CN106349231A - Benzoquinazoline tyrosine kinase inhibitor containing halothiophene sulfonamide structure - Google Patents
Benzoquinazoline tyrosine kinase inhibitor containing halothiophene sulfonamide structure Download PDFInfo
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- CN106349231A CN106349231A CN201610659664.8A CN201610659664A CN106349231A CN 106349231 A CN106349231 A CN 106349231A CN 201610659664 A CN201610659664 A CN 201610659664A CN 106349231 A CN106349231 A CN 106349231A
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- compound
- tyrosine kinase
- kinase inhibitor
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- benzoquinazoline
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- 0 *c([s]1)ccc1S(N)(=O)=O Chemical compound *c([s]1)ccc1S(N)(=O)=O 0.000 description 2
- LLLHRNQLGUOJHP-UHFFFAOYSA-N COc(c(OC)cc1ncn2)cc1c2Cl Chemical compound COc(c(OC)cc1ncn2)cc1c2Cl LLLHRNQLGUOJHP-UHFFFAOYSA-N 0.000 description 1
- KUNZZSCNFCAUML-UHFFFAOYSA-N COc1cc2c(C(c(cc3)ccc3F)O)ncnc2cc1OC Chemical compound COc1cc2c(C(c(cc3)ccc3F)O)ncnc2cc1OC KUNZZSCNFCAUML-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N O=Cc(cc1)ccc1F Chemical compound O=Cc(cc1)ccc1F UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of tumor diseases, in particular to a novel benzoquinazoline tyrosine kinase inhibitor containing a halothiophene sulfonamide structure, a preparation method of the novel benzoquinazoline tyrosine kinase inhibitor and application of the novel benzoquinazoline tyrosine kinase inhibitor to preparation of drugs for treating the tumor diseases. The novel benzoquinazoline tyrosine kinase inhibitor is shown as the structural formula, wherein X is selected from a halogen substituent.
Description
Technical field
The present invention relates to the drug world of tumor.In particular it relates to have medicative to above-mentioned disease
One class contains the tyrosine kinase inhibitor of new Benzoquinazole analog derivative of halo thiophene sulfonamides structure, its preparation method
And purposes.
Background technology
Tumor is seriously to threaten one of human life and the principal disease of quality of life, and according to who statistics, the whole world is dead every year
Patient about 6,900,000 in tumor.Due to the change of living environment and life habit, in the work of poor environment and some unfavorable factors
With under, the M ＆ M of tumor is in rapid increase trend in recent years.
Protein kinase forms one of maximum family of people's fermentoid, and to be adjusted on protein by adding phosphate group
The many different signal transduction processes of section.Especially, tyrosine kinase phosphorylating protein is in the phenol moieties of tyrosine residue.Cheese
Histidine kinase family includes controlling the member of cell growth, migration and differentiation.Abnormal kinase activity has been directed to many mankind
Disease, including cancer, autoimmune disease and inflammatory diseasess.Because protein kinase belongs to the crucial regulation of cellular signal transduction
Agent, their offers adjust the target of cell function with small molecule kinase inhibitors, and therefore become good medicine and set
Meter target.Except the treatment of kinase mediated lysis, the selectivity of kinase activity and effective inhibitor can be additionally used in studying
Cell signaling processes and the other cell target with therapeutic potential of identification.
The conventional treatment to tumor by discovery tumor and destroys to realize, now with to cellular signal transduction way
What footpath was studied deepens continuously, and it is more and more deep that people understand to the oncogene of inside tumor cells and the effect of antioncogene,
Increasingly receive publicity for the new antitumor drug of the specific molecular shot design of tumor, become the hot fields of research,
And anti-tumor drugs targeting has also been applied to clinic as a kind of new Therapeutic Method, and obtain notable in recent years
Progress.It is well known that protein tyrosine kinase (protein tyrosinekinases, ptk) signal path and tumor cell
Propagation, differentiation, migration and apoptosis have substantial connection, using ptk inhibitor interference or block tyrosine kinase path can use
In oncotherapy.Ptk be normal with abnormality proliferation during becoming in the cancer protein that plays an important role and proto-protein family
Member, is a kind of a kind of enzyme of the tyrosine residue phosphorylation that can optionally make different substrates, and they are catalyzed the γ-phosphoric acid of atp
Group-transfer, on the tyrosine residue of many key proteins, makes phenolic hydroxyl group phosphorylation.Protein tyrosine kinase is divided into receptor cheese
Histidine kinase (receptor tyrosine kinase, rtk), nonreceptor tyrosine kinase and ir and janus kinases etc.
(robinson d.r., et al, oncogene, 2000,19,5548-5557), wherein most is receptor type tyrosine kinase
(rtk).Rtk is that a class has intrinsic protein tyrosine kinases, participates in the regulation and control of various kinds of cell activity, replicates in active cell
The conduction of mitogenesis signal in there is extremely important status, regulate and control growth and the differentiation of cell.All of rtk is
Belong to i type memebrane protein, its molecule has similar topological structure: a big glycosylated extracellular ligand binding domain, dredge for one
The single pass transmembrane area of water, and an intracellular tyrosine kinase catalyst structure domain and regulating and controlling sequence.The combination of part is (as epidermis
Somatomedin (egf) and the combination of egfr) lead to the kinase activation of the internal Coded of recipient cell to activate, make in target protein
Key tyrosine phosphorylation, lead to proliferation signals cross over cytoplasma membrane transduction.
In recent years, people are devoted to suppressing cellular signal transduction pathways to develop new target spot antitumor drug.Signal turns
Lead existence and the proliferation signal that inhibitor lowers tumor, promote apoptosis, rather than pass through cytotoxicity, therefore selectivity
Higher, toxic and side effects are less.Have ten several signal transduction inhibitors at present and be applied to clinical treatment tumour, predominantly tyrosine
What the compound of kinase inhibitor series antineoplastic medicament, wherein 4- (substituted anilinic) quinazoline structure type was developed relatively becomes
Ripe, such as the micromolecular inhibitor gefitinib (iressa) of egfr tyrosine kinase target spot, erlotinib (tarceva) and
Lapatinib (lapatinib) etc..
Gefitinib (gefitinib), trade name iressa (IRESSA), the egfr tyrosine of astrazeneca exploitation
Kinase inhibitor, is the epidermal growth factor recipient tyrosine kinase inhibitor entering clinical research earliest, in 2002 in day
This listing, next year lists in the U.S., for treating the late period previously receiving chemotherapy or Metastatic Nsclc
(nsclc).Erlotinib (erlotinib), trade name tarceva (Tarceva), the egfr tyrosine kinase of osi company exploitation
Inhibitor, is transferred from genentech and Roche Holding Ag.List in the U.S., for treating nsclc and cancer of pancreas within 2004.Belong to
The first generation treat nsclc aniline quinazoline type small molecular inhibitor, be also currently the only confirmed to Advanced Non-Small Cell
Pulmonary carcinoma has the egfr tyrosine kinase inhibitor of survival advantage, all effective to all kinds of Patients with Non-small-cell Lungs, and toleration
Good, no bone marrow depression and neurotoxicity, can significantly extend life cycle, improve patients ' life quality.
Small molecule tyrosine kinase inhibitors, as new anti-tumor drugs targeting, are that the treatment and prevention of tumor open
One fan new window, and its side effect is slight, has good toleration.Although having more than 10 small molecule tyrosine kinase at present
Inhibitor has made very big contribution for clinical cancer therapy, but still needs to find some than existing tyrosine-kinase enzyme level
Agent has the other compound of the pharmacological characteristics of more preferable activity in vivo and/or improvement.Therefore develop new improved or
More efficient tyrosine kinase inhibitor, gains more insight into the relation between such medicine and known target protein and its performance
The mechanism of antitumor action has great importance to clinical therapy of tumor.
The invention discloses a class contains the new Benzoquinazole class tyrosine-kinase enzyme level of halo thiophene sulfonamides structure
Agent, these compounds can be used for preparing the medicine of tumor.
Content of the invention
It is an object of the present invention to provide a kind of tyrosine kinase inhibitor with formula i.
It is a further object to provide the method that preparation has the compound of formula i.
It is also another object of the present invention to provide the compound containing formula i is as effective ingredient, and it is swollen in treatment
The application of tumor aspect.
In conjunction with the purpose of the present invention, present invention is specifically described.
The compound that the present invention has formula i has a following structural formula:
The compound preferably with formula i is as follows,
Formula i compound of the present invention can be synthesized by following route:
First with n-buli process, the aryl lithium intermediate obtaining and benzaldehyde iii react compound ii, obtain compound
iv；Compound iv and thiophene sulfonamide v reacting by heating in the presence of triphenylphosphine and diethylazodicarboxylate, obtain compound
i；X is defined as described above.
Formula i compound of the present invention has tyrosine kinase inhibitory activity, can be used for preparing swollen as effective ingredient
The medicine of tumor.The activity of formula i compound of the present invention is by vitro inhibition egfr and her2 kinases and to suppress thin
Born of the same parents proliferation experiment is verifying.
The formula i compound of the present invention is effective in comparatively wide dosage range.The dosage for example taken daily is about
In the range of 1mg-500mg/ people, it is divided into and being administered once or for several times.The actual dosage taking formula i compound of the present invention can be by curing
Take root for determining according to relevant situation.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.Those skilled in the art all should according to the various change that the teachings of the present invention is made
Within protection domain required by the application claim.
The synthesis of embodiment 1 compound i-1
The synthesis of step 1. compound iv
Compound ii (2.25g, 10mmol) is dissolved in the thf that 25ml is dried, and stirred under nitrogen atmosphere, with liquid nitrogen-ethanol
It is cooled to -78 DEG C, with the hexane solution (6.25ml) of the syringe slowly n-buli of Deca 1.6m, after completion of dropping, reaction
Mixture at such a temperature continue stir 1h, then again with syringe slowly Deca iii-1 (1.24g, 10mmol) be dissolved in 3ml do
The solution that dry thf makes.After completion of dropping, compound of reaction continues stirring 3 hours under being room temperature, and tlc display has been reacted
Become.Reactant mixture carefully pours in 200ml frozen water, and stirring, with 50ml × 3ch2cl2Extraction, merges extraction phase, uses saline
(100ml) wash, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, obtains compound
Iv, white solid, esi-ms, m/z=315 ([m+h]+).
The synthesis of step 2. compound i-1
Diethylazodicarboxylate (dead, 1.74g, 10mmol) is dissolved in the thf that 20ml is dried, stirring, and ice-water bath is cold
But under, slowly Deca triphenylphosphine (2.62g, 10mmol) is dissolved in the solution that the dry thf of 5ml makes, and then adds compound
V-1 (1.09g, 6mmol), mixture stirs 1 hour at such a temperature, adds compound iv (1.99g, 6mmol).Reaction mixing
Thing reacts overnight at room temperature, then flows back 12 hours again.Tlc display reaction completes.Reactant mixture carefully pours into 200ml
In frozen water, stirring, with 50ml × 3ch2cl2Extraction, merges extraction phase, is washed with saline (100ml), anhydrous sodium sulfate drying.Take out
Filter desiccant, filtrate is evaporated on a rotary evaporator, obtain compound i-1, white solid.Esi-ms, m/z=478 ([m
+h]+).
Embodiment 2-5
With reference to the method for embodiment 1, synthesize compound listed in Table.
The suppression egfr and her2 analysis of embodiment 6 Compound ira vitro
Compound of the present invention can be measured using following experiment in vitro to erbb family tyrosine kinase (egfr
And her2) activity inhibition.
The vitro kinase assay htscan egfreceptor of cell signaling technology company
Kinase assay kit and htscan her2/erbb2kinaseassay kit detection.Operating procedure is with reference to test kit explanation
Book, the method detects that testing compound is made to the suppression of peptide substrate phosphorylation to egfr or her2 receptor tyrosine kinase in vitro
With.Incubate atp and peptide substrate and testing compound in kinase reaction buffer under room temperature, after incubation a period of time, add eventually
Stop liquid terminating reaction and transfer the sample in coated 96 orifice plates of Streptavidin, wash plate the anti-substrate phosphorus with hrp labelling
Phosphorylation level on acidifying antibody test peptide substrate, with tmb colour developing, 2m sulphuric acid stopped reaction.Detection 450nm absorbing wavelength,
Calculate ic50Value (nm).Result see table.
| Compound | egfr ic50(nm) | her2 ic50(nm) |
| Compound i-1 | 3.7 | 34 |
| Compound i-2 | 5.5 | 9.3 |
| Compound i-3 | 9.2 | 8.3 |
| Compound i-4 | 12.6 | 11.3 |
| Reference compound r | 54 | 31 |
The compound that can be seen that the present invention from upper table result has very strong inhibitory action to egfr and her2, permissible
As preparing anti-tumor drug.
The inhibitory action of embodiment 7 compound on intracellular propagation
Cell inhibitory effect test adopts human breast cancer cell bt474, SGC-7901 nci-n87, human lung carcinoma cell
Calu-3 and application on human skin cancerous cell a431, wherein bt474 high expression her2 receptor, n87 high expression egfr and her2 receptor.Containing
In dulbecco improvement eagle culture medium (dmem) of 10% hyclone, 2mm L-Glutamine and non essential amino acid, 37
DEG C, 5%co2Cultured cells in cell culture incubator, application trypsin/ethylenediaminetetraacetic acid (edta) is received from Tissue Culture Flask
Obtain cell.Cell adds 96 porocyte culture plates adherent overnight with 4000/ hole (0.1ml culture medium), adds 0.1ml test compounds
The diluent of thing, the ultimate density of dmso is 0.25%, by Tissue Culture Plate at 37 DEG C, 5% co2Under the conditions of incubate 72h.So
Examine under a microscope the change of cellular morphology afterwards, then every hole adds trichloroacetic acid (tca) the 50 μ l of 50% (mass/volume)
Fixing cell.Final concentration of the 10% of tca, places 1h in 4 DEG C of refrigerators after standing 5min, culture plate each hole deionized water is rushed
Wash 5 times, to remove tca, dry, air drying is to no wet mark.Every hole add 0.4% (mass/volume) srb 100 μ l, room temperature
Place 10min, rinsed 5 times with 1% acetic acid after discarding each in the hole liquid, air uses ph after being dried be 10.5,10mm tris (three
Hydroxymethyl aminomethane) 150 μ l extractions, the absorbing wavelength of detection 540nm.Result ic50Value (nm) see table.
As can be seen from the above table, the compound of the present invention has very high suppression to the tumor cell of the high expression of egfr and her2
System activity, can be used as preparing anti-tumor drug.
Claims (4)
1. formula i structural compounds,
Wherein, x is selected from halogenic substituent.
2. formula i compound defined in claim 1, is selected from,
3. the method for formula i compound defined in synthesis any one of claim 1-2:
First with n-buli process, the aryl lithium intermediate obtaining and benzaldehyde iii react compound ii, obtain compound iv；Change
Compound iv and thiophene sulfonamide v reacting by heating in the presence of triphenylphosphine and diethylazodicarboxylate, obtain compound i；X's
Definition is as described in any one of claim 1-2.
4. application in terms of preparation treatment tumor disease medicine for the formula i compound defined in any one of claim 1-2.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610659664.8A CN106349231A (en) | 2016-08-09 | 2016-08-09 | Benzoquinazoline tyrosine kinase inhibitor containing halothiophene sulfonamide structure |
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| CN201610659664.8A CN106349231A (en) | 2016-08-09 | 2016-08-09 | Benzoquinazoline tyrosine kinase inhibitor containing halothiophene sulfonamide structure |
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Citations (8)
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|---|---|---|---|---|
| CN1387527A (en) * | 1999-11-05 | 2002-12-25 | 阿斯特拉曾尼卡有限公司 | Qinazoline derivs. as VEGF inhibitors |
| CN1542004A (en) * | 2003-04-30 | 2004-11-03 | 黄文林 | Tyrosine kinase inhibitor, preparation method and use thereof |
| CN101128456A (en) * | 2005-02-26 | 2008-02-20 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as tyrosine kinase inhibitors |
| WO2010015523A1 (en) * | 2008-08-08 | 2010-02-11 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy-substituted heterocyclics, medicines containing these compounds and method for the production thereof |
| CN101648947A (en) * | 2002-03-30 | 2010-02-17 | 贝林格尔英格海姆法玛两合公司 | 4-(n-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors |
| CN101935316A (en) * | 2009-06-30 | 2011-01-05 | 江苏先声药物研究有限公司 | Quinazoline compound and application thereof |
| CN102432552A (en) * | 2003-08-14 | 2012-05-02 | 阿雷生物药品公司 | Quinazoline analogs as receptor tyrosine kinase inhibitors |
| CN104350049A (en) * | 2012-05-07 | 2015-02-11 | 苏州韬略生物科技有限公司 | Substituted aminoquinazolines useful as kinases inhibitors |
-
2016
- 2016-08-09 CN CN201610659664.8A patent/CN106349231A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1387527A (en) * | 1999-11-05 | 2002-12-25 | 阿斯特拉曾尼卡有限公司 | Qinazoline derivs. as VEGF inhibitors |
| CN101648947A (en) * | 2002-03-30 | 2010-02-17 | 贝林格尔英格海姆法玛两合公司 | 4-(n-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors |
| CN1542004A (en) * | 2003-04-30 | 2004-11-03 | 黄文林 | Tyrosine kinase inhibitor, preparation method and use thereof |
| CN102432552A (en) * | 2003-08-14 | 2012-05-02 | 阿雷生物药品公司 | Quinazoline analogs as receptor tyrosine kinase inhibitors |
| CN101128456A (en) * | 2005-02-26 | 2008-02-20 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as tyrosine kinase inhibitors |
| WO2010015523A1 (en) * | 2008-08-08 | 2010-02-11 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy-substituted heterocyclics, medicines containing these compounds and method for the production thereof |
| CN101935316A (en) * | 2009-06-30 | 2011-01-05 | 江苏先声药物研究有限公司 | Quinazoline compound and application thereof |
| CN104350049A (en) * | 2012-05-07 | 2015-02-11 | 苏州韬略生物科技有限公司 | Substituted aminoquinazolines useful as kinases inhibitors |
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