CN104771396B - The application of 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles - Google Patents
The application of 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles Download PDFInfo
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Abstract
The invention belongs to medicinal chemistry arts, 4- of the invention (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or prodrug are provided and preparing the application in the drug for treating Mammalian Ovary tumour.The anti ovary tumour that the compound of the present invention has had the function of.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to diphenyl ethylene derivatives 4- (3,5- dimethoxy phenyl) -5- (3-
Hydroxyl -4- methoxyphenyl) imidazoles application.
Background technique
4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles is a known compound, is had
Such as flowering structure:
The compound discloses in CN201110422678.5, this document is hereby incorporated by ginseng with entire contents
It examines.CN201110422678.5 reports 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles with micro-
Tubulin assembly inhibitory activity.4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles is Combretastatin
(combretastatin A4) derivative specifically acts on tumor neogenetic blood vessels as tumor vessel disrupting agent, to swollen
The selectivity of tumor blood vessel is strong, the influence very little to other histoorgans, can be to avoid some serious of classical cytotoxic drug
Adverse reaction.
It is well known that most chemotherapeutics are not to all have inhibition or killing effect to all tumours, for
Different tumours has a different therapeutic schemes, such as alkylating agent is to chronic leukemia, malignant lymphoma, Hodgkin's disease, multiple
Property myeloma there is curative effect, and antimetabolite is usually used in treating breast cancer, oophoroma, gastric cancer and acute and chronic leukemia.In tumour
In therapy field, selects that there is certain types of tumour and significantly inhibit or killing effect and the small drug of toxic side effect are research
Important directions.
Oophoroma is common one of the malignant tumour of gynaecology, and the disease incidence in female sex organ malignant tumour accounts for third
There are about 200,000 new hair oophoroma cases in position, the whole world every year, and 120,000 are died of related disease, and case fatality rate occupies gynecologic malignant tumor
First.Oophoroma clinical early stage is asymptomatic, and making a definite diagnosis Shi Duoyi is advanced stage.Find that tumour is confined to ovary in row exploratory laparotomy
Only account for 30%, it is most of to have spread to uterus bilateral attachment, omentum majus and each organ of pelvic cavity.Therefore, chemotherapy is in oophoroma, spy
It is not that highly important status is occupied in management of advanced epithelial ovarian.Platinum class and paclitaxel plus are current treatment refractory ovarian cancers
Preferred option, but being widely used just because of these drugs, there are drug resistances by most of patient, so that cancer is easily multiple
Hair, it is refractory to be cured.Therefore, the drug of the new treatment oophoroma of searching is needed.
CN 201110422678.5 discloses the 3,5- Dimethoxyphenyl replaced in A ring containing 4 from the general extent
Imidazoles, oxazole and thiazoles Combretastatin A4 derivative can be used for treating tumour.However, CN
201110422678.5 do not disclose, prompt or instruct 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) miaow
Azoles can be used for treating ovarian neoplasm.
Summary of the invention
The object of the present invention is to provide 4- of the invention (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls)
Imidazoles or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or prodrug are for treating answering for ovarian neoplasm
With.
Astoundingly, the present inventor is it has been found that 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxy
Base phenyl) imidazoles have excellent ovarian cancer resistance effect.Experiment in vitro proves, 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -
4- methoxyphenyl) imidazoles can inhibit ovarian cancer cell significantly, to the IC of cell strain HO-891050Value is about 5nM, and body
Interior experiment shows 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles in dose-dependent inhibition people ovum
The growth of nest cancer cell SKOV-3 tumor-bearing mice tumour, 50mg/kg, 75mg/kg and 100mg/kg dosage tumour inhibiting rate are respectively
33.07%, 61.39% and 94.40%.
The present invention provide 4- of the invention (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles or its
Pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or prodrug are used to treat answering for oophoroma in mammal
With.Preferably, the mammal is behaved.
It can be by the compound of the present invention or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or preceding
Medicine and pharmaceutically acceptable carrier, diluent or excipient are prepared by mixing into pharmaceutical preparation, be suitable for it is oral or parenterally to
Medicine.Medication is including but not limited to intravenous, intradermal, intramuscular, peritonaeum is interior, subcutaneous, intranasal and peroral route.The preparation can
To be applied by any approach, for example, by infusion, instil or inject, pass through transepithelial or mucocutaneous (such as oral mucosa
Or rectum etc.) absorb approach application.Administration can be systemic administration or local application.The preparation can be by known in the art
Method preparation.
Preferably, the compound of the present invention or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or
Prodrug is with Parenteral.An embodiment according to the present invention, drug of the invention are formulated as injection, Ke Yiwei
Infusion solution, liquid drugs injection, concentrated solution for injection etc..Another embodiment according to the present invention, drug of the invention are formulated as powder
Agent can be freeze-dried powder type, aseptic powdery agent etc..
According to the dose lonvestion relationship between different genera mammal, according to preferred embodiment, for parenteral
Administration, with 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles poidometer, the compound of the present invention or
Its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or prodrug can be to be greater than 0.1mg/kg body in people
Weight/day, such as 0.1-30mg/kg body weight/day, preferably greater than 0.2mg/kg body weight/day, such as 0.2-20mg/kg body weight/day,
The more preferably greater than amount of 0.5mg/kg body weight/day, such as the dosage of 0.5-10mg/kg body weight/day are administered alone.In another reality
It applies in scheme, with 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles poidometer, chemical combination of the invention
Object or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or prodrug are in people to be greater than 0.1mg/kg body
Weight/day, such as 0.1-30mg/kg body weight/day, preferably greater than 0.2mg/kg body weight/day, such as 0.2-20mg/kg body weight/day,
The more preferably greater than amount of 0.5mg/kg body weight/day, for example, 0.5-10mg/kg body weight/day dosage combined with other activating agents to
Medicine.
Preferably, in one embodiment, the mode through intravenous injection can connect the compound of the present invention or its pharmacy
Salt, solvate, hydrate, stereoisomer or the prodrug administration received are in mammal.
In a preferred embodiment, the compound of the present invention or its pharmaceutically acceptable salt, solvate, hydration
Object, stereoisomer or prodrug are with 0.1-30mg/kg body weight/day, preferably 0.2-20mg/kg body weight/day, more preferable 0.5-
The dosage range of 10mg/kg body weight/day is once a day, 3-5 days continuous, locally or systemically such as intravenously administrable, then interval 2-3
Day, 7 days as a course for the treatment of, sustainable several courses for the treatment of such as 1-10 or 10 or more the courses for the treatment of, or 1-3 times locally or systemically such as weekly
Intravenously administrable, 5-7 days as a treatment course, sustainable several courses for the treatment of such as 1-10 or 10 or more the courses for the treatment of.The dosage of actual use
It can be changed according to the needs of patient and the severity for the treatment of illness.
Although foregoing provide the compound of the present invention or its pharmaceutically acceptable salt, solvate, hydrate, solid are different
The typical doses of structure body or prodrug, but clinician can allow according to the state of an illness for the treatment of patient using different dosage.
In one embodiment, the present invention provides the method for the treatment of, prevention or control ovarian neoplasm, the method includes
It is given to patient with this need and treats or prevents a effective amount of 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxybenzene
Base) imidazoles or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or prodrug.
In another embodiment, the present invention provides the method for the treatment of, prevention or control ovarian neoplasm, the method packet
It includes before, during or after implementing ovarian neoplasm operation, is given to patient with this need and treat or prevent a effective amount of 4-
(3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles or its pharmaceutically acceptable salt, solvate, hydration
Object, stereoisomer or prodrug.
In another embodiment, the present invention provides treatment, prevention or control the ovary resistant to routine treatment
The method of tumour, the method includes giving to treat or prevent a effective amount of 4- (3,5- dimethoxy-benzenes to patient with this need
Base) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer
Or prodrug.
In one embodiment, the ovarian neoplasm includes malignant ovarian or borderline tumor, is not limited to epithelioma such as
Slurries tumor, myxoma, for example interior blastular tumor of germinoma, immature teratoma, dysgerminoma, sex cord-stromal tumor as
Granulocyte tumor, theca cell tumor, fibroma, non-specific mesenchymal neoplasm such as fibroma, liomyoma and metastatic tumor etc..
In one embodiment, the present invention provides a kind of pharmaceutical composition, and it includes 4- (3,5- dimethoxy phenyl) -5-
(3- hydroxyl -4- methoxyphenyl) imidazoles or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or prodrug
And second activating agent.Second activating agent is immunomodulator, immunosuppressor, anticarcinogen, corticosteroid, COX-2
Inhibitor etc..
In one embodiment, the present invention provide the compound of the present invention or its pharmaceutically acceptable salt, solvate,
The application of hydrate, stereoisomer or prodrug in the drug of preparation treatment, prevention or control oophoroma.
Unless otherwise indicated, all technical and scientific terms used herein has and common skill of the art
The normally understood identical meaning of art personnel.
As used herein, term " pharmaceutically acceptable salt " includes hydrochloride, phosphate, nitrate, sulfate, citric acid
Salt, maleate, tartrate, sulfonate or amino-acid salt etc..
The pharmaceutically acceptable salt includes 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) miaow
The phosphate of azoles or the salt of sulphonic acid ester, such as alkali metal salt, alkali salt or amino butanetriol salt.The salt is preferably 4-
The organic phosphate disodium salt of (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles.
The pharmaceutically acceptable salt of the compound of the present invention can be used conventional salifying method and obtain, or referring to CN
The preparation of method disclosed in 201110422678.5.Further, optically pure compound of the invention can be by using known
Resolution reagent or chiral column and other standard organic chemical synthetic technologys synthesize.
Term " solvate " refers to form the present inventionization of the complex of solid-state or liquid by being coordinated with solvent molecule
Close the form of object.Hydrate is the special shape of solvate, wherein being coordinated with water.Within the scope of the present invention, solvent closes
Object is preferably hydrate.
The institute that term " prodrug ", which refers to, to be hydrolyzed (in vitro or in vivo) under biological environment, oxidation or other reactions obtain
State the derivative of compound.The example of prodrug includes but is not limited to containing the hydrolyzable such as biological hydrolyzable acyl of group of biology
Amine, the hydrolyzable ester of biology, the hydrolyzable carbamate of biology, the hydrolyzable carbonic ester of biology, the hydrolyzable uride of biology
And the derivative of the compound of the present invention of the hydrolyzable phosphate of biology.
Specific embodiment
The present invention is further elaborated below with reference to embodiment, but the present invention is not limited to these Examples.
1 4- of embodiment (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles organic phosphate disodium salt pair
The inhibitory activity of endothelial cell proliferation, segment dislocation and existing segment dislocation
Key instrument is CO2Saturated humidity incubator Thermo Forma 3111(Marietta, OH, USA)；Microscope
Olympus IX70(Tokyo, Japan)；Disecting microscope Leica MPS30(Heerbrugg, Switzerland)；Chicken embryo is incubated
Change incubator Lyon(Chula Vista, CA, USA)；Wavelengthtunable declines orifice plate microplate reader Molecular Devices
Spectra MAX190(Sunnyvale, CA, USA).
Main agents are complete medium (Sai Ersi Bioisystech Co., Ltd, Shanghai Australia, China)；Sulphonyl rhodamine B
(sulforodamine B, SRB, Sigma company)；Basement Membrane Matrix, Phenol Red-free(goods
Number #356237, BD company)；Trichloroacetic acid (TCA), acetic acid (HAC) and Tris Base Buffer, it is commercially available, it is domestic
It analyzes pure.Human umbilical vein endothelial's cell is purchased from Sai Ersi Bioisystech Co., Ltd, Chinese Shanghai Australia.
(the letter herein of the compound of the present invention 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles
Claim C118) and (letter herein of 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles organic phosphate disodium salt
Claim C118P), the method preparation as disclosed in CN 201110422678.5.Taxol is purchased from Jiangsu Province, China Olympic Competition health medicine company stock
Part Co., Ltd.Mitomycin (Mitomycin, MMC) is purchased from Kyowa Hakkokogyo Co., Ltd.
The Proliferation Ability of 1.1 pairs of human umbilical vein endothelial's cells
C118 is configured to 10mM packing with DMSO, -20 DEG C are kept in dark place, and C118P is configured to 100mM points with ultrapure water
Dress, -20 DEG C are kept in dark place.It is with physiological saline that the DMSO solution of C118, the aqueous solution of C118P and taxol difference is dilute to face the used time
It releases to after 10 μM, successively 5 times of dilutions, totally 8 concentration, obtains the test medicine compound of series of concentrations.
By human umbilical vein endothelial's cell inoculation in 2-5 generation in 96 orifice plates, 8000/hole.After overnight incubation, it is added
Above-mentioned various concentration test-compound is in 37 DEG C, 5%CO2After middle culture 72 hours, incline culture solution, with 10% pre-cooling TCA(trichlorine
Acetic acid) fixed cell, 4 DEG C place 1 hour after be washed with distilled water 5 times, spontaneously dried in air.Then 100 μ l are added in every hole
The 4mg/ml SRB solution prepared by 1% glacial acetic acid, room temperature dye 15 minutes, discard dye liquor, washed 5 times with 1% acetic acid, and air is dry
It is dry.It is eventually adding the Tris solution in 150 holes μ l/, measures OD value under microplate reader 560nm wavelength.Measured object is calculated according to the following formula
The inhibiting rate of cell proliferation: inhibiting rate=(control group OD value-administration group OD value)/control group OD value × 100%, and use
Logit method calculates IC50.Experimental result is as shown in table 1.
1 untested compound of table acts on human umbilical vein endothelial's cell inhibitory effect
| Compound | IC50(nM, mean value ± SD) |
| C118 | 18.5±0.5 |
| C118P | 8.8±0.5 |
| Taxol | 6.3±0.5 |
Experimental result shows that C118P and its active matter C118 all have stronger increasing to human umbilical vein endothelial's cell
Grow inhibiting effect, IC50Value is respectively 8.8nM and 18.5nM, suitable with the activity of taxol.
Influence of 1.2 the compound of the present invention to human umbilical vein endothelial's cell segment dislocation
Matrigel glue is in solid-state in -20 DEG C of storages, is in a liquid state at 0 DEG C, congeals into glue again at 37 DEG C.It takes
Matrigel glue is put on ice, is allowed to melt, while take arms head and 96 orifice plates are pre-chilled in -20 DEG C.It is taken with the pipette tips of pre-cooling
Matrigel glue 50 holes μ l/ (Becton Dickinson Labware, MA, the U.S.) are added in 96 orifice plates of pre-cooling, pay attention to keeping away
Exempt to form bubble, placing 5min on ice makes Matrigel liquid level, and 37 DEG C of placement 1h of plate are then made its solidification.Every hole adds
Enter to use the diluted Human umbilical vein endothelial cells (2.0 × 10 of complete culture solution4A cells/well), while it is dense that a series of differences are added
The test-compound (1nM, 10nM, 100nM) of degree, 37 DEG C of incubation 8h are observed and are clapped under microscope (Olympus, IX70, Japan)
According to.Complete lumen quantity is counted, inhibiting rate is calculated according to the following formula: inhibiting rate=(negative control lumen number-dosing lumen number)/
Negative control lumen number × 100%.Experiment is repeated 3 times, and data are expressed as mean value ± SD.
The compound of the present invention is as shown in table 2 below to the suppression result of human umbilical vein endothelial's cell segment dislocation.
Inhibition of 2 untested compound of table to human umbilical vein endothelial's cell segment dislocation
| Compound | Inhibiting rate (%, mean value ± SD) |
| C118 1nM | 12.7±9.7 |
| C118 10nM | 77.9±12.9 |
| C118 100nM | 100.0±0.0 |
| C118P 1nM | 8.5±8.4 |
| C118P 10nM | 88.8±10.2 |
| C118P 100nM | 100.0±0.0 |
| Taxol 1nM | 24.8±8.8 |
| Taxol 10nM | 76.5±9.5 |
| Taxol 100nM | 91.5±3.3 |
In the later period that new vessels generate, the endothelial cell of proliferation and migration can be rearranged into streak, eventually form
One new lumen, endothelial cell lumen, which forms experiment, can simulate this process.Matrigel glue provides in this experiment
One good segment dislocation environment, in vehicle control group, human umbilical vein endothelial's cell has formd on Matrigel
Whole reticular structure, and pass through various concentration untested compound effect after, endothelial cell formed on Matrigel it is imperfect,
Sparse reticular structure, or even completely disappeared in some regions.By the counting to complete lumen, as the result is shown C118P and its
Active matter C118 has dose-dependent inhibiting effect to human umbilical vein endothelial's cell segment dislocation, under 10nM dosage
The segment dislocation of endothelial cell can be significantly inhibited, inhibiting rate is respectively 77.9% and 88.8%, with taxol with the suppression under dosage
Rate processed is quite (76.5%).After C118P and its active matter C118 is acted on 8 hours, luminal structure is destroyed completely.
It is aobvious that the above results show that C118P and its active matter C118 have human umbilical vein endothelial's cell segment dislocation
The inhibiting effect of work, action intensity are suitable with taxol.
The effect that 1.3 the compound of the present invention destroy the existing lumen of human umbilical vein endothelial's cell
Matrigel glue is in solid-state in -20 DEG C of storages, is in a liquid state at 0 DEG C, congeals into glue again at 37 DEG C.It takes
Matrigel glue is put on ice, is allowed to melt, while take arms head and 96 orifice plates are pre-chilled in -20 DEG C.It is taken with the pipette tips of pre-cooling
50 holes μ l/ Matrigel glue (Becton Dickinson Labware, MA, USA) in 96 orifice plates of pre-cooling, pay attention to avoiding shape
At bubble, placing 5min on ice makes Matrigel liquid level, and 37 DEG C of placement 1h of plate are then made its solidification.Every hole, which is added, to be used
Containing the diluted Human umbilical vein endothelial cells (2.0 × 10 of complete culture solution4A cells/well), then 37 DEG C of incubation 12h are added one
The test-compound (1nM, 10nM, 100nM) of serial various concentration is observed and is clapped under microscope (Olympus, IX70, Japan)
According to.Count complete lumen quantity, and according to: inhibiting rate=(negative control lumen number-dosing lumen number)/negative control lumen number
× 100%, calculate inhibiting rate.Experiment is repeated 3 times, and data are expressed as mean value ± SD.
The compound of the present invention is shown in Table 3 to the inhibition assay result of the existing segment dislocation of human umbilical vein endothelial's cell.
Inhibition of 3 the compound of the present invention of table to the existing segment dislocation of human umbilical vein endothelial's cell
Endothelial cell forms the process of the process simulation of lumen new vessels generation on matrigel, is forming lumen
After continue to keep growth, reach 12 small stylish is formationed lumens arrangements and have reached maturation, for completely streak distribution, analog was both
At lumen.The untested compound processing of various concentration is added at this time, observes in different time points.C118P and its active matter C118
Active quite to act on 3 hours, 100nM concentration can significantly destroy the lumen formed, and bar rope is broken, and reticular structure is complete
It destroys (inhibiting rate is respectively 95.1% and 90.4%)；C118P and its active matter C118 is acted on 6 hours, 10nM and 100nM compound
It all produces apparent lumen destruction to be compared with control group with significant difference, C118P is in 10nM and 100nM concentration
Inhibiting rate be respectively 44.4% and 100.0%, C118P is respectively 56.3% and 94.6% in the inhibiting rate of 10nM and 100nM concentration.
Show that C118P and its active matter C118 can destroy existing lumen with dose dependent and time dependence.Under 10nM dosage,
The activity of C118P and its active matter C118 is suitable with taxol inhibitory activity；Under 100nM dosage, C118P and its active matter
The activity of C118 is better than taxol.
This it is experimentally confirmed that C118P and its active matter C118 to human umbilical vein endothelial's cell existing lumen experiment have compared with
Apparent destruction, has dose dependent and time dependence, and activity is better than taxol.
2 4- of embodiment (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles is to different tumour cells
The inhibitory activity of strain
Cell strain used in the present embodiment is purchased from Shanghai Inst. of Cytobiology, Chinese Academy of Sciences.
C118 is configured to 10mM packing with DMSO, -20 DEG C are kept in dark place, and C118P is configured to 100mM points with ultrapure water
Dress, -20 DEG C are kept in dark place.Face the used time with physiological saline is diluted to 10 μM for the aqueous solution of the DMSO solution of C118, C118P respectively
Afterwards, successively 5 times of dilutions, totally 10 concentration, obtains the test medicine compound of series of concentrations.
By cell dissociation set forth below, count, be made concentration be 5 × 104The cell suspension of a/ml, every hole in 96 orifice plates
100 μ L cell suspension (every holes 5 × 10 are added3A cell)；96 orifice plates are placed in 37 DEG C, 5%CO2It is cultivated 24 hours in incubator；With
Complete medium is serially diluted the drug to required concentration, and the 100 corresponding pastille culture mediums of μ L are added in every hole, while setting up pair
According to group；96 orifice plates are placed in 37 DEG C, 5%CO2It is cultivated 72 hours in incubator；96 orifice plates are subjected to MTT dyeing, λ=490nm, measurement
OD value.Measuring method is that 20 μ L MTT(5mg/ml are added in every hole), continue culture 4 hours in incubator；Discard culture medium, every hole
150 μ L DMSO dissolution is added, mixes gently within shaking table 10 minutes；λ=490nm, microplate reader read the OD value in every hole, calculate and inhibit
Rate, inhibiting rate (%)=(OD control-OD administration)/OD control × 100%.Experimental result is shown in Table 4.
Proliferation inhibition activity of 4 the compound of the present invention of table to different tumour cells
The above Vitro Experimental Results show compared with the tumour cells such as gastric cancer, colon cancer, kidney, the compound of the present invention
There is strong inhibitory activity, the IC of 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles to oophoroma50
Value is only about 5-6nM.
3 4- of embodiment (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles disodic alkaliine is to people
The inhibiting effect of oophoroma SKOV-3 cell Xenografts in nude mice
It is used after C118P is faced used time normal saline dilution to required concentration.Three dosage groups are arranged in C118P, respectively
For 50mg/kg, 75mg/kg and 100mg/kg group.If negative control medicine and positive control drug, positive control drug MMC, dosage is
5mg/kg。
BALB/cA nude mice, female, 4-5 week old, 20 ± 2g of weight are provided by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences, yin
Property control group 12, remaining each group 6.
Human ovarian cancer SKOV-3 cell strain is provided by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences.Nude mice is inoculated with the cell strain
Right side armpit is subcutaneous, and cell inoculation amount is 5 × 106A/only, it is used after passing for 2 generations in nude mouse again after formation transplantable tumor.
Specific experimental method is as follows: the tumor tissue of growth animated period being taken to cut into 1.5mm3Left and right, aseptically, connects
Kind armpit on the right side of nude mice is subcutaneous.Xenografts in nude mice vernier caliper measurement transplantable tumor diameter, to tumour growth to 100-
200mm3Animal is grouped at random afterwards.C118P dosage group is 50mg/kg, 75mg/kg and 100mg/kg group, daily vein
It is administered once, continuous 5 days, rests 2 days, three periods totally 21 days.MMC 5mg/kg, it is primary in first day intravenously administrable.Solvent
Control group then gives equivalent injection physiological saline.In whole experiment process, transplantable tumor diameter is measured 2 times a week, while weighing small
Mouse weight.
The calculation formula of gross tumor volume (tumor volume, TV) are as follows: TV=1/2 × a × b2, wherein a, b respectively indicate swollen
Tumor length and width.Relative tumour volume (relative tumor volume, RTV), calculation formula are calculated according to the result of measurement
Are as follows: RTV=Vt/V0, wherein V0For (i.e. d before sub-cage administration0) measurement gained gross tumor volume, VtTumour body when to measure each time
Product.The evaluation index of anti-tumor activity are as follows: 1) Relative tumor proliferation rate T/C (%), calculation formula is as follows: T/C (%)=(TRTV/
CRTV) × 100%, TRTVFor treatment group RTV, CRTVFor negative control group RTV；2) gross tumor volume growth inhibition rate GI%, calculation formula
It is as follows: GI%=[1- (TVt-TV0)/(CVt-CT0)] × 100%, TVt be treatment group measure every time knurl product；TV0For treatment group
Gained knurl product before sub-cage administration；CVt is the knurl product that control group measures every time；CV0For gained tumor before control group sub-cage administration
Volume.D refers to that day, such as d1 indicate the 1st day.
Experimental result is as illustrated in tables 5-7.
Influence of the table 5C118P to human ovarian cancer SKOV-3 transplanted tumor in nude mice gross tumor volume
Influence of the table 6C118P to the Relative tumor proliferation rate of human ovarian cancer SKOV-3 transplanted tumor in nude mice
Gross tumor volume growth inhibition rate of the table 7C118P to human ovarian cancer SKOV-3 transplanted tumor in nude mice
C118P is administered with 50mg/kg, 75mg/kg and 100mg/kg dosage to human ovarian cancer it can be seen from table 5-7
The growth of SKOV-3 Xenografts in nude mice significantly inhibits effect, is respectively about in the 21st day (d21) gained gross tumor volume TV
1229mm3、706mm3And 115mm3, Relative tumor proliferation rate (T/C) is respectively 66.93%, 38.61% and 5.60%, gross tumor volume
Growth inhibition rate (GI) is respectively 39.12%, 68.175% and 101.41%, and is in dose dependent.Meanwhile invention of the invention
People observes, for the C118P of above-mentioned dosage, animal well-tolerated, without overt toxicity effect.Therefore, the compound of the present invention
With efficient ovarian cancer resistance effect, the prospect having had for treatment oophoroma.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair
The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.Interest field of the invention is not limited to
Detailed description made by above, and claims should be belonged to.
Claims (16)
1.4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles or its pharmaceutically acceptable salt or solid
Isomers is preparing the application in the drug for treating Mammalian Ovary tumour.
2. application according to claim 1, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl)
The pharmaceutically acceptable salt of imidazoles is its hydrochloride, phosphate, nitrate, sulfate, citrate, maleate, tartaric acid
Salt, sulfonate or amino-acid salt, phosphate ester salt or sulphonic acid ester salt.
3. application according to claim 2, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl)
The pharmaceutically acceptable salt of imidazoles is 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl) imidazoles phosphate two
Sodium salt.
4. the application of -3 any one according to claim 1, wherein the mammal is behaved.
5. application according to claim 4, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl)
The dosage of imidazoles or its pharmaceutically acceptable salt or stereoisomer is 0.1-30mg/kg body weight/day.
6. application according to claim 4, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl)
The dosage of imidazoles or its pharmaceutically acceptable salt or stereoisomer is 0.2-20mg/kg body weight/day.
7. application according to claim 4, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyl)
The dosage of imidazoles or its pharmaceutically acceptable salt or stereoisomer is 0.5-10mg/kg body weight/day.
8. according to the application of any one of preceding claims 1-3,5-7, wherein the ovarian neoplasm is epithelioma, reproduction cell
Tumour, sex cord-stromal tumor, non-specific mesenchymal neoplasm and metastatic tumor.
9. according to the application of preceding claims 4, wherein the ovarian neoplasm is epithelioma, germinoma, sex cords interstitial
Tumour, non-specific mesenchymal neoplasm and metastatic tumor.
10. according to the application of any one of preceding claims 1-3,5-7, wherein the 4- (3,5- dimethoxy phenyl) -5- (3-
Hydroxyl -4- methoxyphenyl) imidazoles or its pharmaceutically acceptable salt or stereoisomer be formulated as locally or systemically form of administration.
11. according to the application of preceding claims 4, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyl group
Phenyl) imidazoles or its pharmaceutically acceptable salt or stereoisomer be formulated as locally or systemically form of administration.
12. according to the application of any one of preceding claims 1-3,5-7, wherein the 4- (3,5- dimethoxy phenyl) -5- (3-
Hydroxyl -4- methoxyphenyl) imidazoles or its pharmaceutically acceptable salt or stereoisomer be formulated as parenteral dosage forms.
13. according to the application of preceding claims 4, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyl group
Phenyl) imidazoles or its pharmaceutically acceptable salt or stereoisomer be formulated as parenteral dosage forms.
14. according to the application of preceding claims 12, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyl group
Phenyl) imidazoles or its pharmaceutically acceptable salt or stereoisomer be formulated as by mucosa absorption or percutaneous absorbtion it is parenteral to
Pharmaceutically dosage form.
15. according to the application of preceding claims 13, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyl group
Phenyl) imidazoles or its pharmaceutically acceptable salt or stereoisomer be formulated as by mucosa absorption or percutaneous absorbtion it is parenteral to
Pharmaceutically dosage form.
16. according to the application of preceding claims 14 or 15, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- first
Phenyl) imidazoles or its pharmaceutically acceptable salt or stereoisomer be formulated as intravenous administration dosage form.
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| CN101602730A (en) * | 2008-06-12 | 2009-12-16 | 北大方正集团有限公司 | The imdazole derivatives that replaces |
| CN102863388A (en) * | 2011-07-05 | 2013-01-09 | 南京圣和药业有限公司 | Tumor targeted drug Combretastatin A4 derivatives |
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| CN101602730A (en) * | 2008-06-12 | 2009-12-16 | 北大方正集团有限公司 | The imdazole derivatives that replaces |
| CN102863388A (en) * | 2011-07-05 | 2013-01-09 | 南京圣和药业有限公司 | Tumor targeted drug Combretastatin A4 derivatives |
Non-Patent Citations (2)
| Title |
|---|
| A Phase Ib trial of CA4P (combretastatin A-4 phosphate),carboplatin, and paclitaxel in patients with advanced cancer;GJ Rustin,et al.;《British Journal of Cancer》;20100413;第103卷;第1355-1360页 |
| New antitubulin derivatives in the combretastatin A4 series: synthesis and biological evaluation;Christine Borrel,et al.;《Bioorganic & Medicinal Chemistry》;20050409;第13卷;第3853-3864页 |
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