CN105147710B - A kind of hypoglycemic drug and its preparation method and application - Google Patents
A kind of hypoglycemic drug and its preparation method and application Download PDFInfo
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- CN105147710B CN105147710B CN201510578171.7A CN201510578171A CN105147710B CN 105147710 B CN105147710 B CN 105147710B CN 201510578171 A CN201510578171 A CN 201510578171A CN 105147710 B CN105147710 B CN 105147710B
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- acid
- pyrocincholic
- quinovopyranosyl
- compound
- glucopyranosyl
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- 210000000683 abdominal cavity Anatomy 0.000 description 1
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Abstract
Pyrocincholic acid type triterpenoid saponins in yellow Populus deltoides, phalanges frame is containing there are one pyrocincholic acid, the C 3 of pyrocincholic acid is connected with 1 ' position of a β D quinovose base by oxygen atom, and the triterpenoid saponin that is connected by oxygen atom of 28 carboxyls of C and 1 " position of a β D glucosyl group and other three derivatives with skeleton structure; preferred formula (I) compound represented; in formula (I), R1=β D quinovopyranosyl, R2=β D glucose.Wherein triterpene saponin compound 14 is the anti-type-II diabetes hypoglycemic drug in novel plant source.It provides using the yellow Populus deltoides triterpenoid saponin extract containing Pyrocincholic acid type triterpenoid saponins and its monomeric compound as the pharmaceutical composition of active constituent, their preparation method and the application in preparing hypoglycemic drug.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular, to pyrocincholic acid types in a kind of yellow Populus deltoides
Triterpenoid saponin or the pharmaceutical composition that yellow Populus deltoides triterpenoid saponin extract is active ingredient, preparation method and its drop blood preparing
Application in sugared drug, and the application in preparing the hypoglycemic drug of anti-type-II diabetes.
Background technology
Type-II diabetes are a kind of chronic metabolic diseases characterized by hyperglycemia, at present incidence in the world
Persistently increase, has become the third-largest non-biography for seriously threatening health of people and life after cardiovascular and cerebrovascular diseases and malignant tumour
Infectious diseases.It is shown according to international diabetes association data, global diabetic's sum is up to 3.66 hundred million within 2011, it is contemplated that this
Number is up to 5.52 hundred million to the year two thousand thirty, and there are about 90-95% to belong to type II diabetes in diabetic.With living standard
It improves, aging of population and the increase of fat incidence, diabetes morbidity increase rapidly and have rejuvenation trend.Diabetes
Persistent high blood sugar and long-term metabolic disorder etc. can lead to body tissue's organ, especially eye, kidney, angiocarpy and nervous system
Damage and its dysfunction and failure.(Weill et al.,2004).Currently, the anti-type-II diabetes drop blood clinically used
Sugared drug mainly has insulin sensitivity enhancing class (such as biguanides and thiazolidinediones), and (such as lattice arrange Drugs Promoting Insulin Secretion sulfonylureas
U.S. urea etc.), alpha-glucosidase restrainer (such as acarbose and voglibose), exendin-4 (such as Ai Sai
That peptide etc.), DPP-4 inhibitor (such as Xi Gelieting).These drugs are all substantially chemical synthetic drug, although this its use takes
Preferable curative effect was obtained, the concentration of glucose in blood can be made to be decreased obviously, but blood glucose cannot be all controlled very well after being used for a long time
Concentration.In addition, these drugs also have certain side effect, such as liver renal toxicity, edema, diarrhea, therefore in dyshepatia
Its application is subject to certain restrictions in patient, and some patientss cannot be resistant to its treatment for a long time.Therefore, novel blood sugar lowing medicine is ground
Hair is always the emphasis of type II diabetes resisting drug research.Natural products is the Nature by long-term evolution and selects to optimize
The main source of compound and mankind's disease preventing and treating drug, have structure-rich, curative for effect, safety and low toxicity and without according to
The advantages that patience.In the small molecule new chemical entities (NCE) of the past few decades listing, nearly 60% is directly or indirectly to derive from
Natural products, natural products are still the important source of drug or lead compound research and development.So finding more to pacify from plant
Complete effective anti-type-II diabetes hypoglycemic drug has highly important academic significance and good application prospect.
Diabetes B is a kind of metabolic synthetic disease, forms the life with modern's high glucose and high fat and lack of exercise
Mode living is closely related.Streptozotocin (STZ) injects low dosage to the selective destruction of the beta Cell of islet of mouse
STZ can induce it to generate type-II diabetes.Mouse high-calorie feed raises certain time and fasting, by a certain amount of intraperitoneal injection
STZ can prepare animal model of diabetes mellitus type II, and have overweight, Impaired Glucose Tolerance Treated, blood fat liter by the model that the method is prepared
The characteristics of high, serum insulin increases and combination rate of insulin receptor is reduced with insulin resistance is similar to type II diabetes disease
The Clinical symptoms of people.For the diabetes mice of STZ inductions because its period is shorter, method is easy, is that research human type II diabetes control
Treat the ideal model of new drug.
Yellow Populus deltoides is Rubiaceae Huang Populus deltoides category single platymiscium, and pyrocincholic acid types triterpenoid saponins are in the plant
In that there are types is few, only therefrom isolated 4 at present.Such triterpenoid saponin because its content is relatively low and without UV absorption etc. it is former
Because of more difficult separation.In the prior art, triterpenoid saponin ingredient is detached from the plant published following method：Yellow Populus deltoides drying
9 kilograms of bark is crushed, three times with the extraction of methanol room temperature, is concentrated under reduced pressure, obtains 1668 grams of methanol extract.Methanol extract is dissolved in hot water
19 grams of petroleum ethers, 85 grams of chloroforms, 780 grams of n-butanols and 884 grams of water are obtained with petroleum ether, methanol and extracting n-butyl alcohol respectively afterwards
It is segmented position.Chloroform is segmented position through silica gel column chromatography (1.7kg SiO2；CHCl3/MeOH/H2O gradient elutions), obtain Fr.1-
8, Fr.7 chromatograph (SiO repeatedly through silicagel column and RP-C18 columns2:CHCl3/CH3OH/H2O 8:2:0.2；Rp-18:CH3OH/H2O
7.5:2.5) (22mg) the n-butanols of compound 1 are obtained through silica gel column chromatography (3.5kg SiO2；CHCl3/MeOH/H2O gradients are washed
It is de-), it obtains 7 segmentation position 1-7. segmentations positions 3 and chromatographs (SiO repeatedly through silicagel column and RP-C18 columns2:CHCl3/CH3OH/
H2O 8:2:0.2；Rp-18:CH3OH/H2O 7:3) obtain compound 2 (36mg) and 3 (29mg), segmentation position 4 through silicagel column and
RP-C18 columns chromatograph (SiO repeatedly2:CHCl3/CH3OH/H2O 7:3:0.3；Rp-18:CH3OH/H2O 6.5:3.5) chemical combination is obtained
Object 4 (35mg).Referring to：Zhang,Y.M.；Tan,N.H.；Huang,H.Q.；Zeng,G.Z.,Triterpernoid
saponins from Metadina trichotoma.Z.Naturforsch 2007,62b,745-748.The disadvantage is that our
Method uses yellow Populus deltoides bark part, larger to the destruction of resource, and compound (1), (2), (3), the content of (4) are low, separation
Purification step is more, and the mixed solvent system of organic solvent and water, the mixed solvent recovered temperature are repeatedly used in detaching
Height is unfavorable for the recycling of solvent, is unfavorable for industrial mass production.
It there are no pyrocincholic acid types triterpenoid saponin in yellow Populus deltoides in the prior art, yellow Populus deltoides triterpenoid saponin carries
Take object as the report of anti-type-II diabetes hypoglycemic drug.
Invention content
For in place of deficiencies of the prior art, the purpose of the present invention is to provide a kind of pyrocincholic
Acid types triterpenoid saponin and triterpene saponin componds and its salt pharmacologically allowed, or yellow Populus deltoides triterpenoid saponin extraction
Object is the hypoglycemic pharmaceutical composition of anti-type-II diabetes of active constituent, their preparation method, and its resists two types preparing
Application in diabetes hypoglycemic drug.Triterpene saponin of the present invention with anti-type-II diabetes hypoglycemic effect
It is to find its hypoglycemic activity for the first time to close object, prepares the method controllability and favorable reproducibility of such compound, and sample loss is few, at
This is relatively low, easy to operate, can be easier to isolated class pyrocincholic acid triterpenoid saponin, solvent can recycle repeatedly
It utilizes, is also applied for industrial production.
In order to realize the above-mentioned purpose of the present invention, the present invention provides following technical solutions：
Pharmaceutical composition, wherein the Pyrocincholic acid type triterpene saponin componds containing therapeutically effective amount,
Or its salt for pharmacologically allowing and pharmaceutically acceptable carrier, the Pyrocincholic acid type triterpene saponins
Compound refers to the positions C-3 of pyrocincholic acid, pyrocincholic acid and a β-D- there are one skeleton contains
1 ' position of quinovose base is connected by oxygen atom, and 1 " position of C-28 carboxyls and a β-D-Glucose base passes through oxygen atom
The triterpenoid saponin and other three derivatives with skeleton structure being connected.
Pharmaceutical composition, wherein the pyrocincholic acid triterpene saponin compound 1-4 containing therapeutically effective amount, or
Its salt pharmacologically allowed and pharmaceutically acceptable carrier, the pyrocincholic acid triterpene saponin compounds
1-4 is to have the following structural formula compound：pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-
O-β-D-glucopyranoside(1),pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-
3 β-O- β-D- of D-glucopyranosyl- (1 → 6)-β-D-glucopyranoside (2), pyrocincholic acid
glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-β-D-glucopyranoside(3),
pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-
β-D-glucopyranosyl-( 1→6)-β-D-glucopyranoside(4)
In formula, R1=β-D- quinovoses bases or β-D-Glucose-(1 → 4)-β-D- quinovose bases；R2=β-D-Glucose base
Or β-D-Glucose-(1 → 6)-β-D-Glucose bases,
Present invention simultaneously provides with pyrocincholic acid types triterpene saponin componds or its pharmacologically allow
Salt be active ingredient hypoglycemic drug, the Pyrocincholic acid type triterpenoid saponins refer to there are one skeleton contains
The positions C-3 of pyrocincholic acid, pyrocincholic acid and 1 ' position of a β-D- quinovose base pass through oxygen original
Son is connected, and the triterpenoid saponin that is connected by oxygen atom of C-28 carboxyls and 1 " position of a β-D-Glucose base and other
Three derivatives with skeleton structure.
Using pyrocincholic acid triterpene saponin compounds 1-4 or its salt pharmacologically allowed as active ingredient
The hypoglycemic drug of anti-type-II diabetes, the pyrocincholic acid triterpene saponin compounds 1-4 are with following
The compound of structural formula：pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-
glucopyranoside(1),pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-
3 β-O- β-D- of glucopyranosyl- (1 → 6)-β-D-glucopyranoside (2), pyrocincholic acid
glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-β-D-glucopyranoside (3),
pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-
β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside(4)
In formula, R1=β-D- quinovoses bases or β-D-Glucose-(1 → 4)-β-D- quinovose bases；R2=β-D-Glucose base
Or β-D-Glucose-(1 → 6)-β-D-Glucose bases,
The present invention also provides the methods for preparing above-mentioned pharmaceutical composition and drug, take yellow Populus deltoides branches and leaves, through drying, crush
Afterwards, it is fully extracted with 90% methanol room temperature cold soaking；After methanol extract plus water are suspended, fully extracted with chloroform and n-butanol successively
It takes；N-butanol fraction uses silica gel, Sephadex LH-20, the various chromatography column separating purifications of RP-18 repeatedly, in conjunction with triterpenoid saponin
TLC detection methods obtain pyrocincholic acid type triterpene saponin compounds, then obtained with traditional drug formulations preparation method
The pharmaceutical composition and the drug.
And the pharmaceutical composition or the method for drug are prepared, yellow Populus deltoides branches and leaves are taken, after drying, smashing, are used
90% methanol room temperature cold soaking extracts 3 times, and the time is respectively 7,3,3 days every time, and extracting solution is through being concentrated under reduced pressure to obtain methanol extract；By first
It after alcohol medicinal extract adds water to be suspended, is fully extracted with chloroform and n-butanol successively, three times, recycling design obtains chloroform for isometric each extraction
Partly, n-butanol fraction and water section；By n-butanol fraction through silica gel column chromatography, with 100:0,15:1,9:1,6:1,2:1,0:
100 chloroform/methanol gradient elution, thin-layer chromatography merge therein 9 in conjunction with triterpenoid saponin TLC detection methods:1 and 6:1 contains
There is the part of triterpenoid saponin；Each step below must all be isolated and purified in conjunction with triterpenoid saponin TLC detection methods, be merged
Medicinal extract afterwards is again through silica gel column chromatography, first with 15:1 chloroform/methanol isocratic elution is gone unless triterpenoid saponin part, then with
80:10 chloroform/methanol isocratic elution merges into three component Fr.1-Fr.5 according to the difference of triterpenoid saponin point；Fr.1 components
Through Sephadex LH-20 gel filtration chromatographies, 1:1 chloroform/methanol elution, merging obtain three subfraction Fr.1-1-Fr.1-
3；Fr.1-2 inverted RP-18 column chromatographies again, first with 40:60 methanol/water elution removal impurity, then with 55:45 methanol/water
Afford 3 β-O- β-D-quinovopyranosyl-28-O- β-D- of compound pyrocincholic acid
glucopyranoside(1)；Fr.2 group lease making Sephadex LH-20 gel filtration chromatographies, with 1:1 chloroform/methanol is eluant, eluent
Except depigmentaton, the triterpenoid saponin that is enriched with inverted RP-18 column chromatographies again, first with 38:62 methanol/water elution goes to clean
Matter, gained triterpenoid saponin is most afterwards through silica gel column chromatography, with 80:10 chloroform/methanol isocratic elution, through TLC combining data detections, decompression
3 β-O- β-D-quinovopyranosyl-28-O- β-D- of compound pyrocincholic acid are obtained after being evaporated
glucopyranosyl-(1→6)-β-D-glucopyranoside(2)；Fr.3 group lease making Sephadex LH-20 gel column layers
Analysis, 1:1 chloroform/methanol elution, merging obtain three subfraction Fr.3-1-Fr.3-3, Fr.3-2 inverted RP-18 columns layer again
Analysis, first with 35:65 methanol/water elution removal impurity, then with 46:54 methanol/water affords compound
pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-
β-D-glucopyranoside(3)；Fr.4 group lease making MCI column chromatographies, with 20：80 methanol/water elution is miscellaneous except depigmentaton etc.
Matter, then with 50:50 methanol/waters afford triterpenoid saponin part Fr.4-2, Fr.4-2 inverted RP-18 column chromatographies again, with 32:
68 methanol/water affords compound pyrocincholic acid 3 β-O- β-D-glucopyranosyl- (1 → 4)-β-
D-quinovopyranosyl-28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside(4)；Then
The pharmaceutical composition and the drug is made with the conventional method for preparing drug again.
The present invention still further provide the pharmaceutical composition or in which active constituent pyrocincholic acid
The application of type triterpene saponin componds or its salt pharmacologically allowed in preparing anti-type-II diabetes hypoglycemic drug.
And the pharmaceutical composition or in which active constituent pyrocincholic acid triterpenoid saponin chemical combination
Applications of the object 1-4 in preparing anti-type-II diabetes hypoglycemic drug.
Again, the present invention provides the yellow Populus deltoides triterpenoid saponin extracts containing therapeutically effective amount and pharmaceutically acceptable
Carrier pharmaceutical composition, the yellow Populus deltoides triterpenoid saponin extract, with 90% methanol, is filled made from following methods
Sub-dip proposes the medicinal extract containing yellow Populus deltoides triterpene and its saponins compound, recycles organic solvent abstraction technique by above-mentioned triterpene
And its saponins compound is enriched to n-Butanol soluble position, then adsorption chromatography is carried out with forward chromatographic column, with chloroform/methanol
System gradient elution, separation and concentration are obtained containing the less yellow Populus deltoides triterpenoid saponin extract (chloroform/methanol 9 of pigment:1 to chloroform/
Methanol 6:1 position), which contains the pyrocincholic acid triterpene saponin compounds 1-4 not less than 23.8%.
And application of the yellow Populus deltoides triterpenoid saponin extract in preparing anti-type-II diabetes hypoglycemic drug, it is described
Yellow Populus deltoides triterpenoid saponin extract be made from following methods, with 90% methanol, fully extract out containing yellow Populus deltoides triterpene and
The medicinal extract of its saponins compound recycles organic solvent abstraction technique to be enriched to above-mentioned triterpene and its saponins compound just
Butanol dissolves position, then carries out adsorption chromatography with forward chromatographic column, with chloroform/methanol system gradient elution, separation and concentration obtains
To containing the less yellow Populus deltoides triterpenoid saponin extract (chloroform/methanol 9 of pigment:1 to chloroform/methanol 6:1 position), which contains
There is the pyrocincholic acid triterpene saponin compounds 1-4 not less than 23.8%.
The present invention carries out Rubiaceae Huang Populus deltoides platymiscium Huang Populus deltoides the triterpenoid saponin chemical constitution study of system, using more
It plants and isolates and purifies means, including positive reversed-phase silica gel column chromatography, Sephadex LH-20 gel chromatographies, MCI and RP-C18 etc., therefrom
Obtain a series of pyrocincholic acid triterpenoid saponins.Later, to triterpenoid saponin ingredient pyrocincholic acid
3β-O-β-D-quinovopyranosyl-28-O-β-D-glucopyranoside(1),pyrocincholic acid 3β-
O-β-D-quinovopyranosyl-28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside(2)、
pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-
β-D-glucopyranoside(3),pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-
Quinovopyranosyl-28-O- β-D-glucopyranosyl- (1 → 6)-β-D-glucopyranoside (4) are in mouse
Its hypoglycemic effect is detected on hyperglycemia In vivo model, finds 3 β-O- β-D- of pyrocincholic acid
quinovopyranosyl-28-O-β-D-glucopyranoside(1), pyrocincholic acid 3β-O-β-D-
quinovopyranosyl-28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside(2)、
pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-
β-D-glucopyranoside(3),pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-
Quinovopyranosyl-28-O- β-D-glucopyranosyl- (1 → 6)-β-D-glucopyranoside (4) are in vivo
The hypoglycemic activity for exhibiting improvements over positive control drug melbine (being administered with concentration) is the anti-two types sugar in novel plant source
The sick hypoglycemic activity compound of urine, can be used for preparing the hypoglycemic drug of anti-type-II diabetes.
Pyrocincholic acid types triterpenoid saponins or its salt pharmacologically allowed in the yellow Populus deltoides of the present invention,
Can enumerate such as with inorganic acid hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid or maleic acid, fumaric acid, tartaric acid, breast
The organic acids such as acid, citric acid, acetic acid, methanesulfonic acid, p- benzene methanesulfonic acid, adipic acid, palmitic acid, tannic acid, lithium, the alkali gold such as sodium, potassium
Belong to, the alkaline-earth metal such as calcium, magnesium, the basic amino acids such as lysine at salt.
The pharmaceutical composition or drug for the treatment of type-II diabetes relevant disease of the present invention, by yellow Populus deltoides
Pyrocincholic acid types triterpene saponin compounds or yellow Populus deltoides triterpenoid saponin extract and pharmaceutically acceptable carrier
The pharmaceutical dosage form of preparation includes that tablet, capsule, oral solution, injection, injection be freeze-dried or powder-injection etc..Due to tablet, capsule,
Oral solution, injection, injection be freeze-dried or the preparation of the pharmaceutical dosage forms such as powder-injection be this field Conventional wisdom, therefore, by Huang
The various pharmaceutical dosage forms that pyrocincholic acid types triterpenoid saponin is prepared with respective carrier in Populus deltoides also can be by this field
Technical staff realizes.
The above pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as：Diluent,
Excipient such as water etc., filler such as starch, sucrose etc.；Binder such as cellulose derivative, alginates, gelatin and polyvinyl pyrrole
Alkanone；Wetting agent such as glycerine；Disintegrant such as agar, calcium carbonate and sodium bicarbonate；Sorbefacient such as quaternary ammonium compound；It lives on surface
Property agent such as hexadecanol；Absorption carrier such as kaolin and soap clay；Lubricant such as talcum powder, calcium stearate and magnesium stearate, with
And polyethylene glycol etc..In addition it can which other adjuvants such as flavouring agent, sweetener etc. are added in the composition.
The extract or compound of the present invention can pass through oral, nasal inhalation, rectum or parenteral in the form of compositions
The mode of administration is applied to the patient for needing this treatment.When for taking orally, can be made into conventional solid pharmaceutical preparation such as tablet,
Liquid preparation such as water or oil-suspending agent or other liquid preparations such as syrup, elixir etc. are made in pulvis, granula, capsule etc.；For intestines
When stomach external administration, solution, water or oleaginous suspension of injection etc. can be made into.The various dosage forms of pharmaceutical composition of the present invention
It can be prepared according to the conventional production process of pharmaceutical field.Such as active constituent is made to be mixed with one or more carriers, then will
Required dosage form is made in it.
The pharmaceutical composition of the present invention preferably comprises the active constituent that weight ratio is 0.1%~99.5%, most preferably
The active constituent that weight ratio is 0.5%~95%.
Extract of the present invention or the amount of application of compound can be according to route of administration, the age of patient, weight, the diseases treated
Variations, the daily doses such as the type and severity of disease can be 0.01~10mg/kg weight, preferably 0.1~5mg/kg weight.
It one or many can apply.
Pyrocincholic acid type triterpenoid saponins extract in Huang Populus deltoides triterpenoid saponin extract of the invention and yellow Populus deltoides
Method is advantageous in that, what plant sample was chosen is branches and leaves part, abundant raw material and conducive to the protection of plant resources and can hold
Continuous to utilize, extraction separation thinking has novelty, successfully utilizes chromatographic techniques will be in other small molecules and yellow Populus deltoides
Pyrocincholic acid type triterpenoid saponins detach, the pyrocincholic acid type triterpenoid saponins more concentrated,
Recycle the pyrocincholic acid type triterpenoid saponins of the isolated purifying such as positive and reversed Column chromatography techniques.Briefly
It says, because of the also other types of triterpenoid saponin of the main chemical compositions of yellow Populus deltoides, in pyrocincholic acid type triterpene soaps
In glycosides separation process, there are a large amount of other types of triterpene saponin compound interference, especially Usu acid type triterpenoid saponin, usually
With pyrocincholic acid type triterpenoid saponins are mixed in together is not readily separated.
The invention firstly uses 90% methanol, fully extract out triterpene and its saponins compound, recycle organic solvent
Triterpenoid saponin is enriched to n-Butanol soluble position by abstraction technique, then carries out adsorption chromatography with forward chromatographic column, with chloroform/first
Alcohol system gradient elution is successfully separated enrichment and obtains containing the less yellow Populus deltoides triterpenoid saponin part (chloroform/methanol 9 of pigment:1 to
Chloroform/methanol 6:1 position, that is, yellow Populus deltoides triterpenoid saponin extract), in conjunction with various chromatographic materials include positive silica gel with
And a variety of separation means such as reversed RP-18 include recrystallization etc., isolate and purify pyrocincholic acid type triterpenoid saponins
Sterling.Secondly, the chromatographic material, including positive reverse phase silica gel, Sephadex LH-20 etc. conventional merely with laboratory or industrially,
Special chromatographic material such as aminopropyl bonded silica gel need not be used, is also avoided with the stronger activated carbon of adsorptivity and aluminium oxide etc.
Chromatographic material；Finally, it must be combined in the separation process of pyrocincholic acid type triterpenoid saponins in yellow Populus deltoides
The TLC detection methods of pyrocincholic acid type triterpenoid saponins.In short, extraction separation method controllability of the present invention and reproduction
Property it is good, sample loss is few, and cost is relatively low, easy to operate, separable to obtain micro pyrocincholic acid type triterpenoid saponins,
Solvent can recycle repeatedly, be also applied for industrial production.
Description of the drawings：
Fig. 1 be the present invention yellow Populus deltoides in pyrocincholic acid type triterpenoid saponin extract and compound preparation
Method flow diagram；
Fig. 2 is pyrocincholic acid type triterpene saponin compound structural formulas in the yellow Populus deltoides of the present invention.
Specific implementation mode：
Below in conjunction with the accompanying drawings, the essentiality content further illustrated the present invention with the embodiment of the present invention, but not with
This limits the present invention.The improvement that essence according to the present invention carries out the present invention belongs to the scope of the present invention.
Embodiment 1：
Pyrocincholic acid type triterpenoid saponins in yellow Populus deltoides triterpenoid saponin extract and yellow Populus deltoides
pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-glucopyranoside(1),
pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-glucopyranosyl-(1→6)-
β-D-glucopyranoside(2),pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-
quinovopyranosyl-28-O-β-D-glucopyranoside(3),pyrocincholic acid 3β-O-β-D-
glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-β-D-glucopyranosyl-(1→6)-β-
The preparation of D-glucopyranoside (4) and Structural Identification：
Yellow Populus deltoides branches and leaves part 20kg is taken, after drying, smashing, is extracted 3 times with 90% methanol room temperature cold soaking, time difference
It it is every time 7,3,3 days, extracting solution is through being concentrated under reduced pressure to obtain methanol extract；After methanol extract plus water are suspended, successively with chloroform and just
Butanol fully extracts, and three times, recycling design obtains chloroform portion, n-butanol fraction and water section for isometric each extraction；By positive fourth
Alcohol part is through silica gel column chromatography, with 100:0,15:1,9:1,6:1,2:1,0:100 chloroform/methanol gradient elution, thin layer
Analysis merges therein 9 in conjunction with triterpenoid saponin TLC detection methods:1 and 6:1 two contain pyrocincholic acid type triterpenes
Part (namely yellow Populus deltoides triterpenoid saponin extract of the invention) 15.7g of saponin(e；Each step below all must be in conjunction with three
Terpene saponin(e TLC detection methods are isolated and purified；Medicinal extract after merging is again through silica gel column chromatography, first with 15:1 chloroform/
Methanol isocratic elution is gone unless triterpenoid saponin part, then with 80:10 chloroform/methanol isocratic elution, according to triterpenoid saponin point
Difference merges into three component Fr.1-Fr.5.
Fr.1 group lease making Sephadex LH-20 gel filtration chromatographies, 1:1 chloroform/methanol elution, merging obtain three Asias
Component Fr.1-1-Fr.1-3；Fr.1-2 inverted RP-18 column chromatographies again, first with 40:60 methanol/water elution removal impurity, then
With 55:45 methanol/water affords 3 β-O- β-D-quinovopyranosyl- of compound pyrocincholic acid
28-O-β-D-glucopyranoside(1)720mg。
Fr.2 group lease making Sephadex LH-20 gel filtration chromatographies, with 1:1 chloroform/methanol is that eluant, eluent removes depigmentaton；It is rich
Collect obtained triterpenoid saponin inverted RP-18 column chromatographies again, first with 38:62 methanol/water elution removal impurity；Gained triterpene soap
Glycosides is most afterwards through silica gel column chromatography, with 80:10 chloroform/methanol isocratic elution is changed through TLC combining data detections after evaporated under reduced pressure
3 β-O- β-D-quinovopyranosyl-28-O- β-D-glucopyranosyl- of conjunction object pyrocincholic acid (1 →
6)-β-D-glucopyranoside(2)1.15g。
Fr.3 group lease making Sephadex LH-20 gel filtration chromatographies, 1:1 chloroform/methanol elution, merging obtain three Asias
Component Fr.3-1-Fr.3-3；Fr.3-2 inverted RP-18 column chromatographies again, first with 35:65 methanol/water elution removal impurity, then
With 46:54 methanol/water afford 3 β-O- β-D-glucopyranosyl- of compound pyrocincholic acid (1 →
4)-β-D-quinovopyranosyl-28-O-β-D-glucopyranoside(3)1.02g。
Fr.4 group lease making MCI column chromatographies, with 20：80 methanol/water elution removes the impurity such as depigmentaton, then with 50:50 methanol/
Water elution obtains triterpenoid saponin part Fr.4-2, Fr.4-2 inverted RP-18 column chromatographies again, with 32:68 methanol/water elutes
To compound pyrocincholic acid 3 β-O- β-D-glucopyranosyl- (1 → 4)-β-D-
quinovopyranosyl-28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside(4)854mg。
In formula, R1=β-D- quinovoses bases or β-D-Glucose-(1 → 4)-β-D- quinovose bases；R2=β-D-Glucose base
Or β-D-Glucose-(1 → 6)-β-D-Glucose bases.
Pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-glucopyranoside
(1) Structural Identification data are：
Pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-glucopyranoside
(1):White powder, C41H66O12,ESI-MS:749[M-H]-；1H NMR(500MHz,Pyr-d5)δ:6.32 (1H, d, J=
7.2Hz, H-1 "), 4.86 (1H, d, J=7.2Hz, H-1 '), 3.26 (1H, dd, J1=11.2, J2=4.3Hz, H-3), 1.65
(1H, d, J=5.0Hz, H-6 '), 1.19 (3H, s, H-23), 1.12 (3H, s, H-26), 0.90 (3H, s, H-24), 0.88 (3H,
S, H-29), 0.85 (3H, s, H-30), 0.77 (3H, s, H-25).13C NMR(125MHz,Pyr-d5)δ:38.5 (C-1), 26.9
(C-2), 90.0 (C-3), 39.7 (C-4), 55.8 (C-5), 18.9 (C-6), 39.6 (C-7), 38.1 (C-8), 56.5 (C-9),
37.2 (C-10), 18.1 (C-11), 32.1 (C-12), 130.3 (C-13), 136.9 (C-14), 21.0 (C-15), 23.6 (C-
16), 45.8 (C-17), 39.6 (C-18), 41.5 (C-19), 30.6 (C-20), 34.3 (C-21), 31.7 (C-22), 28.2 (C-
23), 16.7 (C-24), 16.7 (C-25), 20.8 (C-26), 176.9 (C-28), 32.4 (C-29), 25.0 (C-30), 106.8
(C-1 '), 76.0 (C-2 '), 78.4 (C-3 '), 77.0 (C-4 '), 72.8 (C-5 '), 18.9 (C-6 '), 95.7 (C-1 "),
74.3 (C-2 "), 79.4 (C-3 "), 71.2 (C-4 "), 78.9 (C-5 "), 62.3 (C-6 ").
Pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-glucopyranosyl-
The Structural Identification data of (1 → 6)-β-D-glucopyranoside (2) are：
Pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-glucopyranosyl-
(1 → 6)-β-D-glucopyranoside (2), white powder, C47H76O17,ESI-MS:911[M-H]-；1H NMR(500MHz,
Pyr-d5)δ:6.24 (1H, d, J=8.2Hz, H-1 "), 4.85 (1H, d, J=7.7Hz, H-1 '), 4.71 (1H, d, J=
5.3Hz, H-1 " '), 4.60 (1H, d, J=8.0Hz, H-1 "), 3.28 (1H, dd, J1=10.9, J2=4.1Hz, H-3), 1.65
(1H, d, J=6.0Hz, H-6 '), 1.33 (3H, s, H-23), 1.15 (3H, s, H-26), 0.96 (3H, s, H-24), 0.88 (3H,
S, H-29), 0.87 (3H, s, H-30), 0.77 (3H, s, H-25).13C NMR(125MHz,Pyr-d5)δ:38.7 (C-1), 27.0
(C-2), 89.1 (C-3), 39.7 (C-4), 56.0 (C-5), 18.9 (C-6), 39.8 (C-7), 38.2 (C-8), 56.7 (C-9),
37.2 (C-10), 18.2 (C-11), 32.2 (C-12), 130.4 (C-13), 137.1 (C-14), 21.1 (C-15), 23.9 (C-
16), 45.8 (C-17), 39.7 (C-18), 41.6 (C-19), 30.7 (C-20), 34.5 (C-21), 31.8 (C-22), 28.3 (C-
23), 16.8 (C-24), 16.8 (C-25), 21.0 (C-26), 176.9 (C-28), 32.3 (C-29), 25.0 (C-30), 106.8
(C-1 '), 76.1 (C-2 '), 78.0 (C-3 '), 77.0 (C-4 '), 72.8 (C-5 '), 18.9 (C-6 '), 95.7 (C-1 "), 75.3
(C-2 "), 78.8 (C-3 "), 71.7 (C-4 "), 78.5 (C-5 "), 69.6 (C-6 "), 105.3 (C-1 " '), 74.1 (C-2 " '),
78.5 (C-3 " '), 71.1 (C-4 " '), 78.5 (C-5 " '), 62.8 (C-6 " ').
Pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-
The Structural Identification data of quinovopyranosyl-28-O- β-D-glucopyranoside (3) are：
Pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-
Quinovopyranosyl-28-O- β-D-glucopyranoside (3), white powder, C47H76O17,ESI-MS:911[M-
H]-；1H NMR(500MHz,Pyr-d5)δ:6.31 (1H, d, J=8.1Hz, H-1 " '), 5.37 (1H, d, J=7.5Hz, H-1 "),
4.80 (1H, d, J=7.6Hz, H-1 '), 3.29 (1H, dd, J1=11.0, J2=4.4Hz, H-3), 1.58 (1H, d, J=
6.6Hz, H-6 '), 1.29 (3H, s, H-23), 1.12 (3H, s, H-26), 1.08 (3H, s, H-24), 0.90 (3H, s, H-29),
0.88 (3H, s, H-30), 0.80 (3H, s, H-25).13C NMR(125MHz,Pyr-d5)δ:38.4 (C-1), 26.8 (C-2),
89.3 (C-3), 39.8 (C-4), 55.9 (C-5), 18.7 (C-6), 39.8 (C-7), 38.1 (C-8), 56.5 (C-9), 37.3 (C-
10), 18.1 (C-11), 32.2 (C-12), 130.3 (C-13), 137.0 (C-14), 21.1 (C-15), 23.8 (C-16), 45.8
(C-17), 39.6 (C-18), 41.6 (C-19), 30.7 (C-20), 34.4 (C-21), 31.7 (C-22), 28.2 (C-23), 16.7
(C-24), 16.7 (C-25), 20.9 (C-26), 176.7 (C-28), 32.4 (C-29), 25.0 (C-30), 105.0 (C-1 '),
76.5 (C-2 '), 78.0 (C-3 '), 83.7 (C-4 '), 71.8 (C-5 '), 18.6 (C-6 '), 106.0 (C-1 "), 75.3 (C-
2 "), 78.6 (C-3 "), 71.3 (C-4 "), 78.3 (C-5 "), 62.8 (C-6 "), 95.8 (C-1 " '), 74.3 (C-2 " '), 79.3
(C-3 " '), 71.7 (C-4 " '), 78.9 (C-5 " '), 62.4 (C-6 " ').
Pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-
The structure of quinovopyranosyl-28-O- β-D-glucopyranosyl- (1 → 6)-β-D-glucopyranoside (4)
Appraising datum is：
Pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-
Quinovopyranosyl-28-O- β-D-glucopyranosyl- (1 → 6)-β-D-glucopyranoside (4), white powder
End, C53H86O22,ESI-MS:1073[M-H]-；1H NMR(500MHz,Pyr-d5)δ:6.22 (1H, d, J=8.1Hz, H-1 " '),
5.37 (1H, d, J=7.5Hz, H-1 "), 5.00 (1H, d, J=7.6Hz, H-1 " "), 4.80 (1H, d, J=7.60Hz, H-1 '),
3.28(1H,dd,J1=10.9, J2=3.9Hz, H-3), 1.59 (1H, d, J=5.6Hz, H-6 '), 1.27 (3H, s, H-23),
1.12 (3H, s, H-26), 1.06 (3H, s, H-24), 0.88 (3H, s, H-29), 0.86 (3H, s, H-30), 0.80 (3H, s, H-
25)。13C NMR(125MHz,Pyr-d5)δ:38.6 (C-1), 27.0 (C-2), 89.3 (C-3), 39.8 (C-4), 56.0 (C-5),
19.1 (C-6), 39.8 (C-7), 38.2 (C-8), 56.7 (C-9), 37.3 (C-10), 18.2 (C-11), 32.2 (C-12),
130.4 (C-13), 137.1 (C-14), 21.1 (C-15), 24.6 (C-16), 45.8 (C-17), 39.6 (C-18), 41.6 (C-
19), 30.7 (C-20), 34.6 (C-21), 31.4 (C-22), 28.3 (C-23), 16.6 (C-24), 16.8 (C-25), 21.0 (C-
26), 176.9 (C-28), 32.5 (C-29), 25.1 (C-30), 105.0 (C-1 '), 76.7 (C-2 '), 78.0 (C-3 '), 83.6
(C-4 '), 72.6 (C-5 '), 18.7 (C-6 '), 106.0 (C-1 "), 75.2 (C-2 "), 78.8 (C-3 "), 71.1 (C-4 "),
78.5 (C-5 "), 62.8 (C-6 "), 95.7 (C-1 " '), 74.1 (C-2 " '), 78.5 (C-3 " '), 71.7 (C-4 " '), 78.5 (C-
5 " '), 69.6 (C-6 " '), 105.3 (C-1 " "), 75.2 (C-2 " "), 78.3 (C-3 " ") and, 71.8 (C-4 " "), 78.0 (C-
5 " "), 62.8 (C-6 " ").
Embodiment 2：
Pyrocincholic acid type triterpenoid saponins in Huang Populus deltoides triterpenoid saponin extract of the invention and yellow Populus deltoides
3 β-O- β-D-quinovopyranosyl-28-O- β-D-glucopyranoside (1) of object pyrocincholic acid are closed,
pyrocincholic acid 3β-O-β-D-quinovopyranosyl-28-O-β-D-glucopyranosyl-(1→6)-
β-D-glucopyranoside(2),pyrocincholic acid 3β-O-β-D-glucopyranosyl-(1→4)-β-D-
quinovopyranosyl-28-O-β-D-glucopyranoside(3),pyrocincholic acid 3β-O-β-D-
glucopyranosyl-(1→4)-β-D-quinovopyranosyl-28-O-β-D-glucopyranosyl-(1→6)-β-
The mouse type-II diabetes that D-glucopyranoside (4) (hereinafter referred to as compound 1-4) induces streptozotocin (STZ)
Hyperglycemia has therapeutic effect.Experimental principle, method and result are as follows：
Experimental principle：Streptozotocin (STZ) makes it generate sugar the selective destruction of the beta Cell of islet of mouse
Disease mouse high-calorie feed raising certain time and fasting 12h are urinated, STZ is injected intraperitoneally by 100mg/kg weight, II type can be prepared
Diabetes animal model, and there is overweight, Impaired Glucose Tolerance Treated, blood fat raising, serum insulin liter by the model that the method is prepared
High and combination rate of insulin receptor reduces the characteristics of with insulin resistance, is similar to the Clinical symptoms of Patients with NIDDM.STZ
For the diabetes mice of induction because its period is shorter, method is easy, is the ideal model studied human type II diabetes and treat new drug.
Experimental method：Take 6~8 week old, the ICR male mices of 25-30g, high glucose and high fat forage feed 4 weeks, fasting 12h,
It is noted by 100mg/kg (solvent is citric acid-sodium citrate buffer solution, PH-4.5) weight abdominal cavity with 1mL disposable sterilized injectors
STZ is penetrated, fasting fasting blood sugar overnight is detected after 3 days, it is modeling success mouse that blood glucose value, which is more than or equal to 11.1mmol/ml then,.
It is primary according to 50mg/kg bodyweight p gastric infusions daily from the modeling same day, continue ten days, until experiment terminates.Modeling is worked as
It measures mouse fasting blood-glucose, empty body weight.After experiment, fasted mice fasting blood sugar overnight and weight are detected.
Experimental result：
Yellow Populus deltoides triterpenoid saponin extract and compound 1-4 can significantly reduce the empty stomach of the diabetic mice of STZ inductions
Blood glucose loses weight (table 1).
Hypoglycemic effects of the 1. compound 1-4 of table to the STZ hyperglycemia mouse induced
The experimental results showed that yellow Populus deltoides triterpenoid saponin extract and compound 1-4 can significantly reduce the glycosuria of STZ inductions
The fasting blood-glucose of sick mouse reduces the fasting blood-glucose of the hyperglycemia mouse of STZ inductions up to 36.61 to 41.12%, drops blood
Sugar is with obvious effects to be better than positive control medicine melbine group (19.11%)；And yellow Populus deltoides triterpenoid saponin extract and compound
1-4 also can significantly reduce the empty body weight of the diabetic mice of STZ inductions, reduce the empty stomach of the hyperglycemia mouse of STZ inductions
Weight loses weight effect and is better than positive control medicine melbine group (10.15%) up to 10.12 to 11.93%；It proves
Yellow Populus deltoides triterpenoid saponin extract and compound (1)-(4) containing compound (1)-(4) can become treatment type-II diabetes
A kind of hypoglycemic medicine.
Embodiment 3：
4% ethanol solution of sulfuric acid is added in 1 gained compound 1-4 of embodiment, and PH=4 is filtered, dry, and sulfate is made
Compound 1-4.
Embodiment 4：
4% hydrochloric acid solution is added in 1 gained compound 1-4 of embodiment, and PH=4 is filtered, dry, and hydrochloride chemical combination is made
Object 1-4.
Embodiment 5：
4% tartaric acid solution is added in 1 gained compound 1-4 of embodiment, and PH=4 is filtered, dry, and tartrate is made
Compound 1-4.
Embodiment 6：
4% citric acid solution is added in 1 gained compound 1-4 of embodiment, and PH=4 is filtered, dry, and citrate is made
Compound 1-4.
Embodiment 7：
Tablet：By the salt 10mg obtained by embodiment 1 gained compound 1-4 or embodiment 4-6, lactose 180mg, starch
55mg, magnesium stearate 5mg, newborn sugar and starch mix, and are uniformly moistened with water, the mixture after moistening is sieved and is dried, after
Magnesium stearate is added in sieve, then by mixture tabletting, every weight 250mg, compounds content 10mg.
Embodiment 8：
Ampulla：By the salt 2mg obtained by embodiment 1 gained compound 1-4 or embodiment 4-6, sodium chloride 10mg is dissolved in
In suitable water for injection, acquired solution is filtered, is aseptically fitted into ampoule bottle.
Embodiment 9：
Injection is freeze-dried：Salt 10mg, sodium bicarbonate 2mg obtained by embodiment 1 gained compound 1-4 or embodiment 4-6,
Mannitol 252mg.
Preparation method：It by sodium bicarbonate, mannitol, is dissolved in water for injection, adds activated carbon adsorption 30min depyrogenations, mistake
Deactivation charcoal is filtered out, compound or its salt is added in filtrate, supersound process makes dissolving, and it is 5.0-7.0 to adjust PH with 1N hydrochloric acid,
Miillpore filter filter, add water for injection, dispense, freeze-drying, top plug, roll lid to get.
Embodiment 10：
Capsule：Salt 10mg obtained by embodiment 1 gained compound 1-4 or embodiment 4-6, lactose 187mg, magnesium stearate
3mg；Preparation method：Compound or its salt and cosolvent are mixed, sieving uniformly mixes, and obtained mixture is packed into hard bright
Glue capsule, each capsule weight 200mg, active component content 10mg.
Claims (1)
1.pyrocincholic acid types triterpene saponin componds (1)-(4) or its salt pharmacologically allowed are anti-in preparation
Application in type-II diabetes hypoglycemic drug,
The pyrocincholic acid triterpene saponin compounds 1-4 is to have the following structural formula compound：
pyrocincholic acid 3β‐O‐β‐D‐quinovopyranosyl‐28‐O‐β‐D‐glucopyranoside(1),
pyrocincholic acid
3β‐O‐β‐D‐quinovopyranosyl‐28‐O‐β‐D‐glucopyranosyl‐(1→6)‐β‐D‐
Glucopyranosid e (2), pyrocincholic acid
3β‐O‐β‐D‐glucopyranosyl‐(1→4)‐β‐D‐quinovopyranosyl‐28‐O‐β‐D‐
glucopyranosid e(3),pyrocincholic acid
3β‐O‐β‐D‐glucopyranosyl‐(1→4)‐β‐D‐quinovopyranosyl‐28‐O‐β‐D‐
glucopyranosyl‐(1→6)‐β‐D‐glucopyranoside(4)
In formula, R1=β-D- quinovoses bases or β-D-Glucose-(1 → 4)-β-D- quinovose bases；R2=β-D-Glucose base or β-
D-Glucose-(1 → 6)-β-D-Glucose bases,
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