CN105541807B - A kind of novel quinazoline quinoline derivant LU1506 and its preparation method and application - Google Patents
A kind of novel quinazoline quinoline derivant LU1506 and its preparation method and application Download PDFInfo
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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
Abstract
The invention discloses a kind of novel quinazoline quinoline derivant LU1506 and preparation method thereof, its chemical name is 4 base of N { [(4 dimethylamino) phenyl] methyl } 4 N [7 methoxyl group 6 (2 pyrrolidinyl) ethoxy] quinazoline } benzene Isosorbide-5-Nitrae diamines.The present invention quinazoline derivant and its pharmaceutically acceptable salt, solvate and hydrate to MCF 7, SK BR 3, MDA MB 468, U 118 MG, HCT116, U 87 MG there is outstanding antitumor In vitro and in vivo activity, there is preferable application prospect on antitumor drug is prepared.
Description
Technical field
The invention belongs to biomedicine field, more particularly to a kind of novel quinazoline quinoline derivant LU1506 and its preparation side
Method and application.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, in the past 20 years, China's tumor mortality
Rate rises 29.42%.In the middle prime of life crowd of 35 to 59 years old, tumour, which has arranged, to be occupied first of all kinds of causes of the death.It data show：I
State's tumor incidence is about 2,00/,100,000 people, more than about 2,200,000 people of annual new cases, is controlling more than about 6,000,000 people of patient.It is swollen
The treatment method of knurl has operative treatment, radiotherapy and chemotherapy.At present, chemotherapy is still the master of clinical treatment tumour
Want means.Seeking antitumor medicine is one of hot spot of new drug research.In recent years, 4- amino-quinazoline compounds are because having
Excellent bioactivity, enjoys the extensive concern of people, becomes biological educational circles and hot spot that region of chemistry scholars study.They are right
EGF receptor or pdgf receptor tyrosine kinase produce good inhibiting effect, show with anti-lung cancer, stomach cancer, colon cancer, breast
The effects such as the effect of gland cancer, gallbladder cancer and prostate cancer etc., antibacterial, AntiHIV1 RT activity, anti-inflammatory, treatment diabetes, such as Gefitinib, strategic point
Lip river is for marketed drugs such as Buddhist nun, xylene monosulfonic acid Lapatinibs.Inventor's discovery, N- { [(4- dimethylaminos) phenyl] methyl } -4-
N- [7- methoxyl groups -6- (1- pyrroles -2- bases) ethoxy] base of quinazoline -4 } benzene-Isosorbide-5-Nitrae-diamines has certain antitumor activity, invents
People proposes and N- { [(4- dimethylaminos) phenyl] methyl } -4-N- [7- methoxyl groups -6- (1- pyrroles -2- bases) ethoxy] quinoline azoles
The base of quinoline -4 } benzene-Isosorbide-5-Nitrae-diamines either pharmaceutically acceptable salt of the compound, solvate or prodrug or solid
Isomers either dynamic isomer or the relevant invention of metabolin.
The content of the invention
Goal of the invention：To solve problems of the prior art, the present invention provides a kind of novel quinazoline quinoline derivant
LU1506, its chemical name are N- { [(4- dimethylaminos) phenyl] methyl } -4-N- [7- methoxyl groups -6- (1- pyrroles -2- bases) hydroxyls
Ethyl] base of quinazoline -4 } benzene-Isosorbide-5-Nitrae-diamines, it is to MCF-7, SK-BR-3, MDA-MB-468, U-118MG, HCT116, U-
Six plants of tumor cell proliferations of 87MG have inhibitory activity.
Technical solution：To realize above-mentioned technical purpose, the present invention provides a kind of novel quinazoline quinoline derivant LU1506, its
Chemical name is N- { [(4- dimethylaminos) phenyl] methyl } -4-N- [7- methoxyl groups -6- (1- pyrroles -2- bases) ethoxy] quinoline azoles
The base of quinoline -4 } benzene-Isosorbide-5-Nitrae-diamines, its structural formula is as follows：
Present invention further proposes the preparation method of above-mentioned novel quinazoline quinoline derivant LU1506, include the following steps：
S1：Under nitrogen protection, pyrroles is dissolved in tetrahydrofuran, EtMgBr diethyl ether solutions is slowly added dropwise under ice bath, stir
Mix 30 minutes~2 it is small when, when 0~60 DEG C of reaction solution stirring 30 minutes~2 is small, 0~60 DEG C adds methyl bromoacetate and stirs 30 points
When clock~2 are small, compound (1), i.e. 2- (1- pyrroles -2- bases) acetic acid esters are generated；
S2：Under nitrogen protection, compound (1) is dissolved in tetrahydrofuran, is added portionwise while stirring under ice bath
LiAlH4More than 30 minutes, obtain reduzate compound (2), i.e. 2- (1- pyrroles -2- bases) ethanol；
S3：Under nitrogen protection, by compound (2) and the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3It is dissolved in tetrahydrochysene
Furans, is added portionwise DTAD while stirring under ice bath, when reaction 6 is small more than, preferably 6~10h generation compounds (3), i.e.,
The chloro- 7- methoxyl groups -6- of 4- [2- (1- pyrroles -2- bases) ethoxy] quinazoline；
S4：4- amino methyls-n,N-Dimethylaniline, the fluoro- 4- nitrobenzenes of 1- and sodium carbonate are dissolved with DMSO, 60~
When 120 DEG C of stirring reactions 4~12 are small, compound (4), i.e. N- [4- (4- dimethylamino) phenyl] methyl-4-nitrophenylamine are generated；
S5：By compound (4), dissolved with tetrahydrofuran, add Raney's nickel, be passed through hydrogen, 25~100 DEG C of stirrings 3~12
Hour, into generation compound (5), i.e. N- { [(4- dimethylamino) phenyl] methyl } benzene-Isosorbide-5-Nitrae-diamines；
S6：Compound (3) and compound (5) are dissolved in n-butanol, when 60~120 DEG C of stirring reactions 1~6 are small, generationization
Compound (6), i.e. N- { [(4- dimethylaminos) phenyl] methyl } -4-N- [7- methoxyl groups -6- (1- pyrroles -2- bases) ethoxy] quinoline azoles
The base of quinoline -4 } benzene-Isosorbide-5-Nitrae-diamines.
Preferably, in step S1, the concentration of EtMgBr diethyl ether solutions is 3M, and drop speed is 5~10ml/min, EtMgBr second
Ether, methyl bromoacetate, tetrahydrofuran, the amount ratio of pyrroles are 100~500mL: 20~50g: 250~1000m1: 20~50g.
In step S2, LiAlH4Dosage be per g of compound (1) add 0.25~2g.
In step S3, the DTAD points of 3~6 batches of additions, when interval 2~4 is small/time, wherein, the chloro- 7- methoxyl groups quinolines of 4-
Oxazoline -6- alcohol, PPh3, DTAD, compound (2) mole dosage ratio be 1: 1: 1: 0.8~1.4.
In step S4, the mole dosage ratio of the fluoro- 4- nitrobenzenes of 4- amino methyls-n,N-Dimethylaniline, 1- and sodium carbonate
For 1: 1: 0.3~3.
In step S5, the dosage of Raney's nickel adds 0.2~2.0g of Raney's nickel for every 1 g of compound (4).
In step S6, compound (5), the mole dosage ratio of compound (3) are 1: 0.6~1.2.Present invention further propose that
Application of the above-mentioned novel quinazoline quinoline derivant in antitumor agent is prepared.
The present invention proposes a kind of pharmaceutical composition at the same time, and said composition includes the compound described in the claims 1
And pharmaceutically acceptable carrier.
Closer, the present invention proposes above-claimed cpd, or above-mentioned pharmaceutical composition is in medicament is prepared
Purposes.
Meanwhile can pharmaceutically connect the invention also provides above-mentioned novel quinazoline quinoline derivant LU1506 or the compound
The salt received, solvate either prodrug or stereoisomer or dynamic isomer or metabolin prepare it is antitumor
Application in agent.
Finally, the present invention proposes the pharmaceutically acceptable of above-mentioned novel quinazoline quinoline derivant LU1506 or the compound
Salt, either prodrug or stereoisomer or dynamic isomer or metabolin and one or more resist solvate
Cancer medicament, which is incorporated in prepare, to be used to treat the purposes on the medicine of tumour.
Beneficial effect：Its suppression is evaluated the invention discloses a kind of novel quinazoline quinoline derivant LU1506, and using mtt assay
Six plants of proliferative activity o f tumors of MCF-7, SK-BR-3, MDA-MB-468, U-118MG, HCT116, U-87MG, calculate and suppress this
The IC of six kinds of tumor cell proliferations50Value, the results showed that prepared novel quinazoline quinoline derivant LU1506 is to above-mentioned tumour cell
It is inhibited, available for preparing anti-tumor agent.
Brief description of the drawings
Fig. 1 is the synthetic route chart of quinazoline derivant, wherein：I) methyl bromoacetate, EtMgBr, THF；Ii) THF,
LiAlH4；Iii) the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3, DTAD, THF；iv)Na2CO3, DMSO, 4- amino methyl-N,
Accelerine；V) Raney's nickel, H2, THF；vi)n-BuOH
Embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used for the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares 2- (1- pyrroles -2- bases) acetic acid esters (compound 1).
500mL tetrahydrofurans are placed in four neck round-bottom flasks of nitrogen protection of 2000mL, add 50g pyrroles.Ice bath
Under 266.8mL 3M EtMgBr diethyl ether solutions be slowly added dropwise and stir 30min.Reaction solution stir at room temperature 1 it is small when, drip under ice bath
Add 45.7g methyl bromoacetates, reaction solution be stirred at room temperature 1 it is small when.Add 500mL of 1N HCl and terminate reaction.Reaction solution
It is extracted with ethyl acetate 3 times, combined ethyl acetate layer, saturated sodium-chloride water solution is washed 3 times.The ethyl acetate layer of merging is separated,
When addition anhydrous sodium sulfate drying 6 is small in 250mL triangular flasks, it is filtered under diminished pressure.Filtrate decompression is concentrated to dryness, and is obtained through column chromatography
19g (yield 46%) compound 1, is brown oil.
Embodiment 2 prepares 2- (1- pyrroles -2- bases) ethanol (compound 2).
19g 2- (1- pyrroles -2- bases) acetic acid esters (compound 1) is dissolved in 200mL tetrahydrofurans, is placed in the nitrogen of 500mL
(divide 4 batches, every batch of interval 10min) in batches in four neck round-bottom flasks of gas shielded, under ice bath and add 5.6g LiAlH4, stirring
30min.5.6mL water is added into reaction solution, 15%NaOH 16.8mL, are stirred at room temperature 10min, terminate reaction.In 250mL tri-
When addition anhydrous sodium sulfate drying 6 is small in the bottle of angle, it is filtered under diminished pressure.Filtrate decompression is concentrated to dryness, and 10g (yields are obtained through column chromatography
66%) compound 2, are brown oil.
The compound 2 of preparation is carried out1H-NMR standards are as a result as follows：
1H-NMR：(300MHz, DMSO-d6, ppm)：δ 8.52 (brs, 1H), 6.73-6.71 (m, 1H), 6.19-6.14 (m,
1H), 6.01-6.00 (m, 1H), 3.87-3.83 (t, J=5.7Hz, 2H), 2.88-2.84 (t, J=5.7Hz, 2H)
Embodiment 3 prepares 4- chloro- 7- methoxyl groups -6- [2- (1- pyrroles -2- bases) ethoxy] quinazoline (compound 3).
By the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 12.6g4-, 6g 2- (1- pyrroles -2- bases) ethanol (compound 2),
17.1gPPh3150mL tetrahydrofurans are dissolved in, are placed in the three neck round bottom of 250mL nitrogen protection, (divide 3 in batches under ice bath
Batch, every batch of interval 2h) 15g DTAD are added, it is stirred overnight at room temperature.Reaction mixture filters out solid residue, and filtrate decompression is dense
It is reduced to dry.Obtained residue obtains 8.8g (yield 54%) compound 3 with through column chromatography, is colourless powder.
Embodiment 4 prepares N- [4- (4- dimethylamino) phenyl] methyl-4-nitrophenylamine (compound 4).
By 6.4g 4- amino methyls-n,N-Dimethylaniline, the fluoro- 4- nitrobenzenes of 6g 1-, 100mLDMSO, 9g sodium carbonate
It is placed in 250mL three-neck flasks, 100 DEG C are stirred overnight.Reaction solution ice bath is cooled to room temperature, after adding 200mL frozen water to dilute, decompression
Filtering, obtained solid obtains 11g (yield 95%) compound 4 through column chromatography, is yellow powder.
Embodiment 5 prepares N- { [(4- dimethylamino) phenyl] methyl } benzene-Isosorbide-5-Nitrae-diamines (compound 5)
Three necks that 10gN- [4- (4- dimethylamino) phenyl] methyl-4-nitrophenylamine (compound 4) is placed in 100mL are burnt
In bottle, dissolved with 50mL tetrahydrofurans, add 3g Raney's nickels, be passed through hydrogen, be stirred overnight at room temperature.It is filtered under diminished pressure, filtrate concentration
To doing, 6g (yield 67%) compound 5 is obtained through column chromatography, is colourless powder.
Embodiment 6 prepares N- { [(4- dimethylaminos) phenyl] methyl } -4-N- [7- methoxyl groups -6- (1- pyrroles -2- bases) hydroxyls
Ethyl] base of quinazoline -4 } benzene-Isosorbide-5-Nitrae-diamines (compound 6)
By the chloro- 7- methoxyl groups -6- of 2g4- [(1- pyrroles -2- bases) ethoxy] quinazoline (compound 3), 1.59gN- { [(4-
Dimethylamino) phenyl] methyl } benzene-Isosorbide-5-Nitrae-diamines (compound 5), 50mL n-butanols are dissolved in, are placed in 100mL round-bottomed flasks,
When 75 DEG C of oil bath stirrings 1.5 are small.Ice bath is cooled to room temperature, and sodium carbonate liquor adjustment pH to 9 is added dropwise, reaction solution is extracted with ethyl acetate
Take 2 times, merge organic layer, saturated sodium-chloride water solution is washed 2 times.Separate organic layer and add anhydrous slufuric acid in 250mL triangular flasks
When sodium drying 6 is small, it is filtered under diminished pressure.Filtrate decompression is concentrated to dryness, and 1.2g (yield 36%) compound 6 is obtained through column chromatography, for Huang
Color powder.
The compound 6 of preparation is carried out ESI-MS,1H-NMR standards are as a result as follows：
ESI-MS(m/z)：509[M+H ]+；1H-NMR (300MHz, DMSO-d6, ppm)：δ 10.70 (s, 1H), 9.23 (s,
1H), 8.29 (s, 1H), 7.79 (s, 1H), 7.28-7.25 (d, J=6.9Hz, 2H), 7.21-7.18 (d, J=8.7Hz, 2H),
7.12 (s, 1H), 6.70-6.64 (m, 3H), 6.60-6.57 (d, J=8.7Hz, 2H), 6.01-6.5.97 (t, J=5.7Hz,
1H), 4.27-4.22 (t, J=7.5Hz, 2H), 4.14-4.12 (d, J=5.7Hz, 2H), 3.92 (s, 3H), 3.20-3.17 (t,
J=7.5Hz, 2H), 2.85 (s, 6H)
7 compound of experimental example, 6 anti-tumour cell proliferative activity is evaluated.
(1) given the test agent：
The compound 6 of the present invention is configured to required concentration with the culture medium containing 0.1%DMSO.
(2) cell line：
MCF-7 (human breast cancer cell, ATCC：HTB-22), SK-BR-3 (human breast cancer cell, ATCC：HTB-30)、
HCT116 (human colon cancer cell, ATCC：CCL-247), U-118MG (human brain astrocytes' blastoma, ATCC：HTB-15)、
U-87MG (human brain astrocytes' blastoma, ATCC：HTB-14), MDA-MB-468 (human breast cancer cell, ATCC：HTB-
132) 6 plants of tumour cells are purchased from Unite States Standard type culture collection institute (ATCC).
(3) key instrument and material
Ultra-pure water instrument：MILLIPORE Direct-Q 3；
High-pressure sterilizing pot：HVE-50, Hirayama company；
Digital display thermostat water bath：HH-4, Guo Hua Electrical Appliances Co., Ltd；
Super-clean bench：VS-1300-U clean benches, SuZhou Antai Air Tech Co., Ltd.；
Cell incubation case：HF151UVCO2 incubators, Shanghai power Shengong department；
Refrigerated centrifuge：Anting Scientific Instrument Factory, Shanghai
Microplate reader：ELx800, Biotek company
Oscillator plate：ZD-9556, Taicang science and education equipment factory；
96 porocyte culture plates, 25cm2Blake bottle：Corning Costar companies；
2mL cryopreservation tubes：Corning Costar companies；
(4) main agents
RPMI-1640 culture mediums：Gibco companies；
DMEM culture mediums：Gibco companies；
McCoy ' s 5A culture mediums：Gibco companies；
L-15 culture mediums：Gibco companies；
MEM culture mediums：Gibco companies；
PBS buffer：Gibco companies；
Hyclone：Gibco companies；
0.25% trypsin solution：Hyclone companies；
MTT (four tetrazolium bromides)：Sigma companies, are dissolved in PBS solution, and the solution of 5mg/mL is made, makes after filtration sterilization
With being kept in dark place；
Adriamycin (ADR)：Beijing Hua Feng United Technologies Corp.s.
DMSO：Dimethyl sub-maple, Sigma companies；
(5) test method
MCF-7, U-118MG cell select DMEM culture mediums, and U-87MG cells select MEM culture mediums, and MDA-MB-468 is thin
Born of the same parents select L-15 culture mediums, and 116 cells of HCT select McCoy ' s 5A culture mediums, other cells select RPMI-1640 culture mediums.
Hyclone and 80UmL in culture medium containing 10% fire extinguishing-1Penicillin and 0.08mgmL-1Streptomysin.
By growth conditions are good, MCF-7, SK-BR-3 in exponential phase, MDA-MB-468, U-118MG,
HCT116, U-87MG cell press 1 × 104The density of a/mL is inoculated in 96 orifice plates, per 100 μ l of hole.It is placed in 37 DEG C, 5%CO2Culture
Treated when culture 12 is small in case adherent.Dosing cell hole is dissolved in culture by be measured, the sterilized processing of default concentration gradient addition
The compound 6 of base, per 200 μ l of hole, blanc cell hole adds isometric culture medium, and default concentration gradient is pressed in control cell hole
Add isometric adriamycin (ADR) for being dissolved in culture medium, parallel 6 hole.In 37 DEG C, 5%CO2After when culture 48 is small in incubator,
The MTT solution that 10 μ l concentration are 5mg/mL is added per hole, continues to be placed in 37 DEG C, 5%CO2When culture 4 is small in incubator.It is careful to inhale
Going out supernatant, 150 μ l DMSO dissolving purple powders (first a ceremonial jade-ladle, used in libation) are added per hole, Oscillating Flat makes precipitation all dissolve for 10 minutes,
In measure O.D. values (absorbance), wavelength 570nm in microplate reader.
According to formula, " relative survival rate=(D drug containing-D blank)/(D control-D blank) × 100% " calculates each sample
The inhibiting rate of sample under product concentration to tumour cell.
Test it is parallel be repeated 3 times, with inhibiting rate to compound concentration map, calculate the compounds of this invention 6 IC50(half
Effective inhibition concentration) value.Positive control medicine is used as using adriamycin (ADR) at the same time.
(6) experimental result
1 compound 6LU1506 anti-tumour cell proliferative activities (IC of table50±SDμM)
| Compound | MCF-7 | SK-BR-3 | HCT 116 | U-118MG | U-87MG | MDA-MB-468 |
| ADR | 3.98±0.07 | 4.65±0.02 | 26.57±0.12 | 13.49±1.75 | 82.47±7.15 | 2.45±0.31 |
| Compound 6 | 89.22±6.17 | 25.26±4.49 | 79.83±4.07 | ＞ 100 | ＞ 100 | 21.02±3.34 |
As shown in table 1, the test result of 6 anti-tumour cell proliferative activity of compound is given, the results showed that prepared
Novel quinazoline quinoline derivant is inhibited to above-mentioned tumour cell, available for preparing anti-tumor agent.
Claims (6)
1. a kind of preparation method of quinazoline derivant LU1506, wherein, the structure of LU1506 is：
Include the following steps：
S1：Under nitrogen protection, pyrroles is dissolved in tetrahydrofuran, EtMgBr diethyl ether solutions, stirring 30 is slowly added dropwise under ice bath
When minute~2 are small, when 0~60 DEG C of stirring 30 minutes~2 of reaction solution is small, 0~60 DEG C adds methyl bromoacetate stirring 30 minutes~2
Hour, generation compound (1), i.e. 2- (1- pyrroles -2- bases) acetic acid esters；
S2：Under nitrogen protection, compound (1) is dissolved in tetrahydrofuran, LiAlH is added portionwise while stirring under ice bath4 30
More than minute, reduzate compound (2), i.e. 2- (1- pyrroles -2- bases) ethanol are obtained；
S3：Under nitrogen protection, by compound (2) and the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3It is dissolved in tetrahydrofuran,
Be added portionwise DTAD while stirring under ice bath, when reaction 6 is small more than, generate compound (3), the i.e. chloro- 7- methoxyl groups -6- of 4-
[2- (1- pyrroles -2- bases) ethoxy] quinazoline；
S4：4- amino methyls-n,N-Dimethylaniline, the fluoro- 4- nitrobenzenes of 1- and sodium carbonate are dissolved with DMSO, 60~120 DEG C
When stirring reaction 4~12 is small, compound (4), i.e. N- [4- (4- dimethylamino) phenyl] methyl-4-nitrophenylamine are generated；
S5：By compound (4), dissolved with tetrahydrofuran, add Raney's nickel, be passed through hydrogen, when 25~100 DEG C of stirrings 3~12 are small,
Generate compound (5), i.e. N- { [(4- dimethylamino) phenyl] methyl } benzene-Isosorbide-5-Nitrae-diamines；
S6：Compound (3) and compound (5) are dissolved in n-butanol, when 60~120 DEG C of stirring reactions 1~6 are small, generate compound
(6), i.e. LU1506.
2. the preparation method of quinazoline derivant LU1506 according to claim 1, it is characterised in that in step S1,
The concentration of EtMgBr diethyl ether solutions is 3M, and drop speed is 5~10ml/min, EtMgBr ether, methyl bromoacetate, tetrahydrofuran, pyrrole
The amount ratio coughed up is 100~500mL：20~50g：250~1000ml：20~50g；In step S2, LiAlH4Dosage be every
G of compound (1) adds 0.25~2g.
3. the preparation method of quinazoline derivant LU1506 according to claim 1, it is characterised in that in step S3, institute
The DTAD stated points of 3~6 batches of additions, when interval 2~4 is small/time, wherein, the chloro- 7- methoxyquinazoline hydrochlorides -6- alcohol of 4-, PPh3、DTAD、
The mole dosage ratio of compound (2) is 1:1:1:0.8~1.4.
4. the preparation method of quinazoline derivant LU1506 according to claim 1, it is characterised in that in step S4,4-
The mole dosage ratio of the fluoro- 4- nitrobenzenes of amino methyl-N, accelerine, 1- and sodium carbonate is 1:1:0.3~3.
5. the preparation method of quinazoline derivant LU1506 according to claim 1, it is characterised in that in step S5, thunder
The dosage of Buddhist nun's nickel adds 0.2~2.0g of Raney's nickel for every 1 g of compound (4).
6. the preparation method of quinazoline derivant LU1506 according to claim 1, it is characterised in that in step S6, change
Compound (5), the mole dosage ratio of compound (3) are 1:0.6~1.2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391562A (en) * | 1999-09-21 | 2003-01-15 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives as pharmaceuticals |
| CN1993349A (en) * | 2004-06-04 | 2007-07-04 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as ERBB receptor tyrosine kinases |
| CN102532042A (en) * | 2010-12-30 | 2012-07-04 | 上海医药工业研究院 | Aryl urea compound as well as intermediate and application thereof |
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| US20090143399A1 (en) * | 2003-10-14 | 2009-06-04 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Protein Kinase Inhibitors |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391562A (en) * | 1999-09-21 | 2003-01-15 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives as pharmaceuticals |
| CN1993349A (en) * | 2004-06-04 | 2007-07-04 | 阿斯利康(瑞典)有限公司 | Quinazoline derivatives as ERBB receptor tyrosine kinases |
| CN102532042A (en) * | 2010-12-30 | 2012-07-04 | 上海医药工业研究院 | Aryl urea compound as well as intermediate and application thereof |
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