CN103772411B - Sulfur-bearing 6-furyl quinazoline-4-amines and its production and use - Google Patents
Sulfur-bearing 6-furyl quinazoline-4-amines and its production and use Download PDFInfo
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Abstract
The invention belongs to pharmaceutical synthesis field, relate to sulfur-bearing 6 furyl quinazoline 4 amines of logical formula I, particularly relate to a kind of sulfur-bearing N [3 chlorine 4 [(3 fluorophenyl) methoxyl group] phenyl] 6 (2 furyl) quinazoline 4 aminated compounds for quaternary heterocycle or spirane structure, and preparation method thereof and application medically.The compound of the present invention is tested by anti tumor activity in vitro, and result shows, described compound has good anti-tumor activity, can prepare new antitumor drug further.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to novel sulfurized 6-furyl quinazoline-4-amines, preparation method and
Application.Be specifically related to a kind of sulfur-bearing for quaternary heterocycle or spirane structure N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-
6-(2-furyl) quinazoline-4-amines, and preparation method thereof and application medically.
Background technology
Malignant tumor has become the commonly encountered diseases that serious harm people's life is healthy.According to incompletely statistics, the whole world is the most about
There are the new cases of 20,000,000；The annual new cases of China are about 160-200 ten thousand, and dead 1,300,000.Owing to tumor has in early days
The ability of transfer, in clinical diagnosis primary tumo(u)r, the patient of about 50% has produced amphi position transfer, and tumor cell length is fast, variable
Different, thus produce multidrug resistance, cause chemotherapy failure, according to the relevent statistics, wherein more than 90% with the multidrug resistance of tumor cell
Relevant, the antitumor drug applied the most clinically is far from the requirement of satisfied treatment.
EGF-R ELISA (EGFR) belongs to one of tyrosine kinase receptor family member, including HER1
(erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3) and HER4 (erbB4).EGFR is distributed widely in mammal
The cell surfaces such as epithelial cell, fibroblast, glial cell, horn cell, EGFR signal path is to the growth of cell, propagation
Play an important role with physiological process such as differentiation.Research shows to exist high expressed or the exception of EGFR in many entity tumors
Express.EGFR is relevant with the propagation of tumor cell, angiogenesis, tumor invasion, transfer and apoptotic suppression.The mistake of EGFR
Express and play an important role in the evolution of malignant tumor, glial cell, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, cancer of pancreas, breast carcinoma etc.
Tissue has the process LAN of EGFR.Therefore, in more than 20 year of past, drugmaker and biotech company are always by epidermis
Growth factor receptors is as the major target class of oncotherapy.
For the tumor cells targeted drug of EGFR, it is broadly divided into two big classes by its character: a class is monoclonal antibody, as
Cetuximab, Victibix, Buddhist nun's trastuzumab etc.；Another kind of is micromolecular inhibitor, such as gefitinib, Erlotinib with draw
Pa Feini etc..Wherein the mechanism of action of micromolecular inhibitor is mainly by the phosphorus of competitive binding EGFR intracellular section tyrosine kinase
Polyadenylation sites, blocks the interaction of itself and ATP, then suppresses a series of signal of tyrosine phosphorylation and downstream of EGFR to pass
Lead.
Wherein Lapatinib is to be developed, by GlaxoSmithKline PLC company, double target spot tyrosine kinase inhibitors that a class is oral,
Two target spots of EGFR and HER-2 can be simultaneously acted on.In March, 2007 by U.S. FDA approval listing.The adaptation checked and approved at present
Card for being used for late period or the transitivity breast carcinoma of first-line drug Endodontic failure with capecitabine therapeutic alliance.Lapatinib is a kind of 4-
The tyrosine kinase double inhibitor of aniline quinazoline class, it is possible to the ATP site with EGFR/HER-2 tyrosine kinase district is reversible
Property ground combine, the autophosphorylation in suppression receptor kinase district, thus block MARK and the PI3K/AKT path in downstream.
Although the small molecule EGFR inhibitor medicine listed shows preferably curative effect, but owing to toxic and side effects is more,
Individually medication effect is undesirable, and the problems such as medicament-resistant mutation easily occur, and forces people constantly to remove new safe and effective of research and development
Molecular targeted small molecule, anti-tumor drug.
Summary of the invention:
It is an object of the invention to provide the novel sulfurized 6-furyl quinazoline-4-amine compounds with good anti-tumor activity
Thing, is specifically related to a kind of sulfur-bearing N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-6-for quaternary heterocycle or spirane structure
(2-furyl) quinazoline-4-amines.
It is a further object of the present invention to provide the preparation method of above-mentioned sulfur-bearing 6-furyl quinazoline-4-amine, particularly relate to
Prepare sulfur-bearing N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] the phenyl]-6-(2-furyl) for quaternary heterocycle or spirane structure
The method of quinazoline-4-amines.
The sulfur-bearing 6-furyl quinazoline-4-amines of the present invention has a structure of following logical formula (I):
Wherein X=CH2Time, Y=S or SO or SO2
Y=CH2Time, X=S or SO or SO2
In the present invention, preferred compound has a structure of following compound 1,2,3,4,5,6:
As a example by compound 1, the preparation process of the compound of the present invention is as follows:
Compound of the present invention is surveyed by the test of EGFR and HER-2 kinase inhibiting activity and anti tumor activity in vitro
Examination, result shows, described compound has good EGFR and HER-2 kinase inhibiting activity and anti-tumor activity, can enter one
Step is developed as novel antitumor drug.
The present invention carries out inhibitory activity test to epidermal growth factor recipient tyrosine kinase EGFR and HER-2, and result shows
Showing, in the present invention, compound demonstrates that preferable EGFR and HER-2 kinase inhibiting activity, compound 2 and 3 press down for EGFR kinases
System activity IC50Value is less than 20nM, and compound 2 is for HER-2 kinase inhibiting activity IC50Value, less than 7nM, is better than positive control and resists
Tumour medicine Lapatinib.The compound of the present invention can develop EGFR/HER-2 inhibitors of kinases further.
The present invention is studied by Pharmacodynamic, to NCI-N87 stomach cancer cell, BT-474 breast cancer cell and SKBr-3 breast
Adenocarcinoma cell carries out anti tumor activity in vitro test, and result shows, in the present invention compound for NCI-N87 stomach cancer cell,
BT-474 breast cancer cell and SKBr-3 breast cancer cell have relatively powerful antitumor activity, IC50Value is nM level, wherein compound
2 for the extracorporeal anti-tumor IC of NCI-N87 stomach cancer cell50Value is 12nM, and compound 1-6 is for the body of BT-474 breast cancer cell
Outer antitumor IC50Value is respectively less than 1.6nM, and compound 2 is for the extracorporeal anti-tumor IC of SKBr-3 breast cancer cell50Value is
15.3nM, is better than positive control antitumor drug Lapatinib, new type antineoplastic medicine can be developed further.
In the present invention, the pharmacodynamics test method used, is art technology and the method known to personnel；
In the present invention, EGF-R ELISA (EGFR/HER-2) tyrosine kinase used and gastric cancer and breast carcinoma
Tumor line is that art technology can be obtained by commercial approach.
The sulfur-bearing of the present invention for quaternary heterocycle or spirane structure N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-
6-(2-furyl) quinazoline-4-amines especially can prepare treatment malignant tumor medicine, in view of tyrosine kinase receptor is
Participate in the transmembrane protein on the cell membrane that cell signal converts.They have control such as cell growth, variation, angiogenesis and
The growth factor signal of the critical functions such as inhibited apoptosis, passes to intracellular from cell surface.Tyrosine kinase therein is subject to
Body is EGF-R ELISA (EGFR) tyrosine kinase, the overexpression in many human tumors of these receptors, as brain,
Lung, kidney, liver, bladder, stomach, pancreas, mammary gland, incidence, esophagus, prostate, colon, ovary, cervix uteri or thyroid.Therefore, this
Malignant tumor described in invention includes the related neoplasms caused by tyrosine kinase functional disorder, including the brain cancer, pulmonary carcinoma, renal carcinoma, bone
Cancer, hepatocarcinoma, bladder cancer, gastric cancer, cancer of pancreas, breast carcinoma, incidence cancer, esophageal carcinoma, carcinoma of prostate, colon cancer, ovarian cancer, son
Cervical cancer or thyroid carcinoma.
Detailed description of the invention:
Embodiment 1: synthesis compound 1, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-thia-6-nitrogen
Miscellaneous-spiral shell [3,3] heptane-6-base) methyl]-furan-2-base]-quinazoline-4-amine
1) synthesis 6-iodine quinazoline-4-one
Methanamide (5ml) solution of 2-amino-5-iodo-benzoic acid (1g, 3.8mmol) is warming up to 120 DEG C of stirring 4h.It is cooled to
Room temperature, dilutes with 50% ethanol (10ml).Filtering, filter cake is respectively with 50% ethanol (5ml), EtOH/PE (1:1,10ml), PE
(5ml) washing, vacuum drying, obtain native brown solid (0.9g, 93%).
2) synthesis 4-chloro-6-iodine quinazoline
Phosphorus oxychloride is added in dry toluene (2ml) solution of 6-iodine quinazoline-4-one (0.54g, 2mmol)
(0.37g, 2.4mmol), under nitrogen protection, dropping triethylamine (0.24g, 2.4mmol), rise to 80 DEG C of leopard stricture of vagina stirrings after dripping off
2.5h.Reactant liquor is cooled to 2 DEG C of stirring 1h, filters.Filter cake washing with acetone, then with 1mol/L sodium hydrate aqueous solution (3ml)
Washing, then with water and washing with acetone.Vacuum drying, obtains grey-brown powder (0.5g, 88%)
3) synthesis N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-iodo-quinazoline-4-amine hydrochlorate
Under nitrogen protection, by chloro-for 4-6-iodine quinazoline (0.6g, 2mmol) and the chloro-4-of 3-(3-luorobenzyl epoxide) aniline
(0.5g, 2mmol) is stirred at reflux 3.5h in isopropanol (15ml).Be cooled to room temperature, filter, obtain yellow crystalline solid (1g,
96%).
4) synthesis N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[(5-formoxyl) furan-2-base]-4-quinazoline amine
N-[the chloro-4-of 3-(3-fluorine benzyloxy) benzene is added in the mixed solvent of dichloroethanes (30ml) and methanol (15ml)
Base]-6-iodo-quinazoline-4-amine hydrochlorate (1.63g, 3mmol), 5-formylfuran-2-boric acid (0.6g, 4.5mmol), palladium
Carbon (5%, 0.2g), triethylamine (1.21g, 12mmol), be warming up to 50 DEG C of stirring 16h.Through filtered off through Celite palladium carbon, filtrate is dense
Contracting, adds ethyl acetate (120ml), oxolane (60ml), water (20ml) and saturated sodium bicarbonate aqueous solution in residue
(20ml), stirring 15 minutes.Dividing and take organic layer, wash through saturated aqueous common salt, anhydrous sodium sulfate is dried, and concentrates, vacuum drying,
Crocus solid (1.2g, 86%)1H NMR(400MHz,DMSO)δ10.11(s,1H),9.66(s,1H),8.96(s,1H),
8.58 (s, 1H), 8.30 (d, J=9.0Hz, 1H), 7.97 (s, 1H), 7.85 (d, J=8.8Hz, 1H), 7.74 (d, J=
3.7Hz, 1H), 7.70 (d, J=8.7Hz, 1H), 7.46 (dd, J=14.2,7.7Hz, 1H), 7.41 (d, J=3.7Hz, 1H),
7.35–7.26(m,3H),7.22–7.13(m,1H),5.26(s,2H).
5) synthesis N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-thia-6-aza-spiro [3,3] heptane-
6-yl) methyl]-furan-2-base]-quinazoline-4-amine
N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[(5-formoxyl) furan-2-base]-4-quinazoline amine (1eq),
2-thia-6-aza-spiro [3,3] heptane oxalate (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloro
Ethane (keeps solution concentration～0.5mol/L), after half an hour is stirred at room temperature, adds acetic acid sodium borohydride (2.5eq), and 40 DEG C are stirred
Mix 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane and water dilute reaction solution, separatory, organic facies
Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H
NMR (400MHz, DMSO) δ 9.96 (s, 1H), 8.74 (d, J=13.7Hz, 1H), 8.56 (s, 1H), 8.14 (d, J=8.8Hz,
1H), 8.02 (d, J=2.4Hz, 1H), 7.85 7.70 (m, 2H), 7.48 (dd, J=14.3,7.8Hz, 1H), 7.39 7.26
(m, 3H), 7.19 (t, J=8.7Hz, 1H), 7.05 (dd, J=11.0,3.2Hz, 1H), 6.45 (d, J=2.9Hz, 1H), 5.27
(s, 2H), 4.03 (q, J=7.1Hz, 4H), 3.59 (s, 2H), 3.28 (s, 4H) .ESI-MS (m/z): 572.7 [M+H]+.。
Embodiment 2: synthesis compound 2, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-sulfoxide miscellaneous-6-nitrogen
Miscellaneous-spiral shell [3,3] heptane-6-base) methyl]-furan-2-base]-quinazoline-4-amine
N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[(5-formoxyl) furan-2-base]-4-quinazoline amine (1eq),
2-sulfoxide miscellaneous-6-aza-spiro [3,3] heptane oxalate (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-bis-
Ethyl chloride (keeps solution concentration～0.5mol/L), after half an hour is stirred at room temperature, and addition acetic acid sodium borohydride (2.5eq), 40 DEG C
Stir 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation to react, addition dichloromethane and water dilute reaction solution, separatory, organic
Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H
NMR (400MHz, DMSO) δ 9.95 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.13 (d, J=8.5Hz, 1H), 8.00 (d,
J=2.3Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.73 (d, J=8.9Hz, 1H), 7.48 (d, J=6.3Hz, 1H),
7.41 7.24 (m, 3H), 7.18 (d, J=7.5Hz, 1H), 7.04 (d, J=3.3Hz, 1H), 6.45 (d, J=3.1Hz, 1H),
5.27(s,2H),3.91–3.78(m,2H),3.61(s,2H),3.30(m,2H),3.27(s,4H).ESI-MS(m/z):588.7
[M+H]+.。
Embodiment 3: synthesis compound 3, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-sulfone miscellaneous-6-nitrogen
Miscellaneous-spiral shell [3,3] heptane-6-base) methyl]-furan-2-base]-quinazoline-4-amine
N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[(5-formoxyl) furan-2-base]-4-quinazoline amine (1eq),
2-sulfone miscellaneous-6-aza-spiro [3,3] heptane oxalate (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloro
Ethane (keeps solution concentration～0.5mol/L), after half an hour is stirred at room temperature, adds acetic acid sodium borohydride (2.5eq), and 40 DEG C are stirred
Mix 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane and water dilute reaction solution, separatory, organic facies
Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H
NMR (400MHz, DMSO) δ 9.94 (s, 1H), 8.70 (s, 1H), 8.53 (s, 1H), 8.12 (d, J=8.9Hz, 1H), 7.99 (d,
J=1.8Hz, 1H), 7.75 (dd, J=20.3,8.8Hz, 2H), 7.46 (dd, J=14.1,7.8Hz, 1H), 7.37 7.22 (m,
3H), 7.17 (t, J=8.6Hz, 1H), 7.02 (d, J=2.7Hz, 1H), 6.46 (d, J=2.6Hz, 1H), 5.25 (s, 2H),
4.33(s,4H),3.64(s,2H),3.41(s,4H).ESI-MS(m/z):605.2[M+H]+.。
Embodiment 4: synthesis compound 4, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(1-thia-6-nitrogen
Miscellaneous-spiral shell [3,3] heptane-6-base) methyl]-furan-2-base]-quinazoline-4-amine
N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[(5-formoxyl) furan-2-base]-4-quinazoline amine (1eq),
1-thia-6-aza-spiro [3,3] heptane oxalate (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloro
Ethane (keeps solution concentration～0.5mol/L), after half an hour is stirred at room temperature, adds acetic acid sodium borohydride (2.5eq), and 40 DEG C are stirred
Mix 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane and water dilute reaction solution, separatory, organic facies
Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H
NMR (400MHz, DMSO) δ 9.96 (s, 1H), 8.74 (d, J=13.7Hz, 1H), 8.56 (s, 1H), 8.14 (d, J=8.8Hz,
1H), 8.02 (d, J=2.4Hz, 1H), 7.85 7.70 (m, 2H), 7.48 (dd, J=14.3,7.8Hz, 1H), 7.39 7.26
(m, 3H), 7.19 (t, J=8.7Hz, 1H), 7.05 (dd, J=11.0,3.2Hz, 1H), 6.45 (d, J=2.9Hz, 1H), 5.27
(s,2H),3.75-3.61(m,4H),3.55(s,2H),3.21-2.96(m,4H)；ESI-MS(m/z):572.6[M+H]+。
Embodiment 5: synthesis compound 5, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(1-sulfoxide miscellaneous-6-nitrogen
Miscellaneous-spiral shell [3,3] heptane-6-base) methyl]-furan-2-base]-quinazoline-4-amine
N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[(5-formoxyl) furan-2-base]-4-quinazoline amine (1eq),
1-sulfoxide miscellaneous-6-aza-spiro [3,3] heptane oxalate (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-bis-
Ethyl chloride (keeps solution concentration～0.5mol/L), after half an hour is stirred at room temperature, and addition acetic acid sodium borohydride (2.5eq), 40 DEG C
Stir 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation to react, addition dichloromethane and water dilute reaction solution, separatory, organic
Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H
NMR (400MHz, DMSO) δ 9.95 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.13 (d, J=8.5Hz, 1H), 8.00 (d,
J=2.3Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.73 (d, J=8.9Hz, 1H), 7.48 (d, J=6.3Hz, 1H),
7.41 7.24 (m, 3H), 7.18 (d, J=7.5Hz, 1H), 7.04 (d, J=3.3Hz, 1H), 6.45 (d, J=3.1Hz, 1H),
5.27(s,2H),3.65(s,2H),3.61-3.42(m,4H),2.62-2.50(m,2H),1.92-1.84(m,2H)；ESI-MS
(m/z):588.6[M+H]+。
Embodiment 6: synthesis compound 6, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(1-sulfone miscellaneous-6-nitrogen
Miscellaneous-spiral shell [3,3] heptane-6-base) methyl]-furan-2-base]-quinazoline-4-amine
N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[(5-formoxyl) furan-2-base]-4-quinazoline amine (1eq),
1-sulfone miscellaneous-6-aza-spiro [3,3] heptane oxalate (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloro
Ethane (keeps solution concentration～0.5mol/L), after half an hour is stirred at room temperature, adds acetic acid sodium borohydride (2.5eq), and 40 DEG C are stirred
Mix 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane and water dilute reaction solution, separatory, organic facies
Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H
NMR (400MHz, DMSO) δ 9.94 (s, 1H), 8.70 (s, 1H), 8.53 (s, 1H), 8.12 (d, J=8.9Hz, 1H), 7.99 (d,
J=1.8Hz, 1H), 7.75 (dd, J=20.3,8.8Hz, 2H), 7.46 (dd, J=14.1,7.8Hz, 1H), 7.37 7.22 (m,
3H), 7.17 (t, J=8.6Hz, 1H), 7.02 (d, J=2.7Hz, 1H), 6.46 (d, J=2.6Hz, 1H), 5.25 (s, 2H),
3.90-3.71(m,4H),3.64(s,2H),3.41-3.3.33(m,2H),2.49-2.28(s,2H)；ESI-MS(m/z):
605.1[M+H]+。
Embodiment 7: vitro kinase inhibitory activity is tested
Compound vitro inhibition kinase whose to EGFR and HER2 active testing utilizes the mobility of microfluidic chip technology to examine
Survey technology (Mobility-Shift Assay) completes.EGFR and HER-2 kinases is purchased from Carna Biosciences company.
The mobility detection technique (Mobility-Shift Assay) of microfluidic chip technology is by the base of capillary electrophoresis
This theory is applied in microfluidic environment, and the substrate for experiment is with fluorescently-labeled polypeptide, enzyme in reaction system
Under effect, substrate is changed into product, and its electric charge carried also there occurs corresponding change, and Mobility-Shift Assay is just
Utilize substrate and the charged difference of product, the two is separated, and detects respectively.
The source of strength separated sample in micro-fluid chip is in two different aspects, electrodynamics and liquid
Pressure.During work, the reaction system in 384 orifice plates is inhaled in chip by the suction needle of chip bottom under the effect of negative pressure
In the pipeline in portion.Owing to being applied in voltage on separate lines in chip, with fluorescently-labeled peptide substrate and product
Owing to the difference of electric charge is separated, then carry out exciting and detecting of signal at detection window.When detecting each sample, all
The signal of substrate and product can be simultaneously viewed.The amount of product is by calculating in Conversion value, the i.e. aspect ratio at product peak
Substrate peak and product peak heights sum (Product peak height/ (Substrate+Product peak height)),
It is estimated.
Determine positive drug Lapatinib and synthesized compound respectively at 10000nM, 3333nM, 1111nM,
Press down EGFR and HER-2 is kinase whose under ten variable concentrations of 370nM, 123nM, 41nM, 14nM, 4.6nM, 1.5nM and 0.51nM
System activity.EGFR is used ATP Km value is 2.3 μMs, and HER-2 is used ATP Km value is 7.5 Μ m.It is calculated compound pair
EGFR and HER-2 kinase inhibiting activity IC50Value, concrete outcome is shown in Table 1.Result shows, in the present invention, compound demonstrates preferably
Kinase inhibiting activity, wherein compound 2 and 3 is for EGFR kinase inhibiting activity IC50Value less than 20nM, compound 2 for
HER-2 kinase inhibiting activity IC50Value, less than 7nM, is better than positive control antitumor drug Lapatinib.The compound of the present invention can
To develop EGFR/HER-2 inhibitors of kinases further, as new type antineoplastic medicine.
Table 1 is EGFR and the HER2 kinase whose vitro inhibition Activity Results of the compounds of this invention.
Table 1
Embodiment 8: extracorporeal anti-tumor cytoactive is tested
Take and be in the tumor cell kind of Exponential growth stage in 96 orifice plates, cultivate 24h and make cell attachment, remove supernatant, add
200 μ L/ pore area medicine fresh cultures: compound is dissolved in DMSO or normal saline in advance, when tested with cultivating completely
Base is diluted to desired concn.Each concentration sets 6 multiple holes, and sets blank control wells (only adding culture medium) and negative control, equally
If 6 multiple holes.Continuing to cultivate to the EXPERIMENTAL DESIGN time, terminate cultivating, remove supernatant, every hole adds 10% trichloroacetic acid 200 μ L, and 4
DEG C condition fixes lh.Rinsing 5 times with redistilled water, after naturally drying, every hole adds 4mg/mL SRB solution, dyes under room temperature
15min, abandons supernatant, rinses 5 times with the dyestuff removing non-specific binding with 1% acetic acid.Every hole adds 100 μ L 10mM Tris
Solution, surveys OD value under A490 wavelength, and calculates the measured object suppression ratio to growth of cancer cells by following equation.
And make regression equation with the logarithm of compound concentration and suppression ratio, calculate IC50, result shows, chemical combination in the present invention
Thing all demonstrates preferable antineoplastic activity (as shown in table 2), for NCI-N87 stomach cancer cell, BT-474 breast cancer cell
Anti tumor activity in vitro IC with SKBr-3 breast cancer cell50Value is nM level, and wherein compound 2 is thin for NCI-N87 gastric cancer
The extracorporeal anti-tumor IC of born of the same parents50Value is 12nM, the compound 1-6 extracorporeal anti-tumor IC for BT-474 breast cancer cell50It is worth the least
In 1.6nM, compound 2 is for the extracorporeal anti-tumor IC of SKBr-3 breast cancer cell50Value is 15.3nM, is better than positive control anti-swollen
Tumor medicine Lapatinib, can develop new type antineoplastic medicine further.
Table 2 is the extracorporeal anti-tumor cytoactive result of the compounds of this invention.
Table 2
。
Claims (10)
1. sulfur-bearing 6-furyl quinazoline-4-amines, is characterized in that, described compound is that sulfur-bearing is for quaternary heterocycle or spiral shell
N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-6-(2-furyl) quinazoline-4-aminated compounds of ring structure, tool
There is the structure of logical formula (I),
Wherein X=CH2Time, Y=S or SO or SO2
Y=CH2Time, X=S or SO or SO2。
Sulfur-bearing 6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound
For having the compound 1 of following structure,
Sulfur-bearing 6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound
For having the compound 2 of following structure,
Sulfur-bearing 6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound
For having the compound 3 of following structure,
Sulfur-bearing 6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound
For having the compound 4 of following structure,
Sulfur-bearing 6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound
For having the compound 5 of following structure,
Sulfur-bearing 6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound
For having the compound 6 of following structure,
8. the sulfur-bearing 6-furyl quinazoline-4-amines of claim 1 is in preparing EGFR and HER-2 inhibitors of kinases
Purposes.
9. the sulfur-bearing 6-furyl quinazoline-4-amines of claim 1 purposes in preparation treatment malignant tumor medicine.
10. the purposes according to claim 9, it is characterised in that described malignant tumor is caused by tyrosine kinase functional disorder
Related neoplasms, for the brain cancer, pulmonary carcinoma, renal carcinoma, osteocarcinoma, hepatocarcinoma, bladder cancer, gastric cancer, cancer of pancreas, breast carcinoma, incidence cancer, esophagus
Cancer, carcinoma of prostate, colon cancer, ovarian cancer, cervical cancer or thyroid carcinoma.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2345486A (en) * | 1999-01-11 | 2000-07-12 | Glaxo Group Ltd | Heteroaromatic protein tyrosine kinase inhibitors |
| CN102108079A (en) * | 2009-12-25 | 2011-06-29 | 齐鲁制药有限公司 | 4-anilino quinazoline derivatives serving as tyrosine kinase inhibitors |
| CN102711472A (en) * | 2009-07-02 | 2012-10-03 | 纽金药物公司 | Phosphorus containing quinazoline compounds and methods of use |
| WO2013017073A1 (en) * | 2011-08-01 | 2013-02-07 | 杭州民生药物研究所有限公司 | Quinazoline derivative, composition having the derivative, and use of the derivative in preparing medicament |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2345486A (en) * | 1999-01-11 | 2000-07-12 | Glaxo Group Ltd | Heteroaromatic protein tyrosine kinase inhibitors |
| CN102711472A (en) * | 2009-07-02 | 2012-10-03 | 纽金药物公司 | Phosphorus containing quinazoline compounds and methods of use |
| CN102108079A (en) * | 2009-12-25 | 2011-06-29 | 齐鲁制药有限公司 | 4-anilino quinazoline derivatives serving as tyrosine kinase inhibitors |
| WO2013017073A1 (en) * | 2011-08-01 | 2013-02-07 | 杭州民生药物研究所有限公司 | Quinazoline derivative, composition having the derivative, and use of the derivative in preparing medicament |
Non-Patent Citations (1)
| Title |
|---|
| Kinase Scaffold Repurposing for Neglected Disease Drug Discovery:Discovery of an Efficacious, Lapatanib-Derived Lead Compound for Trypanosomiasis;Gautam Patel等;《Journal of Medicinal Chemistry》;20130418;第56卷(第10期);3820−3832 * |
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