CN103772371B - 6-furyl quinazoline-4-amines and its production and use - Google Patents
6-furyl quinazoline-4-amines and its production and use Download PDFInfo
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- CN103772371B CN103772371B CN201310156326.9A CN201310156326A CN103772371B CN 103772371 B CN103772371 B CN 103772371B CN 201310156326 A CN201310156326 A CN 201310156326A CN 103772371 B CN103772371 B CN 103772371B
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to pharmaceutical synthesis field, relate to 6 furyl quinazoline 4 amines of logical formula I, particularly relate to a kind of N containing quaternary heterocycle or spirane structure [3 chlorine 4 [(3 fluorophenyl) methoxyl group] phenyl] 6 (2 furyl) quinazoline 4 aminated compounds, and preparation method thereof and application medically.The compound of the present invention is tested by external EGFR and HER 2 kinase inhibiting activity and anti-tumor activity, and result shows, described compound has good EGFR and HER 2 kinase inhibiting activity and anti-tumor activity, can prepare new antitumor drug further.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to novel 6-furyl quinazoline-4-amines, preparation method and should
With.It is specifically related to a kind of N-containing quaternary heterocycle or spirane structure [the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-6-(2-
Furyl) quinazoline-4-aminated compounds, 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 still suffers from due to toxic and side effects
More, independent medication effect is undesirable, the problems such as medicament-resistant mutation easily occurs, in consideration of it, present inventor intends providing new
The most molecular targeted small molecule, anti-tumor drug.
Summary of the invention
It is an object of the invention to provide the most molecular targeted new small molecule, anti-tumor drug, be specifically related to
There is the novel 6-furyl quinazoline-4-amines of good anti-tumor activity, particularly relate to a kind of containing quaternary heterocycle or volution
N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-6-(2-furyl) quinazoline-4-aminated compounds of structure.
It is a further object of the present invention to provide the preparation method of above-mentioned 6-furyl quinazoline-4-amines, especially relate to
And preparation is containing quaternary heterocycle or N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-6-(2-furyl) quinoline of spirane structure
The method of oxazoline-4-aminated compounds.
The 6-furyl quinazoline-4-amines of the present invention has a structure of following logical formula I:
Wherein R=Or
R1=hydroxyl or the alkoxyl of 1-6 carbon or SO2CH3Or CN or halogen；
R2=H or halogen or the alkyl of 1-6 carbon；
A=nitrogenous quaternary carbocyclic ring or nitrogenous five yuan of carbocyclic rings or nitrogenous six-membered carbon ring；
B=oxygen containing quaternary carbocyclic ring or oxygen containing five yuan of carbocyclic rings or oxygen containing six-membered carbon ring；
A ring is connected in volution mode with B ring.
In the present invention, preferred compound has a structure of following compound 1,2,3,4,5,6,7,8,9,10,11,12:
1
2
3
4
5
6
7
8
9
10
11
12
As a example by compound 9, 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 preferable EGFR and HER-2 kinase inhibiting activity, and all compounds are to EGFR kinase inhibition
Activity IC50It is respectively less than 170nM, to HER-2 kinase inhibiting activity IC50Being respectively less than 100nM, wherein compound 9 is for EGFR kinases
Inhibitory activity IC50Value is less than 20nM, and compound 9 is for HER-2 kinase inhibiting activity IC50Value, less than 7nM, is better than positive control
Antitumor drug Lapatinib；Compound 2,6,10,11 and 12 is for EGFR kinase inhibiting activity IC50Value is less than 30nM, chemical combination
Thing 2,3 and 11 is for HER-2 kinase inhibiting activity IC50Value is less than 20nM, close with Lapatinib.The compound of the present invention is permissible
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
6,7,9 and 11 for the extracorporeal anti-tumor IC of NCI-N87 stomach cancer cell50Value be respectively less than 20nM, compound 6,7,9 and 11 for
The extracorporeal anti-tumor IC of BT-474 breast cancer cell50Value is respectively less than 10nM, and compound 3,9 and 11 is thin for SKBr-3 breast carcinoma
The extracorporeal anti-tumor IC of born of the same parents50Value is respectively less than 25nM, similar to positive control antitumor drug Lapatinib；Compound 5 for
The extracorporeal anti-tumor IC of SKBr-3 breast cancer cell50Value is respectively less than 12nM, is better than Lapatinib, can develop new further
Type antitumor drug.
In the present invention, the pharmacodynamics test method used, is method well-known to those skilled in the art；
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.
N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-6-(2-furyl) quinazoline-4-amine compounds of the present invention
Thing especially can prepare treatment malignant tumor medicine, in view of tyrosine kinase receptor is to participate on the cell membrane that cell signal converts
Transmembrane protein.They have control such as cell growth, variation, the growth of the critical function such as angiogenesis and inhibited apoptosis
Factor signal, passes to intracellular from cell surface.Tyrosine kinase receptor therein is EGF-R ELISA (EGFR) cheese
Histidine kinase, the overexpression in many human tumors of these receptors, such as brain, lung, kidney, liver, bladder, stomach, pancreas, mammary gland, head
Cervical region, esophagus, prostate, colon, ovary, cervix uteri or thyroid.Therefore, malignant tumor of the present invention includes tyrosine-kinase
Related neoplasms caused by enzyme functional disorder, including the brain cancer, pulmonary carcinoma, renal carcinoma, osteocarcinoma, hepatocarcinoma, bladder cancer, gastric cancer, cancer of pancreas, mammary gland
Cancer, incidence cancer, esophageal carcinoma, carcinoma of prostate, colon cancer, ovarian cancer, 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-[(3-methoxyl group-azepine
Tetramethylene .-1-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).Filter, 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 concentrates,
Residue adds ethyl acetate (120ml), oxolane (60ml), water (20ml) and saturated sodium bicarbonate aqueous solution
(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 (400 MHz, DMSO) δ 10.11 (s, 1H), 9.66 (s, 1H),
8.96 (s, 1H), 8.58 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.97 (s, 1H), 7.85 (d,
J = 8.8 Hz, 1H), 7.74 (d, J = 3.7 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.46
(dd, J = 14.2, 7.7 Hz, 1H), 7.41 (d, J = 3.7 Hz, 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-[(3-Methoxy-azetidin-1-base) first
Base]-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),
Amine compound (1eq) is dissolved in 1, and 2-dichloroethanes (keeps solution concentration ~ 0.5mol/L), after half an hour is stirred at room temperature, adds
Acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane
With water dilute reaction solution, separatory, organic facies saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, residue column chromatography
Purification, obtains crocus solid product.1H NMR (METHANOL-d4 ,400MHz) δ 8.95 (s, 1 H), 8.74 (s,
1 H), 8.42 (d, J=8.5 Hz, 1 H), 7.86 - 7.98 (m, 2 H), 7.67 (dd, J=8.9, 2.4 Hz,
1 H), 7.05 - 7.47 (m, 7 H), 6.91 (d, J=3.3 Hz, 1 H), 5.28 (s, 2 H), 4.62 (s,
2 H), 4.52 (dd, J=11.3, 6.3 Hz, 2 H), 4.31 - 4.40 (m, 1 H), 4.17 ppm (dd, J=
11.8, 4.0 Hz, 2 H),3.33 (s, 3 H)
Embodiment 2: synthesis compound 2, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3-methyl-3-hydroxyl
Base-azetidine-1-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),
Amine compound (1eq) is dissolved in 1, and 2-dichloroethanes (keeps solution concentration ~ 0.5mol/L), after half an hour is stirred at room temperature, adds
Acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane
With water dilute reaction solution, separatory, organic facies saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, residue column chromatography
Purification, obtains crocus solid product.1H NMR (METHANOL-d4 ,400MHz) δ 8.98 (s, 1 H), 8.79 (s,
1 H), 8.45 (d, J=8.8 Hz, 1 H), 7.86 - 7.99 (m, 2 H), 7.67 (dd, J=8.9, 2.4 Hz,
1 H), 7.16 - 7.49 (m, 5 H), 7.08 (t, J=8.4 Hz, 1 H), 6.91 (d, J=3.3 Hz, 1 H),
5.25 (s, 2 H), 4.62 (s, 2 H), 4.09 - 4.32 (m, 4 H), 1.56 (br. s., 3 H)；13C
NMR (METHANOL-d4 ,101MHz) δ 164.2, 161.8, 159.9, 153.5, 152.8, 150.3, 145.6,
139.4, 139.3, 137.7, 131.8, 130.7, 130.1, 130.0, 126.3, 123.9, 122.6, 122.5,
122.5, 120.0, 118.2, 115.6, 114.4, 114.2, 114.1, 113.6, 113.6, 113.4, 109.1,
69.7, 66.6
Embodiment 3: synthesis compound 3, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3-mesyl-nitrogen
Azetidine-1-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),
Amine compound (1eq) is dissolved in 1, and 2-dichloroethanes (keeps solution concentration ~ 0.5mol/L), after half an hour is stirred at room temperature, adds
Acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane
With water dilute reaction solution, separatory, organic facies saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, residue column chromatography
Purification, obtains crocus solid product.1H NMR (METHANOL-d4 ,400MHz) δ 8.97 (d, J=1.3 Hz, 1 H),
8.78 (s, 1 H), 8.45 (dd, J=8.8, 1.5 Hz, 1 H), 7.84 - 7.98 (m, 2 H), 7.67 (dd,
J=8.8, 2.5 Hz, 1 H), 7.37 - 7.47 (m, 1 H), 7.15 - 7.35 (m, 4 H), 7.08 (td, J=
8.5, 2.1 Hz, 1 H), 6.92 (d, J=3.3 Hz, 1 H), 5.27 (s, 2 H), 4.49 - 4.67 (m, 7
H), 3.08 (s, 3 H)；13C NMR (METHANOL-d4 ,101MHz) δ 164.2, 161.8, 159.9, 153.7,
152.8, 150.5, 145.4, 139.4, 139.4, 138.2, 131.7, 130.6, 130.1, 130.0, 126.3,
123.9, 122.6, 122.5, 122.5, 120.4, 118.2, 115.8, 114.4, 114.2, 114.1, 113.7,
113.6, 113.4, 109.0, 69.7, 52.6, 50.2, 49.4, 37.8。
Embodiment 4: synthesis compound 4, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3-cyano group-azacyclo-
Butane-1-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),
Amine compound (1eq) is dissolved in 1, and 2-dichloroethanes (keeps solution concentration ~ 0.5mol/L), after half an hour is stirred at room temperature, adds
Acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane
With water dilute reaction solution, separatory, organic facies saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, residue column chromatography
Purification, obtains crocus solid product.1H NMR (METHANOL-d4 ,400MHz) δ 8.92 (s, 1 H), 8.74 (s,
1 H), 8.42 (d, J=8.5 Hz, 1 H), 7.85 - 7.98 (m, 2 H), 7.66 (dd, J=8.8, 2.5 Hz,
1 H), 7.40 - 7.51 (m, 1 H), 7.21 - 7.38 (m, 3 H), 7.04 - 7.17 (m, 2 H), 6.76
(br. s., 1 H), 5.29 (s, 2 H), 4.07 - 4.31 (m, 6 H), 3.80 (t, J=7.5 Hz, 1 H)。
Embodiment 5: synthesis compound 5, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3,3-bis-fluoro-azepines
Tetramethylene .-1-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),
Amine compound (1eq) is dissolved in 1, and 2-dichloroethanes (keeps solution concentration ~ 0.5mol/L), after half an hour is stirred at room temperature, adds
Acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add dichloromethane
With water dilute reaction solution, separatory, organic facies saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, residue column chromatography
Purification, obtains crocus solid product.1H NMR (METHANOL-d4 ,400MHz) δ 8.64 (s, 1 H), 8.48 (s,
1 H), 8.16 (dd, J=8.8, 1.5 Hz, 1 H), 7.92 (d, J=2.3 Hz, 1 H), 7.78 (d, J=8.8
Hz, 1 H), 7.62 (dd, J=8.8, 2.5 Hz, 1 H), 7.37 - 7.47 (m, 1 H), 7.23 - 7.35
(m, 2 H), 7.04 - 7.19 (m, 2 H), 6.95 (d, J=3.3 Hz, 1 H), 6.51 (d, J=3.3 Hz, 1
H), 5.22 (s, 2 H), 3.89 (s, 2 H), 3.78 (t, J=12.2 Hz, 4 H)；13C NMR (METHANOL-
d4 ,101MHz) δ 164.2, 161.8, 153.9, 152.8, 151.4, 151.1, 148.1, 139.8, 132.5,
130.0, 129.9, 129.3, 127.2, 125.2, 122.7, 116.1, 115.5, 114.3, 113.6, 111.1,
107.3, 77.1, 69.8, 63.8, 53.4。
Embodiment 6: synthesis compound 6, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-oxa--5-nitrogen
Miscellaneous-spiral shell [3,4] octane-5-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),
Amine compound oxalates (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloroethanes (keeps solution dense
Degree ~ 0.5mol/L), after half an hour is stirred at room temperature, add acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated
Sodium bicarbonate aqueous solution cancellation is reacted, and adds dichloromethane and water dilute reaction solution, separatory, and organic facies saturated common salt is washed
Washing, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H NMR (METHANOL-
d4 ,400MHz) δ 8.47 (s, 1 H), 8.42 (s, 1 H), 7.99 - 8.06 (m, 1 H), 7.86 (d, J=
2.5 Hz, 1 H), 7.67 (d, J=8.8 Hz, 1 H), 7.54 (dd, J=8.9, 2.4 Hz, 1 H), 7.36
(dd, J=7.9, 6.1 Hz, 1 H), 7.16 - 7.29 (m, 2 H), 6.97 - 7.07 (m, 2 H), 6.86
(d, J=3.3 Hz, 1 H), 6.42 (d, J=3.3 Hz, 1 H), 5.09 (s, 2 H), 4.55 (d, J=7.0
Hz, 2 H), 4.04 - 4.11 (m, 2 H),2.78 (t, J=7.0 Hz, 2 H), 2.16 - 2.25 (m, 2 H),
1.68 - 1.81 (m, 2 H), 1.21 - 1.40 (m, 2 H)；13C NMR (METHANOL-d4 ,101MHz) δ
174.0, 164.2, 161.7, 158.1, 153.7, 153.3, 150.9, 147.7, 139.7, 132.5, 130.0,
129.3, 128.8, 127.0, 124.7, 122.4, 115.7, 115.3, 114.3, 113.7, 113.3, 110.3,
107.4, 79.2, 69.7, 66.4, 51.6, 45.6, 36.3, 20.1, 19.5。
Embodiment 7: synthesis compound 7, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-oxa--6-nitrogen
Miscellaneous-spiral shell [3,5] nonane-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),
Amine compound oxalates (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloroethanes (keeps solution dense
Degree ~ 0.5mol/L), after half an hour is stirred at room temperature, add acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated
Sodium bicarbonate aqueous solution cancellation is reacted, and adds dichloromethane and water dilute reaction solution, separatory, and organic facies saturated common salt is washed
Washing, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H NMR (METHANOL-
d4 ,400MHz) δ 8.67 (d, J=1.3 Hz, 1 H), 8.49 (s, 1 H), 8.20 (dd, J=8.8, 1.5
Hz, 1 H), 7.93 (d, J=2.3 Hz, 1 H), 7.80 (d, J=8.8 Hz, 1 H), 7.63 (dd, J=8.8,
2.5 Hz, 1 H), 7.24 - 7.48 (m, 3 H), 7.18 (d, J=9.0 Hz, 1 H), 7.08 (td, J=8.5,
2.1 Hz, 1 H), 6.98 (d, J=3.3 Hz, 1 H), 6.52 (d, J=3.3 Hz, 1 H), 5.24 (s, 2
H), 4.83 (br. s., 1 H), 4.58 (br. s., 1 H), 4.43 (d, J=6.5 Hz, 2 H), 4.00 (s,
2 H), 2.63 - 2.73 (m, 2 H), 1.96 - 2.03 (m, 2 H), 1.50 - 1.69 (m, 4 H)。
Embodiment 8: synthesis compound 8, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(1-oxa--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),
Amine compound oxalates (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloroethanes (keeps solution dense
Degree ~ 0.5mol/L), after half an hour is stirred at room temperature, add acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated
Sodium bicarbonate aqueous solution cancellation is reacted, and adds dichloromethane and water dilute reaction solution, separatory, and organic facies saturated common salt is washed
Washing, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H NMR (METHANOL-
d4 ,400MHz) δ 8.50 (br. s., 1 H), 8.40 (s, 1 H), 7.98 (d, J=8.8 Hz, 1 H),
7.87 (d, J=2.3 Hz, 1 H), 7.64 (d, J=8.8 Hz, 1 H), 7.56 (dd, J=8.8, 2.3 Hz, 1
H), 7.31 - 7.39 (m, 1 H), 7.14 - 7.26 (m, 2 H), 6.94 - 7.06 (m, 2 H), 6.86
(d, J=3.0 Hz, 1 H), 6.56 (d, J=3.0 Hz, 1 H), 5.05-5.10 (m, 2 H),4.44 - 4.54
(m, 2 H), 4.03 - 4.10 (m, 4 H), 3.86 (d, J=11.3 Hz, 2 H), 2.87 (t, J=7.5 Hz,
2 H)。
Embodiment 9: synthesis compound 9, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-oxa--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),
Amine compound oxalates (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloroethanes (keeps solution dense
Degree ~ 0.5mol/L), after half an hour is stirred at room temperature, add acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated
Sodium bicarbonate aqueous solution cancellation is reacted, and adds dichloromethane and water dilute reaction solution, separatory, and organic facies saturated common salt is washed
Washing, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H NMR (400 MHz,
DMSO) δ 9.95 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H),
8.00 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.73 (dd, J = 8.9, 2.5
Hz, 1H), 7.48 (dd, J = 14.1, 7.9 Hz, 1H), 7.39 – 7.23 (m, 3H), 7.19 (t, J =
8.3 Hz, 1H), 7.03 (d, J = 3.3 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 5.27 (s,
2H), 4.61 (s, 4H), 3.59 (s, 2H), 3.38 (s, 4H). ESI-MS (m/z): 556.7 [M+H] +。
Embodiment 10: synthesis compound 10, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(5-oxa--2-nitrogen
Miscellaneous-spiral shell [3,5] nonane-2-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),
Amine compound oxalates (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloroethanes (keeps solution dense
Degree ~ 0.5mol/L), after half an hour is stirred at room temperature, add acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated
Sodium bicarbonate aqueous solution cancellation is reacted, and adds dichloromethane and water dilute reaction solution, separatory, and organic facies saturated common salt is washed
Washing, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H NMR (METHANOL-
d4 ,400MHz) δ 8.55 (br. s., 1 H), 8.37 - 8.43 (m, 1 H), 7.84 - 8.05 (m, 2 H),
7.52 - 7.69 (m, 2 H), 7.34 (d, J=1.8 Hz, 1 H), 7.13 - 7.27 (m, 2 H), 6.86 -
7.05 (m, 3 H), 6.67 (d, J=3.0 Hz, 1 H), 5.20 (m, 2 H), 4.29 (br. s., 2 H),
3.95 (d, J=10.3 Hz, 2 H), 3.84 (d, J=10.3 Hz, 2 H), 3.63 (d, J=4.0 Hz, 2 H),
1.79 (d, J=5.0 Hz, 2 H), 1.61 (br. s., 2 H), 1.49 ppm (br. s., 2 H)；13C NMR
(METHANOL-d4 ,101MHz) δ 174.8, 164.1, 161.7, 158.0, 154.0, 150.7, 147.9,
146.6, 139.7, 132.5, 130.0, 128.8, 128.4, 127.0, 124.6, 122.4, 116.8, 115.3,
114.3, 113.6, 107.5, 72.0, 69.6, 63.7, 62.8, 51.6, 32.3, 24.6, 20.3。
Embodiment 11: synthesis compound 11, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(6-oxa--1-nitrogen
Miscellaneous-spiral shell [3,5] heptane-1-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),
Amine compound oxalates (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloroethanes (keeps solution dense
Degree ~ 0.5mol/L), after half an hour is stirred at room temperature, add acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated
Sodium bicarbonate aqueous solution cancellation is reacted, and adds dichloromethane and water dilute reaction solution, separatory, and organic facies saturated common salt is washed
Washing, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H NMR (METHANOL-
d4 ,400MHz) δ 8.65 (d, J=1.3 Hz, 1 H), 8.48 (s, 1 H), 8.10 (dd, J=8.8, 1.5
Hz, 1 H), 7.99 (d, J=2.5 Hz, 1 H), 7.73 (d, J=8.8 Hz, 1 H), 7.61 (dd, J=9.0,
2.5 Hz, 1 H), 7.36 - 7.46 (m, 1 H), 7.22 - 7.33 (m, 2 H), 7.02 - 7.15 (m, 2
H), 6.90 (d, J=3.3 Hz, 1 H), 6.46 (d, J=3.3 Hz, 1 H), 5.15 - 5.22 (m, 4 H),
4.73 (d, J=7.5 Hz, 2 H), 3.91 (s, 2 H), 3.26 (t, J=7.0 Hz, 2 H), 2.49 ppm (t,
J=6.9 Hz, 2 H)；13C NMR (METHANOL-d4 ,101MHz) δ 164.2, 161.8, 158.1, 153.9,
152.3, 152.0, 150.8, 148.0, 139.8, 139.7, 132.7, 130.0, 129.9, 129.2, 128.6,
127.2, 124.3, 122.5, 122.4, 121.7, 115.7, 115.4, 114.3, 114.1, 113.9, 113.6,
113.3, 110.2, 107.2, 81.1, 69.8, 69.1, 28.9。
Embodiment 12: synthesis compound 12, N-[the chloro-4-of 3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(1-oxa--6-nitrogen
Miscellaneous-spiral shell [3,4] octane-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),
Amine compound oxalates (1eq, first with in 1.5eq triethylamine with become free state) be dissolved in 1,2-dichloroethanes (keeps solution dense
Degree ~ 0.5mol/L), after half an hour is stirred at room temperature, add acetic acid sodium borohydride (2.5eq), 40 DEG C are stirred 5 hours.Add saturated
Sodium bicarbonate aqueous solution cancellation is reacted, and adds dichloromethane and water dilute reaction solution, separatory, and organic facies saturated common salt is washed
Washing, anhydrous sodium sulfate is dried, and concentrates, and residue column chromatography is purified, and obtains crocus solid product.1H NMR (METHANOL-
d4 ,400MHz) δ 8.47 (br. s., 1 H), 8.37 (s, 1 H), 7.93 (d, J=8.5 Hz, 1 H),
7.86 (d, J=2.0 Hz, 1 H), 7.50 - 7.63 (m, 2 H), 7.32 (d, J=7.3 Hz, 1 H), 7.11
- 7.23 (m, 2 H), 6.78 - 7.02 (m, 3 H), 6.55 (d, J=2.5 Hz, 1 H), 5.00 (br. s.,
2 H), 4.43 (t, J=7.5 Hz, 2 H), 4.06 (d, J=5.0 Hz, 2 H), 3.42 (d, J=12.0 Hz, 1
H), 3.22 (d, J=12.0 Hz, 1 H), 3.05 - 3.13 (m, 2 H), 2.67 - 2.84 (m, 2 H),
2.39 (d, J=6.5 Hz, 1 H), 2.17 - 2.29 (m, 1 H)；13C NMR (METHANOL-d4 ,101MHz) δ
175.0, 164.1, 161.6, 157.9, 153.8, 153.4, 150.6, 148.3, 147.8, 139.6, 132.5,
130.0, 128.7, 126.9, 124.5, 122.4, 122.0, 116.5, 115.2, 114.3, 113.6, 107.5,
90.7, 69.6, 65.2, 64.0, 51.9, 50.8, 38.1, 30.2, 20.3。
Embodiment 13: 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 into chip by the suction needle of chip bottom under the effect of negative pressure
In internal pipeline.Owing to being applied in voltage on separate lines in chip, produce with fluorescently-labeled peptide substrate and reaction
Thing is separated due to the difference of electric charge, then carries out exciting and detecting of signal at detection window.When detecting each sample,
The signal of substrate and product can be simultaneously viewed.The amount of product is by calculating Conversion value, the i.e. aspect ratio at product peak
Upper 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 μMs.It is calculated chemical combination
Thing is to 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, all compounds are to EGFR kinase inhibiting activity IC50It is respectively less than 170nM, to HER-2 kinase inhibition
Activity IC50Being respectively less than 100nM, wherein compound 9 is for EGFR kinase inhibiting activity IC50Value less than 20nM, compound 9 for
HER-2 kinase inhibiting activity IC50Value, less than 7nM, is better than positive control antitumor drug Lapatinib；Compound 2,6,10,11
With 12 for EGFR kinase inhibiting activity IC50Value is less than 30nM, and compound 2,3 and 11 is for HER-2 kinase inhibiting activity IC50
Value is less than 20nM, close with Lapatinib.The compound of the present invention can develop EGFR/HER-2 kinase inhibition further
Agent, 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 14: extracorporeal anti-tumor cytoactive is tested
Take and be in the tumor cell kind of Exponential growth stage in 96 orifice plates, cultivate 24 h and make cell attachment, remove supernatant, add
200 μ L/pore area medicine fresh culture: compound is dissolved in DMSO or normal saline in advance, when tested with training completely
Foster base is diluted to desired concn.Each concentration sets 6 multiple holes, and sets blank control wells (only adding culture medium) and negative control, with
Sample sets 6 multiple holes.Continuing to cultivate to the EXPERIMENTAL DESIGN time, terminate cultivating, remove supernatant, every hole adds 10% trichloroacetic acid 200 μ
L, 4 DEG C of conditions fix l h.Rinsing 5 times with redistilled water, after naturally drying, every hole adds 4 mg/mL SRB solution, room temperature
Lower dyeing 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.
Matched group OD value-treatment group OD value
Suppression ratio= ×100%
Matched group OD value
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 6,7,9 and 11 is for NCI-
The extracorporeal anti-tumor IC of N87 stomach cancer cell50Value is respectively less than 20nM, and compound 6,7,9 and 11 is for BT-474 breast cancer cell
Extracorporeal anti-tumor IC50Value is respectively less than 10nM, and compound 3,9 and 11 is for the extracorporeal anti-tumor IC of SKBr-3 breast cancer cell50
Value is respectively less than 25nM, similar to positive control antitumor drug Lapatinib；Compound 5 is for the body of SKBr-3 breast cancer cell
Outer antitumor IC50Value is respectively less than 12nM, is better than 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
| Compound | Suppression NCI-N87 gastric cancer cell activity IC50(nM) | Suppression BT-474 breast cancer cell activity IC50(nM) | Suppression SKBr-3 breast cancer cell activity IC50(nM) |
| 1 | 158 | 45.3 | 128 |
| 2 | 49.5 | 28.0 | 32.2 |
| 3 | 36.3 | 17.7 | 24.1 |
| 4 | 221 | 94.7 | 855 |
| 5 | 29.9 | 12.2 | 11.9 |
| 6 | 20.7 | 9.6 | 35.2 |
| 7 | 15.1 | 9.6 | 27.9 |
| 8 | 158 | 45.3 | 128 |
| 9 | 16.9 | 10.0 | 18.7 |
| 10 | 104 | 35.4 | 222 |
| 11 | 19.0 | 9.7 | 24.1 |
| 12 | 65.7 | 17.6 | 55.5 |
| Lapatinib | 12.4 | 7.8 | 15.5 |
Claims (11)
1.6-furyl quinazoline-4-amines, is characterized in that, described compound is containing quaternary heterocycle or spirane structure
N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-6-(2-furyl) quinazoline-4-aminated compounds, has logical formula (I)
Structure,
Wherein
The oxygen containing saturated quaternary carbocyclic ring of A=or oxygen containing saturated five yuan of carbocyclic rings or oxygen containing saturated six-membered carbon ring
Saturated quaternary carbocyclic ring that B=is nitrogenous or nitrogenous saturated five yuan of carbocyclic rings or nitrogenous saturated six-membered carbon ring
A ring is connected in volution mode with B ring.
6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound is tool
There is the compound 6 of following structure,
6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound is tool
There is the compound 7 of following structure,
6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound is tool
There is the compound 8 of following structure,
6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound is tool
There is the compound 9 of following structure,
6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound is tool
There is the compound 10 of following structure,
6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound is tool
There is the compound 11 of following structure,
6-furyl quinazoline-4-amines the most according to claim 1, is characterized in that, described compound is tool
There is the compound 12 of following structure,
9. the 6-furyl quinazoline-4-amines of claim 1 use in preparing EGFR and HER-2 inhibitors of kinases
On the way.
10. the 6-furyl quinazoline-4-amines of claim 1 purposes in preparation treatment malignant tumor medicine.
11. purposes according to claim 10, 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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| CN101108848A (en) * | 2006-07-20 | 2008-01-23 | 复旦大学 | Furoquinoline compound and application of the same in manufacturing anti-virus medicament |
| US20080234267A1 (en) * | 2007-03-20 | 2008-09-25 | Karen Elizabeth Lackey | Compounds and Methods of Treatment |
| 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 |
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|---|---|---|---|---|
| CN101108848A (en) * | 2006-07-20 | 2008-01-23 | 复旦大学 | Furoquinoline compound and application of the same in manufacturing anti-virus medicament |
| US20080234267A1 (en) * | 2007-03-20 | 2008-09-25 | Karen Elizabeth Lackey | Compounds and Methods of Treatment |
| 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 |
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