CN106279135A - A kind of Benzoquinazole class tyrosine kinase inhibitor of thiophenesulfonyl amine structure - Google Patents
A kind of Benzoquinazole class tyrosine kinase inhibitor of thiophenesulfonyl amine structure Download PDFInfo
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- CN106279135A CN106279135A CN201610659661.4A CN201610659661A CN106279135A CN 106279135 A CN106279135 A CN 106279135A CN 201610659661 A CN201610659661 A CN 201610659661A CN 106279135 A CN106279135 A CN 106279135A
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- compound
- tyrosine kinase
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- tumor
- thiophenesulfonyl
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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
Abstract
The present invention relates to tumor disease field.Specifically, the present invention relates to a kind of novel Benzoquinazole class tyrosine kinase inhibitor, its preparation method and application in preparation treatment tumor disease thereof containing thiophenesulfonyl amine structure.
Description
Technical field
The present invention relates to the drug world of tumor.In particular it relates to it is medicative to above-mentioned disease tool
A kind of tyrosine kinase inhibitor of novel Benzoquinazole analog derivative containing thiophenesulfonyl amine structure, its preparation method and
Purposes.
Background technology
Tumor is one of principal disease of serious threat human life and quality of life, adds up according to WHO, and the whole world is the most dead
Patient about 6,900,000 in tumor.Due to living environment and the change of life habit, at the work of poor environment He some unfavorable factors
Under with, the M & M of tumor is in recent years in rapid increase trend.
One of maximum family of protein kinase composition people's fermentoid, and adjust on protein by adding phosphate group
The many different signal conductive processes of joint.Especially, tyrosine kinase phosphorylating protein is at the phenol moieties of tyrosine residue.Cheese
Histidine kinase family includes the member controlling cell growth, migrating and break up.Abnormal kinase activity has been directed to many mankind
Disease, including cancer, autoimmune disease and inflammatory diseases.Owing to protein kinase belongs to the crucial regulation of cellular signal transduction
Agent, they offer small molecule kinase inhibitors regulate the target of cell function, and therefore become good medicine and set
Meter target.Except the treatment of kinase mediated lysis, selectivity and effective inhibitor of kinase activity can be additionally used in research
Cell signaling processes and identify that other has the cell target of therapeutic potential.
Treatment to tumor in the past is realized by discovery tumor destruction, now with to cellular signal transduction way
Deepening continuously of footpath research, it is more and more deep that the oncogene of inside tumor cells and the effect of antioncogene are understood by people,
The antitumor drug new for the specific molecular shot design of tumor increasingly receives publicity, and becomes the hot fields of research,
And anti-tumor drugs targeting has 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, break up, migrate and apoptosis has substantial connection, utilize ptk inhibitor interference or block tyrosine kinase path and can use
In oncotherapy.PTK be normally with abnormality proliferation during the cancer protein that plays an important role and becoming in proto-protein family
Member, is a kind of enzyme of a kind of tyrosine residue phosphorylation that can optionally make different substrate, the γ-phosphoric acid of they catalysis 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 majority is receptor type tyrosine kinase
(RTK).RTK is that one has intrinsic protein tyrosine kinases, participates in the regulation and control of various kinds of cell activity, replicates at active cell
Mitogenesis signal conduction in there is extremely important status, regulate and control growth and the differentiation of cell.All of RTK is
Belonging to I type memebrane protein, its molecule has similar topological structure: an outer ligand binding domain of big glycosylated born of the same parents, one thin
The single pass transmembrane district of water, and an intracellular tyrosine kinase catalyst structure domain and regulating and controlling sequence.The combination of part is (such as epidermis
The combination of somatomedin (EGF) and EGFR) cause the kinase activation of code segment in recipient cell to activate, make in target protein
Key tyrosine phosphorylation, cause proliferation signals cross over cytoplasma membrane transduction.
In recent years, people are devoted to suppress cellular signal transduction pathways to develop novel target spot antitumor drug.Signal turns
Lead inhibitor and lower existence and the proliferation signal of tumor, promote apoptosis rather than by cytotoxicity, therefore selectivity
Higher, toxic and side effects is less.Have ten several signal transduction inhibitors at present and be applied to clinical treatment tumour, predominantly tyrosine
Inhibitors of kinases series antineoplastic medicament, what wherein the compound of 4-(substituted anilinic) quinazoline structure type was developed relatively becomes
Ripe, 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
Inhibitors of kinases, is the epidermal growth factor recipient tyrosine kinase inhibitor entering clinical research the earliest, in 2002 in day
This listing, next year lists in the U.S., for treating the late period or Metastatic Nsclc previously received chemotherapy
(NSCLC).Erlotinib (Erlotinib), trade name Tarceva (Erlotinib), the EGFR tyrosine kinase of OSI company exploitation
Inhibitor, is transferred from Genentech and Roche Holding Ag.Within 2004, list in the U.S., be used for treating NSCLC and cancer of pancreas.Belong to
The aniline quinazoline type small molecular inhibitor of first generation treatment NSCLC, is 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, without bone marrow depression and neurotoxicity, can significantly extend life cycle, improve patients ' life quality.
Small molecule tyrosine kinase inhibitors opens as new anti-tumor drugs targeting, the treatment and prevention for tumor
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 is that clinical cancer therapy has made the biggest contribution, but still needs to find that some are 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 improvement or
More efficient tyrosine kinase inhibitor, gains more insight into the relation between such medicine and known target protein and it plays
Clinical therapy of tumor is had great importance by the mechanism of antitumor action.
The invention discloses a kind of novel Benzoquinazole class tyrosine kinase inhibitor containing thiophenesulfonyl amine structure, should
Compound can be used for preparing tumor.
Summary of the invention
It is an object of the present invention to provide a kind of tyrosine kinase inhibitor with Formulas I.
It is a further object to provide the method that preparation has the compound of Formulas I.
It is also another object of the present invention to provide the compound containing Formulas I as effective ingredient, and it is in treatment tumor
The application of aspect.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of Formulas I and has a following structural formula:
Compound of formula I of the present invention can be synthesized by following route:
Compound II is first with n-BuLi process, and the aryl lithium intermediate obtained reacts with benzaldehyde III, obtains compound
IV;Compound IV and thiophene sulfonamide V reacting by heating in the presence of triphenylphosphine and diethylazodicarboxylate, obtain compound
I。
Compound of formula I of the present invention has tyrosine kinase inhibitory activity, can be used for preparing tumor as effective ingredient
Medicine.The activity of compound of formula I of the present invention is to be increased by vitro inhibition EGFR and HER2 kinases and suppression cell
Grow and verify.
The compound of formula I of the present invention is effective in comparatively wide dosage range.The dosage that such as every day takes about exists
In the range of 1mg-500mg/ people, it is divided into once or is administered for several times.The actual dosage taking formula I can be by doctor's root
Determine according to relevant situation.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only for
Illustrate, and be not intended to limit the present invention.Those skilled in the art all should according to the various changes that the teachings of the present invention is made
Within the protection domain required by the application claim.
The synthesis of embodiment 1 compound I
The synthesis of step 1. compound IV-1
Compound II (2.25g, 10mmol) is dissolved in the THF that 25mL is dried, stirred under nitrogen atmosphere, with liquid nitrogen-ethanol
It is cooled to-78 DEG C, slowly drips the hexane solution (6.25mL) of the n-BuLi of 1.6M with syringe, after dropping, reaction
Mixture at such a temperature continue stir 1h, slowly drip with syringe the most again III-1 (1.39g, 10mmol) be dissolved in 3mL do
The solution that dry THF makes.After 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) washing, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, obtains compound
IV-1, white solid, ESI-MS, m/z=330 ([M+H]+)。
The synthesis of step 2. compound I
Diethylazodicarboxylate (DEAD, 1.74g, 10mmol) is dissolved in the THF that 20mL is dried, and stirring, ice-water bath is cold
But slowly drip triphenylphosphine (2.62g, 10mmol) under and be dissolved in the solution that the THF that 5mL is dried makes, then add compound
V (1.06g, 6mmol), mixture stirs 1 hour at such a temperature, adds compound IV-1 (1.97g, 6mmol).Reaction mixing
Thing at room temperature reacts overnight, refluxes 12 hours the most again.TLC display reaction completes.Reactant mixture carefully pours into 200mL
In frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, washs with saline (100mL), and anhydrous sodium sulfate is dried.Take out
Filtering desiccant, filtrate is evaporated on a rotary evaporator, obtains compound I, white solid, ESI-MS, m/z=489 ([M+
H]+)。
The synthesis of embodiment 2 compound R-1
The synthesis of step 1. compound IV-2
Compound II (2.25g, 10mmol) is dissolved in the THF that 25mL is dried, stirred under nitrogen atmosphere, with liquid nitrogen-ethanol
It is cooled to-78 DEG C, slowly drips the hexane solution (6.25mL) of the n-BuLi of 1.6M with syringe, after dropping, reaction
Mixture at such a temperature continue stir 1h, slowly drip with syringe the most again III-2 (1.24g, 10mmol) be dissolved in 3mL do
The solution that dry THF makes.After 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) washing, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, obtains compound
IV-2, white solid.ESI-MS, m/z=315 ([M+H]+)。
The synthesis of step 2. compound R-1
Diethylazodicarboxylate (DEAD, 1.74g, 10mmol) is dissolved in the THF that 20mL is dried, and stirring, ice-water bath is cold
But slowly drip triphenylphosphine (2.62g, 10mmol) under and be dissolved in the solution that the THF that 5mL is dried makes, then add compound
(1.06g, 6mmoD, mixture stirs 1 hour V at such a temperature, adds compound IV-2 (1.89g, 6mmol).Reaction mixing
Thing at room temperature reacts overnight, refluxes 12 hours the most again.TLC display reaction completes.Reactant mixture carefully pours into 200mL
In frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, washs with saline (100mL), and anhydrous sodium sulfate is dried.Take out
Filtering desiccant, filtrate is evaporated on a rotary evaporator, obtains compound R-1, white solid.ESI-MS, m/z=474 ([M
+H]+)。
Embodiment 3 Compound ira vitro suppression EGFR and HER2 analyzes
Following experiment can be used to measure compound of the present invention 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 reference reagent box explanation
Book, the method detects testing compound in vitro and makees EGFR or Her2 receptor tyrosine kinase to the suppression of peptide substrate phosphorylation
With.Incubation ATP and peptide substrate and testing compound in kinase reaction buffer under room temperature, after hatching a period of time, add eventually
Only liquid terminates reaction and transfers the sample in coated 96 orifice plates of Streptavidin, washes plate and with the anti-substrate phosphorus of HRP labelling
Phosphorylation level on acidifying antibody test peptide substrate, develops the color with TMB, 2M sulphuric acid stopped reaction.Detection 450nm absorbing wavelength,
Calculate IC50Value (nM).Result see table.
Compound | EGFR IC50(nM) | HER2 IC50(nM) |
Compound R-1 | 54 | 31 |
Compound I | 9.0 | 8.3 |
From upper table result it can be seen that the compound of the present invention has the strongest inhibitory action to EGFR and HER2, permissible
As preparing anti-tumor drug.
The inhibitory action of embodiment 4 compound on intracellular propagation
Cell inhibitory effect test uses 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 expressed Her2 receptor, N87 high expressed EGFR and Her2 receptor.Containing
In Dulbecco improvement Eagle culture medium (DMEM) of 10% hyclone, 2mM glutamine and non essential amino acid, 37
DEG C, 5%CO2Cultivating cell in cell culture incubator, application trypsin/ethylenediaminetetraacetic acid (EDTA) is received from Tissue Culture Flask
Obtain cell.It is adherent overnight that cell adds 96 porocyte culture plates 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, the CO of 5%2Under the conditions of incubation 72h.So
After examine under a microscope the change of cellular morphology, 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 rushes
Washing 5 times, to remove TCA, dry, air is dried to without wet mark.Every hole adds 0.4% the SRB 100 μ L of (mass/volume), room temperature
Placing 10min, discard in each hole after liquid with 1% acetic acid flushing 5 times, air is 10.5 with pH after drying, 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 the highest pressing down to the tumor cell of EGFR and HER2 high expressed
System activity, can be as preparing anti-tumor drug.
Claims (3)
1. compound of formula I,
2. the method for compound of formula I described in synthesis claim 1:
Compound II is first with n-BuLi process, and the aryl lithium intermediate obtained reacts with benzaldehyde III, obtains compound IV;Change
Compound IV and thiophene sulfonamide V reacting by heating in the presence of triphenylphosphine and diethylazodicarboxylate, obtain compound I.
3. the purposes in terms of preparation treatment tumor disease medicine of the compound of formula I described in claim 1.
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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 |
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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 |
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2016
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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 |
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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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