CN104974145A - Diterpene lactone compounds, pharmaceutical composition containing compounds, and preparation method and application thereof - Google Patents
Diterpene lactone compounds, pharmaceutical composition containing compounds, and preparation method and application thereof Download PDFInfo
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
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Abstract
The invention discloses diterpene lactone compounds, a pharmaceutical composition containing the compounds, and a preparation method and application thereof, belonging to the technical field of drugs. The invention particularly relates to new diterpene lactone compounds (I) separated from cardamom, a pharmaceutical composition containing the compounds (I), and a preparation method and application thereof. The compounds are reported for the first time, can be extracted, separated and purified from cardamom, and have high purity. The in-vitro test proves that the diterpene lactone compounds (I) can inhibit proliferation of stomach cancer cells, can independently display the inhibition activity, can also be combined with other anticancer drugs to enhance the inhibition activity, and can be developed and made into drugs for treating stomach cancer.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to from Elettaria cardamomum (L.) Maton, be separated a kind of new diterpenic lactone (I) obtained, containing its pharmaceutical composition and its preparation method and application.
Background technology
Plant Elettaria cardamomum (L.) Maton is perennial herb.Rhizome is sturdy, red-brown.Leaf two arranges, and blade is long and narrow drapes over one's shoulders needle-like, leaf sheath tool brown color pubescence.Spike is extracted out by basal part of stem.Inflorescence significantly extends, and flower arrangement is sparse, corolla white.The long oval of fruit, pericarp matter is tough, not easy to crack.Seed group's point 3 lobes, 5 ~ 9 pieces, every lobe seed, seed fragrant odour and high strong.Maraba (Malabar) seashore of main product Vietnam, Sri Lanka and South India.Receive during real maturation and adopt, the carpopodium that removing is residual, dry.Use the dry fruit that part is zingiberaceous plant Elettaria cardamomum (L.) Maton.
Medicinal material Elettaria cardamomum (L.) Maton is the dry almost ripe fruit of zingiberaceous plant Elettaria cardamomum (L.) Maton Elettaria cardamomum (L.) Maton, is Tibetan medicine and Uygur medicine medication, begins to be loaded in the Four-Volume Medical Code, now recorded by multinational pharmacopeia with the name of " adding element ".Elettaria cardamomum (L.) Maton is world-renowned plant amedica and spices, is called as " after spices ", originates in South India, Sri Lanka and the ground such as horse traction, melon ground, uses history to exceed bimillennium in Ayurvedic medicine, have dispel the wind, effect of stomach invigorating.The current traditional Chinese medical science seldom uses, and Elettaria cardamomum (L.) Maton once recorded in nineteen fifty-three version Chinese Pharmacopoeia with the name of " cardamom ".
The composition that Elettaria cardamomum (L.) Maton has been reported is mainly volatile oil, and polysaccharide and protein, infers also containing flavonoid compound, but has not yet to see the Isolation and ldentification of flavones ingredient monomer.Volatile oil is activeconstituents important in Elettaria cardamomum (L.) Maton, content up to 7%, the volatile oil that supersound extraction obtains based on α-terpinyl acetate, eucalyptol, phantol, alpha-terpineol, phanteine, with supercritical CO
2extract gained constituent class seemingly; As with normal hexane extraction, volatile oil compositions is different, is limonene, eucalyptol, terpinolene, myrcene.In addition, also containing farnesol, neryl C10H17-acetic ester, firpene, nerolidol, sabinene etc.
Elettaria cardamomum (L.) Maton pharmacologically active is various, especially with anti-tumor activity report at most, relates to the tumour at multiple positions such as skin, lung, colon, also has better protecting effect to gi tract, in addition, also has the effects such as antibacterial, anti-oxidant, anti-inflammatory, analgesia.
Summary of the invention
The object of this invention is to provide and a kind ofly from Elettaria cardamomum (L.) Maton, be separated a kind of new diterpenic lactone (I) obtained, containing its pharmaceutical composition and its preparation method and application.
Above-mentioned purpose of the present invention is achieved by technical scheme below:
There is the compound (I) of following structural formula:
Described pharmaceutical composition, the compound (I) wherein containing treatment significant quantity and pharmaceutically acceptable carrier.
The preparation method of described compound (I), concrete operation step is as follows: Elettaria cardamomum (L.) Maton is pulverized by (a), extract with 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; B step (a) gained acetic acid ethyl ester extract purification on normal-phase silica gel is separated by (), obtain 5 components successively with the methylene chloride-methanol gradient elution that volume ratio is 40:1,20:1,10:1,5:1 and 1:1; C () will. and step (b) obtained component 2 is separated further by purification on normal-phase silica gel, obtains 4 components successively with the methylene chloride-methanol gradient elution that volume ratio is 30:1,25:1,20:1 and 10:1; D the reverse phase silica gel of step (c) obtained component 3 with octadecylsilane bonding is separated by (), be the aqueous methanol gradient wash-out of 40%, 50% and 60% successively by concentration expressed in percentage by volume, each gradient elution 5 column volumes, 60% methanol-water wash-out position concentrates and namely obtains pure compound (I).
The application of described compound (I) in the medicine of preparation treatment cancer of the stomach.
The application of described composition in the medicine of preparation treatment cancer of the stomach.
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.
Figure of description
Fig. 1 is compound (I) structural formula.
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.
1, chemical reagent: ethanol, sherwood oil, ethyl acetate, propyl carbinol, methylene dichloride and methyl alcohol, be analytical pure, purchased from Nanjing Chemistry Reagent Co., Ltd..
2, material and instrument:
Human stomach cancer cell line SGC-7901, is purchased from Sai Er Reagent Company; Chemical compounds I is made by oneself, and normalization method purity is greater than 98%; CTX (endoxan, positive drug), trypsinase, MTT, dimethyl sulfoxide (DMSO) (DMSO), agarose, Glacial acetic acid are purchased from Sigma Co., USA; RPMI-1640 substratum, PBS phosphate buffer soln are purchased from GIBCO company of the U.S.; Foetal calf serum is purchased from Shandong Yin Xiang great achievement company; Trypan blue is purchased from Beijing Bioisystech Co., Ltd of Zhong Shan Golden Bridge; TUNEL test kit is purchased from Kai Ji biotechnology Development Co., Ltd; DAB colouring reagents box is purchased from Beijing biotech firm of Zhong Shan Golden Bridge; Formaldehyde purchased from American Fisher company; Catalase is purchased from new fine chemistry industry development centre, sky, Tianjin.
WD-9403C uv analyzer is purchased from German Biometra company; RKI-1002 type CO2gas incubator is purchased from Japanese Ikemoto company; Bechtop is purchased from Suzhou purification experimental installation company limited; Ultracentrifuge is purchased from Beijing medical apparatus and instruments factory; Low speed centrifuge is purchased from Beijing medical apparatus and instruments factory; Wilovert S type inverted microscope is purchased from Japanese Olympus company; Pressure steam sterilizer is purchased from Shanghai Bo Xun Industrial Co., Ltd.; Thermostat metal water bath is purchased from Hangzhou Ao Sheng Instrument Ltd.; Constant temperature blender with magnetic force is purchased from Tianjin Raul Science and Technology Ltd.; Cell counting count board is purchased from Shanghai precision instrument company; Superpure water machine is purchased from Britain PURELABulTRAGENETIC.
Embodiment 1:
A () Elettaria cardamomum (L.) Maton pulverizes (8.5Kg), extract with 85% alcohol heat reflux, extract three times, each 25L solvent, each extraction 2 hours, united extraction liquid, is concentrated into without alcohol taste, use sherwood oil (2L × 3), ethyl acetate (2L × 3) and water saturated propyl carbinol (2L × 3) to extract successively, obtain petroleum ether extract, acetic acid ethyl ester extract (232g) and n-butyl alcohol extract respectively; B step (a) gained acetic acid ethyl ester extract purification on normal-phase silica gel is separated by (), obtain 5 components successively with the methylene chloride-methanol gradient elution that volume ratio is 40:1,20:1,10:1,5:1 and 1:1; C step (b) obtained component 2 (46g) is separated by purification on normal-phase silica gel by () further, obtain 4 components successively with the methylene chloride-methanol gradient elution that volume ratio is 30:1,25:1,20:1 and 10:1; D the reverse phase silica gel of step (c) obtained component 3 (17g) with octadecylsilane bonding is separated by (), be the aqueous methanol gradient wash-out of 40%, 50% and 60% successively by concentration expressed in percentage by volume, each gradient elution 5 column volumes, 60% methanol-water wash-out position concentrates and obtains pure chemical compounds I (19mg).
Structural identification: the crystallization of white needles, is soluble in chloroform, acetone and methyl alcohol, is insoluble in water; HR-ESIMS shows [M+Na]
+for m/z 353.1716, can obtain molecular formula in conjunction with nuclear-magnetism feature is C
20h
26o
4.Hydrogen nuclear magnetic resonance modal data δ
h(ppm, CDCl
3, 600MHz): 1.64 (1H, dd, 1-Ha), 1.39 (1H, dd, 1-Hb), 3.24 (1H, m, 2-H), 3.04 (1H, d, 3-H), 1.20 (1H, dd, 5-H), 2.35 (1H, dd, 6-Ha), 2.10 (1H, dd, 6-Hb), 2.00 (2H, t, 11-H), 2.00 (2H, t, 12-H), 7.41 (1H, t, 14-H), 4.91 (2H, d, 15-H), 2.13 (3H, s, 17-H), 0.89 (3H, s, 18-H), 0.89 (3H, s, 19-H), 1.24 (3H, s, 20-H), carbon-13 nmr spectra data δ
c(ppm, CDCl
3, 150MHz): 35.1 (CH
2, 1-C), 52.7 (CH, 2-C), 69.6 (CH, 3-C), 37.0 (C, 4-C), 45.1 (CH, 5-C), 30.2 (CH
2, 6-C), 123.0 (C, 7-C), 197.0 (C, 8-C), 181.6 (C, 9-C), 41.7 (C, 10-C), 25.5 (CH
2, 11-C), 24.9 (CH
2, 12-C), 133.8 (C, 13-C), 144.7 (CH, 14-C), 70.2 (CH
2, 15-C), 174.1 (C, 16-C), 29.8 (CH
3, 17-C), 25.3 (CH
3, 18-C), 25.3 (CH
3, 19-C), 19.0 (CH
3, 20-C), carbon atom mark is see accompanying drawing 1.
Embodiment 2:
1, the cultivation of stomach cancer cell SGC-7901
1.1 cell recovery
(1) from liquid nitrogen container, take out cell cryopreservation tube, be placed in rapidly 37 DEG C-42 DEG C, in 75% alcohol, then move in equality of temperature water-bath; (2) rock l-3min cryopreservation tube gently, frozen storing liquid is melted, move to rapidly in super clean bench; (3) frozen storing liquid containing cell is sucked sterile centrifugation tube, add appropriate RPIM-1640 substratum; (4) put into low speed centrifuge, centrifugal 3 minutes of 800rpm/min after piping and druming mixing, remove supernatant liquor; (5) adding appropriate substratum blows even, is inoculated in 10mL culture dish by cell suspension according to concentration; (6) incubator be placed in containing 5% carbonic acid gas, 37 DEG C of saturated humidities is cultivated.
1.2 passage
(1), when the cell attachment in culture dish about 80%, in super clean bench, cell in several culture dish is blown and beaten, to blow dead cell off with the substratum that pipette, extract is old; (2) suck old substratum with transfer pipet, add appropriate 0.25% trypsin digestion cell, be placed in 30 DEG C of incubators and digest; (3) observe under culture dish being placed in after about 3min inverted microscope, retraction shinny until cell periphery then illustrates that cell departs from from wall after becoming circle; (4) in super clean bench, pancreatin is sucked rapidly.Add appropriate substratum and repeatedly blow and beat cell, make cell depart from culture dish completely; (5) cell suspension is seeded in different culture dish respectively by concentration, supplies substratum; (6) be again placed in containing 5%CO
2, 37 DEG C of saturated humidities incubator in cultivate.
2, cell counting
(1) get out cell counting count board and cover glass, the two is all clean by alcohol wipe, is covered by cover glass on tally; (2) after alcohol volatilization, the appropriate cell suspension of sucking-off, drips at cover glass edge, makes suspension be full of between cover glass and tally, notes the glass guide channel not overflowing cover glass and both sides, counting after leaving standstill; (3) find 4 large lattice under the microscope, each large lattice are divided into again 16 little lattice, count the cell count in 4 large lattice respectively, average.On the left of line ball cytometer and top, on the right side of disregarding and below; (4) average cell number × 10000 of cell concn (individual/mL)=each grid; (5) cell suspension is diluted to experiment desired concn.
3, cell viability measures
(1) SGC-7901 stomach cancer cell suspension 0.9mL to be determined is got; (2) in cell suspension, add trypan blue piping and druming mixing; (3) adopt cell counting count board blind counting at least 200 cells, observe under inverted microscope; (4) Microscopic observation cell dyeing situation, dye light blue person in cell for dead cell, the person of being unstained is viable cell, with the vigor (%) of the per-cent of total cellular score shared by viable cell reflection cell.
4, MTT detects inhibitory rate of cell growth
Experiment grouping: 1. negative control group; 2. chemical compounds I group 1, chemical compounds I (50 μm of ol/L); 3. chemical compounds I group 2, chemical compounds I (100 μm of ol/L); 4. CTX group 1, CTX (50 μm of ol/L); 5. CTX group 2, CTX (100 μm of ol/L); 6. drug combination group 1, chemical compounds I (25 μm of ol/L)+CTX (25 μm of ol/L); 7. drug combination group 2, chemical compounds I (50 μm of ol/L)+CTX (50 μm of ol/L).
(1) the SGC-7901 cell of taking the logarithm vegetative period, with cell counting count board counting, adjustment cell concn is 5 × l0
5/ mL; (2) sample injector is used to be inoculated in 96 orifice plates with every hole 100 μ L.Only be inoculated into 60 middle holes when noting inoculation, periphery 36 hole is filled with PBS, spreads 3 96 orifice plates simultaneously; (3) 96 orifice plates completed are placed in 37 DEG C, 5%CO
2in cell culture incubator, take out after 24h cell attachment; (4) 96 orifice plates are divided into chemical compounds I group, (0,50,100 μm of ol/L), CTX group (0,50,100 μm of ol/L), group (0/0,25/25,50/50 μm of ol/L) combined by 2 medicines, sets up not celliferous blank group (only adding substratum) to give different treatment respectively simultaneously; (5) each concentration of each medicine establishes 5 multiple holes, cultivates 24,48 and 72h respectively; (6) respectively at specific end time point taking-up 96 orifice plate, every hole adds MTT (5g/L) solution 20 μ L, puts back to incubator and continues to cultivate 4h, stop cultivating.(7) carefully suck supernatant liquor in hole, every hole adds 150 μ L DMSO, and plate shaker vibration 10min makes crystallization fully dissolve, and basis of microscopic observation particle disappears.(8) measure optical density(OD) (OD) value in each hole in microplate reader 490nm wavelength place, calculate the inhibitory rate of cell growth of each time point.Inhibiting rate=[1-(dosing group OD value-blank group OD value)/(negative control group OD value-blank group OD value)] × 100%.
5, TUNEL method detects apoptotic index
The preparation of 5.1 cell climbing sheets
(1) process of cover glass: cover glass is placed in vitriol oil soaked overnight, next day first with tap water for several times, then be placed in dehydrated alcohol and soak 4h, then clean with deionized water rinsing, be placed on for drying the sterilization of laggard horizontal high voltage in dry case, it is for subsequent use that super clean bench is directly put in taking-up.6 orifice plates are placed in uviolizing 30min in super clean bench; (2) cover glass is placed: after the position preparing to put cover glass in every hole of six orifice plates instills a small amount of substratum, place cover glass again, the tension force making cover glass and orifice plate examine substratum is bonded together, when preventing from adding cell suspension, cover glass hikes up, and causes double-layer cell adherent; (3) the SGC-7901 cell of taking the logarithm vegetative period, cell suspension is blown and beaten in digestion, is l × 10 with cell counting count board adjustment cell concn
6/ mL.(4) add 1mL cell suspension respectively with every hole that sample injector is being placed with cover glass, spread 3 plates simultaneously, be placed in 37 DEG C, 5%CO
2cultivate 24h in incubator and treat cell attachment; In super clean bench, negative control group and experimental group is divided into give different treatment respectively 6 orifice plates after (5) 24 hour cells are adherent, negative control group adds 1mL substratum, experimental group is further divided into chemical compounds I group, CTX group and drug combination group 3 subgroups, and every hole adds 1mL medicine.Chemical compounds I group final concentration is 100 μm of ol/L, CTX group final concentrations is 100 μm of ol/L, 2 medicines combine group final concentration to be 2 kinds of medicines be respectively 50 μm of ol/L often group establish 2 multiple holes.(6) 37 DEG C are placed in, 5%CO
2cell culture incubator in continue cultivate.
5.2 TUNEL method operation stepss
(1) take out 6 orifice plates when 24h is cultivated in cell climbing sheet dosing, carry out following steps successively according to TUNEL specification sheets; (2) supernatant liquor abandoned in every hole is carefully inhaled; (3) each hole adds PBS (4 DEG C) 2mL, and plate shaker rinses 5min × 3 time; (4) every hole adds 1mL precooling cell stationary liquid, and 30min fixed by 4 DEG C of refrigerators.(5) stationary liquid is abandoned in suction, and each hole adds PBS (4 DEG C) 2mL, and plate shaker rinses 5min × 3 time.(6) immerse in confining liquid, room temperature (15 DEG C-25 DEG C) closes 10min.(7) each hole adds PBS (4 DEG C) 2mL, and plate shaker rinses 5min × 3 time.Blot with thieving paper around sample.(8) each sample drips 50 μ LUTdT enzyme reaction solutions, 37 DEG C, lucifuge moistening reaction 60min.(9) each hole adds PBS (4 DEG C) 2mL, and plate shaker rinses 5min × 3 time.Blot with thieving paper around sample.(10) 50 μ LStreptavidin-HRP working fluids are dripped, 37 DEG C, lucifuge moistening reaction 30min.(11) each hole adds PBS (4 DEG C) 2mL, and plate shaker rinses 5min × 3 time.(12) 100 μ L DAB working fluids are dripped, color development at room temperature reaction 10min.(13) each hole adds PBS (4 DEG C) 2mL, and plate shaker rinses 5min × 3 time.(14) optical microphotograph Microscopic observation is taken pictures: random selecting 10 high power (× 100) visuals field, and each visual field counts 100 cells, calculates the mean value adjusting index of dying.Apoptotic index (AI)=(positive cell number/total cell count × 100%).The nucleus of positive cell is brown.
6, statistical analysis
Adopt SPSS 11.5 to analyze, compare and analyze by Oneway-ANOVA method between group, compare between two and adopt LSD-t method, P<0.05 is that difference has statistical significance.
Three, experimental result
1, MTT detection of drugs is to the growth inhibition ratio of SGC-7901 stomach cancer cell
MTT is repeated through 3 times, detected result shows, single drug effect is after stomach cancer cell 72h, and the medicine group of 100 μm of ol/L is all higher to the growth inhibition ratio of stomach cancer cell compared with the medicine group of 50 μm of ol/L, and difference has statistical significance (P<0.05).50 μm of ol/L chemical compounds Is are to the growth-inhibiting effect of stomach cancer cell and drug combination 25/25 μm of ol/L group no significant difference (P>0.05).The CTX of 50 μm of ol/L is to Growth of Gastric restraining effect and drug combination 25/25 μm of ol/L group ratio, and difference has statistical significance (P<0.05).Drug combination 50/50 μm of ol/L is to Growth of Gastric inhibiting rate higher than the growth inhibition ratio of each high density list medicine group (100 μm of ol/L) to stomach cancer cell, and difference has statistical significance (P<0.001), in table 1.
2, TUNEL method detects each group of apoptotic index
Chemical compounds I, CTX and drug combination group all have the effect of Developing restraint to stomach cancer cell SGC-7901, each group all has statistical significance (P<0.001) with negative control group comparing difference, negative control group has the karyon of a small amount of cell to be dyed to brown, each single medicine group and drug combination group apoptotic cell comparatively all have increase compared with negative control group, drug combination group apoptotic index is the highest, more remarkable to stomach cancer cell inhibition.In table 2.
Conclusion shows, chemical compounds I acts solely on the propagation that stomach cancer cell can suppress stomach cancer cell, and promoting the apoptosis of cell, along with the increase of concentration, is enhancing trend to the Developing restraint effect of stomach cancer cell.Promote the apoptosis more remarkable effect of stomach cancer cell after chemical compounds I and CTX combined utilization, all more independent medication group of the growth inhibition ratio of cell and apoptotic index raises.Therefore, chemical compounds I can be developed to separately the medicine for the treatment of cancer of the stomach, also can be developed to compound medicine with the anti-cancer agent in combination such as CTX and treat cancer of the stomach.
Table 1 respectively organizes different time points to stomach cancer cell inhibiting rate (n=5, mean value ± deviation) * P<0.05, * * P<0.01
| Group | n | 24h | 48h | 72h |
| Chemical compounds I 50 μm of ol/L (1) | 5 | 14.87±5.19 | 16.29±4.53 | 55.70±6.67 |
| Chemical compounds I 50 μm of ol/L (2) | 5 | 31.00±6.36 | 59.42±7.74 | 74.32±5.84 |
| CTX50μmol/L(3) | 5 | 24.87±9.04 | 36.83±5.21 | 40.58±7.15 |
| CTX100μmol/L(4) | 5 | 42.86±6.28 | 44.21±8.44 | 50.31±4.63 |
| Drug combination 25/25 μm of ol/L (5) | 5 | 36.43±8.13 | 38.76±10.87 | 58.55±9.53 |
| Drug combination 50/50 μm of ol/L (6) | 5 | 49.38±2.24 | 74.56±10.59 | 96.12±2.25 |
| F | 17.918** | 29.646** | 47.625** | |
| P(1):(2) | 0.001 | <0.001 | <0.001 | |
| (3):(4) | <0.001 | 0.169 | 0.025 | |
| (5):(6) | 0.005 | <0.001 | <0.001 | |
| (1):(5) | <0.001 | <0.001 | 0.49 | |
| (3):(5) | 0.01 | 0.713 | <0.001 | |
| (2):(6) | <0.001 | 0.008 | <0.001 |
| (4):(6) | 0.13 | <0.001 | <0.001 |
Apoptotic index (n=3, mean value ± deviation) the * * P<0.01 of each group cell after table 2 drug effect 24h
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, mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, vehicle is added, pelletizing press sheet than the ratio for 1:10 in itself and excipient weight.
Embodiment 4
The preparation of 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, 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, mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, add vehicle in itself and excipient weight than the ratio for 1:10, 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, 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 the salt of organic acid as tartrate or citric acid or formic acid or oxalic acid, mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid are made to make, 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.
Claims (5)
1. there is the compound (I) of following structural formula:
2. pharmaceutical composition, the compound according to claim 1 (I) wherein containing treatment significant quantity and pharmaceutically acceptable carrier.
3. the preparation method of compound according to claim 1 (I), it is characterized in that concrete operation step is as follows: Elettaria cardamomum (L.) Maton is pulverized by (a), extract with 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; B step (a) gained acetic acid ethyl ester extract purification on normal-phase silica gel is separated by (), obtain 5 components successively with the methylene chloride-methanol gradient elution that volume ratio is 40:1,20:1,10:1,5:1 and 1:1; C step (b) obtained component 2 is separated by purification on normal-phase silica gel by () further, obtain 4 components successively with the methylene chloride-methanol gradient elution that volume ratio is 30:1,25:1,20:1 and 10:1; D the reverse phase silica gel of step (c) obtained component 3 with octadecylsilane bonding is separated by (), be the aqueous methanol gradient wash-out of 40%, 50% and 60% successively by concentration expressed in percentage by volume, each gradient elution 5 column volumes, 60% methanol-water wash-out position concentrates and namely obtains pure compound (I).
4. the application of compound according to claim 1 (I) in the medicine of preparation treatment cancer of the stomach.
5. the application of composition according to claim 2 in the medicine of preparation treatment cancer of the stomach.
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| 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 |
| CN105481937A (en) * | 2016-01-14 | 2016-04-13 | 郑平珍 | Novel limonin compound as well as preparation method and medical application thereof |
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Cited By (7)
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| CN105085452A (en) * | 2015-09-05 | 2015-11-25 | 林天样 | Sesquiterpene naphthoquinone compound as well as preparation method and medical application thereof |
| 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 |
| CN105497007A (en) * | 2015-12-18 | 2016-04-20 | 杭州市第一人民医院 | Medicine composition for treating gastrointestinal cancer |
| CN105646164A (en) * | 2015-12-18 | 2016-06-08 | 杭州市第人民医院 | Neolignan compound for the treatment of gastric cancer |
| CN105481937A (en) * | 2016-01-14 | 2016-04-13 | 郑平珍 | Novel limonin compound as well as preparation method and medical application thereof |
| CN106008427A (en) * | 2016-07-01 | 2016-10-12 | 郑飞珍 | Novel sesquiterpene lactones compound, and preparation method and medical application thereof |
| CN110054633A (en) * | 2019-05-31 | 2019-07-26 | 湖南新汇制药股份有限公司 | It is a kind of from the compound separated in hedgehog fungus mycelium, preparation method and its in the application prepared in anticancer drug |
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