CN108707147A - A kind of novel tubulin inhibitor and its application in antitumor drug - Google Patents
A kind of novel tubulin inhibitor and its application in antitumor drug Download PDFInfo
- Publication number
- CN108707147A CN108707147A CN201810632871.3A CN201810632871A CN108707147A CN 108707147 A CN108707147 A CN 108707147A CN 201810632871 A CN201810632871 A CN 201810632871A CN 108707147 A CN108707147 A CN 108707147A
- Authority
- CN
- China
- Prior art keywords
- compound
- tubulin
- niacin
- yls
- pyrazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of compound, structural formula is, wherein R1、R2It is independently selected from H, OH or F.Find that there is good tubulin inhibitory activity by the test of tubulin polymerization assays kit, it can be obtained by Bel-7402 transplanted human hepatocellular carcinomas Experimental model of small mice, the compounds of this invention has anti-tumor drug activity, can be used for antitumor drug and carries out more deep research and development.
Description
Technical field
The invention belongs to drug design and synthesis fields, are related to a kind of novel tubulin inhibitor and its in antineoplastic
Application in object.
Technical background
Cancer cell is maximum frequent and uncontrolled difference lies in the Mitotic abnomality of cancer cell with normal cell.Cancer
Dynamic circulation (polymerize and depolymerization) between the schizogamy process of cell Showed Very Brisk and tubulin/micro-pipe in the cell cycle
There is close contact.Therefore, by tubulin polymerization during inhibiting tumour cell division at micro-pipe, or inhibit micro-pipe
Depolymerization is tubulin, will cause mitosis that can not carry out or stagnate, and the interruption of cell mitogen process will be to swollen
Oncocyte generates the influence of bigger, and growth is made to be suppressed and induce the apoptosis of tumour cell, what final inducing cell tune was died
Occur, to achieve the purpose that inhibit tumour cell increment growth.
Having now been found that a large amount of natural, synthesis and semi-synthetic compound have influences microtubule system, interferes it normal
The effect of function because of most of its energy and tubulin binding, therefore is referred to as Antitubulin.These tubulins inhibit
Agent has had a wide range of applications in terms of medicine, such as antitumor, antimycotic, expelling parasite, and tubulin has become research and opens
The important target spot of new type antineoplastic medicine is sent out, Antitubulin, which also has become, clinically uses effective important antineoplastic
Object.The mechanism of action of such inhibitor is, by being acted on micro-pipe, to inhibit tubulin poly- in the tumour cell quickly divided
Conjunction prevents spindle from being formed, or promotes tubulin polymerization, and spindle is prevented to be interfered thin from reverting to micro-pipe net again
The positive eumitosis process of born of the same parents makes cell mitogen process interrupt, and is stagnated in the phase, is adjusted so as to cause tumour cell
It dies, plays antitumor action.
Colchicin is a kind of Tropolones biology extracted from the seed and its bulb of liliaceous plant colchicum
Alkali.Colchicin can be incorporated into the colchicin site on tubulin, and α tubulins is made to deform with beta tubulin,
Make tubulin be assembled into micro-pipe this process to be blocked, to make the formation of spindle be obstructed, makes Mitosis arrest
And causes cell to generate tune and die.Colchicin may also interfere with the protein metabolism process of tumour cell, inhibit the work of RNA polymerases
Power, and the transport process of the synthesis and amino acid of cell membrane lipoids on cell membrane is blocked, to induce a variety of entity tumors
Natural death of cerebral cells.Experiment finds that colchicin is significant in efficacy to breast cancer, leukaemia, cutaneum carcinoma, to cervix cancer, the cancer of the esophagus, lung
Cancer also has certain curative effect.Research recently finds that colchicin has apparent inhibition and induction to adjust growth of glioma cells in vitro
The effect of dying.Clinically colchicin is usually used in treating acute gout, arthralgia, familial Mediterranean fever, hepatic sclerosis etc., but because
Toxicity is too big and less for treating tumour.
Invention content
One of the objects of the present invention is to provide a kind of compound, structural formula I is as follows：
Wherein, R1、R2It is independently selected from H, OH or F.
Further, Formula I is selected from
Further, above compound or its pharmaceutically acceptable salt as Antitubulin answering in drug
With.
Further, the purposes of above-mentioned compound or its pharmaceutically acceptable salt in the preparation of antitumor drugs.
Another object of the present invention is to provide a kind of synthetic routes of the compound to be：
Further, specific synthesis step is：
1) 6- (1H- pyrazol-1-yls) niacin (compound 1) undergoes coupling reaction to produce 6- (1H- pyrroles with cyclopropylmethyl bromide
Azoles -1- bases) niacin (Cvclopropvlmethvl) ester (compound 2)；
2) with nitrating agent nitration reaction occurs for compound 2, generates 2- nitros -6- (1H- pyrazol-1-yls) niacin (ring third
Ylmethyl) ester (compound 3)；
3) compound 3 issues raw reduction reaction in suitable reducing condition, generates 2- amino -6- (1H- pyrazol-1-yls) cigarette
Sour (Cvclopropvlmethvl) ester (compound 4)；
4) compound 4 generates corresponding amides product with corresponding acyl chloride reaction.
Further, the nitrating agent in the step 2) has a concentrated nitric acid, fuming nitric aicd, the mixed acid of nitric acid and sulfuric acid with
And dinitrogen pentoxide etc., the preferred mixed acid of nitric acid and sulfuric acid.
Further, the nitro restoring method in the step 3) has ferrous acid reduction method, catalytic hydrogen reduction and hydration
Hydrazine reduction method, preferably ferrous acid reduction method.
Obviously, the above according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Specific implementation mode
Embodiment 1：The conjunction of 2- (isoxazole -5- formamido groups) -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester
At
1, the synthesis of 6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester
6- (1H- pyrazol-1-yls) niacin (compound 1) (4.86g, 25.7mmol) is dissolved in anhydrous DMF (100mL),
Under argon atmosphere, potassium carbonate (10.66g, 77.1mmol) and cyclopropylmethyl bromide (77.1mmol) are added to above-mentioned solution
In, it then stirs mixture 15 hours and is transferred in distilled water (150mL), mixture is extracted three times with diethyl ether (100mL).
Combined extract is washed, magnesium sulfate drying with distilled water (100mL), and be concentrated under vacuum using rotary evaporator, obtained
To crude product 6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester (compound 2), crude Compound 2 is recrystallized in hexane
Purifying, obtains pure compound 2, white solid, 5.25g, yield 84%.1H-NMR(400MHz,CDCl3)δ:1.30(m,4H),
1.76(m,1H),3.98(d,2H),6.64(dd,1H),7.78(d,1H),7.87(d,1H),8.06(d,1H),8.22(dd,
1H),8.86(d,1H).13C-NMR(125MHz,CDCl3)δ:3.52,10.2,69.27,108.16,111.98,122.92,
126.73,136.48,138.69,151.37,155.93,164.76.LC-MS(ESI,pos,ion)m/z:244[M+H].
2, the synthesis of 2- nitros -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester
Compound 2 (5.25g, 21.59mmol) is dissolved in chloroform (100mL), under condition of ice bath (10 DEG C or so), by
It is added dropwise to the mixed acid solution that 65% concentrated nitric acid (2.5mL, 32.03mmol) and 98% concentrated sulfuric acid (2.5mL, 38.90mmol) are made into.
It after being added dropwise, is stirred to react at 10 DEG C about 4 hours, TLC monitors reaction end.After completion of the reaction, reaction solution is concentrated under reduced pressure
It to doing, is gradually poured into ice water, it is neutral to be adjusted to pH with sodium carbonate, filters, obtains light yellow product 2- nitros -6- (1H- pyrroles
Azoles -1- bases) niacin (Cvclopropvlmethvl) ester (compound 3), 5.41g, yield 87%.1H-NMR(400MHz,CDCl3)δ:1.29
(m,4H),1.74(m,1H),4.02(d,2H),6.69(dd,1H),7.77(d,1H),7.86(d,1H),8.17(d,1H),
8.37(d,1H).13C-NMR(125MHz,CDCl3)δ:3.37,10.22,68.97,108.96,115.38,119.57127.52,
142.94,151.86,153.45,162.03.LC-MS(ESI,pos,ion)m/z:289[M+H].
3, the synthesis of 2- amino -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester
Compound 3 (5.41g, 18.78mmol) and ammonium chloride (0.55g, 10.30mmol) are added to 95% second successively
In alcohol (150mL), glacial acetic acid (0.5mL, 2.06mmol) is added, is warming up to 80 DEG C, reaction after ten minutes, is gradually added into also in batches
Former iron powder (9.23g, 164.8mmol), reacts after about 3 hours and finishes, and TLC monitors reaction end.It is filtered while hot to remove dereaction
Iron cement in liquid.Iron cement filter cake is boiled 1 hour under reflux conditions with 95% ethyl alcohol, then is filtered while hot.3 times repeatedly, merge filter
Liquid is concentrated to dryness, and 45 DEG C of vacuum obtains gray solid 2- amino -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester and (changes
Close object 4), 4.37g, yield 90%.1H-NMR(400MHz,CDCl3)δ:1.33(m,4H),1.76(m,1H),3.98(m,2H),
6.58(q,1H),7.09(d,1H),7.46(d,1H),7.67(m,2H),7.77(d,1H),8.15(d,1H).13C-NMR
(125MHz,CDCl3)δ:3.46,10.2,68.74,99.58,108.11,108.95,126.67,143.19,143.66,
155.03,158.97,166.38.LC-MS(ESI,pos,ion)m/z:259[M+H].
4, the synthesis of 2- (isoxazole -5- formamido groups) -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester
Compound 4 (4.37g, 16.90mmol) is added in absolute ethyl alcohol (150mL), isoxazole-is then gradually added into
5- formyl chlorides (28.36mmol), stirring are warming up to reaction reflux.It reacts and finishes after about 6 hours, TLC monitors reaction end.It will be anti-
It after answering liquid to stand cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtains white solid product 2- (isoxazole -5- formyls
Amino) -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester, 5.25g, yield 88%.1H-NMR(400MHz,CDCl3)δ:
1.35(m,4H),1.76(m,1H),4.01(d,2H),6.65(dd,1H),7.15(d,1H),7.80(m,2H),7.93(d,
1H),8.13(d,1H),8.39(d,1H).13C-NMR(125MHz,CDCl3)δ:3.35,3.37,9.10,69.57,101.46,
108.96,109.78,110.13,126.80,140.73,143.50,146.00,153.71,156.25,160.84,164.24,
167.09.LC-MS(ESI,pos,ion)m/z:354[M+H]。
Embodiment 2：2- (4- hydroxyls-isoxazole -5- formamido groups) -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl)
The synthesis of ester
Compound 4 (4.37g, 16.90mmol) is added in absolute ethyl alcohol (150mL), 4- hydroxyls-are then gradually added into
Isoxazole -5- formyl chlorides (28.36mmol), stirring are warming up to reaction reflux.It reacts and finishes after about 6 hours, TLC monitorings reaction is eventually
Point.It after reaction solution is stood cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtains white solid product 2- (4- hydroxyls
Base-isoxazole -5- formamido groups) -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester, 5.43g, yield 87%.LC-MS
(ESI,pos,ion)m/z:370[M+H]。
Embodiment 3：2- (the fluoro- isoxazole -5- formamido groups of 3-) -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester
Synthesis
Compound 4 (4.37g, 16.90mmol) is added in absolute ethyl alcohol (150mL), it is fluoro- different to be then gradually added into 3-
Oxazole -5- formyl chlorides (28.36mmol), stirring are warming up to reaction reflux.It reacts and finishes after about 6 hours, TLC monitorings reaction is eventually
Point.It after reaction solution is stood cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtaining white solid product 2-, (3- is fluoro-
Isoxazole -5- formamido groups) -6- (1H- pyrazol-1-yls) niacin (Cvclopropvlmethvl) ester, 5.65g, yield 90%.LC-MS
(ESI,pos,ion)m/z:372[M+H]。
Test example 1：Tubulin inhibitory activity
With reference to the Tubulin Polymerization Assay Kit (tubulin polymerizations point of Cyroskeleton companies
Analyse kit) specification, it is operated and is measured.With 80mM PIPES pH 6.9,0.5mM EGTA, 2mM MgCl2, 1mM
The glycerol of Mg GTP and 10% at 3mg/ml cow brain tissue tubulin solution.The tubulin solution 100 μ L are taken, it is fast
Speed is added in 96 orifice plates containing various concentration untested compound and colchicin (colchicine), and control wells are added identical
The DMSO (s < of final concentration;0.5%).37 DEG C are set, 5%CO2Lower incubation, initiated polymerization.With multi-function microplate reader measure its
Wavelength is the absorption value of 355nm, primary per 3min readings, 45min is surveyed altogether, with prism Software on Drawing tubulin polymerization power
Curve is learned, and acquires IC50(when a concentration of its original concentration half of tubulin, the concentration for the compound being added).
IC of 1 compound of table to tubulin50
| Compound | IC50(nM) |
| colchicine | 1782 |
| COLO-301 | 44 |
| COLO-302 | 38 |
| COLO-303 | 43 |
| COLO-304 | 47 |
| COLO-305 | 47 |
| COLO-306 | 38 |
| COLO-307 | 49 |
It can be obtained by upper table, listed compound tubulin inhibitory activity IC in table50Value is respectively less than
It is lower to illustrate that compound listed in table reaches the concentration needed when tubulin half inhibits by colchicine.Confirm this
The prepared compound of invention has tubulin inhibitory activity, can carry out antitumor drug as Antitubulin
Exploitation.
Embodiment 2：Bel-7402 transplanted human hepatocellular carcinoma mouse models are studied
One, human liver cancer nude mouse xenotransplant cancer model is established
SPF grades of Balb/c nude mices, male, 4 week old, people's Bel-7402 liver cancer cells nude mice model tumor formations of learning from else's experience, then through naked
2 more than generation tumor mass of mouse passage, is cut into about 2*2*2mm, and it is subcutaneous to be inoculated in nude mice armpit using trochar, establishes human liver cancer nude mice
Heteroplastic transplantation cancer model.
Two, dosage regimen
With the length and width of each animal tumor of vernier caliper measurement, by formula：V=1/2*ab2Knurl product is calculated, waits for that knurl is accumulated
It grows to about 100mm3Start to be administered, all animals are randomly divided into model group, positive drug capecitabine group (400mg/ by knurl product
Kg), medicine group (100mg/kg) to be measured, every group 8, each group gastric infusion, dosage is l0ml/kg, 1 time/d, successive administration
14d。
Three, knurl weight and tumour inhibiting rate
Strip tumor mass within 16th day, assay balance claims knurl weight, calculates tumour inhibiting rate as follows.
Tumour inhibiting rate %=(model group average knurl weight-administration group average knurl weight)/model group average knurl weight * 100%.
Data analysis is carried out to testing result using 5 data processing softwares of GraphPadPrism.
Four, knurl weight and tumour inhibiting rate
The different group Bel-7402 transplanted human hepatocellular carcinoma mouse knurl weights of table 2 and tumour inhibiting rate
Note：* the P< compared with model group;0.05
As can be seen from the above table, compared with model group, the equal conspicuousness of other each group knurl weights reduces, the listed present inventionization in table
It closes object (100mg/kg) tumour inhibiting rate and is higher than capecitabine (400mg/kg), illustrate that the compounds of this invention dosage has in 100mg/kg
There is good tumors inhibition activity.It can be obtained by Bel-7402 transplanted human hepatocellular carcinomas Experimental model of small mice, the compounds of this invention tool
There is anti-tumor drug active, can be used for antitumor drug and carry out more deep research and development.
The above is only a preferred embodiment of the present invention, it is noted that come for those of ordinary skill in the art
It says, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should be regarded as
The content that the present invention is covered.
Claims (4)
1. a kind of compound, which is characterized in that its structural formula I is as follows：
Wherein, R1、R2It is independently selected from H, OH or F.
2. compound as described in claim 1, characterized in that be further selected from：
3. compound as described in claim 1 or its pharmaceutically acceptable salt are as Antitubulin in drug
Using.
4. the purposes of compound as described in claim 1 or its pharmaceutically acceptable salt in treatment is antitumor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810632871.3A CN108707147A (en) | 2018-06-20 | 2018-06-20 | A kind of novel tubulin inhibitor and its application in antitumor drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810632871.3A CN108707147A (en) | 2018-06-20 | 2018-06-20 | A kind of novel tubulin inhibitor and its application in antitumor drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108707147A true CN108707147A (en) | 2018-10-26 |
Family
ID=63872874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810632871.3A Withdrawn CN108707147A (en) | 2018-06-20 | 2018-06-20 | A kind of novel tubulin inhibitor and its application in antitumor drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108707147A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829697A (en) * | 2003-06-04 | 2006-09-06 | 安万特医药股份有限公司 | Aryl-heteroaromatic products, compositions containing same and use thereof |
| CN101142198A (en) * | 2005-02-17 | 2008-03-12 | 辛塔制药公司 | Isoxazole combretastatin derivatives for the treatment of proliferative disorders |
| WO2009003998A2 (en) * | 2007-07-02 | 2009-01-08 | Boehringer Ingelheim International Gmbh | Antiproliferative compounds based on 5-membered heterocycles |
| CN101981013A (en) * | 2008-03-27 | 2011-02-23 | 詹森药业有限公司 | Tetrahydrophenanthridinones and tetrahydrocyclopentaquinolinones as PARP and tubulin polymerization inhibitors |
| CN102227421A (en) * | 2008-09-29 | 2011-10-26 | 贝林格尔.英格海姆国际有限公司 | Anti-proliferation compounds |
| US20160311807A1 (en) * | 2013-12-13 | 2016-10-27 | Dana-Farber Cancer Institute, Inc. | Methods to treat lymphoplasmacytic lymphoma |
| CN106565686A (en) * | 2016-10-11 | 2017-04-19 | 深圳海王医药科技研究院有限公司 | Tubulin inhibitor |
-
2018
- 2018-06-20 CN CN201810632871.3A patent/CN108707147A/en not_active Withdrawn
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829697A (en) * | 2003-06-04 | 2006-09-06 | 安万特医药股份有限公司 | Aryl-heteroaromatic products, compositions containing same and use thereof |
| CN101142198A (en) * | 2005-02-17 | 2008-03-12 | 辛塔制药公司 | Isoxazole combretastatin derivatives for the treatment of proliferative disorders |
| WO2009003998A2 (en) * | 2007-07-02 | 2009-01-08 | Boehringer Ingelheim International Gmbh | Antiproliferative compounds based on 5-membered heterocycles |
| CN101981013A (en) * | 2008-03-27 | 2011-02-23 | 詹森药业有限公司 | Tetrahydrophenanthridinones and tetrahydrocyclopentaquinolinones as PARP and tubulin polymerization inhibitors |
| CN102227421A (en) * | 2008-09-29 | 2011-10-26 | 贝林格尔.英格海姆国际有限公司 | Anti-proliferation compounds |
| US20160311807A1 (en) * | 2013-12-13 | 2016-10-27 | Dana-Farber Cancer Institute, Inc. | Methods to treat lymphoplasmacytic lymphoma |
| CN106565686A (en) * | 2016-10-11 | 2017-04-19 | 深圳海王医药科技研究院有限公司 | Tubulin inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| 施赛健 等: ""抗肿瘤多药耐药微管蛋白调节剂的研究进展"", 《药学实践杂志》 * |
| 胡鸿雨 等: ""吲哚-2-乙醛酰胺类化合物的合成及生物活性研究进展"", 《合成化学》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20200131191A1 (en) | Atropisomerism for increased kinase inhibitor selectivity | |
| CN103030597B (en) | Kidney type glutaminase inhibitor as well as preparation method and application kidney type glutaminase inhibitor | |
| US20090275585A1 (en) | Novel Compounds and Therapeutic Use Thereof for Protein Kinase Inhibition | |
| CN102838590A (en) | Amino quinazoline derivative and application thereof in preparation of antineoplastic drugs | |
| CN104910140A (en) | Quinazoline compound, preparation method and application thereof | |
| CN109467549A (en) | Quinoline replaces chalcone compounds, preparation method and the usage | |
| CN107311905B (en) | A kind of nopinone thiosemicarbazone derivative and its preparation method and application | |
| CN104557871A (en) | Arylmorpholine compounds with spiro substituents as well as preparation method and use thereof | |
| CN108033950B (en) | EGFR tyrosine kinase inhibitor BF with anti-tumor activity3- AZD9291 and its preparation method and application | |
| CN104557913A (en) | Pyridopyrimidine compounds as well as preparation method and application thereof | |
| CN102838539A (en) | Quinolinylenamide derivative and its application in preparation of anti-malignant tumor drugs | |
| CN102746308B (en) | Allopurinol derivative and preparation method and application thereof | |
| KR100817808B1 (en) | Cancer treatment | |
| CN103936762B (en) | Morpholine quinolines, Preparation Method And The Use | |
| CN107903274A (en) | A kind of aminated compounds and its application in antitumor drug | |
| CN108707147A (en) | A kind of novel tubulin inhibitor and its application in antitumor drug | |
| CN108675997A (en) | A kind of novel tubulin inhibitor and its application in antitumor drug | |
| CN108658963A (en) | A kind of antitumor drug acting on tubulin | |
| CN108690004A (en) | A kind of antitumor drug acting on tubulin | |
| CN108675992A (en) | A kind of antitumor drug acting on tubulin | |
| KR20090082155A (en) | New diamine compounds or pharmaceutically acceptable salts thereof, process for the preparation thereof and pharmaceutical composition comprising the same for treatment of cancer | |
| CN108864053A (en) | A kind of novel tubulin inhibitor and its application in anti-tumor drug | |
| CN105646375A (en) | Epidermal growth factor receptor tyrosine kinase inhibitors NXGF and NXGH with antineoplastic activity and preparing method and application thereof | |
| CN108218855A (en) | A kind of novel tubulin inhibitor and its application in antitumor drug | |
| CN107513040A (en) | Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20181026 |
|
| WW01 | Invention patent application withdrawn after publication |