CN105481875A - New limonin compound as well as preparation method and medical application thereof - Google Patents
New limonin compound as well as preparation method and medical application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
The invention discloses a new limonin compound as well as a preparation method and medical application thereof. The compound is reported for the first time, is a limonin compound with a novel structure and can be obtained from dry mature fruits of finger citron through extraction, separation and purification. In vitro tests prove that the compound can achieve the effects of effectively inhibiting growth and proliferation of HepG2 cells and reducing the survival rates of the cells, wherein the reduction degree and the concentration of the compound have a certain dosage effect tendency; meanwhile, at a same concentration, the cell survival rates have a continuous reduction tendency along with increase of the intervention time. The compound can be used for developing medicines for treating liver cancers.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to from the dry mature fruit of Buddha's hand, be separated obtain a kind of and there is limonoid of Hepatoma therapy effect and preparation method thereof.
Background technology
Buddha's hand (CitrusmedicaL.var.sarcodactylisSwingle), Fructus Citri Sarcodactylis, the five fingers tangerine, fly the stalks of rice, wheat, etc., Fructus Citri Sarcodactylis, the five fingers citron, Folium vilicis Negundo, it is the dry fruit of rutaceae Buddha's hand, there is dispersing stagnated hepatoqi, pain relieving and stomach, eliminating dampness and eliminating phlegm effect, be used for the treatment of the diseases such as stagnation of liver-QI and stomach-QI, distending pain in the chest and hypochondrium, gastral cavilty ruffian are full, food few vomiting, coughing with a lot of sputum.Buddha's hand originates in India, at plantation and applicating history that China has more than 400 year, mainly originates in the provinces such as Zhejiang, Guangdong, Guangxi, Fujian, Sichuan, Yunnan.Root, stem, leaf, flower, fruit all can be used as medicine, pungent, bitter, sweet, warm, nontoxic; Enter liver, spleen, stomach three warp, have activating QI to eliminate phlegm, preventing or arresting vomiting dissipate-swelling, liver soothing and the spleen invigorating and the more kinds of medicinal function of stomach.Obvious mitigation is had to the trachitis of the elderly, asthma; Vexed to the maldigestion of common people, chest abdominal distension, there is more significant curative effect.Buddha's hand can be made into several kinds of Chinese medicinal materials, and clothes have the effect of health-care for a long time.
Buddha's hand contains the compositions such as volatile oil, flavones, polysaccharide, trace element.Present pharmacological research show Buddha's hand have relieving cough and asthmaly to eliminate the phlegm, antitumor, anti-oxidant, immunomodulatory, antibacterial, the effect such as anti-inflammatory, antidepressant.
Summary of the invention
The object of this invention is to provide and a kind ofly from the dry mature fruit of Buddha's hand, be separated obtain a kind of there is limonoid of Hepatoma therapy effect and preparation method thereof.
Above-mentioned purpose of the present invention is achieved by technical scheme below:
There is the compound (I) of following structural formula,
The preparation method of described compound (I), comprise following operation steps: the dry mature fruit of Buddha's hand is pulverized by (a), extract with 75 ~ 85% alcohol heat reflux, united extraction liquid, be concentrated into without alcohol taste, use sherwood oil, ethyl acetate and water saturated n-butanol extraction successively, obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract respectively; Acetic acid ethyl ester extract macroporous resin removal of impurities in (b) step (a), first use 10% ethanol elution, 8 column volumes, then use 75% ethanol elution, 10 column volumes, collect 75% ethanol eluate, concentrating under reduced pressure obtains 75% ethanol elution thing medicinal extract; C in () step (b), 75% ethanol elution medicinal extract purification on normal-phase silica gel is separated, obtain 5 components successively with the methylene chloride-methanol gradient elution that volume ratio is 75:1,45:1,20:1,12:1 and 1:1; D in () step (c), component 4 is separated further by purification on normal-phase silica gel, obtain 3 components successively with the methylene chloride-methanol gradient elution that volume ratio is 20:1,12:1 and 5:1; E in () step (d), component 2 reverse phase silica gel of octadecylsilane bonding is separated, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collect 10 ~ 12 column volume elutriants, elutriant concentrating under reduced pressure obtains pure compound (I).
Further, described macroporous resin is AB-8 type macroporous adsorbent resin.
Further, described alcohol heat reflux extracts the alcohol concn adopted is 80%.
A kind of pharmaceutical composition, the described compound (I) wherein containing treatment significant quantity and pharmaceutically acceptable carrier.
Described compound (I) application in the medicine preparing Hepatoma therapy.
The application of described pharmaceutical composition in the medicine preparing Hepatoma therapy.
When the compounds of this invention is used as medicine, directly can uses, or use with the form of pharmaceutical composition.
This pharmaceutical composition contains the compounds of this invention (I) for the treatment of significant quantity, and all the other are acceptable on pharmacology, nontoxic to humans and animals and pharmaceutically acceptable carrier of inertia and/or vehicle.
Described pharmaceutically acceptable carrier or vehicle are that one or more are selected from solid, semisolid and liquid diluent, filler and pharmaceutical preparation assistant agent.Pharmaceutical composition of the present invention is used with the form of per weight dose.Medicine of the present invention is applied to by form that is oral or injection the patient needing treatment.For time oral, tablet, slow releasing tablet, controlled release tablet, capsule, dripping pill, micropill, suspensoid, emulsion, powder or granule, oral liquid etc. can be made into; During for injecting, can be made into water-based or oily solution, aseptic powder injection, liposome or the emulsion etc. of sterilizing.
Accompanying drawing explanation
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 the impact (n=3) of compound (I) on HepG2 and L02 cell proliferation.
Embodiment
Further illustrate essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.Although be explained in detail the present invention with reference to preferred embodiment, those of ordinary skill in the art should be appreciated that and can modify to technical scheme of the present invention or equivalent replacement, and does not depart from essence and the scope of technical solution of the present invention.
Embodiment 1: compound (I) is separated preparation and structural identification
Reagent source: ethanol, sherwood oil, ethyl acetate, propyl carbinol, methylene dichloride are analytical pure, purchased from Shanghai Ling Feng chemical reagent company limited, methyl alcohol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Preparation method: the dry mature fruit (10kg) of Buddha's hand is pulverized by (a), (25L × 3 time) are extracted with 80% alcohol heat reflux, united extraction liquid, be concentrated into without alcohol taste (3L), use sherwood oil (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated propyl carbinol (3L × 3 time) to extract successively, obtain petroleum ether extract, acetic acid ethyl ester extract (431g) and n-butyl alcohol extract respectively; Acetic acid ethyl ester extract AB-8 type macroporous resin removal of impurities in (b) step (a), first use 10% ethanol elution, 8 column volumes, use 75% ethanol elution, 10 column volumes again, collect 75% ethanol eluate, concentrating under reduced pressure obtains 75% ethanol elution thing medicinal extract (157g); C in () step (b), 75% ethanol elution medicinal extract purification on normal-phase silica gel is separated, successively with volume ratio be 75:1 (8 column volumes), the methylene chloride-methanol gradient elution of 45:1 (8 column volumes), 20:1 (8 column volumes), 12:1 (8 column volumes) and 1:1 (5 column volumes) obtains 5 components; D component 4 (49g) is separated further by purification on normal-phase silica gel in () step (c), successively with volume ratio be 20:1 (8 column volumes), the methylene chloride-methanol gradient elution of 12:1 (10 column volumes) and 5:1 (8 column volumes) obtains 3 components; E in () step (d), component 2 (25g) reverse phase silica gel of octadecylsilane bonding is separated, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collect 10-12 column volume elutriant, elutriant concentrating under reduced pressure obtains pure compound (I) (35mg).
Structural identification: HR-ESIMS shows [M+Na]
+for m/z637.2308, can obtain molecular formula in conjunction with nuclear-magnetism feature is C
32h
38o
12, degree of unsaturation is 14.Hydrogen nuclear magnetic resonance modal data δ
h(ppm, DMSO-d
6, 400MHz): H-3 (4.84, s), H-5 (3.20, d, J=5.7), H-6 (4.19, d, J=5.7), H-11 (3.57, m), H-12 (2.01, d, J=16.0), H-12 (2.16, d, J=16.0), H-14 (1.52, dd, J=12.4, 7.2), H-15 (2.66, dd, J=18.9, 7.2), H-15 (2.96, dd, J=18.9, 12.4), H-17 (4.89, s), H-18 (0.99, s), H-19 (1.06, s), H-21 (7.19, s), H-22 (6.05, br, s), H-23 (7.31, t, J=1.6), H-28 (1.01, s), H-29 (0.83, s), H-30 (3.24, s), H-3 ' (6.93, m), H-4 ' (1.86, m), H-5 ' (1.87, s), 6-OH (3.25, s), 8-OH (4.16, s), 7-OCH
3(3.87, s), carbon-13 nmr spectra data δ
c(ppm, DMSO-d
6, 100MHz): 207.7 (C, 1-C), 77.6 (C, 2-C), 85.5 (CH, 3-C), 39.9 (C, 4-C), 46.1 (CH, 5-C), 70.1 (CH, 6-C), 174.8 (C, 7-C), 60.7 (C, 8-C), 61.6 (C, 9-C), 50.2 (C, 10-C), 54.3 (CH, 11-C), 27.2 (CH
2, 12-C), 33.4 (C, 13-C), 37.8 (CH, 14-C), 28.6 (CH
2, 15-C), 168.0 (C, 16-C), 82.1 (CH, 17-C), 22.6 (CH
3, 18-C), 10.1 (CH
3, 19-C), 120.5 (C, 20-C), 140.1 (CH, 21-C), 108.6 (CH, 22-C), 143.2 (CH, 23-C), 22.1 (CH
3, 28-C), 21.7 (CH
3, 29-C), 64.1 (CH, 30-C), 165.8 (C, 1 '-C), 127.6 (C, 2 '-C), 138.7 (CH, 3 '-C), 14.2 (CH
3, 4 '-C), 12.3 (CH
3, 5 '-C), 53.2 (CH
3, 7-OCH
3), carbon atom mark is see Fig. 1.Infrared spectra shows this compound and contains hydroxyl and carbonyl group (3479cm
-1and 1738cm
-1).
13cNMR and DEPT spectrum shows 32 carbon signals altogether, comprise seven methyl (methoxyl group), two methylene radical, 11 methyne (four alkene carbon, five containing oxygen carbon), and 12 quaternary carbons (three contain oxygen quaternary carbon, four carbonyl carbon, two alkene carbon).In addition, this compound contains typical β substituted furan ring (δ H7.19, a s; 6.05, br, s and 7.31, t, J=1.6Hz; δ C120.5,140.1,108.6 and 143.2), a ketone carbonyl (δ C207.7) and three ester carbonyl groups (δ C174.8,168.0 and 165.8).
1h and
13cNMR data analysis shows that this compound is limonoid.In HMBC spectrum, H
3the dependency of-19 (δ H1.06, s) and H-30 and C-1 (δ C207.7) shows that C-1 is ketone carbonyl.Two groups containing oxygen carbon signal (δ C77.6,2-C; 64.1,30-C and δ C61.6,9-C; 54.3,11-C) and corresponding proton signal (δ H3.24, s, H-30 and 3.57, m, H-11) show that this compound contains 30,2-epoxide groups and 9,11-epoxide groups.In addition, C-3 (δ C85.5) position is connected with a crotons acyloxy; In HMBC spectrum, the above-mentioned inference of the relevance verification of H-3 ' (δ H6.93, m) and H-3 (δ H4.84, s) and C-1 ' (δ C165.8).In HMBC spectrum ,-OCH
3with C-7 (δ C174.8), H-6 (δ H4.19, d, J=5.7Hz) and the dependency of C-5 (δ C46.1) and C-7, (δ H3.87, s) shows that C-6 (δ C70.1) is connected with a methoxycarbonyl fragment.In addition, the dependency of 6-OH (δ H3.25, s) and C-5, C-6 and C-7 shows that C-6 position is connected with a hydroxyl.According to H-17 (δ H4.89 in HMBC spectrum, s) with C-20 (δ C120.5), the dependency of C-21 (δ C140.1) and C-22 (δ C108.6), deducibility furan nucleus is positioned on C-17 (δ C82.1) position.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and ROESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine this compound as shown in Figure 1, steric configuration is determined further by ECD test, theoretical value and experimental value basically identical (Fig. 2).
Embodiment 2: compound (I) pharmacological action is tested
One, material and instrument
HepG2 human hepatoma cell strain is purchased from Chinese Academy of Sciences's biological chemistry and Institute of Cell Biology.L02 normal liver cell strain presented by Zhong Shan hospital of Fudan University liver cancer research.Compound (I) is made by oneself, and HPLC normalization method purity is greater than 98%.RPMI-1640 substratum, pancreatin are purchased from Gibco company.Standard calf serum is purchased from Biowest company.3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt (MTT), dimethyl sulfoxide (DMSO) (DMSO), trypan blue (TrypanBLue), dichlorofluorescein diacetate (DCFH-DA) is all purchased from Shanghai Chemical Reagent Co., Ltd., Sinopharm Group.Other common agents are analytical pure.
Microbalance (Switzerland plum Teller-Tuo benefit, METTLRERAE2000).Common desktop whizzer (Anting Scientific Instrument Factory, Shanghai).Digital display electric heating constant-temperature water-bath tank (Shanghai leap medical machinery factory, HH.W21.600S).Carbon dioxide cell incubator (FormaScientific company of the U.S.).High speed freezing centrifuge (Thermo company of the U.S., IECMICROMAXRF).Ultramicron ultraviolet spectrophotometer (ThermoHsher company of the U.S., NanoDrop-1000).Ultraviolet imagery system (Shanhai Furi Science and Technology Co., Ltd., FR-200A).Enzyme-linked immunosorbent assay instrument, spectrophotofluorometer (HitachiF2500).
Two, test method
1, cell cultures
Cell routine is inoculated in the RPMI-1640 substratum containing 10% (volume fraction) calf serum, is placed in 37 DEG C, 5%CO
2cultivate in the incubator of concentration.
2, compound (I) intervenes the configuration of nutrient solution
45.44mg compound (I) be dissolved in the obtained storing solution of 10mL dimethyl sulfoxide (DMSO) (DMSO) and dilute 2 times, 4 times respectively, obtaining compound (I) the application liquid of 2mmol/L, 4mmol/L and 8mmol/L respectively.Before carrying out cell intervention, 50 μ L application liquid are fully mixed with 4950 μ L cellar culture liquid (calf serum containing 10% volume fraction), obtains compound (I) and intervene nutrient solution (20 μm of ol/L, 40 μm of ol/L, 80 μm of ol/L).
3, mtt assay detects cell survival rate
The vegetative period cell of taking the logarithm is inoculated in 96 well culture plates, every hole 200 μ L (5 × 10
3cell).Cultivate 12h after cell attachment, discard original fluid, compound (I) nutrient solution adding 200 μ L different concns (mixes with cellar culture liquid with 1% volume fraction after DMSO dissolved compound (I), compound (I) final concentration is made to be 20 μm of ol/L, 40 μm of ol/L, 80 μm of ol/L), often organize 6 parallel holes.Establish 6 solvent (DMSO) control wells simultaneously.Cultivate 24h, 48h, 72h, within every 24 hours, change compound (I) and intervene nutrient solution.Intervene after terminating, suck nutrient solution, add 20 μ LMTT solution to each hole, 37 DEG C hatch 4h after suck each hole supernatant liquor, add 150 μ LDMSO, put low speed concussion 10min on shaking table, after abundant dissolving to be crystallized, with DMSO zeroing, measure each hole absorbancy with enzyme-linked immunosorbent assay instrument at 490nm place, calculate cell survival rate (survivalrate, SR).SR=experimental group A
490/ control group A
490× 100%
4, trypan blue Ran Se Measuring determines survivaling cell number
By equal amts (2 × 10
6) cell be inoculated in Tissue Culture Flask, cultivate for some time after cell attachment, discard nutrient solution, after washing twice, cell with PBS, the compound (I) adding 5mL intervenes nutrient solution (20 μm of ol/L, 40 μm of ol/L, 80 μm of ol/L).Often organize three bottles of cells, set up three bottles of solvent (DMSO) contrasts simultaneously.After cultivating 48h, use 0.25% trypsin digestion cell, collecting cell suspension, determination of trypan blue staining cell count.
5, DCFH-DA method measures ROS activity in cell
By equal amts (2 × 10
6) cell be inoculated in Tissue Culture Flask, cultivate for some time after cell attachment, suck original fluid, add 5mL compound (I) and intervene nutrient solution, after continuing to cultivate 48h, discard nutrient solution, trypsin digestion cell, collecting cell suspension is in 1.5mLEP pipe, the centrifugal 5min of 1500rpm, abandons supernatant, in precipitation, add 1mLDCFH-DA, piping and druming mixing, hatch 30min for 37 DEG C, add PBS termination reaction, centrifugal collecting precipitation is also dissolved in 1mLPBS, blow and beat uniformly cell suspension, burn light spectrophotometric determination fluorescent value with Hitachi-F2500.Excitation wavelength 488nm, emission wavelength 525nm.
Three, result and conclusion
1, Growth of Cells survival rate
HepG2 cell is after compound (I) intervention cultivates 24h, 48h, 72h, the cell survival rate of basic, normal, high dosage group is all remarkable in solvent control group (P<0.05), and the degree that declines of cell survival rate and compound (I) are intervened between concentration and be there is doses effect trend (table 1
ap<0.05VS control group;
bp<0.05VS low dose group;
cdosage group in P<0.05VS).Under same compound (I) intervenes concentration, cell survival rate presents downward trend along with the increase of intervention time.And under equal conditions, L02 Human normal hepatocyte is after compound (I) is intervened, cell survival rate is without noticeable change (table 2).Trypan Blue cell counts consistent with MTT (Fig. 3,
ap<0.05VS control group;
bp<0.05VS low dose group;
cdosage group in P<0.05VS).
2, in cell, ROS is active
HepG2 human liver cancer cell is after different concns compound (I) is intervened, and compared with control group, intracellular ROS level significantly declines (P<0.05).The results are shown in Table 3 (
ap<0.05VS control group;
bp<0.05VS low dose group).
Conclusion, the compound (I) of different concns is adopted to carry out intervention process to human liver cancer cell HepG2, show through MTT colorimetric and Trypan Blue cell counting, compound (I) effectively can suppress the growing multiplication of HepG2 cell, the survival rate of intervention group cell comparatively control group significantly reduces, and reduction degree and compound (I) concentration present certain dosage effect trend, simultaneously under same compound (I) concentration, cell survival rate presents the trend continuing to reduce along with the increase of intervention time.Meanwhile, compound (I) intervention of same dose does not produce restraining effect to L02 normal liver cell.
Table 1 compound (I) is on the impact (x ± s, n=6) of HepG2 Growth of Cells survival rate
Table 2 compound (I) is on the impact (x ± s, n=6) of L02 Growth of Cells survival rate
Table 3 compound (I) is on the impact (x ± s, n=6) of HepG2 cell ROS level
| Group | Dosage (μm ol/L) | ROS(Fluounit/mgprot) |
| Control group | 0 | 4189±204 |
| Low dosage | 20 | 3215±151 a |
| Middle dosage | 40 | 3080±196 a |
| High dosage | 80 | 2831±212 ab |
Embodiment 3
The preparation of tablet: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, vehicle is added, pelletizing press sheet than the ratio for 1:9 in itself and excipient weight.
Embodiment 4
Prepared by oral liquid: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, oral liquid method for making makes oral liquid routinely.
Embodiment 5
The preparation of capsule or granule: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, add vehicle in itself and excipient weight than the ratio for 1:9, make capsule or granule.
Embodiment 6
The preparation of injection liquid: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, inject with water routinely, essence filter, injection liquid is made in embedding sterilizing.
Embodiment 7
The preparation of aseptic powder injection: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, be dissolved in sterile water for injection, stirring makes molten, filter with aseptic suction funnel, aseptic essence filter again, be sub-packed in ampoule, after frozen drying, aseptic sealing by fusing obtains powder injection.
The effect of above-described embodiment is essentiality content of the present invention is described, but does not limit protection scope of the present invention with this.Those of ordinary skill in the art should be appreciated that and can modify to technical scheme of the present invention or equivalent replacement, and does 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 according to claim 1 (I), it is characterized in that comprising following operation steps: the dry mature fruit of Buddha's hand is pulverized by (a), extract with 75 ~ 85% alcohol heat reflux, united extraction liquid, be concentrated into without alcohol taste, use sherwood oil, ethyl acetate and water saturated n-butanol extraction successively, obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract respectively; Acetic acid ethyl ester extract macroporous resin removal of impurities in (b) step (a), first use 10% ethanol elution, 8 column volumes, then use 75% ethanol elution, 10 column volumes, collect 75% ethanol eluate, concentrating under reduced pressure obtains 75% ethanol elution thing medicinal extract; C in () step (b), 75% ethanol elution medicinal extract purification on normal-phase silica gel is separated, obtain 5 components successively with the methylene chloride-methanol gradient elution that volume ratio is 75:1,45:1,20:1,12:1 and 1:1; D in () step (c), component 4 is separated further by purification on normal-phase silica gel, obtain 3 components successively with the methylene chloride-methanol gradient elution that volume ratio is 20:1,12:1 and 5:1; E in () step (d), component 2 reverse phase silica gel of octadecylsilane bonding is separated, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collect 10 ~ 12 column volume elutriants, elutriant concentrating under reduced pressure obtains pure compound (I).
3. the preparation method of compound according to claim 2 (I), is characterized in that: described macroporous resin is AB-8 type macroporous adsorbent resin.
4. the preparation method of compound according to claim 2 (I), is characterized in that: it is 80% that described alcohol heat reflux extracts the alcohol concn adopted.
5. a pharmaceutical composition, is characterized in that: the compound according to claim 1 (I) wherein containing treatment significant quantity and pharmaceutically acceptable carrier.
6. compound according to claim 1 (I) application in the medicine preparing Hepatoma therapy.
7. the application of pharmaceutical composition according to claim 5 in the medicine preparing Hepatoma therapy.
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| CN105153084A (en) * | 2015-09-13 | 2015-12-16 | 金丽秋 | Novel diterpene compound as well as preparation method and medicinal application thereof |
| CN105566251A (en) * | 2016-02-20 | 2016-05-11 | 杭州富阳伟文环保科技有限公司 | Novel leucothoe alkane type diterpene compound and preparation method and medical application thereof |
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| CN105061413A (en) * | 2015-09-06 | 2015-11-18 | 叶澄 | New limonin compound and pharmaceutical composition containing same, and preparation method and application thereof |
| CN105111269A (en) * | 2015-10-09 | 2015-12-02 | 杭州启澄科技有限公司 | Novel limonin compound as well as preparation method and medical application thereof |
| CN105153084A (en) * | 2015-09-13 | 2015-12-16 | 金丽秋 | Novel diterpene compound as well as preparation method and medicinal application thereof |
| CN105175265A (en) * | 2015-10-19 | 2015-12-23 | 淄博夸克医药技术有限公司 | Novel diterpenoid compound for treating liver cancer |
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| CN105061413A (en) * | 2015-09-06 | 2015-11-18 | 叶澄 | New limonin compound and pharmaceutical composition containing same, and preparation method and application thereof |
| CN105153084A (en) * | 2015-09-13 | 2015-12-16 | 金丽秋 | Novel diterpene compound as well as preparation method and medicinal application thereof |
| CN105111269A (en) * | 2015-10-09 | 2015-12-02 | 杭州启澄科技有限公司 | Novel limonin compound as well as preparation method and medical application thereof |
| CN105175265A (en) * | 2015-10-19 | 2015-12-23 | 淄博夸克医药技术有限公司 | Novel diterpenoid compound for treating liver cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105153084A (en) * | 2015-09-13 | 2015-12-16 | 金丽秋 | Novel diterpene compound as well as preparation method and medicinal application thereof |
| CN105566251A (en) * | 2016-02-20 | 2016-05-11 | 杭州富阳伟文环保科技有限公司 | Novel leucothoe alkane type diterpene compound and preparation method and medical application thereof |
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Address after: 810016 Qinghai University, 251 Ning Ning Road, Chengbei District, Qinghai, Xining Applicant after: Wu Jinfeng Address before: 213003 Jiangsu province Changzhou Yanling West Road Zhonglou District Mingjun homes 2 building room 2407 Applicant before: Wu Jinfeng |
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Application publication date: 20160413 |