CN108619145B - Application of compound in treating tumor - Google Patents
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- CN108619145B CN108619145B CN201810369147.6A CN201810369147A CN108619145B CN 108619145 B CN108619145 B CN 108619145B CN 201810369147 A CN201810369147 A CN 201810369147A CN 108619145 B CN108619145 B CN 108619145B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an application of a compound shown in a formula (I), pharmaceutically acceptable salt thereof or prodrug thereof in preventing and/or treating tumors,
formula (I). The compound shown in the formula (I) can obviously inhibit the proliferation of various human tumor cells, has stronger inhibiting effect on certain specific cell strains in the experiment than that of curcumin serving as a control medicament and EF24 and EF31 serving as lead compounds, particularly achieves nanomolar level on the proliferation inhibiting effect on human pancreatic cancer cells PANC-1.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of a compound in treating tumors.
Background
Pancreatic cancer, known as "cancer king", is one of the most malignant tumors. Pancreatic cancer has a very poor prognosis with median survival less than 6 months and a 5-year survival rate of only 6%. Surgical resection is the first method for radical treatment of pancreatic cancer. However, due to the lack of apparent early clinical symptoms and high metastatic potential, most pancreatic cancer patients have missed the optimal period of surgical treatment when diagnosed. Statistically, less than 20% of patients are eligible for surgical treatment. Chemotherapy is another important means of treating advanced pancreatic cancer, extending patient survival. However, such conventional cytotoxic drugs lack selectivity for tumor cells and normal cells, thereby causing serious irreversible side effects, and greatly limiting the exertion of the therapeutic effects of these drugs.
The targeted therapy has shown great advantages in improving survival period of cancer patients, improving prognosis, overcoming severe adverse reactions brought by chemotherapy, and the like, compared with traditional chemotherapy, the target proteins which are closely related to pancreatic cancer development and development are currently determined to be K-Ras, GSK3 β, Notch, PI3K/Akt, IKK β and the like, IKK is one of serine/threonine kinase family members, and comprises four members of IKK α, IKK β, IKK gamma and IKK epsilon, wherein IKK β plays a decisive role in regulating downstream NF-kappa B signal pathways, NF-kappa B is a transcription factor widely existing in eukaryotic cells, has important regulation and control effects on functions such as cell survival, apoptosis, migration and the like, under the physiological and pathological conditions of a body, a plurality of genes related to immune function and inflammation are regulated by NF-kappa B signal pathways, and under the clinical and pathological conditions, the research finds that in pancreatic cancer cells, NF-kappa B signal pathways mediated by β are continuously developed, and the research of clinical toxicity and the development of NIKK 634-K receptor, the clinical toxicity of NIKK receptor, the receptor of NIKK β, the receptor of the receptor.
Curcumin (curcumin) is an effective anti-tumor active ingredient extracted from the tuberous root of the traditional Chinese medicinal plant curcuma, has good inhibition effect on a plurality of tumor treatment targets including STAT3, IKK β, PKC and the like, and shows lower toxicity under the condition of high-dose use.
In conclusion, the traditional antitumor drugs have poor stability and poor tumor treatment effect, and have cytotoxicity at a lower concentration, so that the development of a drug with high stability and good tumor inhibition effect is urgently needed.
Disclosure of Invention
The invention aims to provide a compound shown in formula (I), which exerts the anti-tumor activity by inhibiting the phosphorylation of IKK β and is used for overcoming the defects of high cytotoxicity, poor stability and poor tumor treatment effect of the conventional anti-tumor drugs.
In order to achieve the above objects, the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof for use in the prevention and/or treatment of tumors,
preferably, the tumor is a pancreatic cancer, and the pancreatic cancer is a ductal pancreatic cancer.
Preferably, the pancreatic cancer cells are selected from human pancreatic cancer cells PANC-1 cells, MiaPaCa-2 cells or BxPC-3 cells.
Preferably, the compound, the pharmaceutically acceptable salt thereof or the prodrug thereof is used for preparing a product for preventing and/or treating pancreatic cancer; products that inhibit the activity of pancreatic cancer stem cells; and
an active product that inhibits primary pancreatic cancer cells.
The pharmaceutical composition comprises effective dose of the compound, the pharmaceutically acceptable salt thereof or the prodrug thereof, and one or more pharmaceutically acceptable pharmaceutical carriers.
Preferably, the drug carrier comprises: diluent, excipient, adhesive, wetting agent, absorption enhancer, surfactant and lubricant.
Preferably, the pharmaceutical composition is in the form of tablets, capsules, oral liquid, injection, powder, paste or external liquid.
In the present invention, the term "prodrug" refers to a compound that is a drug precursor that, when administered, undergoes chemical transformation in vivo, either by metabolic or chemical processes (e.g., exposure to physiological pH or by enzymatic activity), releasing the active drug. . The "prodrug" of the present invention may also include metabolic precursors of the compounds of the present invention, which may not be active when administered to a subject, but may be converted in vivo to a compound of formula (I) of the present invention or a salt and/or solvate thereof. Prodrugs can also be naturally occurring or chemically synthesized compounds.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of a compound of formula (I) or a stereoisomer thereof, or a prodrug thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. Or by mixing a compound represented by the formula (I), or a stereoisomer thereof, or a prodrug thereof with a certain amount of an acid or a base as appropriate (e.g., an equivalent amount). These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
According to the experimental result, the in vitro anti-tumor cell proliferation effect of the compound shown in the formula (I) is caused by inhibiting IKK β, the compound shown in the formula (I) (D6) can be directly combined with IKK β and inhibit a phosphorylation downstream substrate thereof, then the expression of a regulated gene (Bcl-2) is reduced, a Caspase family specific cleavage substrate PARP is activated, and the tumor cell apoptosis is obviously induced.
In the present invention, the pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, such as: diluents, excipients such as water, etc., fillers such as starch, sucrose, etc.; binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; humectants such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and bentonite; lubricants such as talc, calcium/magnesium stearate, polyethylene glycol, and the like. Other adjuvants such as flavoring agent, sweetener, etc. can also be added into the composition.
The pharmaceutical compositions of the present invention are administered to a patient in need of such treatment by oral, nasal inhalation, rectal or parenteral administration. For oral administration, it can be made into conventional solid preparations such as tablet, powder, granule, capsule, etc., liquid preparations such as aqueous or oil suspension, or other liquid preparations such as syrup, elixir, etc.; for parenteral administration, it can be formulated into solution for injection, aqueous or oily suspension, etc.
Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional production methods in the pharmaceutical field. For example, the active ingredient may be combined with one or more carriers and then formulated into the desired dosage form.
The invention has the following advantages:
the compound shown in the formula (I) can obviously inhibit the proliferation of various human tumor cells, has stronger inhibiting effect on certain specific cell strains in the experiment than that of curcumin serving as a control medicament and EF24 and EF31 serving as lead compounds, particularly achieves nanomolar level on the proliferation inhibiting effect on human pancreatic cancer cells PANC-1.
Drawings
FIG. 1 is a schematic diagram of the chemical synthesis of a compound of formula (I) according to the present invention
FIG. 2 is a schematic representation of the interaction assay of the compounds of formula (I) of the present invention with IKK β.
FIG. 3A is a graph showing the expression level changes of phosphorylated IKK β (pIKK β), total IKK β and total IKB detected by Western Blot after stimulating the activation of intracellular IKK β -NF- κ B/Iκ B pathway by TNF- α according to the present invention and adding different treatments to the culture medium (3 uL DMSO only in the blank control group, 3uL DMSO in the negative control group and 1ng/ml of TNF- α in the negative control group, 1 μ M, 2.5 μ M and 5 μ M of compound D6 and TNF- α in the experimental group, respectively, and 5 μ M of EF31 in the positive control group).
FIGS. 3B and 3C are histograms showing the relative expression levels of pIKK β/IKK β and IkB/GAPDH according to the present invention.
FIGS. 4A-4D are Hoechst staining patterns of the compound of formula (I) of the present invention, EF31, for inducing apoptosis in PANC-1 human pancreatic cancer cells. Among them, FIG. 4A is a negative control group to which only DMSO was added, and FIGS. 4B, 4C and 4D are compounds D6 added at 2.5. mu.M and 5. mu.M and EF31 added at 5. mu.M, respectively, in which the more blue fluorescence is observed, the more severe the degree of apoptosis is.
FIG. 5A is a Western Blot result chart showing the apoptosis of PANC-1 cells according to the invention induced by DMSO addition, 2.5. mu.M and 5. mu.M compound D6 addition, and 5. mu.M EF31, indicating the expression level of apoptosis-related protein cleared-PARP and anti-apoptotic protein Bcl-2.
FIG. 5B is a Western Blot result of apoptosis of another pancreatic cancer cell line BxPC-3 after the same treatment as in FIG. 5A.
FIGS. 5C-5F are histograms of the relative expression levels of clear-PARP (5C-5D) and Bcl-2(5E-5F) in PANC-1 and BxPC-3 cells, respectively, according to the present invention, corrected for the internal reference protein GAPDH.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The compounds of formula (I) and D6 are referred to herein as the same compound.
EXAMPLE 1 Synthesis of Compound (D6) of formula (I)
Dissolving 10mmol of 4- (2- (dimethylamino) ethoxy) benzaldehyde and 5mmol of 4-piperidone hydrochloride monohydrate in a mixed solvent of 18mL of absolute ethyl alcohol and 2mL of distilled water, and stirring at room temperature for 10-15min until the solid is completely dissolved, wherein the solution is transparent and clear. Under the condition of ice-water bath (0-4 ℃), slowly dripping 0.5mL of 40% NaOH solution into the reaction solution, slowly carrying out the reaction under the condition of ice bath to room temperature until a large amount of insoluble orange-yellow precipitate appears, detecting the reaction solution by TLC, and showing the chemical equation of the reaction in figure 1. Stopping the reaction when purple spots of the raw material 4- (2- (dimethylamino) ethoxy) benzaldehyde are no longer generated under an ultraviolet lamp of 254nm and product spots are obvious under an ultraviolet lamp of 365nm, filtering the reaction solution, washing the product with 20mL of water, then washing the product with 10mL of 10% ethanol twice, and drying the product in vacuum at 30 ℃ overnight to obtain orange yellowAnd purifying the crude product by silica gel column chromatography to obtain the target compound 3, 5-bis ((E) -4- (2- (dimethylamino) ethoxy) benzylidene) piperidin-4-one (the compound shown in the formula (I), which is abbreviated as the D6 compound), with the yield of 44.48%. Melting point 111.8-113.2 ℃.
1HNMR(500MHz,CDCl
3)δ:7.758(s,2H,Ar-CH＝C×2),7.346(d,J＝8.0Hz,4H,Ar-H2×2,Ar-H6×2),6.937(d,J＝8.0Hz,4H,Ar-H3×2,Ar-H5×2),4.146(s,4H,N-CH2×2),4.059(t,J＝6.0Hz,4H,-OCH2CH2N-×2),2.463(t,J＝7.0Hz,4H,-OCH2CH2N-×2),2.623(s,12H,-NCH3×4),1.975(t,J＝6.5Hz,1H,-NH)。ESI-MS m/z:450.41(M+H)
+,calcd for C
27H
35N
3O
3:449.27.HPLC purity:99.36％。
Example 2 determination of dissociation binding constant for direct interaction of a Compound of formula (I) with IKK β
The SPR experiment was determined by Proteon XPR36Protein Interaction Array system (Bio-Rad Laboratories, Hercules, Calif., USA.) first, the reagents used in the experiment were dissolved in ultra pure water, filtered through a microporous membrane of 0.22 μ M pore size, IKK β -PBST (5mM, pH 7.4) at a concentration of 1mg/mL was diluted to 30 μ g/mL in sodium acetate buffer (pH 4.5), the chip was activated with EDC/NHS (10 μ L/min, 600s), IKK β was then covalently immobilized on the chip at a flow rate of 5 μ L/min, IKK β was immobilized on the chip at approximately 8,000RU, IKK β was not immobilized, eluted with PBS solution (5mM, pH7.4, with 5%, w/v, DMSO) and the data was finally collected by injecting PBS solution (PBS 5mM, pH7.4, w/v, DMSO) in a gradient of 100 μ M DMSO/DMSO concentration of 100 μ M.
As shown in table 1, the interaction between the compound of formula (I)/IKK β was enhanced as the concentration of the compound of formula (I) increased, indicating that there was direct binding between the compound of formula (I) and IKK β, and the KD value (dissociation constant, concentration of drug at which half of the maximal effect was seen (50% of the receptor was occupied) was 22.2 μ M, indicating that the compound of formula (I)/IKK β was strongly binding, indicating that the compound of formula (I) (D6) is most likely to bind directly to a specific domain on IKK β and thereby inhibit its phosphorylation process.
Table 1 shows the half Inhibitory Concentrations (IC) of the compounds of formula (I) of the present invention, EF31, EF24 and CUR, respectively, on IKK β kinase and human pancreatic cancer PANC-1 cells, MiaPaCa-2 cells and BxPC-3 cells
50)。
EXAMPLE 3 in vitro IKK β inhibitory Activity of Compounds of formula (I) and their anti-pancreatic cancer cell proliferation Activity
The kinase inhibitory activity of the compounds of formula (I), EF31, EF24 and curcumin were tested by Shanghai Ruizi chemical company, and the test methods are summarized as follows:
first, 1.25 Xkinase base buffer (62.5mM HEPES, 0.001875% Brij-35, 12.5mM MgCl2, 2.5mM DTT) and Stop buffer (100mM HEPES, 0.015% Brij-35, 0.2% coating reagent No 3, 50mM EDTA) were prepared. Then, 5. mu.L of the test compound dissolved in 10% DMSO was diluted with 10. mu.L of 2.5 × enzyme solution and added to 384-well plates, and at the same time, 10mM EDTA was added to the blank wells to terminate the subsequent phosphorylation reactions. Then, 10. mu.L of peptide solution was added to each well. After incubation at 28 ℃ for 1h, 25. mu.L of stop buffer was added to each well to stop the reaction. Readings were taken by the EZreader from Caliper Life Sciences.
The inhibition rate calculation formula is as follows:
Inhibition％＝(Max-conversion)/(Max-Min)×100％
"Max" represents DMSO control, "Min" represents blank control with EDTA added in advance, and "conversion" represents the average reading of three secondary wells by EZ reader.
By setting 10 large-to-small gradient concentrations, compound concentration-inhibition rate curves were fitted by Graphpadprism software (GraphPad, San Diego, CA, USA) to calculate the half-effective Inhibitory Concentration (IC) of the compound
50)。
Cell lines used for the cell growth activity test were: human pancreatic cancer cell strains PANC-1, MiaPaCa-2 and BxPC-3 were purchased from cell center of Shanghai Life sciences research institute of Chinese academy of sciences.
The cells were inoculated in 96-well culture plates, respectively, and the cell suspension was adjusted to DMEM medium containing 10% heat-inactivated newborn calf serum, penicillin 100U/mL, and streptomycin 100. mu.g/mL, and 100. mu.L of each well was added to make the cell density 5000 cells/well. At 37 ℃ with 5% CO
2Culturing in an incubator with saturated humidity. After 24h, various concentrations of compounds in DMSO were added to the plates and incubated for 72 h. mu.L of MTT (5 mg/ml) was added to each well 3h before termination of the culture. After incubation, carefully removing the liquid in the wells, adding 100. mu.L DMSO into each well, placing on a shaker, oscillating at low speed for 10min to fully dissolve the crystals, and measuring the light absorption value of each well at 570nm wavelength of an enzyme linked immunosorbent detector. The positive control substances are curcumin and mono-carbonyl analogues thereof EF31 and EF 24. The cell growth inhibition rate was calculated from the absorbance. Cell growth inhibition rate [ OD control-OD test]/[ OD control-OD blank]×100％。
The different concentrations of the same drug are used for plotting the tumor cell growth inhibition rate to obtain a dose response curve, and the concentration of the drug with 50 percent of the cell growth inhibition rate is obtained according to a linear regression equation, namely the half inhibition concentration IC
50。
As shown in FIG. 2, the kinase activity and cell proliferation activity of the compound of formula (I) were measured by using a ProteOnXPR36Protein Interaction Array system instrument of Biorad company to determine the binding and dissociation constant of the compound of formula (I) to IKK β. from the figure, it can be seen that the inhibitory activity of the compound of formula (I) on IKK β reached a level of 800nM, while the inhibitory activity on several cell lines such as human pancreatic cancer cell lines PANC-1, MiaPaCa-2 and BxPC-3 was significantly higher than that of positive drugs Curcumin (CUR), EF31 and EF24. furthermore, the kinase activity and the cell activity of the four compounds remained the same, indicating that the corresponding compound exerts its anti-tumor activity mainly by inhibiting phosphorylation of IKK β.
Example 4 dose-dependent inhibition of phosphorylated IKK β and free IkB expression in pancreatic cancer cells by Compounds of formula (I)
In the classical NF-kB signal channel, TLR4 is combined with extramembranous ligand and then is communicatedThrough a series of cell signaling, intracellular IKK β is phosphorylated, phosphorylation of IKK β causes separation of IkB/NF-kB complex, thereby enabling free NF-kB to enter nucleus and regulating transcription of a series of downstream target genes, and simultaneously, free IkB is degraded by a rapid ubiquitination pathway, therefore, the invention detects the influence of D6 and a positive control EF31 on phosphorylated IKK β (pIKK β) and IkB in pancreatic cancer PANC-1 cells through Western Blot, and the invention detects 1 × 10
6After culturing the individual cells in culture fluid at 37 ℃ for 24h, renewing the culture fluid and adding different concentrations of compounds, after further treatment for a corresponding period of time, TNF- α was stimulated for 30 minutes, total protein was collected and cells were assayed for pIKK β, total IKK β and total IkB content using Western Blot, GAPDH as calibrator as shown in FIGS. 3A-3C, which is the inhibitory effect of the compound of formula (I) of the present invention on phosphorylated IKK β protein in pancreatic cancer cell line PANC-1 and significantly reduced degradation of downstream IkB, wherein the expression level of pIKK β was effectively inhibited after treatment with different concentrations of D6, which is very dose-dependent, and the compound of formula (I) was able to simultaneously dose-dependently inhibit the free degradation of IkB, thereby further demonstrating that the inhibitory effect of the compound of formula (I) on phosphorylation of IKK β was significant by comparison, and that the effect of the compound of formula (I) was superior to that of the compound of formula (I) 31 after the action of the same concentrations of formula (I) 31.
Example 5 significant induction of apoptosis in PANC-1 cells of human pancreatic carcinoma by Compounds of formula (I)
PANC-1 cells were seeded in 6-well plates and 24h later compounds of formula (I) and EF31 dissolved in DMSO were added to the plates to final concentrations of compounds of formula (I) (2.5, 5. mu.M), EF31 (5. mu.M), respectively, and incubated for 12 h. Hoechst 33342 dye (Beyotime Biotech, Nantong, China) was then added to 6-well plates according to the kit instructions. The cell mass and its nucleoli, morphology, and the intensity of Hoechst 33342 specific blue fluorescence were recorded by fluorescence microscopy (Nikon, Tokyo, Japan). As shown in FIGS. 4A-4D, the results show that after 12h, the compound of formula (I) shows dose-dependent apoptosis induction, and PANC-1 shows obvious nuclear fragmentation and shrinkage of chromatin in the nucleus under the induction of the compound of formula (I) and is accompanied by strong blue fluorescence. Also at a concentration of 5 μ M, the effect of the compound of formula (I) in inducing apoptosis was significantly better than that of the control compound EF 31.
EXAMPLE 6 the Compound of formula (I) activates Cleaved-PARP and inhibits the expression of Bcl-2
PARP is a cleavage substrate for caspase (caspase), a key apoptosis enzyme, and plays an important role in apoptosis. Under normal physiological and pathological conditions, PARP is Cleaved by caspase to become clear-PARP, and therefore, the increase of the expression level of the clear-PARP is considered to be an important index of apoptosis. In addition, Bcl-2 protein is the most well known core member of the family of anti-apoptotic proteins, and studies have shown that the Bcl-2 gene is one of the many target genes regulated by NF-. kappa.B. Therefore, the effect of the compound of formula (I) on the expression level of cleared-PARP and Bcl-2 was examined. The present invention utilizes 1.2X 10
6The PANC-1 and BxPC-3 cells were cultured in 1640 medium at 37 ℃ for 24 hours, the medium was refreshed, total protein was extracted by treating the cells for 24 hours with different concentrations of the compound of formula (I) and EF31, and the expression levels of Cleaved-PARP and Bcl-2 were measured by Western Blot, respectively, using GAPDH as an internal reference protein. As shown in FIGS. 5A and 5B, after the compound of formula (I) and EF31 act for 72h, clear-PARP in PANC-1 and BxPC-3 cells is obviously increased, and Bcl-2 is obviously reduced, which indicates that the compound of formula (I) and EF31 can better induce pancreatic cancer cells to generate apoptosis. It is more intuitively observed that the effect of the compound of formula (I) in inducing apoptosis in pancreatic cancer cells is superior to EF31 at the same concentration, as shown in fig. 5C-5F by histogram statistics.
Although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (6)
1. The application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparing products for preventing and/or treating pancreatic cancer,
2. the use according to claim 1,
the pancreatic cancer is ductal pancreatic cancer.
3. The use according to claim 2,
the pancreatic cancer cells are selected from human pancreatic cancer cells PANC-1 cells, MiaPaCa-2 cells or BxPC-3 cells.
4. Use according to any one of claims 1 to 3,
the product is a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable pharmaceutical carriers.
5. The use according to claim 4,
wherein the drug carrier comprises: diluent, adhesive, wetting agent, absorption enhancer, surfactant and lubricant.
6. The use according to claim 4,
the dosage form of the pharmaceutical composition is tablets, capsules, oral liquid, injection, powder, paste or external liquid medicine.
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| CN1930126A (en) * | 2004-03-05 | 2007-03-14 | 万有制药株式会社 | Pyridone derivative |
| CN102018690A (en) * | 2009-09-12 | 2011-04-20 | 温州医学院 | Anti-tumor medicament and application thereof |
| CN107737124A (en) * | 2017-01-04 | 2018-02-27 | 温州医科大学 | A kind of application of curcumin analogue in antineoplastic is prepared |
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| CN103222970B (en) * | 2013-04-10 | 2019-03-26 | 温州医科大学 | Asymmetric list carbonyl curcumin analog application in preparation of anti-tumor drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1930126A (en) * | 2004-03-05 | 2007-03-14 | 万有制药株式会社 | Pyridone derivative |
| CN102018690A (en) * | 2009-09-12 | 2011-04-20 | 温州医学院 | Anti-tumor medicament and application thereof |
| CN107737124A (en) * | 2017-01-04 | 2018-02-27 | 温州医科大学 | A kind of application of curcumin analogue in antineoplastic is prepared |
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