CN104546875A - Triterpenoid saponin derivative and medicinal application thereof - Google Patents

Triterpenoid saponin derivative and medicinal application thereof Download PDF

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CN104546875A
CN104546875A CN201310467106.8A CN201310467106A CN104546875A CN 104546875 A CN104546875 A CN 104546875A CN 201310467106 A CN201310467106 A CN 201310467106A CN 104546875 A CN104546875 A CN 104546875A
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pharmaceutically acceptable
compound
present
prodrug
hydrate
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CN104546875B (en
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陈超
高雯
孔德云
成亮
欧阳丹薇
邵燕
周靖
吕峰
刘意
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Abstract

The invention relates to the field of medicine, and particularly relates to a triterpenoid saponin derivative represented by the structural formula (I), or a pharmaceutically acceptable salt, a hydrate or a prodrug thereof, wherein the structural formula (I) is described in the specification, R1 is selected from S1 or S2 having the structures described in the specification, and R2 is selected from -CH2OH or methyl. The triterpenoid saponin derivative represented by the structural formula (I) can be used for treatment of hyperlipidemia.

Description

Triterpene saponin derivant and medical usage thereof
Technical field
The invention belongs to pharmaceutical field, provide a kind of triterpene saponin derivant and medical usage thereof, relate in particular to a kind of medicine can treating hyperlipemia.
Background technology
Hyperlipemia changes into feature with lipoprotein spectrum various in blood plasma, comprises the rising of blood T-CHOL (TC) level, triglyceride (TG) level raises, high density lipoprotein (HDL-C) level reduces and low density lipoprotein, LDL (LDL-C) level raises.Hyperlipemia easily induces arterial wall generation atherosclerotic lesion, increases the unstability of speckle, finally causes the generation of acute cardiovascular disease.
At present, the more lipid lowerers of clinical practice is statins, although such curative effect of medication is remarkable, long-term taking has certain toxic and side effects, and as musclar toxicity, dysbolismus, the intestines and stomach reaction etc., the serious liver transaminases that also can cause raises.Blood fat reducing class tcm product mainly Xuezhikang, zhibituo and Herb Gynostemmae Pentaphylli total glycosides three kinds on market, wherein the above two main component is all the Monacolins utilizing herb fermenting technology to obtain from Qu Hongzhong.The shortcomings such as and other blood fat reducing class tcm products are mostly compound recipe class preparation, ubiquity active chemical is unintelligible, and study on mechanism is weak.So finding new hypolipidemic activity composition from plant is an important research direction.
Fructus Hippophae (Hippophae rhamnoides L) has another name called vinegar willow, and belong to Elaeangnaceae Hippophae, machaka or dungarunga, nature and flavor " sour, puckery, warm ", have the effect of " eliminating phlegm and stopping cough, relieving dyspepsia, blood circulation promoting and blood stasis dispelling ", are the Mongols, Tibetan's conventional crude drugs.1977, Fructus Hippophae was formally listed in " Chinese Pharmacopoeia ", the eighties in 20th century, and Fructus Hippophae is classified as first medicine food dual purpose plant kind of China by health ministry.
Summary of the invention
What the present invention provide firstly a kind of structure formula I can the triterpene saponin derivant of blood fat reducing, or its pharmaceutically acceptable salt, hydrate or prodrug, and wherein structure formula I is:
Wherein R 1be selected from S 1or S 2,
R 2be selected from-CH 2oH or methyl.
The present invention also comprises all accordingly pharmaceutically acceptable salt of above-claimed cpd, hydrate or prodrug.These salt can be formed by part (such as, amido) positively charged in compound and electronegative (such as, the trifluoracetic acid) with opposite-sign; Or formed by part (such as, carboxyl) electronegative in compound and positive charge (such as, sodium, potassium, calcium, magnesium).Compound can contain a nonaromatic double bond, has one or more asymmetric center.So these compounds can exist as racemic mixture, independent enantiomer, independent diastereomer, non-enantiomer mixture, cis or transisomer.All these isomers are all expected.Described " prodrug of the triterpene saponin derivant of structure formula I " is often referred to a kind of material, after using by suitable method, can carry out metabolism or chemical reaction and be transformed at least one compound or its salt of structure formula I in subject.
Compound is below particular compound more of the present invention:
The triterpene saponin derivant of structure formula I of the present invention obtains as alcohol extraction, chromatography etc. extract from the plants such as Fructus Hippophae by the conventional method of this area, also buy by commercial sources or utilize marketable material, being obtained by compou nd synthesis method traditional in prior art synthesis.Those of ordinary skill in the art can synthesize compound of the present invention according to existing known technology.The compound of synthesis can be further purified further by modes such as column chromatography, high performance liquid chromatography or crystallizations.
Synthetic chemistry transformation, protection functional group methodology (protect or go protection) are helpful to synthesis application compound; and be technology commonly known in the art; as R.Larock, Comprehensive Organic Transformations, VCHPublishers(1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3 rded., John Wiley and Sons(1999); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents forOrganic Synthesis, John Wiley and Sons(1994); And L.Paquette, ed., Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons(1995) in have open.
Triterpene saponin derivant of the present invention or its pharmaceutically acceptable salt, hydrate or prodrug can reduce the blood lipid level of animal effectively, so triterpene saponin derivant of the present invention or its pharmaceutically acceptable salt, hydrate or prodrug can be used for the medicine preparing blood fat reducing.
Present invention also offers a kind of compositions, said composition comprises one or more triterpene saponin derivant of the present invention or its pharmaceutically acceptable salt, hydrate or prodrugs, and with pharmaceutically acceptable carrier, said composition can be used for treating hyperlipemia;
Present invention also offers a kind of pharmaceutical preparation, this pharmaceutical preparation comprises one or more triterpene saponin derivant of the present invention or its pharmaceutically acceptable salt, hydrate or prodrugs, and this pharmaceutical preparation can be used for treating hyperlipemia.
The triterpene saponin derivant of described structure formula I or its pharmaceutically acceptable salt, hydrate or the prodrug content in compositions or pharmaceutical preparation such as 0.0001 ~ 50wt%; Preferably 0.001 ~ 30wt%; 0.01 better ~ 20wt%.
Treatment effective dose (that is: can to people and/or animal produce function or activity and can by people and/or animal the amount that accepts) compound of the present invention (be used for the treatment of the carrier of administration with pharmaceutically acceptable carrier, they itself are not necessary active component, and after using, there is no undue toxicity) and can pharmaceutical preparation be formed, these pharmaceutical preparatioies can be prepared into oral formulations, injection, tablet, powder preparation, capsule, dispersible tablet, slow releasing preparation etc.
The consumption of the compositions of the present invention for the treatment of effective dose is between 0.001 ~ 500mg/kg body weight/day, and any consumption within above-mentioned scope is all effective dose of the present invention.Preferably, the consumption of compositions of the present invention is between 0.005 ~ 300mg/kg body weight/day; Preferred, the consumption of compositions of the present invention is between 0.0l-100mg/kg body weight/day.Described " treatment effective dose " can be used for single drug or the drug combination treatment of relevant disease.One of skill in the art can understand, and the consumption when actual administration can higher or lower than above-mentioned dosage range.Can by the impact of factors for " the treatment effective dose " of a certain object (as mammal one people) and concrete therapeutic scheme, comprise the drug activity of compound used therefor or its prodrug, age of administration object, body weight, ordinary circumstance, sex, diet, administration time, disease susceptibility, disease process and accept the judgement etc. of doctor for medical treatment.Described " treatment " refers to be give body (containing tumor, have the symptom of tumor or have the omen of tumor) one or more flavonol derivants of the present invention, to treat, to alleviate, to slow down, to change, to cure, to affect, to improve its hyperlipemia, the symptom of hyperlipemia or the omen of hyperlipemia.
The reactive compound of structure formula I of the present invention or its pharmaceutically acceptable salt, hydrate or prodrug or its compositions or its pharmaceutical preparation can by the administrations such as oral, intravenous, intramuscular, subcutaneous, nasal cavity, internal rectum.Solid carrier is as starch, lactose, phosphoric acid glycol, microcrystalline Cellulose, nigecose and kaolin, and liquid carrier is as sterilized water, Polyethylene Glycol, nonionic surfactant and edible oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami), as long as be applicable to the characteristic of active component and required specific administration mode.In pharmaceutical compositions, normally used adjuvant also can advantageously be included, and e.g., flavoring agent, pigment, antiseptic and antioxidant are as vitamin E, vitamin C, BHT and BHA.
These reactive compounds also can parenteral or intraperitoneal administration.Also solution or the suspension of these reactive compounds (as free alkali or pharmaceutically acceptable salt) can be prepared in the water being suitably mixed with surfactant (as hydroxypropyl cellulose).Also can prepare dispersion liquid in glycerol, Polyethylene Glycol and the mixture in oil thereof.Under conventional storage and service condition, contain antiseptic in these preparations to prevent microbial growth.
The medicament forms being applicable to inject comprises: aseptic aqueous solution or dispersion liquid and aseptic powder (for extemporaneous preparation of sterile injection or dispersion liquid).In all situations, these forms must be aseptic and must be that fluid is to be easy to syringe displacement fluids.Must be stable under conditions of manufacture and storage, and microorganism must be able to be prevented as the pollution of antibacterial and fungus and impact.Carrier can be solvent or disperse medium, wherein containing, for example water, alcohol, their suitable mixture and vegetable oil.
The details of various aspects of the present invention is able to detailed description by chapters and sections subsequently.By hereafter and the description of claim, feature of the present invention, object and advantage will be more obvious.
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percent, ratio, ratio or number by weight.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can combination in any.All features that patent specification discloses can with any composition forms and use, each feature disclosed in description, anyly can provide identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Embodiment 1 extracts compound 1
1) monomer component is extracted
Get Chinese crude drug seed of Fructus Hippophae 2000g, with 8 times of 75% alcohol reflux 2 hours, be concentrated into and do and obtain extract, continuous silica gel column chromatography (400 orders, 30 times of extract qualities, chloroform: methanol: water=8:2:0.2-6:4:1 gradient elution) and reversed-phase silica gel column chromatography (400 orders repeatedly, 50 times of extract qualities, methanol: water=3:7-6:4 gradient elution), be separated and obtain compound 0.02g, yield 0.001%.
2) Structural Identification
Through MS-ESI, 13c-NMR, 1h-NMR measures, and obtains the following spectral data of this compound 1.
Compound 1 1h-NMR and 13the data of C-NMR (400 and 100MHz, pyridine-d 6)
Embodiment 2 is extracted and authenticating compound 2 ~ 4
Compound 2 ~ 4 is that the similar method of applicating adn implementing example l is extracted.Through MS-ESI, 13c-NMR, 1h-NMR measures, and obtains the following spectral data of these compounds.
Compound 2 1h-NMR and 13the data of C-NMR (600 and 150MHz, pyridine-d6)
Compound 3 and 4 1h-NMR and 13the data of C-NMR (600 and 150MHz, pyridine-d6)
The mensuration of the external hypolipidemic activity of embodiment 3 compound 1 ~ 4
Laboratory animal: male KM mice, body weight 25-30g.
Dosage: the test dose of compound 1 ~ 4 is 10mg/kg, and positive drug simvastatin is 10mg/kg.
Emulsion prepare: Adeps Sus domestica 80g is placed in 500ml beaker and on electric furnace heating and melting, add cholesterol 40g and make it to dissolve, add sodium cholate 8g and propylthiouracil sheet 4g again, fully stir evenly, then appropriate distilled water and tween 80, each 80ml of propylene glycol is added, constantly stir evenly, then add distilled water to 400ml and fully mixing, the lipomul of 100g/l cholesterol, 200g/l Adeps Sus domestica, 20g/l sodium cholate and 10g/l propylthiouracil.Put into Refrigerator store, the used time needs heating and melting.
Experimental technique: except Normal group, all the other are respectively organized and gavage Emulsion (0.5ml) every afternoon, the morning next day oral administration, continuous 10d, last day eye socket arterial blood drawing.After centrifuging and taking serum, survey hyperlipemia in mice serum cholesterol (CHO), low density lipoprotein, LDL (LDL) two biochemical indicators.
Experimental result:
Above result of the test shows: compound 1 ~ 4 all has effect for reducing blood fat significantly, when 10mg/kg and the lipid-lowering effect of simvastatin close.
Many aspects involved in the present invention have been done and have as above been set forth.It is to be understood, however, that put before not departing from spirit of the present invention, those skilled in the art can carry out equivalent change and modification to it, and described change and modification fall into the coverage of the claim of present patent application equally.

Claims (4)

1. as a triterpene saponin derivant for structure formula I, or its pharmaceutically acceptable salt, hydrate or prodrug, wherein structure formula I is:
Wherein R 1be selected from S 1or S 2,
R 2be selected from-CH 2oH or methyl.
2. triterpene saponin derivant as claimed in claim 1, or its pharmaceutically acceptable salt, hydrate or prodrug, it is characterized in that, described triterpene saponin derivant is selected from:
3. a pharmaceutical composition, the triterpene saponin derivant as described in claim l containing treatment effective dose or its pharmaceutically acceptable salt, hydrate or prodrug, and pharmaceutically acceptable carrier.
4. triterpene saponin derivant as claimed in claim 1 or its pharmaceutically acceptable salt, hydrate or prodrug are preparing the application in blood lipid-lowering medicine.
CN201310467106.8A 2013-10-09 2013-10-09 Triterpenoid saponin derivative and its medical usage Active CN104546875B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111789873A (en) * 2020-08-04 2020-10-20 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)

* Cited by examiner, † Cited by third party
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
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)

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Title
CHAO CHEN, ET AL.: "Four new triterpenoid glycosides from the seed residue of Hippophae rhamnoides subsp. sinensis", 《JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH》 *
傅建熙 等: "沙棘籽的综合利用I——沙棘籽油渣的化学成分研究", 《沙棘》 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111789873A (en) * 2020-08-04 2020-10-20 中国科学院西北高原生物研究所 Method for extracting high-content seabuckthorn triterpenic acid extract
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

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