CN109535101A - The preparation method of a kind of novel salicyclic acid derivatives and its application in terms of oncotherapy - Google Patents
The preparation method of a kind of novel salicyclic acid derivatives and its application in terms of oncotherapy Download PDFInfo
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention belongs to biomedicine field, the preparation method for specifically providing a kind of novel salicyclic acid derivatives and the application in terms of oncotherapy.We have obtained the compound of a series of new salicyclic acid derivatives class with chemical synthesis process.Our Biological Activity Identifications find that such compound has apparent antagonistic effect to the various kinds of cell strain such as breast cancer, lung cancer, leukaemia, our antitumor mechanism research finds that such compound has significant inhibiting effect to STAT3 cellular signal transduction, it is shown that these compounds are of great significance in terms for the treatment of STAT3 signal transduction Exception Type cancer.
Description
Technical field
The invention belongs to biomedicine field, be related to a kind of novel salicylic acid compound preparation method and derivative, its
Solvate the answering in terms of oncotherapy of pharmaceutically acceptable salt, the solvate of the derivative or the salt
With.
Background technique
Malignant tumour is to threaten human health " number one killer ", and the disease incidence of global tumour is being presented swift and violent increase and is becoming
Gesture.The World Health Organization by 14,000,000 people in 2012, is passed year by year, it is expected that following 20 years global neopathy number of cases will increase by 70%
Increase to 19,000,000 people in 2025,24,000,000 people (Freddie Bray, et al.CA CANCER J CLIN 2018 in 2035；
0:1-31).Drug therapy has always having very important significance to treatment of cancer.From the point of view of medicament categories, the past 10 years whole world
The Medication structure in antitumor field has turned to targeted therapy from hormone: the seventies metal platinum class and antibiotics anticancer drug, make
Clinical chemotherapy technology has strided forward major step to radical-ability purpose；The nineties, plant extracts such as taxol, camptothecin are applied to
Clinic, so that the immune research with tumor suppressor gene of tumour cell is reached the decisive stage the stage；Until 21 century, really opens tumour
The epoch of targeted therapy.The big feature of the one of targeted drug is acted on for specific target spot generation, each not phase the case where each patient
Together, the targeted drug that can be selected also is had nothing in common with each other, and realizes the individualized treatment to tumour to a certain extent.From the demand of drug
From the point of view of trend, significant in efficacy, Small side effects are the major demands directions of future products development, under the driving of this market demand,
The research and development and clinical application of anti-tumor drugs targeting will be one of anti-tumor drug industry future the main direction of development (Lippman
S M, et al.Journal of Clinical Oncology, 2005,23 (2): 346-356).
Niclosamide is a kind of drug listed, is clinically mainly used for the treatment of helminth.It is reported according to lot of documents,
It was found that it is a kind of drug of potential treatment tumour, a large amount of correlative study is carried out around it both at home and abroad, phase is carried out to it
Closing the compound part that structure of modification obtains has good anti-tumor biological.(Li Y, et according to the literature
Al.Cancer Letters, 2014,349 (1): 8-14), possible signal path mode has: Wnt/ β-catenin,
mTORC1,STAT3,NF-κB, Notch.These a large amount of researchs, which are reported as us, develops this kind of drug and provides number abundant
According to also developing target medicine for us and provide reference.
The main structure of niclosamide is the structure of vicinal hydroxyl groups benzanilide, and according to its design feature, we are to phenyl ring
On substituent group carry out structure of modification, obtained multiple compounds, according to the activity of these compounds, obtained relevant structure effect and close
System.We attempt to carry out some variations in hydroxy position, obtain part of compounds by chemical synthesis process.These have good
Anti-tumor biological, and huge activity difference is shown to different tumour cells, there is certain targeting.
STAT3-JAK signal transduction pathway plays the role of positive regulation to the growth of tumour cell, and STAT3 albumen is used as and controls
The biology target spot last decade of cancer is treated by favor, ends 2017, U.S. FDA ratifies the STAT3 signal in clinical trial
Conduction path inhibits kind anti-cancer drugs object to have more than 30 (Johnson D E, et al.Nature Reviews Clinical
Oncology, 2018,15 (4): 234.).The features such as STAT3 inhibitor class anticancer targeting medicine has target spot new and anticancer spectrum width,
Recent clinical test results show that such drug has huge potentiality to be exploited and wide in terms of future tumors clinical treatment
The wealthy market space.It is found by the applicant that vicinal hydroxyl groups benzophenone amine compounds belong to STAT3 inhibitor, such compound suppression
The mechanism of STAT3 processed activation is clear, antagonism growth of tumour cell significant effect.This series of compounds is sharp up to medicine by Henan Province
Science and Technology Ltd.'s research and development.
Summary of the invention
The invention mainly solves the technical problem of providing the preparation method of a kind of novel salicyclic acid derivatives and its
Application in terms of oncotherapy.
For achieving the above object, the present invention provides the preparation methods of the compound of general formula.
Formulas I
Wherein,
R1 is selected from hydrogen, halogen, hydroxyl, aldehyde radical, cyano, nitro, aromatic radical, C1-6 alkyl, C1-6 alkoxy；
R2 is selected from 1- piperidyl, 1- pyrrole radicals, 4- morpholine base；
N takes Arabic numerals 1-10.
Term used in the present invention " alkyl " refers to the linear chain or branched chain monovalent hydrocarbon of saturation, has 1-6 carbon atom
(i.e. C1-6 alkyl), 1-4 carbon atom (i.e. C1-4 alkyl) or 1-3 carbon atom (i.e. C1-3 alkyl).The example of " alkyl " includes
But it is not limited to methyl, ethyl, positive third class, isopropyl, normal-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, 2- methylpent
Base, 2,2- dimethylbutyl, 3,3- dimethylbutyl etc..
Term used herein " halogen " refers to that fluorine, chlorine, bromine or iodine, preferred halogen group are fluorine, chlorine or bromine.
The preparation method of above compound of the present invention, includes the following steps:
The preparation method of compound: compound A reacts to obtain intermediate C through Misunobu with B.Intermediate C passes through hydrogen-oxygen
Acidification obtains compound D after changing lithium hydrolysis.Compound D handles to obtain acyl chlorides E by thionyl chloride.Intermediate E reacts to obtain with F
Target compound G.
Wherein, R1, R2, n are as previously described.
Biological significance of the invention is to have found with strong STAT3 cellular signal transduction inhibiting effect and have more less toxic
The noval chemical compound of property, the growth of such compound on tumor cell have significant antagonistic effect, have in terms of cancer clinical treatment
Wide development space.
The invention further relates to the conjunctions of the solvent of above-mentioned salicyclic acid derivatives, its pharmaceutically acceptable salt, the derivative
The solvate of object or the salt is in preparation for treating or assisting in the treatment of and/or preventing the lung cancer of mammal, breast cancer
And the purposes in the drug of leukaemia.Specifically, the mammal is the mankind.
The invention further relates to the conjunctions of the solvent of above-mentioned salicyclic acid derivatives, its pharmaceutically acceptable salt, the derivative
The solvate of object or the salt is in preparation for treating or assisting in the treatment of and/or preventing what mammal was mediated by STAT3
Tumour or the tumor cell proliferation by STAT3 driving and the purposes in migration drug.Specifically, the mammal is the mankind.
One aspect of the invention is related to above-mentioned salicyclic acid derivatives, its pharmaceutically acceptable salt, the derivative
The preparation of the solvate of solvate or the salt passes in mammal with STAT3 cell signal for treating and/or preventing
Lead the purposes in related disease drug.Specifically, the mammal is the mankind.
The invention will be further described below.
All documents recited in the present invention, their full content are incorporated by reference into the present invention, and if these
Meaning expressed by document and when the inconsistent present invention, is subject to statement of the invention.In addition, the various terms that the present invention uses
With phrase have well known to a person skilled in the art general senses, nonetheless, the present invention is remained desirable at this to these terms
It is described in more detail and explains with phrase, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute of the present invention
Subject to the meaning of statement.
In the method for present invention synthesis compound, the various raw material for reacting used are those skilled in the art according to
There is knowledge that can be prepared, or can be made from the method as well known to document, or business can be passed through and purchased
?.Intermediate used in the above reaction scheme, raw material, reagent, reaction condition etc. can be according to those skilled in the art
Member existing knowledge, which can be made, suitably to be changed.
Detailed description of the invention
Fig. 1 is general formula I attached drawing.
Fig. 2 is compound 4-chloro -2- in embodiment 1 (4- nitroaniline formoxyl)-phenol -4- [2- (1- piperidyl) second
Oxygroup] benzoyl ester and the virtual molecular docking of STAT3 Protein S H2 functional domain experimental result, which is presented on STAT3 egg
On white SH2 functional domain activated interface, nonpolar hydrogen atom (H) is unmarked, on the section STAT3 Protein S H2, with the chemical combination
The key amino acid of object interaction of molecules has: lysine 591 and arginine 609, arginine 595 and serine 611,613,
636 and glutamic acid 612,638 respectively with LYS591, ARG609, ARG595, SER611, GLU612, SER613, SER636 and
GLU638 label；The β-pleated sheet in the section STAT3 Protein S H2, α spiral and random coil are respectively with delaying straight band, hurricane band and tubule
It indicates.It is virtually docking the results show that the phosphorylation site of the compound and STAT3 Protein S H2 functional domain crucial ammonia
Base acid ARG609, LYS591 and ARG595 have highly polar interaction, infer that the compound is to act on STAT3 phosphoric acid
Change the STAT3 signal transduction inhibitor of action site.
Fig. 3 is compound 4-chloro -2- in embodiment 4 (4- nitroaniline formoxyl)-phenol -4- [2- (1- piperidyl) second
Oxygroup] benzoyl ester protein immunoblot result.The result of protein immunoblot experiment is total with the cell after being separated by electrophoresis
Protein is transferred on solid support film from gel, according to the special principle of antigen-antibody, respectively by STAT3, p-STAT3,
The corresponding expressing quantity of β-Actin antibody test.As a result as schemed, it can be seen that under drug effect, increase with drug concentration,
It is constant that MCF-7 expresses STAT3, β-Actin protein content, and p-STAT3 expression quantity is on a declining curve, which obviously inhibits p-
The expression of STAT3.
Specific embodiment
Embodiment 1: compound synthesis experiment
Compound synthesis method is with compound 4-chloro -2- (4- nitroaniline formoxyl)-phenol -4- [2- (1- piperidyl)
Ethyoxyl] for benzoyl ester:
The preparation of the chloro- 2- of 4- (4- nitroaniline formoxyl)-phenol -4- [2- (1- piperidyl) ethyoxyl] benzoyl ester:
N- hydroxyethyl piperidine 1.3g, 4-HBA methyl esters 1.67g, is added in 100mL round-bottomed flask, adds
The dissolution of 30mL tetrahydrofuran.Triphenylphosphine 3.9g is added into reaction system again, in the lower stirring 10min of 0 DEG C of degree.Then slowly
Diisopropyl azodiformate 3.0g is added dropwise into reaction system.It is added dropwise, reaction is stayed overnight at room temperature.End of reaction subtracts
Pressure removal solvent, is added the hydrochloric acid solution 150mL of 2mol/L, stirs 10min.Ethyl acetate 100mL liquid separation, resulting water is added
PH to 9 or so is mutually adjusted, water phase is extracted with ethyl acetate (80mL*2), merges organic phase, and saturated salt solution washed once, anhydrous sulphur
Sour sodium is dry, is concentrated to give product 2.1g.
By above-mentioned resulting product 0.65g, ethyl alcohol 10mL, water 10mL dissolution is added.Hydroxide is added into reaction system
Lithium 0.25g, reaction is overnight.Ethyl alcohol is removed under reduced pressure in end of reaction, and water supplement 10mL, hydrochloric acid tune pH to 4 continue to stir 30min,
Carboxylic acid is obtained by filtration, is directly used in after dry in next step.
Resulting carboxylic acid 0.5g is taken, thionyl chloride 10mL is added, 6h is reacted at 80 DEG C, end of reaction is removed under reduced pressure molten
Agent is directly used in next step.
Acyl chlorides 0.53g is taken, the dissolution of 20mL methylene chloride is added, adds 5- chlorine-2-hydroxyl-N- (4- nitro)-benzoyl
Aniline 0.55g, triethylamine 0.5mL, reacts 4h at room temperature.Solvent is removed under reduced pressure in end of reaction, and ethyl acetate, saturation is added
Saline solution liquid separation crosses column (DCM/MeOH=15/1) after organic phase concentration, obtains target product 0.35g.1H-NMR(6d-
DMSO): δ 11.11 (s, 1H), 8.22-8.19 (d, 2H), 8.03-8.00 (d, 2H), 7.97-7.94 (d, 1H), 7.89-7.86
(m, 3H), 7.52-7.49 (d, 1H), 7.11-7.08 (d, 2H), 4.26-4.22 (t, 2H), 2.92 (s, 2H), 2.67 (s,
4H), 1.57-1.55 (d, 4H), 1.43-1.42 (d, 2H).
1 compound relevant information of table
Embodiment 2: molecular docking (docking) experiment
Method: for the interaction mechanism of compound and STAT3 albumen in verification expression 1, the inventor area STAT3 SH2
Protein template of the phosphorylation tyrosine bond area (pY-705) as computer virtual simulation (docking), it is virtual right
It connects region and is concentrated mainly on phosphorylated tyrosine action site ARG609 and LYS591 near zone.The structure of STAT3 SH2 is sat
Mark is taken at Protein structure databases (PDB data bank, ID:1BG1).The method of molecular docking (docking): all
The experiment of computer coordination simulation (docking) is completed on the operating platform of sybyl X2.1.1, and computer used is matched
The tool of position simulation (docking) is SUEFLEX DOCK.It (mainly include that phosphorylated tyrosine acts on position according to selected site
Point ARG609, LYS591 and ARG595) it is calculated, it determines potential energy level (potential gradient) and matches as computer
The experiment of position simulation (docking).It is analyzed according to the score (Score) and conformation of simulation (docking) and interaction.
Embodiment 3: the MTT experiment of induced breast cancer, lung cancer and leukaemia cancer cell apoptosis
Material: 96 porocyte culture plates, MDA-MB-231, MCF-7, PC9, PC9-AR, PC9-GR, MOLT-13,
Jurkat cell strain, Methyl thiazoly tetrazolium assay (MTT), fetal calf serum.
Method: cell is according to conventional culture methods culture.When test, logarithmic growth phase breast carcinoma cell strain MDA- is collected
MB-231 and MCF-7, colon cancer cell line HCT-116 and HT-29, lung cancer cell line PC9, PC9-AR, PC9-GR and
HCC827, leukemia cell line Jurkat and MOLT-13 are counted, and adjustment concentration of cell suspension is 40000/mL, and every hole is added
200 μ L cell suspensions, that is, 8000, every hole cell；Cell strain adds compound to handle, final concentration is respectively 0.01,0.03,0.1,
0.3,1,3,10,30,100 μM of nine gradient, and blank control is set, continue to cultivate 48h；After drug-treated, thiazole is added in every hole
Blue 20 μ L (5mg/mL) of reagent, 37 DEG C of incubation 4h；Liquid in hole is discarded after incubation, drain well is exhausted with filter paper and remained
Then liquid is added 100ul dimethyl sulfoxide, reacts 7-8min on horizontal oscillator, until bluish violet crystallization is completely dissolved；Use enzyme
Instrument measurement is marked in the OD value that absorbing wavelength is 570nm, records result.
Inhibiting rate (%)=(control wells mean OD value-experimental port mean OD value)/control wells mean OD value × 100%
Data are counted by GrapHPad Prism 7, calculate IC50 value.
2 compound effects of table are in the IC50 value of tumour cell
Note: numerical value is laboratory mean values three times in table；Numerical value after " ± " represents standard deviation
Embodiment 4: the shadow that protein immunoblot (Westernblot) experiment detection compound expresses cell p-STAT3
It rings
Material: 6 porocyte culture plates, MCF-7 cell strain, fetal calf serum, RIPA cell pyrolysis liquid, Protein Assay Reagent
Box, Kynoar (PVDF) film, STAT3/p-STAT3/ β-Actin primary antibody, STAT3/p-STAT3/ β-Actin secondary antibody.
Method:
1, cell culture and dosing
(1) logarithmic growth phase MDA-MB-231 cell, after being digested with pancreatin, with the RPMI- for containing 10% fetal calf serum
The single cell suspension that density is 300000/mL is made in 1640 culture mediums, and it is thin to 6 holes that 2mL cell suspension inoculation is added with every hole
In born of the same parents' culture plate.
(2) 37 DEG C, 5%CO2Incubator is incubated for, and after cell is adherent, it is respectively 1,3,10 and that final compound concentration, which is added,
30 μM, and set blank control group.After 1h in addition to blank control group, it is 1mg/mL interleukin-6 (IL-6) that concentration, which is added, in each group
30 μ L stimulate cell, interleukin 6 (IL-6) final concentration of 30ng/mL.
2, cell cracking, protein extraction and determining the protein quantity
(1) upper layer culture medium is removed, is washed twice in six porocyte culture plates with phosphate buffer (PBS).Pre-cooling is added
RIPA cell pyrolysis liquid (protease inhibitors, inhibitors of phosphatases and phenylmethylsulfonyl fluoride and lysate are with 1:100's
Mixing is added in ratio in advance) 100 μ L.Cell pyrolysis liquid is scraped off with cell scraping clean in advance, is collected into one completely
1.5mL centrifuge tube in.
(2) it places on ice, cracks 30min, be vortexed every 6min primary.
(3) 4 DEG C, 12000rpm, it is centrifuged 12min.
(4) after being centrifuged, cell conditioned medium is collected, is divided into two parts: 5 μ L being taken to be added in the centrifuge tube of 1.5mL, be used for BCA
Protein content is surveyed, 1 × phosphate buffer (PBS) mixing for adding 45 μ L is spare；Remaining 60 μ L of cell conditioned medium quantitative,
5 × SDS sample-loading buffer (Loading Buffer) 15 μ L is added, boils 8min after mixing in boiling water, -20 DEG C of ice after centrifugation
It is saved in case.
(5) determination of protein concentration, specific steps:
A, with 1 × phosphate buffer (PBS) diluted protein standard items, table handling is pressed:
B, BCA working solution is prepared: according to the number of standard items and sample to be tested, A needed for calculating in total and B hybrid working
The amount of liquid.In the ratio of BCA reagent A and B volume ratio 50:1, working solution is prepared, vortex oscillation mixes spare.
C, it by protein standard liquid and the sample supernatant diluted with phosphate buffer (PBS) (10 times of dilutions), respectively takes
25 μ L are added in 96 new orifice plates.Then it is separately added into the BCA working solution that 200 μ L are prepared in advance again, mixes well.Make sure to keep in mind
Generation bubble is not blown and beaten, 96 orifice plate plate lids is covered tightly, reacts 30min in 37 DEG C of insulating boxs.
D, 96 orifice plates are taken out to restore to room temperature, 3-5min, the absorbance value under 562nm wavelength is measured in microplate reader, is made
Out standard curve and 1 μ L/Protein content of each sample is calculated in case albumen loading.
3, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
(1) fixed plastic plate, prepares 12% SDS-PAGE separation gel.
Separation gel: 10mL is prepared according to following table
(2) mixed separation gel is added separately in 2 blocks of offset plates, is added to the position from top 1.0cm, uses dehydrated alcohol
Offset plate is filled up, 30-45min is stood.
(3) after separation gelling is good, remaining dehydrated alcohol is poured out, and blotted remaining dehydrated alcohol only with filter paper.
(4) 5% concentration glue: 5mL is prepared according to following table
(5) prepared concentration glue is slowly added into offset plate, avoids generating bubble, be inserted into sample comb, stands 30-
45min。
(6) protein sample is taken out, 100 DEG C of heating water bath 5min, revolving speed 10000rpm are centrifuged 10min.
(7) offset plate is fixed in electrophoresis tank, SDS-PAGE electrophoretic buffer is added, extract sample comb, in sequence will
The protein sample handled well is added in sample cell.
(8) 80V electrophoresis 40min.
(9) voltage 120V electrophoresis about 1.5h is changed, until bromophenol blue runs out of colloid.
4, transferring film
(1) the SDS-PAGE glue that electrophoresis finishes is put into TBST buffer and is rinsed once, protein adhesive is put into transferring film buffering
It is impregnated in liquid.
(2) one layer of foam-rubber cushion is soaked in film transfer buffer, is clipped on transferring film instrument with tweezers, according to foam-rubber cushion, three
Layer filter paper, protein adhesive, Kynoar (PVDF) film, three layers of filter paper, foam-rubber cushion are sequentially put well, are aligned, are picked up and be put into transferring film instrument
On, when operation, filter paper, foam-rubber cushion are intended to soak in transferring film buffer.If having bubble application teat glass between every layer gently
Rolling is driven out of.
(3) transferring film instrument, 300mA transferring film 75min are opened.
(4) it takes the film out, is put into TBST buffer, the horizontal concussion instrument of 60rpm rinses 3 times, each 8min.
(5) 2h is closed with the horizontal concussion instrument room temperature of 5% bovine serum albumin(BSA) (BSA) confining liquid 20mL, 60rpm.
(6) with the 3mL antibody incubation liquid added with 3 μ L primary antibodies (STAT3 and p-STAT3 1: 1000), 4 DEG C of 60rpm level shakes
Instrument is swung to be incubated overnight.
(7) 10mL TBST is used, the horizontal concussion instrument of room temperature 60rpm washs pvdf film three times, each 10min.
(8) with the 20mL antibody incubation liquid added with 2 μ L secondary antibodies, the horizontal concussion instrument incubation pvdf membrane 2h of room temperature 60rpm.
(9) 10mL TBST is used, the horizontal concussion instrument of room temperature 60rpm washs pvdf membrane three times, each 10min.
(10) chemiluminescent substrate reagent solution A and solution B each 1mL, color development at room temperature 5min are taken.
(11) liquid on film is blotted with filter paper, is developed.
Claims (8)
1. the compound of general formula is as a kind of novel compounds, the solvent of pharmaceutically acceptable salt, affiliated derivative
The solvate of compound or the salt.
Formulas I
Wherein,
R1 is selected from hydrogen, halogen, hydroxyl, aldehyde radical, cyano, nitro, aromatic radical, C1-6 alkyl, C1-6 alkoxy；
R2 is selected from 1- piperidyl, 1- pyrrole radicals, 4- morpholine base.
2. the method for preparing any chemical combination in claim 1, characterized by the following steps:
The preparation method of compound: compound A reacts to obtain intermediate C through Misunobu with B.Intermediate C passes through lithium hydroxide
Acidification obtains compound D after hydrolysis.Compound D handles to obtain acyl chlorides E by thionyl chloride.Intermediate E reacts to obtain target with F
Compound G.
3. such compound and its pharmaceutically acceptable salt, the solvate of affiliated derivative or institute in claim 1
State application of the solvate of salt in preparation tumor therapeutic agent.
4. application according to claim 3, wherein the cancer includes breast cancer.
5. application according to claim 3, wherein the cancer includes lung cancer.
6. application according to claim 3, wherein the cancer includes leukaemia.
7. application according to claim 3 increases including the tumour mediated by STAT3 or by the tumour cell of STAT3 driving
Grow and migrate the purposes in drug.
8. application according to claim 3, including by the purposes in STAT3 cellular signal transduction related disease drug.
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| US20090239919A1 (en) * | 2008-03-08 | 2009-09-24 | Richard Delarey Wood | Glutamate receptor modulators and therapeutic agents |
| CN104710323A (en) * | 2013-12-11 | 2015-06-17 | 中国疾病预防控制中心寄生虫病预防控制所 | Salicylamide ester compound with molluscidal activity, and preparation method and use thereof |
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