha-glucosidase inhibiting drug Acarbose.
Active compound molecular docking results:
results of molecular docking of the compound Villanovane VI and alpha-glucosidase protein (figure 2) show that the carbonyl group on C-19 of Villanovane VI is respectively connected with TRP81
And ASP64
Hydrogen bonds are formed.
Formulation examples:
1. taking the compound Villanovane VI, adding an excipient according to the weight ratio of the Villanovane VI to the excipient of 1:1, and granulating and tabletting.
2. Taking the compound Villanovane VI, adding an excipient according to the weight ratio of the Villanovane VI to the excipient of 1:2, and granulating and tabletting.
3. Taking the compound Villanovane VI, and preparing into capsules according to a conventional capsule preparation method.
4. Compound vilannovane vi was taken and tableted as follows:
5. and (3) capsule preparation: taking 100mg of a compound Villanovane VI, a proper amount of starch and a proper amount of Rumex stearate, and preparing the preparation method: mixing the compound with adjuvants, sieving, mixing in suitable container, and encapsulating the obtained mixture into hard gelatin capsule.
6. Mixing Villanovane VI 1 part and vegetable fat powder 10 parts, and making into solid beverage by conventional method.
Claims (10)
1. A compound Villanovane VI of the formula,
2. a process for the preparation of the compound Villanovane vi as claimed in claim 1, characterized in that it comprises the following steps: crushing roasted Yunnan coffee beans, heating and refluxing the roasted Yunnan coffee beans by using 3-5 times of methanol for twice, wherein the extraction time is 10 hours and 3 hours respectively, combining extracting solutions, recovering a solvent under reduced pressure to obtain a concentrated extract MeOHE, dispersing the extract in a water phase, and sequentially extracting by using petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE respectively; carrying out flow part segmentation on AcOEtE extractum on a normal phase silica gel column by taking petroleum ether/ethyl acetate with volume ratios of 15:1, 10:1, 2:1, 1:1 and 1:4 as a mobile phase and chloroform/methanol with volume ratios of 50:1, 20:1, 10:1, 2:1, 1:1 and 0:1 as a mobile phase to obtain eight component segments Fr.A → Fr.H; and (3) carrying out flow fraction segmentation on the Fr.B part by using a C18 reverse phase chromatographic column and water/methanol of 70:30 → 0:100, and combining the same parts to obtain 9 parts Fr.B-1 → Fr.B-9, wherein the Fr.B-6 part is treated by using a normal phase silica gel column chromatography and petroleum ether/ethyl acetate 4:1 → 0:1 to respectively obtain 6 parts Fr.B-6-1 → Fr.B-6-6, the Fr.B-6-4 is subjected to reverse phase silica gel column chromatography and acetonitrile/water 45:55 purification to obtain a monomer compound Villanovane VI.
3. Use of a compound Villanovane vi according to claim 1 for the manufacture of a medicament for the treatment of diabetes.
4. Use of a compound Villanovane vi according to claim 1 for the preparation of a hypoglycemic agent.
5. Use of the compound Villanovane vi according to claim 1 for the preparation of a food product.
6. A pharmaceutical composition comprising a compound of Villanovane vi according to claim 1 and a pharmaceutically acceptable carrier.
7. A process for preparing a pharmaceutical composition according to claim 6, characterized in that it comprises the following steps: crushing roasted Yunnan coffee beans, heating and refluxing the roasted Yunnan coffee beans by using 3-5 times of methanol for twice, wherein the extraction time is 10 hours and 3 hours respectively, combining extracting solutions, recovering a solvent under reduced pressure to obtain a concentrated extract MeOHE, dispersing the extract in a water phase, and sequentially extracting by using petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE respectively; performing flow part segmentation on AcOEtE extractum by using a normal phase silica gel column, using petroleum ether/ethyl acetate as a mobile phase and chloroform/methanol as a mobile phase, wherein the petroleum ether/ethyl acetate is in a volume ratio of 15:1, 10:1, 2:1, 1:1 and 1:4, and the chloroform/methanol is in a volume ratio of 50:1, 20:1, 10:1, 2:1, 1:1 and 0:1, so as to obtain eight component segments Fr.A → Fr.H; performing fractional division on the Fr.B part by using a C18 reverse phase chromatographic column and water/methanol with a ratio of 70:30 → 0:100, combining the same parts to obtain 9 parts Fr.B-1 → Fr.B-9, wherein the Fr.B-6 part is processed by using a normal phase silica gel column chromatography and petroleum ether/ethyl acetate 4:1 → 0:1 to respectively obtain 6 parts Fr.B-6-1 → Fr.B-6-6, the Fr.B-6-4 part is subjected to reverse phase silica gel column chromatography and acetonitrile/water 45:55 purification to obtain a monomer compound Villanovane VI, and then adding a medicinal carrier.
8. The use of the pharmaceutical composition of claim 6 in the preparation of a medicament for the treatment of diabetes.
9. The use of the pharmaceutical composition of claim 6 for the manufacture of a medicament for lowering blood glucose.
10. Use of the pharmaceutical composition of claim 6 for the preparation of a food product.
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