CN104546875B - Triterpenoid saponin derivative and its medical usage - Google Patents
Triterpenoid saponin derivative and its medical usage Download PDFInfo
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- CN104546875B CN104546875B CN201310467106.8A CN201310467106A CN104546875B CN 104546875 B CN104546875 B CN 104546875B CN 201310467106 A CN201310467106 A CN 201310467106A CN 104546875 B CN104546875 B CN 104546875B
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- triterpenoid saponin
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- saponin derivative
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Abstract
It is more particularly to a kind of such as structural formula the present invention relates to medicine(Ⅰ)Triterpenoid saponin derivative, or its pharmaceutically acceptable salt, hydrate or prodrug, wherein structural formula(Ⅰ)For:Wherein R1Selected from S1Or S2,R2Selected from CH2OH or methyl.Structure above of the invention(Ⅰ)Triterpenoid saponin derivative can be used for treat hyperlipidemia.
Description
Technical field
The invention belongs to pharmaceutical field, there is provided a kind of triterpenoid saponin derivative and its medical usage, relate in particular to
A kind of medicine that can treat hyperlipidemia.
Background technology
Hyperlipidemia is characterized with the change that various lipoprotein in blood plasma are composed, including the rising of blood T-CHOL (TC) level,
Triglycerides (TG) level is raised, HDL (HDL-C) water is dry reduces and low-density lipoprotein (LDL-C) level liter
It is high.Hyperlipemia easily induces arterial wall that atherosclerotic lesion occurs, and increases the unstability of patch, ultimately results in acute painstaking effort
The generation of pipe disease.
At present, the more lipid-lowering medicine of clinical practice is statins, although such curative effect of medication is significantly, long-term taking
With certain toxic and side effect, such as musclar toxicity, dysbolism, stomach reaction, serious can also result in liver transaminases liter
It is high.In the market lipid-loweringing class tcm product is mainly three kinds of Effects of Xuezhikang, Zhibituo and Gypenosides, wherein the above two it is main into
It is the Monacolins obtained from Qu Hongzhong using herb fermenting technology to divide.And other lipid-loweringing class tcm products are mostly compound
Class preparation, generally existing active chemical is unintelligible, the shortcomings of study on mechanism is weak.So, find new from plant
Hypolipidemic activity composition be an important research direction.
Sea-buckthorn (Hippophae rhamnoides L) also known as vinegar willow, belong to Elaeangnaceae Hippophne, machaka or little Qiao
Wood, nature and flavor " sour, puckery, temperature " are that medicine is commonly used by the Mongols, Tibetan the effect of with " cough-relieving apophlegmatic, relieving dyspepsia is promoting blood circulation and removing blood stasis "
Material.1977, sea-buckthorn was formally listed in《Chinese Pharmacopoeia》, the eighties in 20th century, sea-buckthorn is classified as China first by health ministry
Criticize medical and edible dual purpose plant kind.
The content of the invention
Present invention firstly provides a kind of triterpenoid saponin derivative for being capable of reducing blood lipid of structure formula (I), or it is pharmaceutically
Acceptable salt, hydrate or prodrug, wherein structure formula (I) is:
Wherein R1Selected from S1Or S2,
R2Selected from-CH2OH or methyl.
Corresponding all pharmaceutically acceptable salt, hydrate or prodrug present invention additionally comprises above-claimed cpd.This
A little salt can by part (for example, amido) positively charged in compound with there is the negatively charged (for example, trifluoro of opposite-sign
Acetic acid) formed;Or by part (for example, carboxyl) negatively charged in compound and positive charge (for example, sodium, potassium, calcium, magnesium) shape
Into.Compound can contain a nonaromatic double bond, with one or more asymmetric centers.So, these compounds
Can be as racemic mixture, single enantiomter, single diastereoisomer, diastereoisomer mixing
Thing, cis or trans isomers are present.All these isomers are all expected.Described " the triterpenoid saponin of structure formula (I)
The prodrug of derivative " is often referred to a kind of material, after being applied with appropriate method, can be metabolized in subject or chemistry
React and be transformed at least one compound or its salt of structure formula (I).
Following compound is some particular compounds of the invention:
Compound 1
Compound 2
Compound 3
Compound 4
The triterpenoid saponin derivative of structure formula (I) of the invention can be by the conventional method of this area such as alcohol extracting, chromatography etc.
Extracted from the plants such as sea-buckthorn and obtained, can also bought by commercial sources or utilize marketable material, by passing in the prior art
The compound synthesis method synthesis of system is obtained.One of ordinary skill in the art can synthesize the present invention according to existing known technology
Compound.The compound of synthesis can be with further further by modes such as column chromatography, high performance liquid chromatography or crystallizations
Purifying.
Synthesis chemical improvement, protection functional group methodology (protection is deprotected) are helpful to synthesis application compound
, and technology is well known in the prior art, such as R.Larock, Comprehensive Organic
Transformations, VCH Publishers (1989);T.W.Greene and P.G.M.Wuts, Protective
Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999);L.Fieser and
M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wiley and
Sons(1994);And L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis,
There is disclosure in John Wiley and Sons (1995).
Triterpenoid saponin derivative of the invention or its pharmaceutically acceptable salt, hydrate or prodrug can be effectively reduced
The blood lipid level of animal, so triterpenoid saponin derivative of the invention or its pharmaceutically acceptable salt, hydrate or prodrug can
Medicine for preparing reducing blood lipid.
Present invention also offers a kind of composition, said composition includes one or more triterpenoid saponin derivatives of the invention
Or its pharmaceutically acceptable salt, hydrate or prodrug, with pharmaceutically acceptable carrier, said composition can be used to treat fat high
Mass formed by blood stasis;
Present invention also offers a kind of pharmaceutical preparation, the pharmaceutical preparation spreads out including one or more triterpenoid saponins of the invention
Biological or its pharmaceutically acceptable salt, hydrate or prodrug, the pharmaceutical preparation can be used to treat hyperlipidemia.
The triterpenoid saponin derivative or its pharmaceutically acceptable salt, hydrate or prodrug of the structure formula (I) are in combination
Content such as 0.0001~50wt% in thing or pharmaceutical preparation;Preferably 0.001~30wt%;More preferably 0.01~
20wt%.
Therapeutically effective amount is (i.e.:People and/or animal can be produced function or activity and can be received by people and/or animal
Amount) compound of the invention (for the carrier of therapeutic administratp, themselves is not with pharmaceutically acceptable carrier
There is no undue toxicity after necessary active component, and administration) pharmaceutical preparation can be constituted, these pharmaceutical preparations can be prepared into
Oral formulations, injection, tablet, powder preparation, capsule, dispersible tablet, sustained release preparation etc..
The consumption of the composition of the invention of therapeutically effective amount between 0.001~500mg/kg body weight/days, Ren Hejie
Consumption within above range is all effective dose of the invention.Preferably, the consumption of composition of the invention between 0.005~
Between 300mg/kg body weight/days;It is furthermore preferred that the consumption of composition of the invention between 0.01-100mg/kg body weight/days it
Between.Described " therapeutically effective amount " can be used for the single drug of relevant disease or drug combination treatment.One of skill in the art
It is understood that the consumption in actually administration can be higher or lower than above-mentioned dosage range.For a certain object (such as mammal one
People) " therapeutically effective amount " and specific therapeutic scheme can be influenceed by factors, including compound used therefor or its prodrug medicine
Effect activity, the age of administration object, body weight, ordinary circumstance, sex, diet, administration time, disease susceptibility, disease process with
And accept the judgement of doctor for medical treatment etc..
The reactive compound or its pharmaceutically acceptable salt, hydrate or prodrug of structure formula (I) of the invention or its group
Compound or its pharmaceutical preparation can be administered by the approach such as in oral, intravenous, intramuscular, subcutaneous, nasal cavity, in rectum.Solid
Carrier is such as:Starch, lactose, phosphoric acid glycol, microcrystalline cellulose, brown sugar and white bole, and liquid carrier is such as:Sterilized water, poly- second two
Alcohol, nonionic surface active agent and edible oil (such as corn oil, peanut oil and sesame oil), as long as being adapted to the characteristic of active component
With required specific administration mode.Usually used adjuvant also can advantageously be included in pharmaceutical composition is prepared, and e.g., adjust
Taste agent, pigment, preservative and antioxidant such as vitamin E, vitamin C, BHT and BHA.
These reactive compounds also can parenteral or intraperitoneal administration.Also surfactant (such as hydroxyl can be mixed with appropriate
Propyl cellulose) water in prepare solution or the suspension of these reactive compounds (as free alkali or pharmaceutically acceptable salt)
Liquid.Dispersion liquid can also be prepared in the mixture in glycerine, polyethylene glycol and its in oil.Under conventional storage and use condition,
Containing preservative preventing the growth of microorganism in these preparations.
Medicament forms suitable for injecting include:Aseptic aqueous solution or dispersion liquid and aseptic powder (are used for extemporaneous preparation of sterile
Parenteral solution or dispersion liquid).In all situations, these forms must be aseptic and must be that fluid is discharged with being easy to syringe
Fluid.Must be under conditions of manufacture and storage stable, and must be able to prevent pollution and the shadow of microorganism such as bacterium and fungi
Ring.Carrier can be solvent or decentralized medium, wherein containing such as water, alcohol, their appropriate mixture and vegetable oil.
The details of various aspects of the present invention will be able to detailed description in subsequent chapters and sections.By hereafter and claim
Description, the features of the present invention, purpose and advantage will become apparent from.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip
Part or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise all of percentage, ratio, ratio or number are pressed
Weight meter.
Unless otherwise defined, all specialties used in text and scientific words and meaning familiar to one skilled in the art institute
Justice is identical.Additionally, during any method similar to described content or impartial and material all can be applied to the inventive method.Wen Zhong
Described preferable implementation only presents a demonstration with material and is used.
The features described above that the present invention is mentioned, or the feature that embodiment is mentioned can be in any combination.Patent specification is taken off
The all features shown can be used in combination with any combinations thing form, and each feature disclosed in specification can provide phase with any
The alternative characteristics substitution of same, impartial or similar purpose.Therefore except there is special instruction, disclosed feature is only impartial or similar
The general example of feature.
Embodiment 1 extracts compound 1
1) monomer component is extracted
Chinese medicine seabuckthorn seeds 2000g is taken, is extracted 2 hours with 8 times of 75% alcohol reflux, be concentrated to dryness and obtain final product extract, even
Continuous silica gel column chromatography (400 mesh, 30 times of extract qualities, chloroform: methyl alcohol: water=8: 2: 0.2-6: 4: 1 gradient elution) repeatedly and
Reversed-phase silica gel column chromatography (400 mesh, 50 times of extract qualities, methyl alcohol: water=3: 7-6: 4 gradient elutions), isolated compound
0.02g, yield 0.001%.
2) Structural Identification
Through MS-ESI,13C-NMR、1H-NMR is determined, and obtains the following spectral data of the compound 1.
Compound 11H-NMR and13Data (400 and 100MHz, the pyridine-d of C-NMR6)
Embodiment 2 is extracted and authenticating compound 2~4
Compound 2~4 is that the similar method of applicating adn implementing example 1 is extracted.Through MS-ESI,13C-NMR、1H-NMR is determined,
Obtain the following spectral data of these compounds.
Compound 21H-NMR and13The data (600 and 150MHz, pyridine-d6) of C-NMR
Compound 3 and 41H-NMR and13The data (600 and 150MHz, pyridine-d6) of C-NMR
The measure of the external hypolipidemic activity of 3 compound of embodiment 1~4
Experimental animal:Male KM mouse, body weight 25-30g.
Dosage:The test dose of compound 1~4 is 10mg/kg, and positive drug Simvastatin is 10mg/kg.
Emulsion is prepared:Lard 80g is placed in 500ml beakers and the heating and melting on electric furnace, cholesterol 40g is added and is made
Dissolve, add sodium taurocholate 8g and propylthiouracil piece 4g, fully stir evenly, be subsequently adding appropriate distilled water and tween-
80th, each 80ml of propane diols, constantly stirs evenly, then add distilled water is to 400ml and fully mixes, 100g/l cholesterol, 200g/l
The fat emulsion of lard, 20g/l sodium taurocholates and 10g/l propylthiouracils.Refrigerator store is put into, the used time needs heating and melting.
Experimental technique:In addition to Normal group, remaining each group gavages emulsion (0.5ml) every afternoon, and morning next day is oral
Administration, continuous 10d, last day eye socket arterial blood drawing.After centrifuging and taking serum, survey hyperlipemia in mice serum cholesterol (CHO),
Two biochemical indicators of low-density lipoprotein (LDL).
Experimental result:
Above result of the test shows:Compound 1~4 is respectively provided with significantly effect for reducing blood fat, and him is cut down with pungent in 10mg/kg
The lipid-lowering effect in spit of fland is approached.
Many aspects involved in the present invention have been explained as above.However, it should be understood that without departing from spirit of the invention
Under the premise of, those skilled in the art can carry out equivalent change and modification to it, and the change and modification equally fall into this patent
The coverage of the claim of application.
Claims (4)
1. a kind of triterpenoid saponin derivative such as structure formula (I), or its pharmaceutically acceptable salt, wherein structure formula (I) is:
Wherein R1Selected from S1Or S2,
R2Selected from-CH2OH or methyl.
2. triterpenoid saponin derivative as claimed in claim 1, or its pharmaceutically acceptable salt, it is characterised in that described
Triterpenoid saponin derivative is selected from:
3. a kind of pharmaceutical composition, triterpenoid saponin derivative as claimed in claim 1 or its pharmacy containing therapeutically effective amount
Upper acceptable salt, and pharmaceutically acceptable carrier.
4. triterpenoid saponin derivative as claimed in claim 1 or its pharmaceutically acceptable salt are in blood lipid-lowering medicine is prepared
Using.
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Families Citing this family (1)
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CN111789873B (en) * | 2020-08-04 | 2022-05-27 | 中国科学院西北高原生物研究所 | Method for extracting high-content seabuckthorn triterpenic acid extract |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101857625A (en) * | 2009-11-18 | 2010-10-13 | 青海清华博众生物技术有限公司 | Method for extracting oleanolic acid from sea-buckthorn |
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2013
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101857625A (en) * | 2009-11-18 | 2010-10-13 | 青海清华博众生物技术有限公司 | Method for extracting oleanolic acid from sea-buckthorn |
Non-Patent Citations (3)
Title |
---|
Four new triterpenoid glycosides from the seed residue of Hippophae rhamnoides subsp. sinensis;Chao Chen, et al.;《Journal of Asian Natural Products Research》;20141231;第16卷(第3期);231-239 * |
中国沙棘果皮化学成分的研究(I);路平 等;《沙棘》;20021231;第15卷(第4期);25-26 * |
沙棘籽的综合利用I——沙棘籽油渣的化学成分研究;傅建熙 等;《沙棘》;20060930;第19卷(第3期);30-32 * |
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