CN105601695A - Triterpenoid compound, preparation method and medical application in treatment of prostate cancer - Google Patents
Triterpenoid compound, preparation method and medical application in treatment of prostate cancer Download PDFInfo
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Abstract
The invention discloses a triterpenoidcompound, a preparation method and medical application in treatment of prostate cancer. The compound is reported for the first time, is a triterpenoid compound with a novel structure, and can be obtained through extraction, separation and purification from dry herba artemisiae scopariae. An in-vitro test proves that the compound has inhibiting functions on prostate cancer cell strains PC3 and DU145, and the inhibiting functions have concentration and time dependence relationships. The compound (I) may become a potential choice in the treatment of later period prostate cancer, and can be used to be developed into a drug treating prostate cancer.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to separate the one obtaining and have before treatment from dry oriental wormwoodTriterpene compound of row gland cancer effect and preparation method thereof.
Background technology
Oriental wormwood is feverfew shore wormwood artemisia (ArtemisiascopariaWaldst.etKit.) or Artemisia capillaris(A.CapillarisThunb.) dry aerial parts. All there is distribution China most areas, main product in Anhui, Zhejiang, riverThe provinces such as Soviet Union, Shaanxi, Shanxi. The habit of gathering spring claims " capillary wormwood ", and the habit of gathering autumn claims " flower oriental wormwood ". Oriental wormwood hardship, pungent, micro-Cold, return spleen, stomach, liver and gall warp, effect of tool clearing heat and promoting diuresis, normalizing gallbladder to cure jaundice.
Oriental wormwood contains number of chemical composition, comprises Coumarins, flavonoids, chromogen ketone, organic acid, eneyne class, threeTerpene, steroid and aldoketones etc. Can trace back to the sixties in 20th century even more early to the research of cumarin in oriental wormwood. Oriental wormwoodIn Coumarins composition be mainly simple cumarin and furocoumarin. Flavone compound in oriental wormwood is mainly flavonolsGlucosides and aglycon. In oriental wormwood, contain multiple organic phenol acid compounds, its Content of Chlorogenic Acid (chlorogenicacid), coffeeAcid (caffeicacid) etc. has the aspect effects such as obvious cholagogic and anti-inflammation.
Modern pharmacological research shows, oriental wormwood has loose biliary tract to expand about flesh, promotes choleresis, increases cholic acid and courage in bileThe effects such as red pigment discharge rate. Oriental wormwood and prescription thereof are often applied to treating fatty liver, alcoholic liver, virus hepatitis etc. clinicallyLiver disease. Research shows, oriental wormwood has protection liver plasma membrane integrality and good permeability, prevents necrosis of liver cells, shortEnter liver cell regeneration and improve Microcirculation of Liver, suppress glucuronic acid enzymatic activity, strengthen the functions such as liver detoxification. In Artemisia capillarisCoumarin kind compound there is hemangiectasis, impel vascular endothelial cell to discharge nitric oxide and prostacyclin, reducing blood lipid, anti-The effects such as blood coagulation. It is prominent that Artemisia capillaris can reduce mutagens AFB1 micronuclei, chromosome aberration, sister chromatids exchange and geneBecome; The expression of proto-oncogene c-myc, C-fos, V-sis is had to certain inhibitory action, natrium nitrosum and N methylbenzylamine are luredThe cancer effect of sending out has blocking effect. Caffeic acid in oriental wormwood etc. can increase leucocyte number, and vegetable protein wherein has and inducesThe effect of interferon. Main component 6 in oriental wormwood, 7-escoparone has significant hypothermal effect to normal mouse temperature,Draft beer yeast, 2,4-DNP pyrogenicity rat are also had to obvious antipyretic effect, and there is obvious analgesic activity.
Summary of the invention
The object of this invention is to provide a kind of one obtaining that separates and there is treatment prostate cancer work from dry oriental wormwoodWith triterpene compound and preparation method thereof.
Above-mentioned purpose of the present invention is to be achieved by technical scheme below:
There is the compound (I) of following structural formula,
The preparation method of described compound (I), comprises following operating procedure: (a) dry oriental wormwood is pulverized, with 75～85% alcohol heat reflux extracts, and merges extract, is concentrated into without alcohol taste, uses successively benzinum, ethyl acetate and just water saturatedButanols extraction, obtains respectively petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract; (b) acetic acid second in step (a)The macroreticular resin removal of impurities of ester extract, first uses 8 column volumes of 10% ethanol elution, then uses 12 column volumes of 75% ethanol elution,Collect 75% ethanol eluate, reduced pressure concentration obtains 75% ethanol elution thing medicinal extract; (c) in step (b), 75% ethanol elution thing soaksCream separates by purification on normal-phase silica gel, washes successively by the methylene chloride-methanol gradient that volume ratio is 80:1,50:1,30:1,15:1 and 1:1Take off and obtain 5 components; (d) component 4 use purification on normal-phase silica gel further separate in step (c), successively with volume ratio be 20:1,15:1 andThe methylene chloride-methanol gradient elution of 5:1 obtains 3 components; (e) the middle component 2 use octadecylsilane bondings of step (d) is anti-Phase silica gel separates, and the methanol aqueous solution isocratic elution that is 75% by concentration expressed in percentage by volume, collects 8～10 column volume eluents,Eluent reduced pressure concentration obtains pure compound (I).
Further, in step (a), with 80% alcohol heat reflux extraction, merge extract.
Further, described macroreticular resin is AB-8 type macroporous absorbent resin.
A kind of pharmaceutical composition, this pharmaceutical composition contain treat effective dose compound claimed in claim 1 (I) andPharmaceutically acceptable carrier.
The application of described compound (I) in the medicine of preparation treatment prostate cancer.
The application of described pharmaceutical composition in the medicine of preparation treatment prostate cancer.
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) for the treatment of effective dose, and all the other are acceptable on materia medica, rightPharmaceutically suitable carrier and/or the excipient of the nontoxic and inertia of humans and animals.
Described pharmaceutically suitable carrier or excipient are that one or more are selected from solid, semisolid and liquid diluent, fillerAnd pharmaceutical preparation assistant agent. Pharmaceutical composition of the present invention is used with the form of per weight dose. Medicine of the present invention canBe applied to by form oral or injection the patient who needs treatment. When oral, can be made into tablet, sustained release tablets, controlRelease sheet, capsule, dripping pill, micropill, supensoid agent, emulsion, powder or granule, oral liquid etc.; While being used for injecting, can be made into sterilizingWater-based or oily solution, aseptic powder injection, liposome or emulsion etc.
Brief description of the drawings
Fig. 1 is compound (I) structural formula;
Fig. 2 is that the theoretical ECD value of compound (I) compares with experiment ECD value;
Fig. 3 is PC3 and DU145 survival rate after variable concentrations compound (I) effect 72h;
Fig. 4 is PC3 and DU145 survival rate after 10.0mg/L compound (I) effect different time.
Detailed description of the invention
Further illustrate essentiality content of the present invention below in conjunction with embodiment, protect model but do not limit the present invention with thisEnclose. Although the present invention is explained in detail with reference to preferred embodiment, those of ordinary skill in the art should be appreciated that can be rightTechnical scheme of the present invention is modified or is equal to replacement, and does not depart from essence and the scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, benzinum, ethyl acetate, n-butanol, carrene are that analysis is pure, insult peaking purchased from ShanghaiLearn reagent Co., Ltd, methyl alcohol, analyze pure, purchased from Jiangsu Han Bang chemical reagent Co., Ltd.
Through identify oriental wormwood for feverfew shore wormwood artemisia (ArtemisiascopariaWaldst.etKit.) drylyUpper part.
Preparation method: (a) dry oriental wormwood (8kg) is pulverized, with 80% alcohol heat reflux extraction (25L × 3 time), mergeExtract, is concentrated into without alcohol taste (3L), uses successively benzinum (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated positive fourthAlcohol (3L × 3 time) extraction, obtains respectively petroleum ether extract, acetic acid ethyl ester extract (363g) and n-butyl alcohol extract; (b) stepSuddenly AB-8 type macroreticular resin removal of impurities for acetic acid ethyl ester extract in (a), first uses 8 column volumes of 10% ethanol elution, then uses 75%12 column volumes of ethanol elution, collect 75% ethanol eluate, and reduced pressure concentration obtains 75% ethanol elution thing medicinal extract (145g); (c)In step (b), 75% ethanol elution medicinal extract separates by purification on normal-phase silica gel, is 80:1 (8 column volumes), 50:1 (8 successively by volume ratioIndividual column volume), the methylene chloride-methanol gradient of 30:1 (6 column volumes), 15:1 (8 column volumes) and 1:1 (5 column volumes)Wash-out obtains 5 components; (d) in step (c), component 4 (47g) further separates by purification on normal-phase silica gel, is 20:1 successively by volume ratioThe methylene chloride-methanol gradient elution of (8 column volumes), 15:1 (10 column volumes) and 5:1 (6 column volumes) obtains 3 groupsPoint; (e) component 2 (26g) separates with the reverse phase silica gel of octadecylsilane bonding in step (d), by concentration expressed in percentage by volume is75% methanol aqueous solution isocratic elution, collects 8-10 column volume eluent, and eluent reduced pressure concentration obtains pure compound(Ⅰ)(39mg)。
Structural identification: clear crystal (methyl alcohol); HR-ESIMS shows [M+Na]+For m/z509.2918, in conjunction with nuclear-magnetism spyLevying and can obtaining molecular formula is C29H42O6, degree of unsaturation is 9. Proton nmr spectra data δH(ppm，DMSO-d6，500MHz)：H-1(1.93，m)，H-1(1.71，m)，H-4(2.21，dq，J＝12.6，6.4)，H-5(1.62，ddd，J＝12.6，12.6，4.6)，H-6(1.73，ddd，J＝15.8，6.5，4.6)，H-6(1.51，dd，J＝15.8，12.6)，H-7(3.21，d，J＝6.4)，H-11(1.93，m)，H-11(1.97，m)，H-12(1.48，m)，H-12(1.91，m)，H-15(1.46，m)，H-15(1.27，ddd，J＝12.5，12.5，5.4)，H-16(1.31，m)，H-16(1.96，m)，H-17(1.54，m)，H-18(0.91，s)，H-19(0.91，s)，H-20(1.37，m)，H-21(0.87，d，J＝6.5)，H-22(1.11，m)，H-22(1.35，m)，H-23(1.79，m)，H-23(2.07，m)，H-24(5.01，tt，J＝7.1，1.4)，H-26(1.67，s)，H-27(1.72，s)，H-28(0.97, d, J=6.5); Carbon-13 nmr spectra data δC(ppm，DMSO-d6，176Hz)：35.9(CH2，1-C)，197.1(C，2-C)，199.7(C，3-C)，43.1(CH，4-C)，40.7(CH，5-C)，25.8(CH2，6-C)，69.8(CH，7-C)，80.2(C，8-C)，85.6(C，9-C)，37.7(C，10-C)，21.8(CH2，11-C)，33.4(CH2，12-C)，45.1(C，13-C)，58.8(C，14-C)，19.7(CH2，15-C)，26.8(CH2，16-C)，51.1(CH，17-C)，15.3(CH3，18-C)，14.9(CH3，19-C)，35.7(CH，20-C)，17.7(CH3，21-C)，36.7(CH2，22-C)，23.9(CH2，23-C)，124.1(CH，24-C)，130.6(C，25-C)，17.1(CH3，26-C)，24.5(CH3，27-C)，11.9(CH3, 28-C), 177.1 (C, 30-C); CarbonAtom mark is referring to Fig. 1. IR spectrum shows that this compound contains ketone group (1710cm- 1) and lactone (1770cm- 1) group.1HNMRSpectrum show contain four unimodal methyl signals δ H0.91 (Me-18), 0.91 (Me-19), 1.67 (Me-26), 1.72 (Me-27) withAnd two bimodal signal δ H0.87 (Me-21, d, J=6.5Hz) and 0.97 (Me-28, d, J=6.5Hz).13CNMR and DEPT spectrumShow 29 carbon signals, comprise six methyl, six methines (an alkene carbon, one containing oxygen methine), eight methyleneAnd nine quaternary carbons (two containing oxygen quaternary carbon for three carbonyl carbon, an alkene carbon). In addition, side chain has 24 (25)-bis-key (δC130.6,124.1 and δ H5.01, tt, J=7.1,1.4Hz) signal, Me-26 and Me-27 and C-24 and C-25 in HMBC spectrum,Me-21 and C-17, C-20 and C-22, and H-24 and C-22, C-23, Me-26, the correlation of Me-27 has been verified above-mentioned inference.In HMBC spectrum, H2-1 and C-2, and H-4 and Me-28 show C-2 (δ C197.1) and C-3 (δ C199.7) with the peak that intersects of C-3For ketone carbonyl. In addition an ester carbonyl group signal [δ C177.1 (C-30)] and two carbon signals [δ C85.6 (C-9) and 58.8 (C-,14)] illustrate that this compound exists a gamma lactone structure. Me-18 and C-14 in HMBC spectrum, H2-15 and C-30, H2-11 and C-9,H-11 α and C-8, and the correlation of Me-19 and C-9 has been verified the connection of this functional group of 30,9-. C-7 (δ C69.8) and C-8The chemical shift of (δ C80.2) shows that they are respectively connected with a hydroxyl. Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, Yi JiwenOffer about correlation type nuclear magnetic data, can substantially determine this compound as shown in Figure 1, spatial configuration is further tested by ECDDetermine theoretical value and experiment value basically identical (Fig. 2).
Embodiment 2: compound (I) pharmacological action test
One, material and instrument
Prostatic cancer cell lines PC3 (ArCC-CRL-1435), Prostatic cancer cell lines DU145 (ATCC-HTB-81). ChangeCompound (I) self-control, HPLC normalization purity is greater than 98%, is mixed with the storage that concentration is 1.0g/L with dimethyl alum (DMSO)Liquid is for subsequent use. CCK-8 kit is Japanese colleague's chemistry institute product. RPMI-1640 culture medium is purchased from Gibco company. Tire oxSerum (FBS) is purchased from Hyelone company. Green grass or young crops/streptomysin is Shanghai pioneer's medicine company product. Trypsase is purchased from magnificent bioengineeringCompany. Dimethyl sulfoxide (DMSO) (DMSO) is purchased from Shanghai Hua Shun bio-engineering corporation. Agar (Agarose), dithiothreitol (DTT) (DTT),Benzyl sulfonephthalein fluorine (PMSF), tetramethylethylenediamine (TEMED) are Sigma company product. Dodecyl sodium sulfate (SDs), threeChloromethyl alkyl methane (Tris) Tris-Hcl, Tritonx-100 are Promega company product. Propylene phthalein amine, persulfuric acid money(AP) be purchased from Suzhou chemical reagent factory product.
CO2Cell culture incubator (ShellLab), inverted phase contrast microscope (Nikon), superclean bench (Suzhou cleaning equipmentFactory), flow cytometer (BD), F039300A type ELIASA (Sunrise), autoclave sterilizer (HirayamaHA-300MD), low temperature ultracentrifuge (Kubota3740), Universal table (TS-92 of Jiangsu kylin medical apparatus factory), electrophoresis apparatus(Gibco company), LXJ-II type centrifuge (Shanghai medical analytical instrument factory), DK600 type electric heating constant-temperature water-bath tank (Shanghai precisionTesting equipment company), electronic balance (METTLERTOLEDO), desk-top drying box (the gloomy reliable Instrument Ltd. that tests in Shanghai),Uv-spectrophotometric instrument (Beckman).
Two, test method
1, cell is cultivated and maintenance
1.1 cells are cultivated
Cell line is incubated at central laboratory of tumour hospital. Be incubated at the RPMI-1640 culture medium containing 10% hycloneIn, separately add paddy ammonia phthalein amine (2mmol/L) and antibiotic (l00U/ penicillin and 100mg/L streptomysin), put 37 DEG C, saturated wetSpend, contain 5%CO2In the incubator of gas, cultivate.
1.2 passage
1. under inverted phase contrast microscope, observation of cell covers with adherently, can go down to posterity. Before going down to posterity with 75% alcohol wipe warpCross superclean bench and both hands that ultraviolet ray is irradiated. 2. suck the old nutrient solution in blake bottle with suction pipe, with PBS cleaning 3 times. 3.Add 0.02%EDTA-0.25% trypsin solution 2mL to digest, leave standstill approximately 5 minutes, and frequently at inverted phase contrast microscopeLower observation, when kytoplasm retraction, no longer connects between cell time in blocks, adds the appropriate fresh culture containing serum to stop tryptoseThe effect of enzyme. 4. with dropper, the cell having digested is blown and beaten into cell suspension, suck equilibrium centrifugation (1000 in 10mL centrifuge tubeRev/min) 5 minutes. 5. abandoning supernatant, adds 2mL nutrient solution, blows and beats gently cell make cell suspension, 1:2～3 with dropperBe distributed into new blake bottle, add nutrient solution and in incubator, continue in right amount to cultivate.
2, morphological observation
Inverted microscope is observed: exponential phase PC3 and DU145 cell are inoculated in to 6cm culture dish, after cultivation 24h, addEnter 10.0mgL-1, after compound (I) processing 24,48,72h, under inverted phase contrast microscope, observation of cell form changes also respectivelyRecord.
3, cytotoxicity test (CCK-8 method)
1. the cell dissociation in blake bottle becomes single cell suspension, after cell count according to 3 × 104Individual cells/well is inoculated in96 orifice plates, every hole adds 0.lmL culture medium, cellar culture in 37 DEG C, containing 5%CO2In the incubator of gas. 2. test grouping: establishNegative control group (having cell but not dosing, 0.1%DMSO), blank group (acellular only have nutrient solution), compound (I) pointOther 2.5mg/L, 5.0mg/L, totally 6 groups of 10.0mg/L and 20.0mg/L. 3. after 24 hours, observation of cell adherent growth is good, respectivelyTo dosing in 96 orifice plates, establish 6-8 repeating hole by above-mentioned test grouping for every group. 4. after dosing, 96 orifice plates moved into 37 DEG C, contain 5%CO2In the incubator of gas, continue to cultivate respectively 24,48 and 72 hours. 5. every hole adds CCK-810 μ L when every group of off-test,In 37 DEG C of incubators, continue to cultivate ELIASA after 4 hours and detect absorbance (OD) value in 450 every holes, mensuration wavelength is 450nm, joinsExamining wavelength is 600nm. 6. calculate cell survival rate (cellviability) according to following formula, be then depicted as chart,Value when survival rate is 50% is IC50. Cell survival rate (%)=[(As-Ab)/(Ac-Ab)] × 100%. Wherein As is examinationVerify, Ac is control wells, and Ab is blank well.
4, colony-forming test
1. the cell in growth period of taking the logarithm, after counting with 3 × l02Individual 6 orifice plates that are inoculated in, every hole adds 2mL culture medium, conventional trainingSupport in 37 DEG C, containing 5%CO2In the incubator of gas. 2. after 24h, observation of cell adherent growth is good, adds respectively variable concentrations(0,2.5,5.0,10.0,20.0mg/L) compound (I) is processed, and establishes 3 repeating holes for every group. 3. after dosing, 6 orifice plates are moved into 37DEG C, containing 5%CO2In the incubator of gas, continue 14 days. 4. 10% methyl alcohol is fixed, Giemsa dyeing, calculate every hole colony number (>=50 cells count a colony). 5. calculate colony-forming efficiency: colony sum/inoculating cell number × 100%.
Three, result and conclusion
1, the impact of compound (I) gas on PC3 and DU145 cellular morphology
Under mirror, see cellular control unit adherent growth, flanking cell merges in flakes, and cell is similar round or fusiformis, and volumeGreatly, arrange closely, the smooth of the edge, kytoplasm is full, and the structure outlines such as nuclear membrane, kernel are obvious, and Growth of Cells is rapid; Through 10.0mg/LAfter compound (I) is processed, cell density reduces gradually, and the speed of growth obviously slows to almost and stagnates, and cell comes off gradually and floatsFloat in nutrient solution. Cell volume dwindles, and after birth shrinkage becomes small circular or irregular form, common fine granularity material in born of the same parents.Drug treating time is longer, and morphological changes of cell is more obvious.
2, cytotoxicity test
Variable concentrations compound (I) all has inhibitory action to the growth of Prostatic cancer cell lines PC3 and DU145. 2.5,Survival rate (table l and table as shown in the table after two kinds of cells 24,48 of 5.0,10.0,20.0mg/L compound (I) effect and 72h2). Wherein, 10.0mg/L compound (I) acts on PC3 and DU145 cell 24,45, and the cell survival rate after 72h is respectively56.2%, 42.5%, 24.3% and 50.8%, 32.6%, 20.7%; 2.5,5.0,10.0,20.0mg/L, compound (I) is doneBe respectively 54.3%, 37.7% by the survival rate after two kinds of cell 72h, 24.3%, 13.2% and 52.4%, 32.8%,20.7%, 11.2% (seeing Fig. 3 and Fig. 4). Difference tool between variable concentrations and different time processed group is shown in two factor variance analysesHave statistical significance (P < 0.05), prompting compound (I) is time-concentration to the growth inhibition effect of PC3 and DU145 and relies on.
3, colony-forming test
Test demonstration, the colony-forming efficiency of control group PC3 and DU145 is respectively 67.7 and 64%, and 2.5,5.0,10.0,20.0mg/L compound (I) processed group is respectively 60.7%, 51.3,39.3%, 27.0% and 49.7%, 34.0%, 27.7%,15.7% (in table 3). This has further confirmed that compound (I) has inhibited proliferation to PC3 and DU145 cell.
Conclusion, verifies that by CCK-8 method and colony-forming test compound (I) is to Prostatic cancer cell lines in this testThe effect of PC3 and DU145, and inhibitory action has concentration---Time Dependent sexual intercourse. Compound (I) may become before late periodA potential selection of tool in the treatment of row gland cancer.
Table l variable concentrations compound (I) acts on the cell survival rate after PC3
| Time/concentration | 2.5mg/L | 5.0mg/L | 10.0mg/L | 20.0mg/L |
| 24h | 0.825 | 0.731 | 0.562 | 0.422 |
| 48h | 0.69 | 0.53 | 0.425 | 0.226 |
| 72h | 0.543 | 0.377 | 0.243 | 0.132 |
Table 2 variable concentrations compound (I) acts on the cell survival rate after DU145
| Time/concentration | 2.5mg/L | 5.0mg/L | 10.0mg/L | 20.0mg/L |
| 24h | 0.809 | 0.604 | 0.508 | 0.375 |
| 48h | 0.646 | 0.481 | 0.326 | 0.173 |
| 72h | 0.542 | 0.328 | 0.207 | 0.112 |
The colony-forming efficiency of the lower PC3 of table 3 variable concentrations compound (I) effect and DU145
Embodiment 3
The preparation of tablet: first make compound (I) by embodiment 1 method, and utilize organic acid as tartaric acid or lemonThe salt that acid or formic acid or ethanedioic acid etc., inorganic acid example hydrochloric acid or sulfuric acid or phosphoric acid are made is 1:9 by itself and excipient weight ratioRatio adds excipient, pelletizing press sheet.
Embodiment 4
Oral liquid preparation: first make compound (I) by embodiment 1 method, and utilize organic acid as tartaric acid or lemonThe salt that acid or formic acid or ethanedioic acid etc., inorganic acid example hydrochloric acid or sulfuric acid or phosphoric acid are made, oral liquid method for making is made oral routinelyLiquid.
Embodiment 5
The preparation of capsule or granule: first make compound (I) by embodiment 1 method, and utilize organic acid as wineThe salt that stone acid or citric acid or formic acid or ethanedioic acid etc., inorganic acid example hydrochloric acid or sulfuric acid or phosphoric acid are made, by itself and excipient weightAmount, than for the ratio of 1:9 adds excipient, is made capsule or granule.
Embodiment 6
The preparation of parenteral solution: first make compound (I) by embodiment 1 method, and utilize organic acid as tartaric acid or lemonThe salt that lemon acid or formic acid or ethanedioic acid etc., inorganic acid example hydrochloric acid or sulfuric acid or phosphoric acid are made, injects water routinely, essence filter,Parenteral solution is made in embedding sterilizing.
Embodiment 7
The preparation of aseptic powder injection: first make compound (I) by embodiment 1 method, and utilize organic acid as tartaric acid orThe salt that citric acid or formic acid or ethanedioic acid etc., inorganic acid example hydrochloric acid or sulfuric acid or phosphoric acid are made, is dissolved in sterile water for injectionIn, stirring makes molten, with aseptic suction funnel filtration, more aseptic essence filter, be sub-packed in ampoule aseptic sealing by fusing after frozen dryingObtain powder-injection.
The effect of above-described embodiment is to illustrate essentiality content of the present invention, but does not limit protection of the present invention with thisScope. Those of ordinary skill in the art should be appreciated that and can modify or be equal to replacement technical scheme of the present invention,And do not depart from essence and the protection domain of technical solution of the present invention.
Claims (7)
1. there is the compound (I) of following structural formula,
2. the preparation method of compound claimed in claim 1 (I), is characterized in that comprising following operating procedure: (a) will be driedOriental wormwood pulverize, with 75～85% alcohol heat reflux extract, merging extract, be concentrated into without alcohol taste, use successively benzinum, acetic acidEthyl ester and water saturated extracting n-butyl alcohol, obtain respectively petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract;(b) acetic acid ethyl ester extract macroreticular resin removal of impurities in step (a), first uses 8 column volumes of 10% ethanol elution, then uses 75% second12 column volumes of alcohol wash-out, collect 75% ethanol eluate, and reduced pressure concentration obtains 75% ethanol elution thing medicinal extract; (c) in step (b)75% ethanol elution thing medicinal extract separates by purification on normal-phase silica gel, is the dichloro of 80:1,50:1,30:1,15:1 and 1:1 successively by volume ratioMethane-methyl alcohol gradient elution obtains 5 components; (d) in step (c), component 4 use purification on normal-phase silica gel further separate, and use successively volumeThan obtaining 3 components for the methylene chloride-methanol gradient elution of 20:1,15:1 and 5:1; (e) component 2 use 18 in step (d)The reverse phase silica gel of alkyl silane bonding separates, and the methanol aqueous solution isocratic elution that is 75% by concentration expressed in percentage by volume collects 8～10Individual column volume eluent, eluent reduced pressure concentration obtains pure compound (I).
3. the preparation method of compound according to claim 2 (I), is characterized in that: in step (a), use 80% ethanolHot reflux is extracted, and merges extract.
4. the preparation method of compound according to claim 2 (I), is characterized in that: described macroreticular resin is AB-8 typeMacroporous absorbent resin.
5. a pharmaceutical composition, is characterized in that: this pharmaceutical composition contains claimed in claim 1ization for the treatment of effective doseCompound (I) and pharmaceutically acceptable carrier.
6. the application of compound claimed in claim 1 (I) in the medicine of preparation treatment prostate cancer.
7. the application of pharmaceutical composition claimed in claim 5 in the medicine of preparation treatment prostate cancer.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175428A (en) * | 2015-10-26 | 2015-12-23 | 章丽珍 | New clerodane diterpenoid compounds, and preparation method and medical application thereof |
| CN105294727A (en) * | 2015-10-09 | 2016-02-03 | 杭州启澄科技有限公司 | Novel clerodane diterpenoid compound, preparation method of clerodane diterpenoid compound and medical application of novel clerodane diterpenoid compound |
| CN105330716A (en) * | 2015-10-21 | 2016-02-17 | 淄博夸克医药技术有限公司 | New withanolides compound, and preparation method and medical application thereof |
| CN105330714A (en) * | 2015-11-25 | 2016-02-17 | 杨飞杰 | Novel limonin compound as well as preparation method and medical application thereof in treatment of prostatic cancer |
| CN106083974A (en) * | 2016-06-03 | 2016-11-09 | 郑巧丹 | A kind of new lanostane-type triterpene compounds and preparation method thereof and medical usage |
-
2015
- 2015-12-30 CN CN201511022691.6A patent/CN105601695A/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294727A (en) * | 2015-10-09 | 2016-02-03 | 杭州启澄科技有限公司 | Novel clerodane diterpenoid compound, preparation method of clerodane diterpenoid compound and medical application of novel clerodane diterpenoid compound |
| CN105330716A (en) * | 2015-10-21 | 2016-02-17 | 淄博夸克医药技术有限公司 | New withanolides compound, and preparation method and medical application thereof |
| CN105175428A (en) * | 2015-10-26 | 2015-12-23 | 章丽珍 | New clerodane diterpenoid compounds, and preparation method and medical application thereof |
| CN105330714A (en) * | 2015-11-25 | 2016-02-17 | 杨飞杰 | Novel limonin compound as well as preparation method and medical application thereof in treatment of prostatic cancer |
| CN106083974A (en) * | 2016-06-03 | 2016-11-09 | 郑巧丹 | A kind of new lanostane-type triterpene compounds and preparation method thereof and medical usage |
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Application publication date: 20160525 |