CN103772371A - 6-furyl quinazoline-4-amine compound as well as preparation method and application thereof - Google Patents
6-furyl quinazoline-4-amine compound as well as preparation method and application thereof Download PDFInfo
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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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- C07D491/00—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
- 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
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
The invention belongs to the field of drug synthesis, and relates to 6-furyl quinazoline-4-amines in the general formula I (refer to the Specification), particularly to an N-[3-chlorine-4-[(3-fluorophenyl) methoxyl] phenyl]-6-(2-furyl) quinazoline-4-amine compound with a quaternary heterocyclic ring or a spiral structure, as well as a preparation method and medical application thereof. The compound provided by the invention is subjected to the in vitro EGFR and HER-2 kinase inhibitory activity and antineoplastic activity tests, and the result shows that the compound has excellent EGFR and HER-2 kinase inhibitory activity, and can be used for further preparing a novel antitumor drug.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to novel 6-furyl quinazoline-4-amine compound, preparation method and application.Be specifically related to a kind of chloro-4-[(3-fluorophenyl of N-[3-containing quaternary heterocycle or spirane structure) methoxyl group] phenyl]-6-(2-furyl) quinazoline-4-aminated compounds, and preparation method thereof and in application medically.
Background technology
Malignant tumour has become the common disease of serious harm people's life health.According to incompletely statistics, the whole world approximately has 2,000 ten thousand new cases every year; The annual new cases of China are about 160-200 ten thousand, and dead 1,300,000.Because tumour has the ability of transfer in early days, in clinical diagnosis primary tumo(u)r, approximately 50% patient has produced amphi position transfer, tumor cell growth soon, easily variation, thereby generation multidrug resistance, cause chemotherapy failure, according to the relevent statistics, wherein more than 90% relevant to the multidrug resistance of tumour cell, the antitumor drug of applying clinically at present far can not meet the requirement for the treatment of.
EGF-R ELISA (EGFR) belongs to one of Tyrosylprotein kinase receptor family member, comprises HER1(erbB1, EGFR), HER2(erbB2, NEU), HER3(erbB3) and HER4(erbB4).The physiological processs such as EGFR is distributed widely in the cell surfaces such as Mammals epithelial cell, inoblast, spongiocyte, keratinocyte, growth, propagation and the differentiation of EGFR signal path to cell play an important role.Research shows to exist high expression level or the unconventionality expression of EGFR in many noumenal tumours.EGFR is relevant with propagation, vasculogenesis, tumor invasion, transfer and the apoptotic inhibition of tumour cell.The expression of crossing of EGFR plays an important role in the evolution of malignant tumour, has crossing of EGFR to express in the tissues such as spongiocyte, kidney, lung cancer, prostate cancer, carcinoma of the pancreas, mammary cancer.Therefore, in the past more than 20 year, drugmaker and biotech company be the main target spot using EGF-R ELISA as oncotherapy always.
For the tumour molecular targeted agents of EGFR, be mainly divided into two large classes by its character: a class is monoclonal antibody, as Cetuximab, Victibix, Buddhist nun's trastuzumab etc.; Another kind of is micromolecular inhibitor, as Gefitinib, Tarceva and La Pafeini etc.Wherein the mechanism of action of micromolecular inhibitor is mainly by the phosphorylation site of competitive binding EGFR born of the same parents inner segment Tyrosylprotein kinase, blocks itself and the interaction of ATP, and a series of signal of tyrosine phosphorylation and downstream that then suppresses EGFR conducts.
Wherein lapatinibditosylate is developed the oral two target spot tyrosine kinase inhibitors of a class by GlaxoSmithKline PLC company, can act on two target spots of EGFR and HER-2 simultaneously.Gone on the market by U.S. FDA approval in March, 2007.The indication of checking and approving is at present to treat failed late period or transitivity breast cancer with capecitabine combination therapy for first-line drug.Lapatinibditosylate is a kind of Tyrosylprotein kinase double inhibitor of 4-aniline quinazoline class, can be with the reversibly combination of ATP site in EGFR/HER-2 Tyrosylprotein kinase district, suppress the autophosphorylation in receptor kinase district, thus MARK and the PI3K/AKT path in blocking-up downstream.
Although the small molecules EGFR inhibitor medicaments having gone on the market has shown preferably curative effect, but still exist because toxic side effect is more, medication effect is undesirable separately, easily there is the problems such as medicament-resistant mutation, Given this, present inventor intends providing new molecular targeted small molecules antitumor drug safely and effectively.
Summary of the invention
The object of this invention is to provide new molecular targeted small molecules antitumor drug safely and effectively, be specifically related to have novel 6-furyl quinazoline-4-amine compound of good anti-tumor activity, relate in particular to a kind of chloro-4-[(3-fluorophenyl of N-[3-containing quaternary heterocycle or spirane structure) methoxyl group] phenyl]-6-(2-furyl) quinazoline-4-aminated compounds.
Another object of the present invention is to provide the preparation method of above-mentioned 6-furyl quinazoline-4-amine compound, relates in particular to the N-[3-chloro-4-[(3-fluorophenyl of preparation containing quaternary heterocycle or spirane structure) methoxyl group] phenyl] method of-6-(2-furyl) quinazoline-4-aminated compounds.
6-furyl quinazoline-4-amine compound of the present invention has the structure of following logical formula I:
Wherein R=
or
R
1alkoxyl group or the SO of=a hydroxyl or 1-6 carbon
2cH
3or CN or halogen;
R
2the alkyl of=a H or halogen or 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 the 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
Take compound 9 as example, the preparation process of compound of the present invention is as follows:
Compound of the present invention is by EGFR and the test of HER-2 kinase inhibiting activity and anti tumor activity in vitro test, result shows, described compound has good EGFR and HER-2 kinase inhibiting activity and anti-tumor activity, can further develop as novel antitumor drug.
The present invention suppresses active testing to epidermal growth factor recipient tyrosine kinase EGFR and HER-2, result demonstration, and in the present invention, compound demonstrates good EGFR and HER-2 kinase inhibiting activity, and all compounds are to EGFR kinase inhibiting activity IC
50all be less than 170nM, to HER-2 kinase inhibiting activity IC
50all be less than 100nM, wherein compound 9 is for EGFR kinase inhibiting activity IC
50value is less than 20nM, and compound 9 is for HER-2 kinase inhibiting activity IC
50value is less than 7nM, is better than positive control antitumor drug lapatinibditosylate; Compound 2,6,10,11 and 12 is for EGFR kinase inhibiting activity IC
50value is less than 30nM, and compound 2,3 and 11 is for HER-2 kinase inhibiting activity IC
50value is less than 20nM, approaches with lapatinibditosylate.Compound of the present invention can further be developed EGFR/HER-2 kinase inhibitor.
The present invention studies by Pharmacodynamic, NCI-N87 stomach cancer cell, BT-474 breast cancer cell and SKBr-3 breast cancer cell are carried out to anti tumor activity in vitro test, result shows, in the present invention, compound is for NCI-N87 stomach cancer cell, BT-474 breast cancer cell and SKBr-3 breast cancer cell are had compared with powerful antitumor activity, IC
50value is nM level, and wherein compound 6,7,9 and 11 is for the extracorporeal anti-tumor IC of NCI-N87 stomach cancer cell
50value is all less than 20nM, and compound 6,7,9 and 11 is for the extracorporeal anti-tumor IC of BT-474 breast cancer cell
50value is all less than 10nM, and compound 3,9 and 11 is for the extracorporeal anti-tumor IC of SKBr-3 breast cancer cell
50value is all less than 25nM, similar to positive control antitumor drug lapatinibditosylate; Compound 5 is for the extracorporeal anti-tumor IC of SKBr-3 breast cancer cell
50value is all less than 12nM, is better than lapatinibditosylate, can further develop new type antineoplastic medicine.
In the present invention, the pharmacodynamics test method adopting, is method well-known to those skilled in the art;
In the present invention, EGF-R ELISA (EGFR/HER-2) Tyrosylprotein kinase adopting and cancer of the stomach and breast cancer tumour strain are that art technology can obtain by commercial approach.
The chloro-4-[(3-fluorophenyl of N-[3-of the present invention) methoxyl group] phenyl]-6-(2-furyl) quinazoline-4-amine compound especially can prepare treatment malignant tumor medicine, in view of tyrosine kinase receptor is the transmembrane protein participating on cytolemma that cell signal transforms.They have controls such as Growth of Cells, variation, and the growth factor signal of the critical functions such as vasculogenesis and inhibited apoptosis, passes in cell from cell surface.Tyrosine kinase receptor is wherein EGF-R ELISA (EGFR) Tyrosylprotein kinase, the overexpression in many human tumors of these acceptors, as brain, lung, kidney, liver, bladder, stomach, pancreas, mammary gland, incidence, esophagus, prostate gland, colon, ovary, uterine cervix or Tiroidina.Therefore, malignant tumour of the present invention comprises the related neoplasms due to Tyrosylprotein kinase functional disorder, comprises the cancer of the brain, lung cancer, kidney, osteocarcinoma, liver cancer, bladder cancer, cancer of the stomach, carcinoma of the pancreas, mammary cancer, incidence cancer, esophagus cancer, prostate cancer, colorectal carcinoma, ovarian cancer, cervical cancer or thyroid carcinoma.
Embodiment
Embodiment 1: synthetic compound 1, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3-methoxyl group-azetidine-1-yl) methyl]-furans-2-yl]-quinazoline-4-amine
1) synthetic 6-iodine quinazoline-4-one
Methane amide (5ml) solution of 2-amino-5-iodo-benzoic acid (1g, 3.8mmol) is warming up to 120 ℃ and stirs 4h.Be chilled to room temperature, dilute with 50% ethanol (10ml).Filter, filter cake is used respectively 50% ethanol (5ml), EtOH/PE(1:1,10ml), PE(5ml) washing, vacuum-drying, obtains drabon look solid product (0.9g, 93%).
2) the synthetic chloro-6-iodine of 4-quinazoline
In dry toluene (2ml) solution of 6-iodine quinazoline-4-one (0.54g, 2mmol), add phosphorus oxychloride (0.37g, 2.4mmol), under nitrogen protection, drip triethylamine (0.24g, 2.4mmol), after dripping off, rise to 80 ℃ of leopard lines and stir 2.5h.Reaction solution is cooled to 2 ℃ and stirs 1h, filters.Filter cake washing with acetone, then use 1mol/L aqueous sodium hydroxide solution (3ml) washing, then water and washing with acetone.Vacuum-drying, obtains beige powder (0.5g, 88%)
3) the synthetic chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl] the iodo-quinazoline-4-of-6-amine hydrochlorate
Under nitrogen protection, the stirring and refluxing 3.5h in Virahol (15ml) by chloro-4-6-iodine quinazoline (0.6g, 2mmol) and the chloro-4-of 3-(3-luorobenzyl oxygen base) aniline (0.5g, 2mmol).Be chilled to room temperature, filter, obtain yellow crystal solid (1g, 96%).
4) the synthetic chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine
In the mixed solvent of ethylene dichloride (30ml) and methyl alcohol (15ml), add the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl] the iodo-quinazoline-4-of-6-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 ℃ and stir 16h.Through diatomite filtering palladium carbon, filtrate is concentrated, adds ethyl acetate (120ml), tetrahydrofuran (THF) (60ml), water (20ml) and saturated sodium bicarbonate aqueous solution (20ml) in residuum, stirs 15 minutes.Divide and get organic layer, through saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, vacuum-drying, obtains safran 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) the synthetic chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3-methoxyl group-azetidine-1-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex (1eq) is dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 2, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3-methyl-3-hydroxyl-azetidine-1-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex (1eq) is dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 3, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3-methylsulfonyl-azetidine-1-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex (1eq) is dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 4, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3-cyano group-azetidine-1-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex (1eq) is dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 5, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(3, the fluoro-azetidine-1-of 3-bis-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex (1eq) is dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 6, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-oxa--5-aza-spiro [3,4] octane-5-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex oxalate (1eq; first be neutralized into free state with 1.5eq triethylamine) be dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 7, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-oxa--6-aza-spiro [3,5] nonane-6-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex oxalate (1eq; first be neutralized into free state with 1.5eq triethylamine) be dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 8, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(1-oxa--6-aza-spiro [3,3] heptane-6-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex oxalate (1eq; first be neutralized into free state with 1.5eq triethylamine) be dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 9, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(2-oxa--6-aza-spiro [3,3] heptane-6-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex oxalate (1eq; first be neutralized into free state with 1.5eq triethylamine) be dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 10, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(5-oxa--2-aza-spiro [3,5] nonane-2-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex oxalate (1eq; first be neutralized into free state with 1.5eq triethylamine) be dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 11, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(6-oxa--1-aza-spiro [3,5] heptane-1-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex oxalate (1eq; first be neutralized into free state with 1.5eq triethylamine) be dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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: synthetic compound 12, the chloro-4-of N-[3-(3-fluorine benzyloxy)-phenyl]-6-[5-[(1-oxa--6-aza-spiro [3,4] octane-6-yl) methyl]-furans-2-yl]-quinazoline-4-amine
The chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (1eq), amino-complex oxalate (1eq; first be neutralized into free state with 1.5eq triethylamine) be dissolved in 1; 2-ethylene dichloride (keeping strength of solution ~ 0.5mol/L); after stirring at room temperature half an hour; add acetic acid sodium borohydride (2.5eq), 40 ℃ are stirred 5 hours.Add saturated sodium bicarbonate aqueous solution cancellation reaction, add methylene dichloride and water dilute reaction solution, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, residuum column chromatography purification, obtains safran solid phase prod.
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 suppresses active testing
Compound utilizes the mobility detection technique (Mobility-Shift Assay) of microfluidic chip technology to complete to EGFR and the kinase whose vitro inhibition active testing of HER2.EGFR and HER-2 kinases are purchased from Carna Biosciences company.
The mobility detection technique (Mobility-Shift Assay) of microfluidic chip technology is applied to the basic concept of capillary electrophoresis in microfluidic environment, with fluorescently-labeled polypeptide for the substrate of testing, in reaction system under the effect of enzyme, substrate changes product into, its with electric charge also there is corresponding variation, Mobility-Shift Assay utilizes substrate and the charged difference of product just, the two is separated, and detect respectively.
The source of strength in micro-fluid chip, sample being separated in two different aspect, electrodynamics and liquid pressure.When work, the reaction system in 384 orifice plates is inhaled in the pipeline of chip internal by the suction needle of chip bottom under the effect of negative pressure.On pipeline, be applied in voltage owing to separating in chip, difference separated with fluorescently-labeled peptide substrate and reaction product due to electric charge, then carries out exciting and detecting of signal at detection window.In the time detecting each sample, can see the signal of substrate and product simultaneously.The amount of product is by calculating Conversion value, i.e. substrate peak and product peak heights sum (Product peak height/(Substrate+Product peak height) in the aspect ratio at product peak), assess.
Measure respectively positive drug lapatinibditosylate and synthesized compound at 10000nM, 3333nM, 1111nM, 370nM, 123nM, 41nM, 14nM, 4.6nM, active to EGFR and the kinase whose inhibition of HER-2 under ten different concns of 1.5nM and 0.51nM.It is 2.3 μ M that EGFR is adopted to ATP Km value, and it is 7.5 μ M that HER-2 is adopted to ATP Km value.Calculate compound to EGFR and HER-2 kinase inhibiting activity IC
50value, concrete outcome is in table 1.Result shows, in the present invention, compound demonstrates good kinase inhibiting activity, and all compounds are to EGFR kinase inhibiting activity IC
50all be less than 170nM, to HER-2 kinase inhibiting activity IC
50all be less than 100nM, wherein compound 9 is for EGFR kinase inhibiting activity IC
50value is less than 20nM, and compound 9 is for HER-2 kinase inhibiting activity IC
50value is less than 7nM, is better than positive control antitumor drug lapatinibditosylate; Compound 2,6,10,11 and 12 is for EGFR kinase inhibiting activity IC
50value is less than 30nM, and compound 2,3 and 11 is for HER-2 kinase inhibiting activity IC
50value is less than 20nM, approaches with lapatinibditosylate.Compound of the present invention can further be developed EGFR/HER-2 kinase inhibitor, as new type antineoplastic medicine.
Table 1 is EGFR and the active result of the kinase whose vitro inhibition of HER2 of the compounds of this invention.
Table 1
Embodiment 14: extracorporeal anti-tumor cytoactive test
Get tumour cell kind in Exponential growth stage in 96 orifice plates, cultivate 24 h and make cell attachment, remove supernatant, add 200 μ L/pore area medicine fresh cultures: compound is dissolved in DMSO or physiological saline in advance, in the time of test, be diluted to desired concn with perfect medium.Each concentration is established 6 multiple holes, and establishes blank hole (only adding substratum) and negative control, establishes equally 6 multiple holes.Continue to be cultured to the test design time, stop cultivating, remove supernatant, every hole adds 10% trichoroacetic acid(TCA) 200 μ L, 4 ℃ of fixing l h of condition.With redistilled water flushing 5 times, naturally dry rear every hole and add 4 mg/mL SRB solution, the 15min that dyes under room temperature, abandons supernatant, with 5 times dyestuffs with removal non-specific binding of 1% acetic acid flushing.Every hole adds 100 μ L 10mM Tris solution, surveys OD value under A490 wavelength, and calculates the inhibiting rate of analyte to growth of cancer cells by following formula.
Control group OD value-treatment group OD value
Inhibiting rate=
× 100%
Control group OD value
And make regression equation with logarithm and the inhibiting rate of compound concentration, calculate IC
50, result shows, in the present invention, compound all demonstrates good antineoplastic activity (as shown in table 2), for the anti tumor activity in vitro IC of NCI-N87 stomach cancer cell, BT-474 breast cancer cell and SKBr-3 breast cancer cell
50value is nM level, and wherein compound 6,7,9 and 11 is for the extracorporeal anti-tumor IC of NCI-N87 stomach cancer cell
50value is all less than 20nM, and compound 6,7,9 and 11 is for the extracorporeal anti-tumor IC of BT-474 breast cancer cell
50value is all less than 10nM, and compound 3,9 and 11 is for the extracorporeal anti-tumor IC of SKBr-3 breast cancer cell
50value is all less than 25nM, similar to positive control antitumor drug lapatinibditosylate; Compound 5 is for the extracorporeal anti-tumor IC of SKBr-3 breast cancer cell
50value is all less than 12nM, is better than lapatinibditosylate, can further develop new type antineoplastic medicine.
Table 2 is extracorporeal anti-tumor cytoactive results of the compounds of this invention.
Table 2
| Compound | Suppress the active IC of NCI-N87 stomach cancer cell 50（nM） | Suppress the active IC of BT-474 breast cancer cell 50（nM） | Suppress the active IC of SKBr-3 breast cancer cell 50（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 |
| Lapatinibditosylate | 12.4 | 7.8 | 15.5 |
Claims (16)
1.6-furyl quinazoline-4-amine compound, it is characterized in that, described compound is the chloro-4-[(3-fluorophenyl of N-[3-containing quaternary heterocycle or spirane structure) methoxyl group] phenyl]-6-(2-furyl) quinazoline-4-aminated compounds, there is the structure of general formula (I)
Wherein R=
or
R
1alkoxyl group or the SO of=a hydroxyl or 1-6 carbon
2cH
3or CN or halogen;
R
2the alkyl of=a H or halogen or 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.
2. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 1 with following structure,
1 。
3. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 2 with following structure,
2 。
4. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 3 with following structure,
3 。
5. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 4 with following structure,
4 。
6. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 5 with following structure,
5 。
7. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 6 with following structure,
6 。
8. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 7 with following structure,
7 。
9. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 8 with following structure,
8 。
10. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 9 with following structure,
9 。
11. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 10 with following structure,
10 。
12. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 11 with following structure,
11 。
13. 6-furyl quinazoline-4-amine compound according to claim 1, is characterized in that, described compound is the compound 12 with following structure,
12 。
The purposes of 6-furyl quinazoline-4-amine compound of 14. claims 1 in preparation EGFR and HER-2 kinase inhibitor.
The purposes of 6-furyl quinazoline-4-amine compound of 15. claims 1 in preparation treatment malignant tumor medicine.
16. by the purposes of claim 15, it is characterized in that, described malignant tumour is the related neoplasms due to Tyrosylprotein kinase functional disorder, comprises the cancer of the brain, lung cancer, kidney, osteocarcinoma, liver cancer, bladder cancer, cancer of the stomach, carcinoma of the pancreas, mammary cancer, incidence cancer, esophagus cancer, prostate cancer, colorectal carcinoma, 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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