CN105017164A - Tyrosine kinase inhibitor containing novel benzo quinazoline and ortho chlorine structure and application - Google Patents
Tyrosine kinase inhibitor containing novel benzo quinazoline and ortho chlorine structure and application Download PDFInfo
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- CN105017164A CN105017164A CN201510528977.5A CN201510528977A CN105017164A CN 105017164 A CN105017164 A CN 105017164A CN 201510528977 A CN201510528977 A CN 201510528977A CN 105017164 A CN105017164 A CN 105017164A
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- tyrosine kinase
- kinase inhibitor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The invention relates to the field of tumorous diseases, in particular to a tyrosine kinase inhibitor containing a novel benzo quinazoline and ortho chlorine substitution structure, a preparation method of the tyrosine kinase inhibitor and an application of the tyrosine kinase inhibitor in preparation of medicine for treating the tumorous diseases. The tyrosine kinase inhibitor has a structural formula shown in the specification, wherein X is selected from a halogen substituent.
Description
Technical field
The present invention relates to the pharmaceutical field of tumour.Specifically, the present invention relates to the tyrosine kinase inhibitor, its preparation method that the medicative class of above-mentioned disease tool are replaced to structure containing novel Benzoquinazole and ortho position chlorine, and at pharmaceutical applications.
Background technology
Tumour is one of principal disease of serious threat human life and quality of life, and according to WHO statistics, the patient about 6,900,000 of tumour is died from the whole world every year.Due to the change of living environment and life habit, under the effect of poor environment and some unfavorable factors, the M & M of tumour is in recent years in quick ascendant trend.
One of maximum family of protein kinase composition people fermentoid, and regulate many different intracellular signaling processes by adding on phosphate group to protein.Especially, tyrosine kinases phosphorylate protein is at the phenol moieties of tyrosine residues.Family tyrosine kinase comprises the member controlling Growth of Cells, migration and differentiation.Abnormal kinase activity has related to many human diseasess, comprises cancer, autoimmune disease and inflammatory diseases.Because protein kinase belongs to the key regulator of cell signaling, they provide the target regulating cell function with small molecule kinase inhibitors, and therefore become good medicinal design target.Except the treatment of kinase mediated lysis, the selectivity of kinase activity and effective inhibitor also can be used for studying cell signaling processes and identifying that other has the cell target of therapeutic potential.
The treatment of tumour was realized by finding tumour and destroying in the past, now along with deepening continuously of studying cell signaling pathway, people to the effect of the oncogene of inside tumor cells and antioncogene understand more and more deep, the antitumor drug new for the specific molecular shot design of tumour more and more receives publicity, become the hot fields of research, and anti-tumor drugs targeting has also been applied to clinical as a kind of new methods for the treatment of, and obtain significant progress in recent years.Now known, protein tyrosine kinase (Proteintyrosinekinases, PTK) propagation of signal path and tumour cell, differentiation, migration and apoptosis have substantial connection, utilize ptk inhibitor to disturb or block Tyrosylprotein kinase path to may be used for oncotherapy.PTK is the member in the cancer protein and proto-protein family played an important role in normal and abnormality proliferation process, it is a kind of a kind of enzyme that optionally can make the tyrosine residues phosphorylation of different substrate, γ-the phosphate of their catalysis ATP is transferred on the tyrosine residues of many key proteins, makes phenolic hydroxyl group phosphorylation.Protein tyrosine kinase is divided into receptor tyrosine kinase (receptor tyrosine kinase, RTK), (the Robinson D.R. such as nonreceptor tyrosine kinase and IR and Janus kinases, et al, Oncogene, 2000,19,5548-5557), wherein majority 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, has extremely important status, regulate and control the Proliferation and differentiation of cell in the conduction of the mitogenesis signal copied at active cell.All RTK belong to I type membranin, and its molecule has similar topological framework: an outer ligand binding domain of large glycosylated born of the same parents, a hydrophobic single pass transmembrane district, and an intracellular tyrosine kinase catalyst structure domain and regulating and controlling sequence.The combination (as Urogastron (EGF) and the combination of EGFR) of part causes the kinase activation of code segment in recipient cell to activate, make the key tyrosine phosphorylation in target protein, cause proliferation signals to cross over cytoplasmic membrane transduction.
In recent years, people are devoted to T suppression cell signal transduction pathway with development of new target spot antitumor drug.Signal transduction inhibitor lowers existence and the proliferation signal of tumour, promotes apoptosis, instead of by cytotoxicity, therefore selectivity is higher, toxic side effect is less.Existing tens kinds of signal transduction inhibitors are applied to clinical treatment tumour at present, be mainly tyrosine kinase inhibitor series antineoplastic medicament, the wherein comparative maturity of the compound exploitation of 4-(substituted anilinic) quinazoline structure type, as the micromolecular inhibitor Gefitinib (Iressa) of EGFR Tyrosylprotein kinase target spot, erlotinib (Tarceva) and lapatinibditosylate (Lapatinib) etc.
Gefitinib (Gefitinib), trade(brand)name Iressa (Iressa), the EGFR tyrosine kinase inhibitor of AstraZeneca exploitation, it is the epidermal growth factor recipient tyrosine kinase inhibitor entering clinical study the earliest, went on the market in 2002 in Japan, next year goes on the market in the U.S., is used for the treatment of the late period or Metastatic Nsclc (NSCLC) that previously receive chemotherapy.Erlotinib (Erlotinib), trade(brand)name Tarceva (Erlotinib), the EGFR tyrosine kinase inhibitor of OSI company exploitation, assigns in Genentech and Roche Holding Ag.Within 2004, in U.S.'s listing, be used for the treatment of NSCLC and carcinoma of the pancreas.Belong to the aniline quinazoline type small molecular inhibitor of first-generation treatment NSCLC, also be current uniquely confirmed EGFR tyrosine kinase inhibitor advanced Non-small cell lung to survival advantage, all effective to all kinds of Patients with Non-small-cell Lung, and better tolerance, without bone marrow depression and neurotoxicity, can significant prolongation lifetime, improve patients ' life quality.
Small molecule tyrosine kinase inhibitors is as new anti-tumor drugs targeting, and for the treatment of tumour and prevention open a fan new window, and its side effect is slight, has good tolerance.Although existing more than 10 small molecule tyrosine kinase inhibitors is that clinical cancer therapy has made very large contribution at present, but still needs to find that some have the other compound of the pharmacological characteristics of better activity in vivo and/or improvement than existing tyrosine kinase inhibitor.Therefore develop new improvement or more efficient tyrosine kinase inhibitor, more in depth understand relation between such medicine and known target protein and its mechanism playing antitumor action has great importance to clinical therapy of tumor.
The invention discloses the tyrosine kinase inhibitor of the novel Benzoquinazole of a class and ortho position chlorine replacement structure, these compounds can be used for the medicine preparing tumour.
Summary of the invention
An object of the present invention is to provide a kind of tyrosine kinase inhibitor with general formula I.
Another object of the present invention is to provide the method that preparation has the compound of general formula I.
Another object of the present invention is to provide compound containing general formula I as effective constituent and the application in treatment tumour thereof.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, X is selected from halogenic substituent.
The compound preferably with general formula I is as follows,
Compound of Formula I of the present invention can be synthesized by following route:
Compound II per and methane amide react under the condition heated, and obtain compound III; Compound III uses phosphorus oxychloride process, obtains compound IV; Compound IV is reacted with compound V in the presence of a base, obtains compound VI; Compound VI is at CuCl
2with isopropyl acrylate addition under catalysis, obtain VII; Compound VI I and VIII at high temperature reacts, and obtains Compound I; The definition of X as previously mentioned.
Compound of Formula I of the present invention has tyrosine kinase inhibitory activity, can be used as the medicine of effective constituent for the preparation of tumour.The activity of compound of Formula I of the present invention is verified by vitro inhibition EGFR and HER2 kinases and antiproliferative effect experiment.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-500mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
the synthesis of embodiment 1 Compound I-1
The synthesis of step 1. compound III-1
Compound II per-1 (2.11g, 10mmol) is dissolved in 20mL methane amide, refluxes and spend the night in nitrogen atmosphere, and TLC shows reaction to be completed.Reaction mixture carefully pours in 200mL frozen water, stirs, with 50mL × 3CH
2cl
2extraction, merges extraction phase, with salt solution (100mL × 3) washing, and anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, obtains compound III-1, white solid.ESI-MS,m/z＝207([M+H]
+)。
The synthesis of step 2. compound IV-1
Compound III-1 (1.44g, 7mmol) is dissolved in the POCl that 20mL heavily steams
3in, then temperature rising reflux 5 hours, TLC shows reaction to be completed.Reaction mixture carefully pours in 200mL frozen water, stirs, with 50mL × 3CH
2cl
2extraction, merges extraction phase, uses saturated NaHCO successively
3solution and with salt solution (100mL × 3) washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, obtains compound IV-1, white solid.ESI-MS,m/z＝225([M+H]
+)。
The synthesis of step 3. compound VI-1
Compound IV-1 (0.90g, 4mmol), compound V-1 (0.58g, 4mmol) and diisopropyl ethyl amine (DIPEA, 1.29g, 10mmol) be dissolved in 15mL toluene, temperature rising reflux in a nitrogen atmosphere, until reacted (about 5 hours).Reaction mixture carefully pours in 200mL frozen water, stirs, with 50mL × 3CH
2cl
2extraction, merges extraction phase, uses 1% dilute hydrochloric acid and salt solution (100mL × 3) washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, obtains compound VI-1, white solid.ESI-MS,m/z＝334([M+H]
+)。
The synthesis of step 4. compound VI I-1
Compound VI-1 (1.00g, 3mmol) and isopropyl acrylate (1.14g, 10mmol) are dissolved in the DMF of 10mL drying, stir, add solid CuCl
2(0.40g, 3mmol), then temperature rising reflux in a nitrogen atmosphere, until reacted (usual 12 hours).Reaction mixture carefully pours in 200mL frozen water, stirs, with 50mL × 3CH
2cl
2extraction, merges extraction phase, uses 0.5% dilute hydrochloric acid, 0.5%EDTA solution and salt solution (100mL × 3) to wash successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, obtains compound VI I-1, white solid.ESI-MS,m/z＝448([M+H]
+)。
The synthesis of step 5. Compound I-1
Compound VI I-1 (0.89g, 2mmol) and hydroxyethyl piperazine VIII-1 (1.30g, 10mmol) is dissolved in 10mL dimethylbenzene, temperature rising reflux in nitrogen atmosphere, until reacted (usual 6 hours).Reaction mixture carefully pours in 200mL frozen water, stirs, with 50mL × 3CH
2cl
2extraction, merges extraction phase, with salt solution (100mL × 5) washing, and anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, obtains Compound I-1, white solid.ESI-MS,m/z＝518([M+H]
+)。
embodiment 2-4
With reference to the method for embodiment 1, synthesize compound listed in Table.
embodiment 5 Compound ira vitro suppresses EGFR and HER2 to analyze
Use following experiment to measure compound of the present invention in vitro to the activity inhibition of erbB family Tyrosylprotein kinase (EGFR and HER2).
Vitro kinase assay the HTScanEGFReceptor Kinase Assay Kit of Cell Signaling Technology company and HTScan HER2/ErbB2KinaseAssay Kit detect.Operation steps reference reagent box specification sheets, the method detects testing compound in vitro to the restraining effect of EGFR or Her2 receptor tyrosine kinase to peptide substrate phosphorylation.Incubation ATP and peptide substrate and testing compound in kinase reaction damping fluid under room temperature, after hatching for some time, add stop buffer termination reaction and sample transferred in 96 orifice plates of Streptavidin bag quilt, wash plate and with HRP mark anti-substrate phosphorylation antibody test peptide substrate on phosphorylation level, with TMB colour developing, 2M sulfuric acid stopped reaction.Detect 450nm absorbing wavelength, calculate IC
50value (nM).The results are shown in following table.
| Compound | EGFR IC 50(nM) | HER2IC 50(nM) |
| Compound I-1 | 9.2 | 6.8 |
| Compound I-2 | 10.8 | 9.3 |
| Compound I-3 | 14.1 | 11.2 |
| Compound I-4 | 16.5 | 15.7 |
As can be seen from upper table result, compound of the present invention has very strong restraining effect to EGFR and HER2, can as preparing anti-tumor drug.
the restraining effect of embodiment 6 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 human skin cancer cells A431, wherein BT474 high expression level Her2 acceptor, N87 high expression level EGFR and Her2 acceptor.Improve in Eagle substratum (DMEM), at 37 DEG C, 5%CO at the Dulbecco containing 10% foetal calf serum, 2mM glutamine and non-essential amino acid
2culturing cell in cell culture incubator, application trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) harvested cell from Tissue Culture Flask.Cell adds 96 porocyte culture plate attach overnight with 4000/ hole (0.1mL substratum), adds the diluent of 0.1mL testing compound, and the ultimate density of DMSO is 0.25%, by Tissue Culture Plate at 37 DEG C, and the CO of 5%
2incubation 72h under condition.Then examine under a microscope the change of cellular form, then every hole adds trichoroacetic acid(TCA) (TCA) the 50 μ L fixed cell of 50% (mass/volume).The final concentration of TCA is 10%, places 1h, culture plate each hole deionized water rinsing 5 times after leaving standstill 5min in 4 DEG C of refrigerators, to remove TCA, dries, and dry air is to the wet mark of nothing.Every hole adds the SRB 100 μ L of 0.4% (mass/volume), room temperature places 10min, discard in each hole and rinse 5 times with 1% acetic acid after liquid, be 10.5 with pH after dry air, 10mM Tris (Tutofusin tris) 150 μ L extracts, and detects the absorbing wavelength of 540nm.Result IC
50value (nM) sees the following form.
As can be seen from the above table, the tumour cell of compound of the present invention to EGFR and HER2 high expression level has very high inhibit activities, can as preparing anti-tumor drug.
Claims (4)
1. there is the compound of general formula I,
Wherein, X is selected from halogenic substituent.
2. the compound of Formula I that defines of claim 1, is selected from following compounds,
3. synthesize the method belonging to the compound of general formula I that any one of claim 1-2 defines:
Compound II per and methane amide react under the condition heated, and obtain compound III; Compound III uses phosphorus oxychloride process, obtains compound IV; Compound IV is reacted with compound V in the presence of a base, obtains compound VI; Compound VI is at CuCl
2with isopropyl acrylate addition under catalysis, obtain VII; Compound VI I and VIII at high temperature reacts, and obtains Compound I; The definition of X is as described in any one of claim 1-2.
4. the compound of Formula I that any one of claim 1-2 defines is preparing the application in treatment tumor disease medicine.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1882580A (en) * | 2003-09-25 | 2006-12-20 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as antiproliferative agents |
| WO2013138951A1 (en) * | 2012-03-23 | 2013-09-26 | 无锡新融合药业有限公司 | Quinazoline derivate and use thereof as apoptosis inhibitor |
| CN103608336A (en) * | 2011-02-01 | 2014-02-26 | 勃林格殷格翰国际有限公司 | 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof |
| WO2015079251A1 (en) * | 2013-11-29 | 2015-06-04 | Cancer Research Technology Limited | Quinazoline compounds |
-
2015
- 2015-08-25 CN CN201510528977.5A patent/CN105017164A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1882580A (en) * | 2003-09-25 | 2006-12-20 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as antiproliferative agents |
| CN103608336A (en) * | 2011-02-01 | 2014-02-26 | 勃林格殷格翰国际有限公司 | 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof |
| WO2013138951A1 (en) * | 2012-03-23 | 2013-09-26 | 无锡新融合药业有限公司 | Quinazoline derivate and use thereof as apoptosis inhibitor |
| WO2015079251A1 (en) * | 2013-11-29 | 2015-06-04 | Cancer Research Technology Limited | Quinazoline compounds |
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