CN106432202B - Quinazoline derivative and its application - Google Patents
Quinazoline derivative and its application Download PDFInfo
- Publication number
- CN106432202B CN106432202B CN201610839689.6A CN201610839689A CN106432202B CN 106432202 B CN106432202 B CN 106432202B CN 201610839689 A CN201610839689 A CN 201610839689A CN 106432202 B CN106432202 B CN 106432202B
- Authority
- CN
- China
- Prior art keywords
- methyl
- base
- nitro
- imidazoles
- quinazoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
The invention belongs to field of medicinal chemistry, and in particular to a kind of 4- anilinoquinazoline analog derivative containing 1- methyl -2- nitro -5- methylene imidazoles, structure are as follows:；Wherein, R1ForOr-(CH2)nR6, n=2,3,4,5 or 6, R6For morpholinyl, piperidyl, pyrrolidinyl, piperazinyl or dimethylamino；R2ForOr hydrogen；R3、R4And R5It is each independently selected from hydrogen, chlorine, fluorine, bromine, acetenyl or trifluoromethyl.Pharmacological evaluation shows that such compound and its pharmaceutically acceptable salt have the function of inhibiting tumor cell proliferation.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to 4- of the one kind containing 1- methyl -2- nitro -5- methylene imidazoles
Anilinoquinazoline analog derivative and its purposes in therapeutic field of tumor.
Background technique
EGF-R ELISA (epidermal growth factor receptor, EGFR) is a kind of in cell letter
The kinases to play a significant role in breath transmitting.EGFR overexpression with it is a variety of including non-small cell type lung cancer, colon cancer
The occurrence and development of solid tumor are closely related.In recent years, using EGFR as therapy target, two class drugs are rapidly developed, i.e., singly
Clonal antibody and micromolecular inhibitor.In micromolecular inhibitor, representative drug is 4- anilinoquinazoline derivatives, they
Played in the treatment of tumour huge effect (W. Cheng, et al., Curr. Med. Chem., 2014,21,
4374-4404；R. Roskoski, Pharmacol. Res., 2014,79,34-74).
In addition, the occurrence and development of solid tumor make it inevitably produce low-oxygen environment, for tumor hypoxia environment, greatly
The Bioreductive drugs of amount are developed, and 2- nitro imidazole derivatives are one such.In the normal tissue, due to
Oxygen is sufficient, the presence that 2- nitroimidazole can be stable, and in tumor tissues, in the double action of low-oxygen environment and reductase
Under, 2- nitroimidazole is reduced activation, generates lethal effect (L. J. O ' Connor, Org. Chem. to tumour cell
Front., 2015,2,1026-1029).2- nitroimidazole is introduced into 4- anilinoquinazoline class compound similar to object,
Obtained recruit exists in the form of raw medicine in the normal tissue, does not have physiological activity.In tumor tissues, low-oxygen environment makes
2- nitroimidazole group in molecule is reduced activation, generates lethal effect to tumour cell, meanwhile, the molecule after reduction activation
4- anilinoquinazoline class raw medicine is released, targeted inhibition effect is generated to tumour again.Therefore, the 4- containing 2- nitroimidazole
Anilinoquinazoline analog derivative have dual antineoplastic action (J.X. Duan, et al., J. Med. Chem.,
2008,51,2412-2420).
Summary of the invention
It is an object of that present invention to provide the quinazoline derivatives that a kind of pair of tumour cell has inhibited proliferation.
It is a further object to provide purposes of the above-mentioned quinazoline derivative in medicine and pharmacology.
To achieve the above object, the present invention adopts the following technical scheme:
Quinazoline derivative and its pharmaceutically acceptable salt provided by the invention, have the following structure general formula:
,
Wherein, R1ForOr-(CH2)nR6, n=2,3,4,5 or 6, R6For morpholinyl, piperidyl, pyrrolidinyl,
Piperazinyl or dimethylamino；
R2ForOr hydrogen；
R3、R4And R5It is each independently selected from hydrogen, chlorine, fluorine, bromine, acetenyl or trifluoromethyl.
Quinazoline derivative and its pharmaceutically acceptable salt of the present invention, can selected from following compounds it
One:
N- (the chloro- 4- fluorophenyl of 3-) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group] quinoline azoles
Quinoline -4- amine；
N- (3- bromophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group] quinazoline -4-
Amine；
N- (3- ethynyl phenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group] quinoline azoles
Quinoline -4- amine；
N- (the chloro- 4- fluorophenyl of 3-) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group]-N-
[(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine；
N- (3- bromophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group]-N- [(1- first
Base -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine；
N- (3- ethynyl phenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group]-N-
[(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine；
N- (the chloro- 4- fluorophenyl of 3-) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] -6- (3-
Morpholinopropoxy) quinazoline -4- amine；
N- (3- bromophenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] -6- (3- morpholine
Base propoxyl group) quinazoline -4- amine；
N- (3- ethynyl phenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] -6- (3-
Morpholinopropoxy) quinazoline -4- amine.
Above-mentioned quinazoline derivative or its pharmaceutically acceptable salt are preparing the application in anticancer drug.
Above-mentioned quinazoline derivative or its pharmaceutically acceptable salt are in preparation prevention and treatment lung-cancer medicament or knot
Application in bowelcancer medicine.
The present invention has stronger targeting and dual antitumor work compared with existing EGFR type small molecular inhibitor
With.
Specific embodiment
Technical solution of the present invention is further discussed in detail with reference to embodiments, but protection scope of the present invention
It is not limited thereto.
Embodiment 1:4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (1)
Reference literature method (W. Cheng, et al., Eur. J. Med. Chem., 2015,89,826-834) is made.
It is specific as follows: 10 mL methanol are added in 1.0 g 4- (the chloro- 4- fluoroanilino of 3-) -6- acetoxyl group -7- methoxyquinazoline hydrochloride
In, (25%) 0.5 mL of concentrated ammonia liquor is added, 3 h are reacted at room temperature.Processing: filtering, and filter cake is eluted with cold methanol, collects, and does
It is dry, obtain white solid.Yield: > 95%.Fusing point: > 250 DEG C.ESI-MS m/z: 320 [M+H]+。
Embodiment 2:4- (3- bromobenzene amido) -6- hydroxyl -7- methoxyquinazoline hydrochloride (2)
Preparation method is referring to embodiment 1, wherein is replaced with 4- (3- bromobenzene amido) -6- acetoxyl group -7- methoxyquinazoline hydrochloride
For 4- (the chloro- 4- fluoroanilino of 3-) -6- acetoxyl group -7- methoxyquinazoline hydrochloride, white solid is obtained.Yield: > 95%.Fusing point:
111 -113℃。ESI-MS m/z: 346 [M+H]+。
Embodiment 3:4- (3- acetylene anilino-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (3)
Preparation method is referring to embodiment 1, wherein uses 4- (3- acetylene anilino-) -6- acetoxyl group -7- methoxyquinazoline hydrochloride
4- (the chloro- 4- fluoroanilino of 3-) -6- acetoxyl group -7- methoxyquinazoline hydrochloride is substituted, obtains white solid, yield: 93%.Fusing point:
238 - 240℃。ESI-MS m/z: 292 [M+H]+。
Embodiment 4:4- (the chloro- 4- fluoroanilino of 3-) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride (4)
Reference literature method (W. Cheng, et al., Eur. J. Med. Chem., 2015,89,826-834) is made.
Specifically: by 64mg(0.20mmol) 4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (1) and 50mg
(0.24mmol) 4- (3- bromopropyl) morpholine is added in 3mL dimethylformamide (DMF), adds 14mg(0.10 mmol)
K2CO3, reaction system is in 70 DEG C of reaction 12h.Processing: being concentrated under reduced pressure, concentrate saturated salt solution and methylene chloride (volume ratio
It 1:1) extracts, collects organic phase, concentration dry with anhydrous sodium sulfate, pillar layer separation (VMethylene chloride: VMethanol=100:3), it obtains white
Solid.Yield: 78%.Fusing point: 193-195 DEG C.ESI-MS m/z: 447 [M+H]+。
Embodiment 5:4- (3- bromobenzene amido) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride (5)
Preparation method is referring to embodiment 4, wherein is replaced with 4- (3- bromobenzene amido) -6- hydroxyl -7- methoxyquinazoline hydrochloride (2)
For 4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (1), white solid is obtained, yield: 81%.Fusing point: 203-
205℃。ESI-MS m/z: 475 [M+H]+。
Embodiment 6:4- (3- acetylenylbenzene amido) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride (6)
Preparation method is referring to embodiment 4, wherein uses 4- (3- acetylene anilino-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (3)
4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (1) is substituted, obtains white solid, yield: 84%.Fusing point: 167
- 169℃。ESI-MS m/z: 419 [M+H]+。
Embodiment 7:1- methyl -2- nitro -5- hydroxy methylimidazole (7)
Reference literature (L.J. O ' Connor, Org. Chem. Front., 2015,2,1026-1029) is made.It is molten
Point: 136-138 DEG C.ESI-MS m/z: 158 [M+H]+。
Embodiment 8:1- methyl -2- nitro -5- chloromethyl imidazoles (8)
Reference literature (L.J. O ' Connor, Org. Chem. Front., 2015,2,1026-1029) is made.It is molten
Point: 121-123 DEG C.ESI-MS m/z: 176 [M+H]+。
Embodiment 9:N- (the chloro- 4- fluorophenyl of 3-) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Oxygroup] quinazoline -4- amine (Ia)
By 4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (1) (64mg, 0.2mmol), 1- methyl -
2- nitro -5- hydroxy methylimidazole (7) (32mg, 0.2mmol) and triphenyl phosphorus (105mg, 0.4mmol) are dissolved in DMF(3mL) in,
N,N-diisopropylethylamine (DIEA, 52mg, 0.4mmol) is added under ice bath, to be added to finish, normal-temperature reaction 5h.Processing: decompression
DMF, residue water and methylene chloride (volume ratio 1:1) extraction are removed, organic phase is collected, pillar layer separation obtains white solid,
Yield 59%, fusing point: 178-180 DEG C.1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.69 (dd, J =
6.5, 2.7 Hz, 1H), 7.47 – 7.35 (m, 1H), 7.28 (s, 2H), 7.09 (s, 1H), 7.07 (s,
1H), 6.61 (s, 1H), 5.40 (s, 2H), 4.75 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H),
3.82 (s, 3H)。ESI-MS m/z: 459 [M+H]+。
Embodiment 10:N- (3- bromophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group]
Quinazoline -4- amine (Ib)
Preparation method is referring to embodiment 9, wherein by 4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride
(1) it is changed to 4- (3- bromobenzene amido) -6- hydroxyl -7- methoxyquinazoline hydrochloride (2).White solid is obtained, yield: 62%, fusing point:
151-153℃。1H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.20 (s, 1H), 8.55 (s,
1H), 8.07 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.35 – 7.22 (m, 3H), 7.10 (s,
1H), 5.49 (s, 2H), 4.00 (s, 3H), 3.90 (s, 3H)。ESI-MS m/z: 487 [M+H]+。
Embodiment 11:N- (3- ethynyl phenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Oxygroup] quinazoline -4- amine (Ic)
Preparation method is referring to embodiment 9, wherein by 4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride
(1) it is changed to 4- (3- acetylene anilino-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (3).White solid is obtained, yield: 53%, fusing point:
184-186℃。1H NMR (500 MHz, DMSO) δ 9.55 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H),
7.84 (s, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.27 (s, 1H), 7.23-7.18 (m, 2H), 5.27
(s, 2H), 4.20 (s, 1H), 3.92 (s, 3H), 3.88 (s, 3H)。ESI-MS m/z: 431 [M+H]+。
Embodiment 12:N- (the chloro- 4- fluorophenyl of 3-) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Oxygroup]-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine (Id)
By 4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (1) (64mg, 0.2mmol) and 1- methyl -
2- nitro -5- chloromethyl imidazoles (8) (74mg, 0.42mmol) is dissolved in DMF(3mL) in, add potassium carbonate (28mg,
0.2mmol), it reacts at room temperature overnight (12h).Processing: decompression removal solvent, residue water and methylene chloride (volume ratio 1:1)
Extraction, collects organic phase, and pillar layer separation obtains yellow solid, yield 41%, fusing point: 79-81 DEG C.1H NMR (500 MHz,
DMSO) δ 9.07 (s, 1H), 9.00 (s, 1H), 8.08 (dd, J = 6.8, 2.5 Hz, 1H), 7.82 (m,
1H), 7.59 (m, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 6.05 (s, 2H),
5.63 (s, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.98 (s, 3H)。ESI-MS m/z: 598 [M+H
]+。
Embodiment 13:N- (3- bromophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxy
Base]-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine (Ie)
Preparation method is referring to embodiment 12, wherein by 4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride
(1) it is changed to 4- (3- bromobenzene amido) -6- hydroxyl -7- methoxyquinazoline hydrochloride (2).Yellow solid is obtained, yield: 45%, fusing point: 64-
66℃。1H NMR (500 MHz, DMSO) δ 8.71 (s, 1H), 8.23 (s, 1H), 7.95-7.78 (m, 2H),
7.46 (s, 1H), 7.39-7.15 (m, 3H), 6.63 (s, 1H), 5.43 (s, 2H), 4.77 (s, 2H),
3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H)。ESI-MS m/z: 626 [M+H]+。
Embodiment 14:N- (3- ethynyl phenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Oxygroup]-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine (If)
The preparation method is the same as that of Example 12, and 4- (the chloro- 4- fluoroanilino of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (1) is replaced
For 4- (3- acetylene anilino-) -6- hydroxyl -7- methoxyquinazoline hydrochloride (3).Yellow solid is obtained, yield: 47%, fusing point: 73-75 DEG C
。1H NMR (500 MHz, DMSO) δ 8.72 (s, 1H), 7.52 (s, 1H), 7.44 – 7.36 (m, 2H),
7.34 – 7.29 (m, 1H), 7.26 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 6.54 (s, 1H),
5.46 (s, 2H), 4.61 (s, 2H), 4.28 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.81
(s, 3H)。ESI-MS m/z: 570 [M+H]+。
Embodiment 15:N- (the chloro- 4- fluorophenyl of 3-) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Base] -6- (morpholinyl propoxyl group) quinazoline -4- amine (Ig)
By 4- (the chloro- 4- fluoroanilino of 3-) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride (4) (90mg,
0.2mmol) and 1- methyl -2- nitro -5- chloromethyl imidazoles (8) (74mg, 0.42mmol) is dissolved in DMF(3mL) in, add carbon
Sour potassium (28mg, 0.2mmol) reacts at room temperature overnight (12h).Processing: decompression removal solvent, residue water and methylene chloride
(volume ratio 1:1) extraction, collects organic phase, and pillar layer separation obtains yellow solid, yield 31%, fusing point: 48-50 DEG C.1H NMR
(500 MHz, CDCl3) δ 8.67 (s, 1H), 7.19 – 7.13 (m, 2H), 7.10 (t, J = 8.5 Hz,
1H), 6.90 (s, 1H), 6.89 – 6.84 (m, 1H), 6.29 (s, 1H), 5.26 (s, 2H), 4.04 (s,
3H), 3.92 (s, 3H), 3.73 – 3.60 (m, 4H), 3.53 – 3.42 (m, 2H), 2.48 – 2.28 (m,
6H), 1.85 – 1.74 (m, 2H)。ESI-MS m/z: 586 [M+H]+。
Embodiment 16:N- (3- bromophenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] -
6- (morpholinyl propoxyl group) quinazoline -4- amine (Ih)
Preparation method is referring to embodiment 15, wherein by 4- (the chloro- 4- fluoroanilino of 3-) -6- (morpholinyl propoxyl group) -7-
Methoxyquinazoline hydrochloride (4) is changed to 4- (3- bromobenzene amido) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride (5).It obtains yellow
Color solid, yield: 29%, fusing point: 55-57 DEG C.1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 7.46 –
7.40 (m, 1H), 7.36 – 7.32 (m, 1H), 7.28 – 7.24 (m, 1H), 7.22 (s, 1H), 7.02 –
6.95 (m, 2H), 6.39 (s, 1H), 5.35 (s, 2H), 4.09 (s, 3H), 3.96 (s, 3H), 3.86 –
3.71 (m, 4H), 3.58 – 3.45 (m, 2H), 2.62 – 2.42 (m, 6H), 1.94 – 1.81 (m, 2H)。
ESI-MS m/z: 614 [M+H]+。
Embodiment 17:N- (3- ethynyl phenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Base] -6- (morpholinyl propoxyl group) quinazoline -4- amine (Ii)
Preparation method is referring to embodiment 15, wherein by 4- (the chloro- 4- fluoroanilino of 3-) -6- (morpholinyl propoxyl group) -7-
Methoxyquinazoline hydrochloride (4) is changed to 4- (3- acetylenylbenzene amido) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride (6).
Yellow solid is obtained, yield: 27%, fusing point: 52-54 DEG C.1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 7.43-
7.38 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.31-7.29 (m, 1H), 7.20 (s, 1H), 7.09
(s, 1H), 7.04-7.01 (m, 1H), 6.99 (s, 1H), 6.37 (s, 1H), 5.35 (s, 2H), 4.73
(s, 3H), 3.95 (s, 3H), 3.80 -3.68 (m, 4H), 3.50-3.45 (m, 2H), 2.63-2.31 (m,
6H), 1.91-1.76 (m, 2H)。ESI-MS m/z: 558 [M+H]+。
Application test: gained compound is in normal oxygen (20% O2) and hypoxemia (1% O2) under the conditions of to human colon cancer cell HT-
The inhibiting rate of 29 and human lung carcinoma cell line H460.
Experimental method:
(1) human colon cancer cell HT-29, human lung carcinoma cell line H460 cell strain: are selected；
(2) it by after the cell dissociation of logarithmic growth phase, blows and beats into single cell suspension, is inoculated in 96 well culture plates；H460 is thin
Born of the same parents, HT-29 cell equal 5 × 103Cells/well.It is 200 μ that 1640 culture medium of RPMI containing 10% serum to total volume, which is added, in every hole
L is individually placed to 20% O2、1% O2Incubator in overnight incubation；
(3) after cell is adherent, 50 μM of test-compound is added and is further cultured for 72h in normal oxygen incubator；
(4) using the percent inhibition of srb assay measurement drug cell proliferation ability；
(5) microplate reader detects each hole OD value (Detection wavelength: 490 nm), and records result.Inhibit according to the following formula
Rate: inhibiting rate (%)=(OD control-OD administration)/OD control × 100%.
Experimental result is as shown in table 1 below.From compound to HT-29 cell and H460 cell under normal oxygen and hypoxia condition
Inhibiting rate can be seen that the inhibiting rate of 9 to 17 compound of embodiment under low oxygen conditions and be apparently higher than normal oxygen, illustrate that compound exists
It can be reduced activation under hypoxia condition, play stronger anti-tumor activity.
1. compound of table (50 μM) is under hypoxemia and normal oxygen condition to the inhibiting rate of HT-29 and H460 cell
Claims (4)
1. quinazoline derivative, structure is as follows:
, wherein
R1ForOr-(CH2)nR6, R2For, n=2,3,4,5 or 6；
R6For morpholinyl, piperidyl, pyrrolidinyl, piperazinyl or dimethylamino；
R3、R4And R5It is each independently selected from hydrogen, chlorine, fluorine, bromine, acetenyl or trifluoromethyl.
2. quinazoline derivative according to claim 1, which is characterized in that the quinazoline derivative are as follows:
N- (the chloro- 4- fluorophenyl of 3-) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group]-N- [(1-
Methyl -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine；
N- (3- bromophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group]-N- [(1- methyl -
2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine；
N- (3- ethynyl phenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group]-N- [(1- first
Base -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine；
N- (the chloro- 4- fluorophenyl of 3-) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] -6- (3- morpholine
Base propoxyl group) quinazoline -4- amine；
N- (3- bromophenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] -6- (morpholinyl third
Oxygroup) quinazoline -4- amine；
Or N- (3- ethynyl phenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] -6- (3-
Quinoline base propoxyl group) quinazoline -4- amine.
3. quinazoline derivative of any of claims 1 or 2 or its pharmaceutically acceptable salt are in preparing anticancer drug
Using.
4. quinazoline derivative of any of claims 1 or 2 or its pharmaceutically acceptable salt prevent and treat lung in preparation
Application in cancer drug or colon cancer drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610839689.6A CN106432202B (en) | 2016-09-22 | 2016-09-22 | Quinazoline derivative and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610839689.6A CN106432202B (en) | 2016-09-22 | 2016-09-22 | Quinazoline derivative and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106432202A CN106432202A (en) | 2017-02-22 |
| CN106432202B true CN106432202B (en) | 2019-04-02 |
Family
ID=58166675
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610839689.6A Active CN106432202B (en) | 2016-09-22 | 2016-09-22 | Quinazoline derivative and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106432202B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658946B (en) * | 2017-03-28 | 2020-06-16 | 焦玉奇 | Novel quinazoline inhibitors |
| CA3059670A1 (en) | 2017-04-15 | 2018-10-18 | Natco Pharma Limited | An improved process for the preparation of n-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy) quinazolin -4-amine dihydrochloride |
| WO2019067543A1 (en) * | 2017-09-26 | 2019-04-04 | The Regents Of The University Of California | Compositions and methods for treating cancer |
| CN109438423A (en) * | 2018-09-12 | 2019-03-08 | 通化师范学院 | A kind of new method of the synthesis technology of lung cancer target compound AZD-3759 |
| CR20210498A (en) | 2019-03-15 | 2022-01-11 | Univ California | Compositions and methods for treating cancer |
| CN112608302B (en) * | 2020-12-28 | 2022-05-24 | 郑州大学第一附属医院 | Quinazoline derivative for activating target ubiquitination degradation of EGFR protein through low-oxygen reduction and application thereof |
| CN113004251B (en) * | 2021-03-05 | 2022-09-27 | 郑州大学第一附属医院 | Quinazoline derivative containing 2-nitroimidazole and application thereof |
| CN116239594B (en) * | 2023-03-05 | 2023-09-22 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| CN101003513A (en) * | 2005-02-05 | 2007-07-25 | 孙飘扬 | Compound in quinazoline class or its pharmaceutical salt preparation method, and medical usage |
-
2016
- 2016-09-22 CN CN201610839689.6A patent/CN106432202B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| CN101003513A (en) * | 2005-02-05 | 2007-07-25 | 孙飘扬 | Compound in quinazoline class or its pharmaceutical salt preparation method, and medical usage |
Non-Patent Citations (2)
| Title |
|---|
| Design, synthesis and biological evaluation of 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazolines as efficient EGFR inhibitors exerting cytotoxic effects both under normoxia and hypoxia;Weiyan Cheng，等;《European Journal of Medicinal Chemistry》;20141106;第89卷;826-834 * |
| Synthesis and in vitro antitumor activities of novel 4-anilinoquinazoline derivatives;Venkateshappa Chandregowda，等;《European Journal of Medicinal Chemistry》;20080726;3046–3055 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106432202A (en) | 2017-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106432202B (en) | Quinazoline derivative and its application | |
| CN105461695B (en) | Pyrimidine or pyrrolotriazine derivatives and its production and use | |
| US10377747B2 (en) | 2-arylamino pyridine, pyrimidine or triazine derivatives, preparation method and use thereof | |
| JP6139782B2 (en) | Substituted pyrazolopyrimidine compounds, and pharmaceutically acceptable salts thereof, and solvates, stereoisomers, and tautomers thereof, and pharmaceutical compositions containing them | |
| EP3392245A1 (en) | Novel egfr and alk dual inhibitor | |
| US9353062B2 (en) | Substituted quinolines as bruton's tyrosine kinases inhibitors | |
| WO2011065541A1 (en) | Anti-tumor effect potentiator | |
| Zhang et al. | Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors | |
| EP3181553B1 (en) | Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof | |
| US20200024280A1 (en) | Pyrrolo[1,2-b]pyridazine compounds and compositions useful for treating disorders related to kit and pdgfr | |
| JP7036939B2 (en) | A novel pyrimidine derivative showing a growth inhibitory effect on cancer cells and a pharmaceutical composition containing the same. | |
| Yin et al. | Design, synthesis and biological activities of novel oxazolo [4, 5-g] quinazolin-2 (1H)-one derivatives as EGFR inhibitors | |
| EP3102571B1 (en) | Substituted pyrimidines useful as egfr-t790m kinase inhibitors | |
| CN102875570A (en) | Quinazoline derivative, and preparation method and application thereof | |
| US20150210702A1 (en) | Novel pyrrolopyrimidine compounds as inhibitors of protein kinases | |
| US9388160B2 (en) | Quinazoline derivatives as kinases inhibitors and methods of use thereof | |
| Das et al. | In vivo efficacy studies of novel quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors, in lung cancer xenografts (NCI-H1975) mice models | |
| CN101372475B (en) | Aromatic heterocyclic substituted acardite derivative and use thereof | |
| US11427559B2 (en) | Substituted quinolines useful as kinase inhibitors | |
| CN111362925A (en) | 4-pyrimidine formamide compound, pharmaceutical composition, preparation method and application | |
| CN101671301B (en) | Heterocyclic substituent acardite derivate and application thereof | |
| TW201427958A (en) | Aryl amine substituted pyrimidine and quinazoline and their use as anticancer drugs | |
| CN106892922A (en) | As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application | |
| CN105985321B (en) | Pyrazoles phthalazine compound and its preparation method and application | |
| CN104230913A (en) | Piperazine-substituted quinazoline compound and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |