CN106243065A - A kind of new sesquiterpenoid and biomedical uses thereof - Google Patents
A kind of new sesquiterpenoid and biomedical uses thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/35—Caprifoliaceae (Honeysuckle family)
- A61K36/355—Lonicera (honeysuckle)
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Abstract
The invention discloses a kind of new sesquiterpenoid and biomedical uses thereof, it is provided that this compound structure, containing its pharmaceutical composition and its preparation method and application.This compound is reported first, is the sesquiterpene of a kind of novel structure, can obtain by extracting and developing purification from Flos Lonicerae.Pharmacological testing proves, this compound can improve the HepG2 consumption to glucose, reduces the blood glucose of diabetic mice；This compound can also suppress the growth of transplanted human hepatocellular carcinoma.As can be seen here, this compound can develop into the medicine for the treatment of diabetes or hepatocarcinoma, for the therapeutic scheme that the treatment offer of diabetes clinically and hepatocarcinoma is new.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, relate to a kind of new natural product, be specifically related to one and divide from Flos Lonicerae
The sesquiterpenoid separated out and medical usage thereof.
Background technology
Flos Lonicerae the most just medical value with it is extensive and famous.Its effect is mainly heat-clearing and toxic substances removing, cures mainly temperature
Sick heating, toxic-heat and blood stasis, carbuncle furunculosis etc..Modern study proves, Flos Lonicerae contains the pharmacologically active such as chlorogenic acid, luteolin glycosides
Composition, has stronger to the various pathogens such as Hemolytic streptococcus, staphylococcus aureus and upper respiratory tract infection Causative virus etc.
Restraint, the most also can enhancing immunity, antiearly pregnancy, hepatoprotective, antitumor, antiinflammatory, antipyretic, hemostasis (blood coagulation), suppression intestinal inhale
Receiving cholesterol etc., its clinical application widely, can be used for treating respiratory tract infection, bacillary dysentery with other medicines compatibility, acute secrete
Urinary system infection, hypertension etc. more than 40 plant disease.
Flos Lonicerae is cold in nature, sweet in the mouth, enters lung, the heart, stomach warp, has heat-clearing and toxic substances removing, antiinflammatory, effect of qi-restoratives treatment wind, cures mainly swollen
Disease, epidemic febrile disease is completely descended to generate heat, the disease such as pyretic toxicity carbuncle and ulcer and tumor.It makees thirsty, hyperhidrosis unhappiness, enteritis, bacterium for dizzy dizzy, xerostomia
Dysentery, measles, pneumonia, encephalitis b, epidemic encephalitis, acute mastitis, septicemia, appendicitis, skin infection, carbuncle furuncle, erysipelas, the parotid gland
The diseases such as inflammation, suppurative tonsillitis all have certain curative effect.
Sesquiterpene refers to the natural terpenoids in molecule containing 15 carbon atoms.Sesquiterpenoids is distributed more widely,
In Magnoliales, Folium Symplocoris Caudatae mesh, Cornales and chrysanthemum mesh plant the abundantest.Sesquiterpenoids is more, no matter goes back from number
It is from the type of structural framework, is all most in terpenoid one.Sesquiterpenoid is many by the carbon of its structure
Number of rings is classified, such as ring-like without ring-like, mononuclear type, double ring type, tricyclic and four.Also have by the magnitude classification of ring, such as five, six,
Heptatomic ring, until ten unitary macro ring have.As classified by the oxygen-containing group of sesquiterpene structure, then it is easy to recognize their physicochemical property
And physiologically active, such as sesquiterpenoid, aldehyde, lactone etc..
The chemical composition contained in Flos Lonicerae is various, but main based on flavonoids, sesquiterpenoids composition
Study the most deep enough, the sesquiterpene negligible amounts of report.
Summary of the invention
The first object of the present invention is to provide a kind of sesquiterpenoid of isolated from Flos Lonicerae, this compound
For finding from nature first；
The second object of the present invention is to provide the preparation method of above-mentioned sesquiterpene；
The third object of the present invention is to provide the medical usage of above-mentioned sesquiterpene.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
A kind of pharmaceutical composition, compound (I) described in the claim 1 containing therapeutically effective amount and pharmaceutically acceptable
Carrier.
The preparation method of described compound (I) comprises following operating procedure: Flos Lonicerae is pulverized by (a), water-soluble with ethanol
Liquid circumfluence distillation, united extraction liquid, it is concentrated into without alcohol taste, successively by petroleum ether, ethyl acetate and water saturated n-butyl alcohol extraction
Take, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol takes thing use
Macroporous resin remove impurity, first with 8 column volumes of 25% ethanol elution, then with 12 column volumes of 70% ethanol elution, collects 70% and washes
De-liquid, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel is divided
From, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 85:1,45:1,25:1 and 15:1 successively；(d) step
Suddenly in (c), component 4 separates further by purification on normal-phase silica gel, is the methylene chloride-methanol of 20:1,15:1 and 1:1 by volume ratio successively
Gradient elution obtains 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and uses volume
Percentage concentration is the methanol aqueous solution isocratic elution of 72%, collects 10～16 column volume eluents, and eluent concentrating under reduced pressure obtains
To compound (I).
Further, described macroporous resin is AB-8 type macroporous adsorbent resin.
Further, ethanol water described in step (a) is 75～85% ethanol.
Further, ethanol water described in step (a) is 80% ethanol.
The application in the medicine of preparation treatment diabetes of the described compound (I).
The application in the medicine of preparation treatment diabetes of the described pharmaceutical composition.
The application in the medicine of preparation treatment hepatocarcinoma of the described compound (I).
The application in the medicine of preparation treatment hepatocarcinoma of the described pharmaceutical composition.
When the compounds of this invention is used as medicine, can directly use, or use with the form of pharmaceutical composition.
This pharmaceutical composition contains the compounds of this invention (I) of therapeutically effective amount, and remaining is the most acceptable, right
Nontoxic and the inert pharmaceutically suitable carrier of humans and animals and/or excipient.
Described pharmaceutically suitable carrier or excipient are that one or more are selected from solid, semisolid and liquid diluent, filler
And pharmaceutical preparation adjuvant.The pharmaceutical composition of the present invention is used with the form of per weight dose.Medicine of the present invention can
It is applied to need the patient for the treatment of by oral or injection form.During for being administered orally, tablet, slow releasing tablet, control can be made into
Release sheet, capsule, drop pill, micropill, suspensoid, Emulsion, powder or granule, oral liquid etc.；During for injecting, can be made into sterilizing
Aqueous or oily solution, aseptic powder injection, liposome or Emulsion etc..
Advantages of the present invention:
The sesquiterpenoid that the present invention provides is reported first, has treatment diabetes and the effect of hepatocarcinoma, Ke Yikai
Send out into the medicine treating diabetes and hepatocarcinoma, for the therapeutic scheme that the treatment offer of diabetes clinically and hepatocarcinoma is new.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit the present invention with this and protect model
Enclose.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, can be right
Technical scheme is modified or equivalent, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Preparation method: Flos Lonicerae (2kg) is pulverized by (a), extracts (15L × 3 time) with 80% alcohol heat reflux, united extraction
Liquid, is concentrated into without alcohol taste (3L), successively with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated n-butyl alcohol
(3L × 3 time) extract, and respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
Acetic acid ethyl ester extract AB-8 type macroporous resin remove impurity, first with 8 column volumes of 25% ethanol elution, then uses 70% ethanol elution
10 column volumes, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, successively with volume ratio be 85:1 (10 column volumes), 45:1 (8 column volumes), 25:1 (10
Individual column volume) and the methylene chloride-methanol gradient elution of 15:1 (8 column volumes) obtain 4 components；Component in (d) step (c)
4 separate further by purification on normal-phase silica gel, successively with volume ratio be 20:1 (10 column volumes), 15:1 (8 column volumes) and 1:1 (6
Column volume) methylene chloride-methanol gradient elution obtain 3 components；E in () step (d), component 2 is bonded by octadecylsilane
Reverse phase silica gel separate, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collect 10～16 column volumes and wash
De-liquid, eluent is concentrated under reduced pressure to give compound (I) (HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 295.1508, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C16H22O5, degree of unsaturation is 6.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-1 (2.88, d, J=3.2Hz),
H-2 (3.06, dd, J=3.2,4.3Hz), H-3 (3.34, d, J=4.3Hz), H-6 (6.03, d, J=4.4Hz), H-7 (2.71,
Ddd, J=4.4,13.1,4.6Hz), H-8 α (1.72, m), H-8 β (1.81, m), H-9 α (1.56, m), H-9 β (1.63, m), H-
13 (5.76, d, J=3.3Hz), and H-13 (6.29, d, J=3.3Hz), H-14 (1.02, s), H-15 (1.47, s), 12-OMe
(3.77, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 73.4 (CH, 1-C), 53.5 (CH, 2-C), 62.9
(CH, 3-C), 64.5 (C, 4-C), 152.6 (C, 5-C), 125.7 (CH, 6-C), 43.5 (CH, 7-C), 20.3 (CH2, 8-C),
33.5(CH2, 9-C), 34.3 (C, 10-C), 144.6 (C, 11-C), 167.3 (C, 12-C), 124.9 (CH2, 13-C), 19.2
(CH3, 14-C), 21.6 (CH3, 15-C), 52.7 (CH3, 12-OMe).13C-NMR, DEPT and hsqc spectrum show 16 carbon letters
Number, including three methyl (methoxyl group), three methylene (an alkene carbon), five methine (three company's oxygen carbon and
Individual alkene carbon), and five quaternary carbons (two alkene carbon, one company's oxygen quaternary carbon of a carbonyl carbon).Function above structure in conjunction with
Insatiable hunger sum shows that this compound is tricyclic structure.1H-NMR spectrum combines hsqc spectrum and shows three methyl proton signal δH 1.02
(3H, s), 1.47 (3H, s) with 3.77 (3H, s), pair of end olefinic proton signals δH6.29 (1H, d, J=3.3Hz) and 5.76
(1H, d, J=3.3Hz), three company oxygen methine proton signal δH2.88 (1H, d, J=3.2Hz), 3.06 (1H, dd, J=
3.2,4.3Hz), 3.34 (1H, d, J=4.3Hz), an olefinic proton signals δH6.03 (1H, d, J=4.4Hz).H NMR spectroscopy number
According to δH3.77 (3H, s) and δCThis compound knowable to 52.7 exists methoxyl group, methoxyl group proton signal and C-12 in HMBC spectrum
Dependency indicate methoxyl group and be connected to C-12 position.According to H NMR spectroscopy data δH3.06 (1H, dd, J=3.2,4.3Hz),
3.34 (1H, d, J=4.3Hz) and δC53.5,62.9 an existence epoxy construction in this compound is understood.Pass through1H-1H COSY composes
Middle H-1/H-2/H-3 and H-6/H-7/H2-8/H2H-1 Yu C-2, C-3 and C-10 of display in-9 coherent signals, and HMBC spectrum,
H-2 Yu C-1, C-3 and C-4, H-3 and C-2, C-3 and C-15, H-6 and C-5, C-7, C-8 and C-10, H-7 Yu C-6, C-8 and C-
11, H2-13 with C-7, C-11 and C-12, H3-14 with C-10 coherent signal, can build the connected mode of this compound, and on
State spectral data and show that this compound is eudesmane.C-1, C-2, C-3, C-4, C-7 and C-10 in this compound
For chiral carbon, confirm relative configuration by NOESY test with H-H coupling constant.NOESY spectrum in H-1/H-2, H-1/H-9 β,
H-1/H-14, H-7/H-13, H-8 β/H-13, H-8 β/H-14 Yu H-14/H-15 coherent signal show this compound C-1, C-2,
C-3, C-4, C-7 and C-10 are configured as 1R, 2R, 3R, 4S, 7S and 10R.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and
Document, about correlation type nuclear magnetic data, can determine that this compound is as follows substantially, and spatial configuration is tested by ECD further
Determining, theoretical value is basically identical with experiment value.
Chemical structural formula and the carbon atoms numbered of this compound are as follows:
Embodiment 2: the therapeutical effect to diabetes
1, materials and methods
1.1 test apparatus
Thermo 6500 CO2 gas incubator, EosBravoW automatic clinical chemistry analyzer, clean JJ-CJ-2F is clean for gold
Workbench, BioTekELX800 microplate reader, ZEISSAxiovert40CFL inverted microscope.
1.2 materials and reagent
Compound (I) is made by oneself, and preparation method is shown in embodiment 1.People hepatocarcinoma embryonic germ HepG2 cultivates purchased from Chinese Typical Representative
Thing preservation center.Superfine hyclone, RPMI1640 culture medium are purchased from Gibco company.Glucose enzymatic assays test kit is purchased from
Bioengineering Research Institute is built up in Nanjing.Trypsin, purchased from Sigma company.People's insuline pro injection is purchased from ten thousand nation's biochemistry medicine
Company.Cleaning grade Kunming mouse, weight 18～22g, animal housing of Third Military Medical University provides.
1.3 cell blood sugar lowering tests
The HepG2 cell digested and diluted is joined in 96 orifice plates, treats that cell is paved with rate and reaches 80%, change former cultivation
Base, cleans 1 time with PBS, by 96 orifice plate random packet, and respectively Normal group and compound (I) group (5 μ g mL-1).Often organize every hole and add the culture fluid of 250 μ l pastilles or not pastille.Utilize glucose enzymatic assays test kit in the most certainly after 24h
Automatic Biochemical Analyzer utilizes end-point method, under 505nm wavelength, detects glucose surplus in culture fluid.
1.4 animal blood sugar lowering experiments
Cleaning grade Kunming mouse, weight 18～22g, purchased from animal housing of Third Military Medical University.Mice balance raises 3d
After, hungry 12h, then tail vein injections alloxan (70mg kg-1).After 3d, detect blood glucose.Take blood glucose be 10～
The mice of 25mmol/L, as hyperglycemia model mice, is divided into 4 groups according to blood glucose, often group 10.It is respectively Normal group, mould
Type matched group, positive controls (gastric hydrochloric acid guanidine, 100mg kg-1) and compound (I) group (80mg kg-1).High sugar model pair
According to group gavage distilled water, gavage medicine 7d, hungry 12h, measure fasting blood sugar.
1.5 statistical method
Significance test is done with SPSS19.0.
2, experimental result
2.1 impacts on the experiment of HepG2 blood sugar lowering
Comparing with Normal group, the consumption of glucose is substantially increased (P ＜ 0.01) by compound (I) group, demonstrates
Significantly blood sugar reducing function.The results are shown in Table 1.
2.2 impacts on diabetic mice blood glucose
After mice gives alloxan, it can be observed that mouse blood sugar increases.Compare with Normal group, model control group
Mouse blood sugar raises (P ＜ 0.01), and modeling success is described；Compare with model control group, compound (I) group and positive drug control group
Blood glucose significantly reduces (P ＜ 0.01).
Experimental result is shown in Table 2.
The table 1 impact (x ± s) on HepG2 glucose utilization
| Group | The consumption C/mmol L of glucose-1 |
| Normal group | 2.170±0.054 |
| Compound (I) group | 5.547±0.062 |
The table 2 impact (x ± s) on blood glucose in diabetic mice
The above results shows, the compound (I) that the present invention provides can improve the HepG2 consumption to glucose, reduces
The blood glucose of diabetic mice, can develop into the medicine preventing and treating diabetes.
Embodiment 3: the therapeutical effect to hepatocarcinoma
1, material and method
1.1 cells and animal
Laboratory meets DB44/61-94 cleaning grade standard.It is micro-that human hepatoma cell strain Bel-7402 derives from Guangzhou Medical College
Biological immunology teaching and research room.Nude mice (BALB/C-nu/nu) is provided by Nanfang Medical Univ's Experimental Animal Center, male, Mus 4-in age
6 weeks, weight 20-25g, average (23.28 ± 1.62) raised in SPF environment.
1.2 reagent and sample
Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
Prepared by 1.3 mice group and model
Transplanted tumor Nude mice model replicates: by frozen hepatoma cell strain Bel-7402 taking-up in liquid nitrogen container, recovery, body
Being incubated at outward in RPM11640, adding volume fraction is the calf serum of 0.1, penicillin 100,000 units/L, streptomycin 100mg/
L, monolayer culture is in CO2In constant-temperature incubation case, cell is Epithelial adherent growth, and every couple of days passes on 1 time, trophophase of taking the logarithm
Cell is used for testing.With the RPM11640 culture fluid diluting cells of the calf serum that volume fraction is 0.1 to containing tumor 1 × 1010L-1, at nude mice left front upper limb axillary fossa subcutaneous vaccination 0.2mL.
Packet: the nude mice of 12 inoculation hepatoma cell strains is randomly divided into merely Normal group and compound (I) group
(60mg·kg-1) totally 2 groups.All nude mices are beginning gastric infusion from inoculation hepatoma cell strain the 3rd day, and Normal group is equivalent
Normal saline gavage, the next day 1 time, gavage 20 times.After drug withdrawal 1 week, de-neck is put to death: completely take out tumor mass, detects tumor weight.Press
Below equation calculating tumor control rate:
Tumor control rate=(matched group average tumor quality-administration group average tumor quality)/matched group average tumor quality ×
100%.
The mensuration of 1.4 microvessel densitys
Use two-step process dyeing: specimen, after formaldehyde is fixing, carries out 3um serial section: by paraffin section de-waxing to water: high
Autoclaving boiling antigen retrieval 3min, volume fraction is the H of 0.032O2Incubated at room 10min, the dropping anti-human factor Ⅷ of rabbit is relevant anti-
Body, 4 liquid of spending Celsius, drip the biotin labeled goat anti-rabbit igg of 1:200, hatch 30min, diaminobenzidine for 37 degrees Celsius
Colour developing 5min, replaces one anti-as blank, with hemangioma as positive control using 0.01mol/L phosphate buffer.Micro-blood
The mensuration of pipe density is with reference to Clinica limportance of the determination of tumor
The method of angiogenesisin breast carcinoma:much more than a new prognostictool.?
Capillary whole blood glucose situation is checked: with neovascular endothelium dye for brown color as Positive judgement standards, take between cancer nests under low power field
The visual field that matter blood vessel is most, under 200 times of visuals field, is counted 3 visuals field by double-blind method by 3 observers: observe and dye palm fibre respectively
The individual cells of color and cell clump, and in this, as a blood vessel: lumen of vessels and intracavity erythrocyte are not as counting, if any muscle layer
Blood vessel or tube chamber > 50 person should get rid of, take the 3 people's weighted mean values microvessel density as this example.
1.5 nude mice Evaluation on quality of lifes
By the nude mice mental status, activity situation, to stimulate reaction, weight fall, appetite and urine, feces 6
The observation of index, evaluates nude mice life quality and medicine toxicity.
1.6 statistical analysis
Being carried out statistical procedures by this seminar application SPSS19.0 software, tumor control rate, microvessel density average are adopted
Analyzing with F and compare between organizing, P < 0.05 is for having statistical significance.
2, experimental result
2.1 impacts on transplanted human hepatocellular carcinoma nude mice life quality
At the end of therapeutic scheme: compound (I) 6 nude mices of group all survive, and Normal group only has 4 survivals.All extremely
The nude mice that dies the most has been dissected and has eliminated due to the lethal possibility of experiment for improper, and nude mice death is to be deteriorated or medicine by tumor itself
Caused by toxicity.Compound (I) the group nude mice mental status, activity situation, the reaction to stimulating, weight fall, food
Be intended to and urine and stool etc. shows no obvious abnormalities, and state is better than Normal group.
The inhibitory action of 2.2 pairs of hepatocellular carcinoma in nude mice transplanted tumoies
Comparing with Normal group, compound (I) group is significantly stronger to tumor inhibition effect, shows as average tumor quality and subtracts
Few (P ＜ 0.01), tumor control rate higher (P ＜ 0.01).The results are shown in Table 3.
2.3 impacts on Tumor angiogenesis
Comparing with Normal group, compound (I) group is significantly stronger to tumor inhibition effect, shows as microvessel density fall
Low (P ＜ 0.01).The results are shown in Table 3.
Table 3 is on hepatocellular carcinoma in nude mice transplanted tumor and the impact of Tumor angiogenesis
The above results shows, compound (I) can significantly inhibit the growth of transplanted human hepatocellular carcinoma, can be developed into the medicine for the treatment of hepatocarcinoma
Thing.
Embodiment 4: the preparation of tablet
First prepare compound (I) by embodiment 1 method, and utilize organic acid such as tartaric acid or citric acid or formic acid or
The salt that ethanedioic acid etc., mineral acid example hydrochloric acid or sulphuric acid or phosphoric acid are made, adds tax with excipient weight than the ratio for 1:9 in it
Shape agent, pelletizing press sheet.
Embodiment 5: the preparation of oral liquid
First prepare compound (I) by embodiment 1 method, and utilize organic acid such as tartaric acid or citric acid or formic acid or
The salt that ethanedioic acid etc., mineral acid example hydrochloric acid or sulphuric acid or phosphoric acid are made, oral liquid preparation method makes oral liquid routinely.
Embodiment 6: capsule or the preparation of granule
First prepare compound (I) by embodiment 1 method, and utilize organic acid such as tartaric acid or citric acid or formic acid or
The salt that ethanedioic acid etc., mineral acid example hydrochloric acid or sulphuric acid or phosphoric acid are made, adds tax with excipient weight than the ratio for 1:9 in it
Shape agent, makes capsule or granule.
Embodiment 7: the preparation of injection
First prepare compound (I) by embodiment 1 method, and utilize organic acid such as tartaric acid or citric acid or formic acid or
The salt that ethanedioic acid etc., mineral acid example hydrochloric acid or phosphoric acid are made, injects routinely and uses water, and fine straining, injection is made in embedding sterilizing.
Embodiment 8: the preparation of aseptic powder injection
First prepare compound (I) by embodiment 1 method, and utilize organic acid such as tartaric acid or citric acid or formic acid or
The salt that ethanedioic acid etc., mineral acid example hydrochloric acid or sulphuric acid or phosphoric acid are made, is dissolved in sterile water for injection, and stirring makes molten, uses
Aseptic suction funnel filters, more aseptic fine straining, is sub-packed in ampoule, and after frozen drying, aseptic sealing by fusing obtains injectable powder.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit the protection of the present invention with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent,
Essence and protection domain without deviating from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. a pharmaceutical composition, it is characterised in that: the compound (I) described in the claim 1 containing therapeutically effective amount and medicine
Acceptable carrier on.
3. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a) is by gold
Flos Lonicerae is pulverized, and uses ethanol water circumfluence distillation, united extraction liquid, is concentrated into without alcohol taste, successively by petroleum ether, ethyl acetate
With water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b) step
Suddenly in (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 25% ethanol elution, then with 70% ethanol elution 12
Individual column volume, collects 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；70% ethanol elution in (c) step (b)
Concentrate purification on normal-phase silica gel separates, and washes by the methylene chloride-methanol gradient that volume ratio is 85:1,45:1,25:1 and 15:1 successively
Take off and obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 20:1,15:1 and
The methylene chloride-methanol gradient elution of 1:1 obtains 3 components；In (e) step (d) component 2 with octadecylsilane be bonded anti-
Phase silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 72%, collects 10～16 column volume eluents,
Eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 3 (I), it is characterised in that: described macroporous resin is AB-8 type
Macroporous adsorbent resin.
The preparation method of compound the most according to claim 3 (I), it is characterised in that: described in step (a), ethanol is water-soluble
Liquid is 75～85% ethanol.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described in step (a), ethanol is water-soluble
Liquid is 80% ethanol.
7. the application in the medicine of preparation treatment diabetes of the compound (I) described in claim 1.
8. the application in the medicine of preparation treatment diabetes of the pharmaceutical composition described in claim 2.
9. the application in the medicine of preparation treatment hepatocarcinoma of the compound (I) described in claim 1.
10. the application in the medicine of preparation treatment hepatocarcinoma of the pharmaceutical composition described in claim 2.
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| CN105330636A (en) * | 2015-12-07 | 2016-02-17 | 西宁意格知识产权咨询服务有限公司 | New flavonoid compound and preparation method and medical application thereof |
| CN105669621A (en) * | 2016-04-23 | 2016-06-15 | 吴珺 | Pharmaceutical composition of chlortetracycline hydrochloride and medical application of pharmaceutical composition |
| CN105837656A (en) * | 2016-04-01 | 2016-08-10 | 胡文杰 | Cycloartane triterpene and medical application thereof |
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|---|---|---|---|---|
| CN105330636A (en) * | 2015-12-07 | 2016-02-17 | 西宁意格知识产权咨询服务有限公司 | New flavonoid compound and preparation method and medical application thereof |
| CN105837656A (en) * | 2016-04-01 | 2016-08-10 | 胡文杰 | Cycloartane triterpene and medical application thereof |
| CN105669621A (en) * | 2016-04-23 | 2016-06-15 | 吴珺 | Pharmaceutical composition of chlortetracycline hydrochloride and medical application of pharmaceutical composition |
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