CN106432202A - Quinazoline derivative and application thereof - Google Patents
Quinazoline derivative and application thereof Download PDFInfo
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- CN106432202A CN106432202A CN201610839689.6A CN201610839689A CN106432202A CN 106432202 A CN106432202 A CN 106432202A CN 201610839689 A CN201610839689 A CN 201610839689A CN 106432202 A CN106432202 A CN 106432202A
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- 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
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- 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 the field of medical chemistry, and particularly relates to 4-anilino quinazoline derivative with 1-methyl-2-nitro-5-methylene imidazole. The structure of the 4-anilino quinazoline derivative is shown as a graph, wherein an R<1> represents a compound shown as a graph or -(CH<2>)<n>R<6>, the n is equal to 2 or 3 or 4 or 5 or 6, and an R<6> represents morpholino or piperidyl or pyrrolidyl or piperazinyl or dimethylamino; an R<2> represents a compound shown as a graph or hydrogen; an R<3>, an R<4> and an R<5> respectively independently selectively represent hydrogen or chlorine or fluorine or bromine or acetenyl or trifluoromethylphenol. The 4-anilino quinazoline derivative has the advantage that as shown by pharmacological experiments, effects of inhibiting tumor cell proliferation can be realized by the 4-anilino quinazoline derivative which is a compound and pharmaceutically acceptable salt of the 4-anilino quinazoline derivative.
Description
Technical field
The invention belongs to medicinal chemistry art is and in particular to a class contains the 4- of 1- methyl -2- nitro -5- methylene imidazoles
Anilinoquinazoline analog derivative and its purposes in therapeutic field of tumor.
Background technology
EGF-R ELISA（Epidermal growth factor receptor, EGFR）It is that a class is believed in cell
The kinases playing a significant role in breath transmission.The overexpression of EGFR with multiple including non-small cell type lung cancer, colon cancer
The generation development of solid tumor is closely related.In recent years, using EGFR as therapy target, two class medicines are developed rapidly, that is, single
Clonal antibody and micromolecular inhibitor.In micromolecular inhibitor, representational medicine is 4- anilinoquinazoline derivatives, they
Huge effect has been played in the treatment of tumour（W. Cheng, et al., Curr. Med. Chem., 2014, 21,
4374-4404；R. Roskoski, Pharmacol. Res., 2014, 79, 34-74）.
In addition, the generation development of solid tumor makes it inevitably create low-oxygen environment, for tumor hypoxia environment, greatly
The Bioreductive drugs of amount are developed, and 2- nitro imidazole derivatives are one kind therein.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, produces lethal effect to tumour cell（L. J. O’Connor, Org. Chem.
Front., 2015, 2,1026-1029）.2- nitroimidazole is similar to thing be incorporated in 4- anilinoquinazoline class compound,
The recruit obtaining is existed with active compound form in the normal tissue, does not have physiologically active.In tumor tissues, low-oxygen environment makes
2- nitroimidazole group in molecule is reduced activation, produces lethal effect, meanwhile, molecule after reduction activation to tumour cell
Discharge 4- anilinoquinazoline class active compound, again tumour is produced with targeted inhibition effect.Therefore, the 4- containing 2- nitroimidazole
Anilinoquinazoline analog derivative has dual antineoplastic action（J.X. Duan, et al., J. Med. Chem.,
2008, 51, 2412–2420）.
Content of the invention
Present invention aim at providing a kind of quinazoline derivative to tumour cell with inhibited proliferation.
It is a further object to provide purposes in medicine and pharmacology for the above-mentioned quinazoline derivative.
For achieving the above object, the present invention adopts the following technical scheme that：
Quinazoline derivative and its pharmaceutically acceptable salt that the present invention provides, have following general structure：
,
Wherein, R1ForOr-(CH2)nR6, n=2,3,4,5 or 6, R6For morpholinyl, piperidyl, pyrrolidinyl, piperazine
Piperazine base or dimethylamino；
R2ForOr hydrogen；
R3、R4And R5It is each independently selected from hydrogen, chlorine, fluorine, bromine, acetenyl or trifluoromethyl.
Quinazoline derivative of the present invention and its pharmaceutically acceptable salt, can selected from following compounds it
One：
N- (3- chloro- 4- fluorophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group] quinazoline -
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] quinazoline -4-
Amine；
N- (3- chloro- 4- fluorophenyl) -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- (3- chloro- 4- fluorophenyl) -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
Epoxide) quinazoline -4- amine；
N- (3- ethynyl phenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] -6- (3- morpholine
Base propoxyl group) quinazoline -4- amine.
The application in preparing cancer therapy drug of above-mentioned quinazoline derivative or its pharmaceutically acceptable salt.
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, compared with existing EGFR type small molecular inhibitor, has higher targeting and dual antitumor work
With.
Specific embodiment
With reference to embodiments technical scheme is further discussed in detail, but protection scope of the present invention
It is not limited thereto.
Embodiment 1：4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）
Reference literature method（W. Cheng, et al., Eur. J. Med. Chem., 2015,89,826-834）It is obtained.Specifically
As follows：1.0 g 4- (3- chloro- 4- fluoroanilino) -6- acetoxyl group -7- methoxyquinazoline hydrochloride is added in 10 mL methyl alcohol, then
Add concentrated ammonia liquor（25%）0.5 mL, room temperature reaction 3 h.Process：Suction filtration, filter cake, with cold methyl alcohol drip washing, is collected, and is dried, obtains white
Color solid.Yield：> 95%.Fusing point：> 250℃.ESI-MS m/z: 320 [M+H]+.
Embodiment 2：4- (3- bromobenzene amido) -6- hydroxyl -7- methoxyquinazoline hydrochloride（2）
Preparation method, with reference to embodiment 1, wherein, substitutes 4- with 4- (3- bromobenzene amido) -6- acetoxyl group -7- methoxyquinazoline hydrochloride
(3- chloro- 4- fluoroanilino) -6- acetoxyl group -7- methoxyquinazoline hydrochloride, obtains white solid.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, with reference to embodiment 1, wherein, is substituted with 4- (3- acetylene anilino-) -6- acetoxyl group -7- methoxyquinazoline hydrochloride
4- (3- chloro- 4- fluoroanilino) -6- acetoxyl group -7- methoxyquinazoline hydrochloride, obtains white solid, yield：93%.Fusing point：238 -
240℃.ESI-MS m/z: 292 [M+H]+.
Embodiment 4：4- (3- chloro- 4- fluoroanilino) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride（4）
Reference literature method（W. Cheng, et al., Eur. J. Med. Chem., 2015,89,826-834）It is obtained.Specifically
For：By 64mg（0.20mmol）4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）With 50mg
（0.24mmol）4- (3- bromopropyl) morpholine adds 3mL dimethylformamide（DMF）In, add 14mg（0.10 mmol）
K2CO3, reaction system is in 70 DEG C of reaction 12h.Process：Reduced pressure concentration, concentrate saturated aqueous common salt and dichloromethane（Volume ratio
1:1）Extraction, collects organic phase, with anhydrous sodium sulfate drying, concentrates, pillar layer separation（VDichloromethane：VMethyl alcohol= 100：3）, obtain white
Solid.Yield：78%.Fusing point：193-195℃.ESI-MS m/z: 447 [M+H]+.
Embodiment 5：4- (3- bromobenzene amido) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride（5）
Preparation method reference embodiment 4, wherein, with 4- (3- bromobenzene amido) -6- hydroxyl -7- methoxyquinazoline hydrochloride（2）Substitute 4-
(3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）, obtain white solid, 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 reference embodiment 4, wherein, with 4- (3- acetylene anilino-) -6- hydroxyl -7- methoxyquinazoline hydrochloride（3）Substitute
4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）, obtain 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）It is obtained.Fusing point：
136-138℃.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）It is obtained.Fusing point：
121-123℃.ESI-MS m/z: 176 [M+H]+.
Embodiment 9：N- (3- chloro- 4- fluorophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Epoxide] quinazoline -4- amine（Ia）
By 4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）（64mg, 0.2mmol）, 1- methyl -2- nitre
Base -5- hydroxy methylimidazole（7）（32mg, 0.2mmol）And triphenyl phosphorus（105mg, 0.4mmol）It is dissolved in DMF（3mL）In, ice bath
Lower addition N, N- diisopropylethylamine（DIEA, 52mg, 0.4mmol）, to be added finish, normal-temperature reaction 5h.Process：Decompression removes
DMF, residue with water and dichloromethane（Volume ratio 1:1）Extraction, collects organic phase, pillar layer separation, obtains white solid, yield
59%, fusing point：178-180℃.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 reference embodiment 9, wherein, by 4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）More
It is changed to 4- (3- bromobenzene amido) -6- hydroxyl -7- methoxyquinazoline hydrochloride（2）.Obtain white solid, 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
Epoxide] quinazoline -4- amine（Ic）
Preparation method reference embodiment 9, wherein, by 4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）More
It is changed to 4- (3- acetylene anilino-) -6- hydroxyl -7- methoxyquinazoline hydrochloride（3）.Obtain white solid, 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- (3- chloro- 4- fluorophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Epoxide]-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine（Id）
By 4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）（64mg, 0.2mmol）With 1- methyl -2- nitre
Base -5- chloromethyl imidazoles（8）（74mg, 0.42mmol）It is dissolved in DMF（3mL）In, add potassium carbonate（28mg, 0.2mmol）, room
Temperature reaction is overnight（12h）.Process：Decompression removes solvent, residue with water and dichloromethane（Volume ratio 1:1）Extraction, collection has
Machine phase, pillar layer separation, obtain yellow solid, yield 41%, fusing point：79-81℃.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 reference embodiment 12, wherein, by 4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）
It is replaced by 4- (3- bromobenzene amido) -6- hydroxyl -7- methoxyquinazoline hydrochloride（2）.Obtain yellow solid, 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
Epoxide]-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) methyl] quinazoline -4- amine（If）
Preparation method with embodiment 12, by 4- (3- chloro- 4- fluoroanilino) -6- hydroxyl -7- methoxyquinazoline hydrochloride（1）It is replaced by 4-
(3- acetylene anilino-) -6- hydroxyl -7- methoxyquinazoline hydrochloride（3）.Obtain yellow solid, yield：47%, fusing point：73-75℃.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- (3- chloro- 4- fluorophenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base) first
Base] -6- (morpholinyl propoxyl group) quinazoline -4- amine（Ig）
By 4- (3- chloro- 4- fluoroanilino) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride（4）（90mg, 0.2mmol）
With 1- methyl -2- nitro -5- chloromethyl imidazoles（8）（74mg, 0.42mmol）It is dissolved in DMF（3mL）In, add potassium carbonate
（28mg, 0.2mmol）, room temperature reaction is overnight（12h）.Process：Decompression removes solvent, residue with water and dichloromethane（Volume
Ratio 1:1）Extraction, collects organic phase, pillar layer separation, obtains yellow solid, yield 31%, fusing point：48-50℃.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 reference embodiment 15, wherein, by 4- (3- chloro- 4- fluoroanilino) -6- (morpholinyl propoxyl group) -7- methoxy
Base quinazoline（4）It is replaced by 4- (3- bromobenzene amido) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride（5）.Obtain yellow solid
Body, yield：29%, fusing point：55-57℃.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 reference embodiment 15, wherein, by 4- (3- chloro- 4- fluoroanilino) -6- (morpholinyl propoxyl group) -7- methoxy
Base quinazoline（4）It is replaced by 4- (3- acetylenylbenzene amido) -6- (morpholinyl propoxyl group) -7- methoxyquinazoline hydrochloride（6）.Obtain yellow
Color solid, yield：27%, fusing point：52-54℃.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-
29 and the inhibiting rate of human lung carcinoma cell line H460.
Experimental technique：
（1）Cell line：From human colon cancer cell HT-29, human lung carcinoma cell line H460；
（2）After the cell dissociation of exponential phase, blow and beat into single cell suspension, be inoculated in 96 well culture plates；H460 cell,
HT-29 cell equal 5 × 103Cells/well.It is 200 μ L that every hole adds RPMI 1640 culture medium to the cumulative volume containing 10% serum, point
It is not placed on 20% O2、1% O2Incubator in overnight incubation；
（3）After cell attachment, 50 μM of test-compound is added to be further cultured for 72h in normal oxygen incubator；
（4）Measure the percent inhibition of medicine cell proliferation ability using srb assay；
（5）ELIASA detects each hole OD value（Detection wavelength：490 nm）, and record result.Inhibiting rate according to the following formula：Suppression
Rate processed（%）=（OD comparison-OD administration）/ OD comparison × 100%.
Experimental result is as shown in table 1 below.From compound under normal oxygen and hypoxia condition to HT-29 cell and H460 cell
Inhibiting rate can be seen that embodiment 9 to 17 compound inhibiting rate under low oxygen conditions apparently higher than normal oxygen, illustrates that compound exists
Activation can be reduced under hypoxia condition, play higher antitumor activity.
Table 1. compound（50μM）The inhibiting rate to HT-29 and H460 cell under hypoxemia and normal oxygen condition
Claims (4)
1. quinazoline derivative, its structure is as follows：
, wherein, R1ForOr-(CH2)nR6, n=2,3,4,5 or 6, R6For
Quinoline base, piperidyl, pyrrolidinyl, piperazinyl or dimethylamino；R2ForOr hydrogen；
R3、R4And R5It is each independently selected from hydrogen, chlorine, fluorine, bromine, acetenyl or trifluoromethyl.
2. quinazoline derivative according to claim 1 is it is characterised in that described quinazoline derivative is：
N- (3- chloro- 4- fluorophenyl) -7- methoxyl group -6- [(1- methyl -2- nitro -1H- imidazoles -5- base) methoxyl group] quinazoline -
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] quinazoline -4-
Amine；
N- (3- chloro- 4- fluorophenyl) -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- (3- chloro- 4- fluorophenyl) -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
Epoxide) quinazoline -4- amine；Or N- (3- ethynyl phenyl) -7- methoxyl group-N- [(1- methyl -2- nitro -1H- imidazoles -5- base)
Methyl] -6- (morpholinyl propoxyl group) quinazoline -4- amine.
3. the quinazoline derivative described in claim 1 or 2 or its pharmaceutically acceptable salt are in preparing cancer therapy drug
Application.
4. the quinazoline derivative described in claim 1 or 2 or its pharmaceutically acceptable salt are in preparation prevention and treatment lung
Application in cancer drug or colon cancer drug.
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| CN108658946A (en) * | 2017-03-28 | 2018-10-16 | 焦玉奇 | Novel quinazoline inhibitor |
| WO2018189747A1 (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 |
| 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 |
| WO2019067543A1 (en) * | 2017-09-26 | 2019-04-04 | The Regents Of The University Of California | Compositions and methods for treating cancer |
| CN112608302A (en) * | 2020-12-28 | 2021-04-06 | 郑州大学第一附属医院 | Quinazoline derivative for activating targeted ubiquitination degradation of EGFR protein through low oxygen reduction and application thereof |
| CN113004251A (en) * | 2021-03-05 | 2021-06-22 | 郑州大学第一附属医院 | Quinazoline derivative containing 2-nitroimidazole and application thereof |
| US11377451B2 (en) | 2019-03-15 | 2022-07-05 | The Regents Of The University Of California | Compositions and methods for treating cancer |
| CN116239594A (en) * | 2023-03-05 | 2023-06-09 | 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 |
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Cited By (12)
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| CN108658946A (en) * | 2017-03-28 | 2018-10-16 | 焦玉奇 | Novel quinazoline inhibitor |
| CN108658946B (en) * | 2017-03-28 | 2020-06-16 | 焦玉奇 | Novel quinazoline inhibitors |
| WO2018189747A1 (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 |
| US11091470B2 (en) | 2017-04-15 | 2021-08-17 | Natco Pharma Limited | Process for the preparation of N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-amine dihydrochloride |
| AU2017409559B2 (en) * | 2017-04-15 | 2021-08-19 | 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 |
| US11377451B2 (en) | 2019-03-15 | 2022-07-05 | The Regents Of The University Of California | Compositions and methods for treating cancer |
| CN112608302A (en) * | 2020-12-28 | 2021-04-06 | 郑州大学第一附属医院 | Quinazoline derivative for activating targeted ubiquitination degradation of EGFR protein through low oxygen reduction and application thereof |
| CN113004251A (en) * | 2021-03-05 | 2021-06-22 | 郑州大学第一附属医院 | Quinazoline derivative containing 2-nitroimidazole and application thereof |
| CN116239594A (en) * | 2023-03-05 | 2023-06-09 | 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 |
| 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 |
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