CN106749368A - The Benzoquinazole class tyrosine kinase inhibitor and purposes of a kind of amino-contained aryl boric acid - Google Patents
The Benzoquinazole class tyrosine kinase inhibitor and purposes of a kind of amino-contained aryl boric acid Download PDFInfo
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- CN106749368A CN106749368A CN201710068050.7A CN201710068050A CN106749368A CN 106749368 A CN106749368 A CN 106749368A CN 201710068050 A CN201710068050 A CN 201710068050A CN 106749368 A CN106749368 A CN 106749368A
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- tyrosine kinase
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- kinase inhibitor
- boric acid
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title abstract description 10
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title abstract description 10
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 title abstract description 9
- 239000004327 boric acid Substances 0.000 title abstract description 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 39
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to tumor disease field.Specifically, the present invention relates to a kind of amino-contained aryl boric acid Benzoquinazole class tyrosine kinase inhibitor, its preparation method and the application in treatment tumor disease is prepared.
Description
Technical field
The present invention relates to the drug field of tumour.In particular it relates to have medicative to above-mentioned disease
A kind of tyrosine kinase inhibitor, its preparation method of the Benzoquinazole analog derivative of new amino-contained aryl boric acid structure,
And the purposes in pharmacy.
Background technology
Tumour is seriously to threaten one of principal disease of human life and quality of life, is counted according to WHO, and the whole world is dead every year
In the patient about 6,900,000 of tumour.Due to the change of living environment and life habit, in poor environment and the work of some unfavorable factors
Under, the morbidity and mortality of tumour are in rapid increase trend in recent years.
One of maximum family of protein kinase composition people's fermentoid, and adjusted by adding phosphate group to protein
Save many different signal transduction processes.Especially, phenol moieties of the EGFR-TK phosphorylating protein in tyrosine residue.Junket
Histidine kinase family includes the member of control cell growth, migration and differentiation.Abnormal kinase activity has been directed to many mankind
Disease, including cancer, autoimmune disease and inflammatory disease.Belong to the crucial regulation of cellular signal transduction due to protein kinase
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 research
Cell signaling processes and identification other there is the cell target of therapeutic potential.
The treatment of tumour was realized by finding tumour and destroying in the past, now with to cellular signal transduction on the way
What footpath was studied deepens continuously, and it is more and more deep that effect of the people to the oncogene and antioncogene of inside tumor cells understands,
Increasingly attracted attention for the new antineoplastic of the specific molecular shot design of tumour, the hot fields as research,
And anti-tumor drugs targeting has also been applied to clinic as a kind of new treatment method, and obtain in recent years significantly
Progress.It is well known that protein tyrosine kinase (Protein tyrosinekinases, PTK) signal path and tumour cell
Propagation, differentiation, migration and apoptosis have substantial connection, using ptk inhibitor disturb or blocking EGFR-TK path can use
In oncotherapy.PTK be in the cancer protein and proto-protein family played an important role during normal and abnormality proliferation into
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 makes phenolic hydroxyl group phosphorylation on the tyrosine residue of many key proteins.Protein tyrosine kinase is divided into acceptor junket
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 a kind of regulation and control for having intrinsic protein tyrosine kinases, participating in various kinds of cell activity, is replicated in active cell
Mitogenesis signal conduction in there is extremely important status, regulate and control the growth of cell with differentiation.All of RTK is
Belong to I type memebrane proteins, its molecule has similar topological structure：One big glycosylated extracellular ligand binding domain, one is dredged
The single pass transmembrane area of water, and an intracellular tyrosine kinase catalyst structure domain and regulating and controlling sequence.Combination (such as epidermis of part
The combination of growth factor (EGF) and EGFR) cause the kinase activation of code segment in recipient cell to activate, in making target protein
Key tyrosine phosphorylation, cause proliferation signals across cytoplasma membrane transduce.
In recent years, people are devoted to suppressing cellular signal transduction pathways to develop new target spot antineoplastic.Signal turns
Existence and proliferation signal that inhibitor lowers tumour are led, promotes Apoptosis, rather than by CDCC, therefore selectivity
Higher, toxic and side effect is smaller.Ten several signal transduction inhibitors are had at present is applied to clinical treatment tumour, predominantly tyrosine
Kinase inhibitor series antineoplastic medicament, wherein 4- (substituted anilinic) quinazoline structure type compound exploitation comparing into
It is ripe, such as the micromolecular inhibitor Gefitinib (Iressa) of EGFR EGFR-TK target spots, Erlotinib (Tarceva) and
Lapatinib (Lapatinib) etc..
Gefitinib (Gefitinib), the EGFR tyrosine of trade name Iressa (Iressa), AstraZeneca exploitation
Kinase inhibitor, is earliest into the epidermal growth factor recipient tyrosine kinase inhibitor of clinical research, in 2002 in day
This listing, next year lists in the U.S., for treating the late period or Metastatic Nsclc that previously receive chemotherapy
(NSCLC).Erlotinib (Erlotinib), trade name Tarceva (Erlotinib), the EGFR EGFR-TKs of OSI companies exploitation
Inhibitor, is transferred from Genentech and Roche Holding Ag.Listed in the U.S. within 2004, for treating NSCLC and cancer of pancreas.Belong to
The first generation treat NSCLC aniline quinazoline type small molecular inhibitor, be also it is currently the only be proved to Advanced Non-Small Cell
Lung cancer has the EGFR tyrosine kinase inhibitors of survival advantage, effective to all kinds of Patients with Non-small-cell Lung, and tolerance
It is good, without bone marrow suppression 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 tumour are opened
One fan new window, and its side effect is slight, there is good tolerance.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 it is 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 kind of new Benzoquinazole class tyrosine kinase inhibitor of amino-contained aryl boric acid structure,
These compounds can be used to prepare the medicine of tumour.
The content of the invention
It is an object of the present invention to provide a kind of tyrosine kinase inhibitor with Formulas I.
Method it is a further object to provide the compound with Formulas I is prepared.
It is also another object of the present invention to provide the compound containing Formulas I as active ingredient, and its in treatment tumour side
The application in face.
Present invention is specifically described in conjunction with the purpose of the present invention.
The compounds of this invention has following structural formula：
Compound of the present invention can be synthesized by following route：
Compound II and 3,5- dibromo aniline III heating response in the presence of a base, obtain compound IV；Compound IV is first used
1 equivalent n-BuLi treatment is changed into corresponding single aryl lithium, and the latter is in BF3·Et2O catalysis is lower and epoxides V reacts, and obtains
Compound VI；Compound VI is first changed into corresponding single aryl lithium with 3 equivalent n-BuLi treatment, and the latter is anti-with trimethylborate again
Should, then by sour water solution, obtain compound I.
Compound of formula I of the present invention has tyrosine kinase inhibitory activity, can be used to prepare tumour as active ingredient
Medicine.The activity of compound of formula I of the present invention is to suppress EGFR and HER2 kinases and suppression cell increasing by external
Experiment is grown to verify.
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.The various change that those skilled in the art's training centre of the invention is made all should
Within the protection domain required by the application claim.
The synthesis of the compound I-1 of embodiment 1
The synthesis of step 1. intermediate compound IV -1
Compound II (2.25g, 10mmol), compound III (2.51g, 10mmol) and diisopropyl ethyl amine (DIPEA,
3.88g, 30mmol) it is dissolved in the dry dimethylbenzene of 50mL, then temperature rising reflux under nitrogen protection, until reaction completes (logical
Normal 5 hours).Reactant mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase,
Washed with 1% watery hydrochloric acid (200mL) and salt solution (100mL) successively, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate exists
It is evaporated on Rotary Evaporators, obtains compound IV, white solid, ESI-MS, m/z=440 ([M+H]+)。
The synthesis of step 2. intermediate VI-1
Compound IV (3.51g, 8mmol) is dissolved in the dry THF of 50mL, and stirred under nitrogen atmosphere is cold with liquid nitrogen-ethanol
But to -78 DEG C, the hexane solution (10mL, 16mmol) of the n-BuLi of 1.6M is slowly added dropwise with syringe, after completion of dropping, instead
Answer mixture to continue to stir 1h at such a temperature, BF is slowly then added dropwise successively with syringe again3·Et2O(1.42g,10mmol)
The solution that the dry THF of 3mL are made is dissolved in V-1 (0.59g, 10mmol).After completion of dropping, compound of reaction is being at room temperature
Continue to stir 3 hours, TLC display reactions are completed.Reactant mixture is carefully poured into 200mL frozen water, stirring, with 50mL ×
3CH2Cl2Extraction, merges extraction phase, is washed with salt solution (100mL), anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate exists
It is evaporated on Rotary Evaporators, obtains compound VI-1, white solid, ESI-MS, m/z=420 ([M+H]+)。
The synthesis of step 3. product I-1
Compound VI-1 (2.10g, 5mmol) is dissolved in the dry THF of 25mL, stirred under nitrogen atmosphere, with liquid nitrogen-ethanol
- 78 DEG C are cooled to, the hexane solution (9.4mL, 15mmol) of the n-BuLi of 1.6M, completion of dropping are slowly added dropwise with syringe
Afterwards, reactant mixture continues to stir 1h at such a temperature, be then slowly added dropwise with syringe again trimethylborate (0.62g,
6mmol).After completion of dropping, compound of reaction is being to continue to stir 3 hours at room temperature, and TLC display reactions are completed.Reaction mixing
Thing is carefully poured into 200mL frozen water, and pH=2 is adjusted using concentrated hydrochloric acid, is stirred 1 hour, then adjusts pH=5, with 50mL ×
3CH2Cl2Extraction, merges extraction phase, is washed with salt solution (100mL), anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate exists
It is evaporated on Rotary Evaporators, obtains compound I-1, white solid, 246-248 DEG C of fusing point, ESI-MS, m/z=383 ([M-
H]-)。
The synthesis of the compound I-2 of embodiment 2
The synthesis of step 1. intermediate compound IV -1
Compound II (2.25g, 10mmol), compound III (2.51g, 10mmol) and diisopropyl ethyl amine (DIPEA,
3.88g, 30mmol) it is dissolved in the dry dimethylbenzene of 50mL, then temperature rising reflux under nitrogen protection, until reaction completes (logical
Normal 5 hours).Reactant mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase,
Washed with 1% watery hydrochloric acid (200mL) and salt solution (100mL) successively, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate exists
It is evaporated on Rotary Evaporators, obtains compound IV, white solid, ESI-MS, m/z=440 ([M+H]+)。
The synthesis of step 2. intermediate VI-2
Compound IV (3.51g, 8mmol) is dissolved in the dry THF of 50mL, and stirred under nitrogen atmosphere is cold with liquid nitrogen-ethanol
But to -78 DEG C, the hexane solution (10mL, 16mmol) of the n-BuLi of 1.6M is slowly added dropwise with syringe, after completion of dropping, instead
Answer mixture to continue to stir 1h at such a temperature, BF is slowly then added dropwise successively with syringe again3·Et2O(1.42g,10mmol)
The solution that the dry THF of 3mL are made is dissolved in V-2 (0.58g, 10mmol).After completion of dropping, compound of reaction is being at room temperature
Continue to stir 3 hours, TLC display reactions are completed.Reactant mixture is carefully poured into 200mL frozen water, stirring, with 50mL ×
3CH2Cl2Extraction, merges extraction phase, is washed with salt solution (100mL), anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate exists
It is evaporated on Rotary Evaporators, obtains compound VI-2, pale solid, ESI-MS, m/z=418,420 ([M+H]+)。
The synthesis of step 3. product I-2
Compound VI-2 (2.09g, 5mmol) is dissolved in the dry THF of 25mL, stirred under nitrogen atmosphere, with liquid nitrogen-ethanol
- 78 DEG C are cooled to, the hexane solution (9.4mL, 15mmol) of the n-BuLi of 1.6M, completion of dropping are slowly added dropwise with syringe
Afterwards, reactant mixture continues to stir 1h at such a temperature, be then slowly added dropwise with syringe again trimethylborate (0.62g,
6mmol).After completion of dropping, compound of reaction is being to continue to stir 3 hours at room temperature, and TLC display reactions are completed.Reaction mixing
Thing is carefully poured into 200mL frozen water, and pH=2 is adjusted using concentrated hydrochloric acid, is stirred 1 hour, then adjusts pH=5, with 50mL ×
3CH2Cl2Extraction, merges extraction phase, is washed with salt solution (100mL), anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate exists
It is evaporated on Rotary Evaporators, obtains compound I-2, white solid, 195-198 DEG C of fusing point, ESI-MS, m/z=382 ([M-
H]-)。
The Compound ira vitro of embodiment 3 suppresses EGFR and HER2 analyses
Can be used it is following experiment come determine compound of the present invention in vitro to erbB families EGFR-TK (EGFR and
HER2 activity inhibition).
The vitro kinase assay HTScan EGFReceptor of Cell Signaling Technology companies
Kinase Assay Kit and HTScan HER2/ErbB2KinaseAssay Kit are detected.Operating procedure is with reference to kit explanation
Book, the method detects that suppression of the testing compound to EGFR or Her2 receptor tyrosine kinases to peptide substrate phosphorylation is made in vitro
With.ATP and peptide substrate and testing compound are incubated in kinase reaction buffer solution at room temperature, after being incubated a period of time, is added eventually
Only liquid terminating reaction and transfer the sample into coated 96 orifice plate of Streptavidin, board-washing and the anti-substrate phosphorus that is marked with HRP
Phosphorylation level on acidifying antibody test peptide substrate, is developed the color with TMB, 2M sulfuric acid stopped reactions.Detection 450nm absorbing wavelengths,
Calculate IC50Value (nM).Result see the table below.
| Compound | EGFR IC50(nM) | HER2IC50(nM) |
| Compound I-1 | 4.1 | 6.7 |
| Compound I-2 | 11.9 | 21.4 |
Can be seen that compound of the invention from upper table result has very strong inhibitory action to EGFR and HER2, can be with
As preparing anti-tumor drug.
The inhibitory action of the compound on intracellular of embodiment 4 propagation
Cell inhibitory effect experiment is using human breast cancer cell BT474, SGC-7901 NCI-N87, human lung carcinoma cell
Calu-3 and application on human skin cancer cell A431, wherein BT474 expression Her2 acceptors high, N87 expression EGFR and Her2 acceptors high.Containing
The Dulbecco of 10% hyclone, 2mM glutamine and nonessential amino acid is improved in Eagle culture mediums (DMEM), 37
DEG C, 5%CO2Cultured cells in cell culture incubator, receives using trypsase/ethylenediamine tetra-acetic acid (EDTA) from Tissue Culture Flask
Obtain cell.Cell adds 96 porocyte culture plates adherent overnight with 4000/ hole (0.1mL culture mediums), adds 0.1mL test compounds
The dilution of thing, the ultimate density of DMSO is 0.25%, by Tissue Culture Plate in 37 DEG C, 5% CO2Under the conditions of incubate 72h.So
The change of cellular morphology is examined under a microscope afterwards, and the μ L of trichloroacetic acid (TCA) 50 of 50% (mass/volume) are then added per hole
Fixed cell.Final concentration of the 10% of TCA, 1h is placed after standing 5min in 4 DEG C of refrigerators, and each hole of culture plate is rushed with deionized water
Wash 5 times, to remove TCA, dry, be air-dried to without wet mark.Per hole add 0.4% (mass/volume) the μ L of SRB 100, room temperature
10min is placed, is discarded in each hole and is rinsed 5 times with 1% acetic acid after liquid, it is 10.5,10mM Tris (three that pH is used after being air-dried
Hydroxymethyl aminomethane) 150 μ L extractions, detect the absorbing wavelength of 540nm.As a result IC50Value (nM) see the table below.
As can be seen from the above table, compound of the invention has suppression very high to the tumour cell of EGFR and HER2 expression high
System activity, can be as preparing anti-tumor drug.
Claims (3)
1. compound of formula I,
2. the method for synthesizing compound described in claim 1：
Compound II and 3,5- dibromo aniline III heating response in the presence of a base, obtain compound IV；Compound IV is first worked as with 1
Amount n-BuLi treatment is changed into corresponding single aryl lithium, and the latter is in BF3·Et2O catalysis is lower and epoxides V reacts, and obtains chemical combination
Thing VI；Compound VI is first changed into corresponding single aryl lithium with 3 equivalent n-BuLi treatment, and the latter reacts with trimethylborate again,
Then by sour water solution, compound I is obtained.
3. application of the compound described in claim 1 in terms for the treatment of tumor disease medicine is prepared.
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| WO2016168704A1 (en) * | 2015-04-16 | 2016-10-20 | Icahn School Of Medicine At Mount Sinai | Ksr antagonists |
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| WO2008015794A1 (en) * | 2006-08-04 | 2008-02-07 | Mebiopharm Co., Ltd. | Boronated quinazoline derivative |
| WO2016168704A1 (en) * | 2015-04-16 | 2016-10-20 | Icahn School Of Medicine At Mount Sinai | Ksr antagonists |
| CN104910083A (en) * | 2015-07-13 | 2015-09-16 | 佛山市赛维斯医药科技有限公司 | Alkoxylphenyl triazole sulfoxide 11beta-HSD1 inhibitor, preparation method and application thereof |
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