CN104844526A - 4,6-pyrimidine diamine compound and preparing method and application thereof - Google Patents
4,6-pyrimidine diamine compound and preparing method and application thereof Download PDFInfo
- Publication number
- CN104844526A CN104844526A CN201510179620.0A CN201510179620A CN104844526A CN 104844526 A CN104844526 A CN 104844526A CN 201510179620 A CN201510179620 A CN 201510179620A CN 104844526 A CN104844526 A CN 104844526A
- Authority
- CN
- China
- Prior art keywords
- general formula
- egfr
- cancer
- pyrimidine
- compound
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a 4,6-pyrimidine diamine compound and a preparing method and an application thereof; the 4,6-pyrimidine diamine compound is an N4,N6-(2,5-dialkoxy phenyl)-pyrimidine diamine compound or an N4-(2,5-dialkoxy phenyl)-N6-(3-alkoxy phenyl)-pyrimidine diamine compound, and in particular, alkoxy can be C1-C4 alkane. The 4,6-pyrimidine diamine compound can be used for broad-spectrum inhibition of the activity of an EGFR kinase and resisting of EGFR expressed tumor cell activity. The EGFR kinase is a wild-type or drug-resistant mutant EGFR kinase, and provides a basis for new drug screening. And the synthesis method of the 4,6-pyrimidine diamine compound provided by the invention is simple in synthesis process and is in favor of industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to a kind of 4,6-pyrimidinediamine compounds and its preparation method and application.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, is characterized in cell or mutant abnormality proliferation.The current mankind account for the second of all mortalities because of death that malignant tumour causes, are only second to cardiovascular and cerebrovascular diseases.Because existing antitumor drug exists, toxicity is large, easy produces the shortcomings such as resistance, so development targeting antineoplastic medicine thing is the field that global Pharma Inc. and national governments pay close attention to and develop always.
EGF-R ELISA (EGFR) is a kind of receptor tyrosine kinase, the signal path that energy activates also inducing cancer cell propagation, survival and moves, thus cause the generation of various epidermal carcinoma (as skin carcinoma, mammary cancer, ovarian cancer and and nonsmall-cell lung cancer, tumor of head and neck, intestinal cancer, bladder cancer).EGFR is a kind of transmembrane receptor protein of catalytic, has a catalysis region inside cytolemma, has a ligand binding region outside cytolemma.When part i.e. Urogastron are attached to calmodulin binding domain CaM, EGFR is activated, and can suppress the activity of EGFR with the catalytic site of Ligand Competition binding site or direct interference EGFR.Since Fry in 1994 etc. find the specific inhibitor of 4-anilinoquinazoline (PD153035) as EGFR Tyrosylprotein kinase, quinazoline compounds becomes one of focus of cancer therapy drug development, has developed the target agent of the first-generation and the s-generation.First-generation EGFR reversible inhibitor Gefitinib ZD1839 (Iressa) and erlotinib OSI-774 (Tarceva) etc. are because of its good antitumour activity commercialization.But they only produce inhibition to growth of cancer cells, effectively cannot kill cancer cells, and life-time service can lead oncogenic resistance, therefore their effects are clinically restricted, and this promotes the research and development of EGFR irreversible inhibitor of new generation.And research shows to detect Secondary cases mutation T 790M, L858R, d746-750 etc. on the EGFR of acquired resistance patient.
At present, the structure activity relationship of EGFR inhibitor is also uncertain, the compound that some structural difference are very little, and its effect suppressed for EGFR but has very big difference.A kind of compound can be invented can produce inhibition for EGFR kinases and the activity of the tumour cell of EGFR high expression level can be resisted, become the technical problem that those skilled in the art are urgently to be resolved hurrily.
Summary of the invention
An object of the present invention is that the structure activity relationship for solving EGFR inhibitor is uncertain, the compound that some structural difference are very little, its effect suppressed for EGFR but has very big difference, can not realize the problem of the activity of tumor cells effectively suppressing EGFR kinases and anti-EGFR high expression level.The present invention is in order to solve the problems of the technologies described above, there is provided a kind of 4,6-pyrimidinediamine compounds and its preparation method and application, the present invention is through a large amount of experiments, have devised and synthesized two kinds have good anti-activity of EGFR containing alkoxy base 4,6-diphenyl amino pyrimidines, it has excellent EGFR
wTinhibition, and to saltant type EFGR
l858R, EGFR
d746-750kinases has the activity of the tumour cell of good inhibit activities and good antagonism EGFR high expression level.
In order to reach above-mentioned technique effect, technical scheme of the present invention comprises:
A kind of 4,6-pyrimidinediamine compounds, has the structure of following general formula (I) or (II):
R1, R2, R3, R4 in formula (I) and formula (II) are respectively the alkyl of C1 ~ C4.
Described R1, R2, R3, R4 are methyl.
One prepares the method for 4,6-pyrimidinediamine compounds, comprises the following steps:
The method that preparation has the compound of the structure of described general formula (I) comprises the following steps:
Step one: prepare intermediate product: get 4,6-dichloro pyrimidine 1g and put into reaction flask and add ethanol 30mL, KI is appropriate, ultrasonic dissolution, magnetic agitation, 80 DEG C of reflux, get 2,5-dialkoxy aniline 1.275g and be placed in another round-bottomed flask, and add 10mL dissolve with ethanol, with every 5 minutes 5 be added dropwise to 4, in 6-dichloro pyrimidine solution, drip off rear continuation backflow 1-2 hour, suction filtration, recrystallization obtains the chloro-N-of intermediate product 6-(2,5-dialkoxy phenyl)-pyrimidine-4-amine;
Step 2: preparation has the crude compound of the structure of described general formula (I): the chloro-N-(2 of intermediate product 6-, 5-dialkoxy phenyl)-pyrimidine-4-amine 100mg puts into flask, and add 3-anisidine 120mg and 30mg p-methyl benzenesulfonic acid is dissolved in 30mL ethanol, stir, 80 DEG C of reflux 6 hours, extract reaction solution and carry out TLC race plate, under Ultraluminescence, observing response is complete, cooling, suction filtration, recrystallization must have the crude compound of the structure of described general formula (I);
Step 3: purify: add saturated NaHCO
3, stir 1 hour, suction filtration, cross the compound that chromatography column obtains the structure of described general formula (I);
The method that preparation has the compound of the structure of described general formula (II) comprises the following steps:
Step one: preparation has the crude compound of the structure of described general formula (II): get 4,6-dichloro pyrimidine 1g puts into reaction flask and adds ethanol 30mL, 0.5mol p-methyl benzenesulfonic acid, ultrasonic dissolution, put into magnetite, stirring, 80 DEG C of reflux, get 2, the amine solvent of 5-dialkoxy aniline 2mol, magnetic agitation, 80 DEG C of reflux 6 hours, extract reaction solution and carry out TLC race plate, under Ultraluminescence, observing response is complete, and suction filtration, recrystallization must have the crude compound of the structure of described general formula (II).
Step 2: purify: prepare to described step one in the crude compound of the structure with described general formula (II) and add saturated NaHCO
3, stir 1 hour, suction filtration, cross the compound that chromatography column obtains the structure with described general formula (II);
Wherein, the alkoxyl group in described 2,5-dialkoxy aniline is the alkyl of C1 ~ C4, and the alkoxyl group in the chloro-N-of described 6-(2,5-dialkoxy phenyl)-pyrimidine-4-amine is the alkyl of C1 ~ C4.
4,6-described pyrimidinediamine compounds, can be used for broad spectrum and suppress EGFR kinase activity, the activity of the tumour cell that antagonism EGFR expresses.Described EGFR kinases is the EGFR kinases of wild-type or medicament-resistant mutation.
A kind of pharmaceutical composition, comprises 4,6-above-mentioned pyrimidinediamine compounds or its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material.
The formulation of described pharmaceutical composition can be any one in capsule, tablet, oral liquid, injection, pulvis, paste or external medicinal liquid.
Described pharmaceutical composition can be used for treating any one in lung cancer, mammary cancer, intestinal cancer, ovarian cancer, kidney, bladder cancer, oral carcinoma, laryngocarcinoma, esophagus cancer, cancer of the stomach.
Beneficial effect of the present invention comprises:
(1) of the present invention a kind of 4,6-pyrimidinediamine compounds and its preparation method and application, through a large amount of experiments, have devised and synthesized two kinds have good anti-activity of EGFR containing alkoxy base 4,6-diphenyl amino pyrimidines, it has excellent EGFR
wTinhibition, and to saltant type EFGR
l858R, EGFR
d746-750kinases has the activity of the tumour cell of good inhibit activities and good antagonism EGFR high expression level, for novel drugs screening provides the foundation.
(2) synthetic method that 4,6-pyrimidinediamine compounds is provided of the present invention, and its synthesis technique is simple, is conducive to suitability for industrialized production.
(3) of the present invention 4,6-pyrimidinediamine compounds and pharmaceutically acceptable same pharmaceutical excipient combination thereof are prepared into pharmaceutical composition, can field of medicaments be widely used in, can be used for treating lung cancer, mammary cancer, intestinal cancer, ovarian cancer, kidney, bladder cancer, oral carcinoma, laryngocarcinoma, esophagus cancer, cancer of the stomach.
Embodiment
Hereafter in detail the specific embodiment of the invention will be described.It should be noted that the combination of technical characteristic or the technical characteristic described in following embodiment should not be considered to isolated, they can mutually be combined thus be reached better technique effect.
A kind of 4,6-pyrimidinediamine compounds, has the structure of following general formula (I) or (II):
R1, R2, R3, R4 in formula (I) and formula (II) are respectively the alkyl of C1 ~ C4.
Preferably, described R1, R2, R3, R4 are methyl, namely 4,6-pyrimidinediamine compounds is N4-(2,5-Dimethoxyphenyl)-N6-(3-p-methoxy-phenyl)-pyrimidinediamine or N4, N6-(2,5-Dimethoxyphenyl)-pyrimidinediamine.
A kind of pharmaceutical composition, containing 4,6-pyrimidinediamine compounds or its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material.This medicine composition dosage form can be any one in capsule, tablet, oral liquid, injection, pulvis, paste or external medicinal liquid, can be used for treating any one in lung cancer, mammary cancer, intestinal cancer, ovarian cancer, kidney, bladder cancer, oral carcinoma, laryngocarcinoma, esophagus cancer, cancer of the stomach
Embodiment 1 prepares N
4-(2,5-Dimethoxyphenyl)-N
6-(3-p-methoxy-phenyl)-pyrimidinediamine
Get 4,6-dichloro pyrimidine 1g put into reaction flask and add ethanol 30mL, KI is appropriate, and ultrasonic dissolution, magnetic agitation, 80 DEG C of reflux, get 2,5-dimethoxyaniline 1.275g and be placed in another round-bottomed flask, and add 10mL dissolve with ethanol.With every 5 minutes 5 be added dropwise in 4,6-dichloro pyrimidine solution, drip off rear continuation backflow 1-2 hour, suction filtration, recrystallization obtains the chloro-N-of 6-(2,5-Dimethoxyphenyl)-pyrimidine-4-amine.Calculate productive rate 78-82%.
Get the chloro-N-(2 of 6-, 5-Dimethoxyphenyl)-pyrimidine-4-amine 100mg puts into flask, and add 3-anisidine 120mg and 30mg p-methyl benzenesulfonic acid is dissolved in 30mL ethanol, stir, 80 DEG C of reflux 6 hours, extract reaction solution and carry out TLC race plate, under Ultraluminescence, observing response is complete.Cooling, suction filtration, recrystallization obtains N
4-(2,5-Dimethoxyphenyl)-N
6-(3-p-methoxy-phenyl)-pyrimidinediamine crude product.Add saturated NaHCO
3, stir 1 hour, suction filtration, cross chromatography column and obtain fine work.Calculate productive rate 70-75%.
Fusing point: 182 DEG C.Nuclear magnetic data (d
6-DMSO): 3.738 (s, 3H ,-OCH
3), 6.204 (s, 2H, N
6-2 '-PhH), 6.551-6.597 (m, 2H, N
4-5 '-PhH), 6.931-6.946 (m, 2H, N
4-3 '-PhH), 7.104-7.117 (m, 2H, N
6-4 '-PhH), 7.190-7.231 (m, 2H, N
6-5 '-PhH), 7.505-7.514 (m, 1H, N
4-6 '-PhH+N
6-6 '-PhH), 8.332 (s, 1H, 5-pyrimidineH), 9.223 (s, 1H, 2-pyrimidineH), 9.335 (s, 1H ,-NH). molecular mass (ESI-MS): 371 [M+H]
+.
Embodiment 2 prepares N
4, N
6-(2,5-Dimethoxyphenyl)-pyrimidinediamine
Get 4,6-dichloro pyrimidine 1g put into reaction flask and add ethanol 30mL, 0.5mol p-methyl benzenesulfonic acid, ultrasonic dissolution, puts into magnetite, stirs, 80 DEG C of reflux, gets 2mol 2,5-dimethoxy benzene amine solvent, magnetic agitation, 80 DEG C of reflux 6 hours.Extract reaction solution and carry out TLC race plate, under Ultraluminescence, observing response is complete.Suction filtration, recrystallization obtains N
4, N
6-(2,5-Dimethoxyphenyl)-pyrimidinediamine crude product.Add saturated NaHCO
3, stir 1 hour, suction filtration, cross chromatography column and obtain fine work.Calculate productive rate 75%-82%.
Fusing point: 187 DEG C.Nuclear magnetic data (d
6-DMSO): 3.669 (s, 6H, 5 '-Ph-OCH
3× 2), 3.752 (s, 6H, 2 '-Ph-OCH
3× 2), 6.257 (s, 1H,-NH), 6.551-6.597 (m, 2H, 5 '-PhH), 6.931-6.946 (m, 2H, 3 '-PhH), 7.472-7.477 (m, 2H, 6 '-PhH), 8.195 (m, 3H ,-pyrimidineH+-NH). molecular mass (ESI-MS): 383 [M+H]
+.
Embodiment 3 compound of the present invention is to the kinase whose inhibit activities test of different EGFR
Experiment employing method is Caliper Mobility Shift Assay, the detection platform that the method is is core with the migration detection technique of microfluidic chip technology.Experimental procedure: configuration 1x kinase reaction damping fluid (50mM HEPES, pH7.5; 0.0015%Brij-35; 10mM MgCl
2, 10mM MnCl
2; 2Mm DTT) and kinase reaction stop buffer (100mM HEPES, pH7.5; 0.015%Brij-35; 0.2%Coating Reagent#3; 50mM EDTA); (DMSO solution is used in the compound solution of the 5x concentration of 5 μ l, dilute with water 10 times) add the 2.5x peptide substrate solution (adding kinases in 1x kinase reaction damping fluid) of 10 μ l, add the 2.5x peptide substrate solution (add FAM and mark peptide and ATP in 1x kinase reaction damping fluid) of 10 μ l after incubated at room 10min again, react the specific time at 28 DEG C after, add 25 μ l kinase reaction stop buffers.On Caliper, test collects data, to inhibiting rate=[(max-conversion)/(max-min)] × 100 of kinase activity." max ", for not adding the DMSO contrast of compound, " min " is low contrast.Measure IC
50in time, often plants sample and establishes each 2 the multiple holes of 4 extent of dilution, repeats for 3 times.
Under 10 concentration such as 10 μMs, 3.333 μMs, 1.111 μMs, 0.37 μM, 0.123 μM, 0.041 μM, 0.014 μM, 0.005 μM, 0.002 μM, 0.001 μM, embodiment 1 and embodiment 2 couples of EGFR are measured respectively by aforesaid method
wT, EGFR
t790M/L858R, EGFR
l858R, EGFR
d746-750kinase whose activity, and calculate its IC
50value, IC
50the results are shown in Table 1.
Table 1 compound of the present invention is to the kinase whose inhibit activities of different EGFR
IC50 refers in apoptosis, can be understood as certain drug-induced apoptosis of tumor cells 50% certain density, this concentration is called 50% inhibition concentration, namely concentration corresponding when apoptotic cell and the ratio of whole cell count equal 50%, IC50 value can be used for weighing the ability of drug-induced apoptosis, namely inducibility is stronger, and this numerical value is lower.
From table 1 data, the compound of embodiment 1 and embodiment 2 is to EGFR
wTtype and saltant type EFGR thereof
l858R, EGFR
d746-750kinases has stronger inhibit activities.To kinases EGFR
t790M/L858R, almost unrestraint is active for FGFR1 and KDR.
Embodiment 4 measures the IC of the compounds of this invention to different tumor cell line
50value
Experiment adopts CTG method, and test the compounds of this invention is to the IC of different tumor cell line
50value.Epidermis squamous cell carcinoma A431, the human lung adenocarcinoma cell NCI-H1975 of EGFR high expression level, human lung carcinoma cell PC-9 cell etc. is selected to carry out proliferation inhibition activity experiment.IC
50value the results are shown in Table 2.
Table 2 the compounds of this invention is to the IC of different tumor cell line
50value
IC50 refers in apoptosis, can be understood as certain drug-induced apoptosis of tumor cells 50% certain density, this concentration is called 50% inhibition concentration, namely concentration corresponding when apoptotic cell and the ratio of whole cell count equal 50%, IC50 value can be used for weighing the ability of drug-induced apoptosis, namely inducibility is stronger, and this numerical value is lower.
From table 2 data, the compound of embodiment 1 and embodiment 2 all has higher inhibit activities to epidermis squamous cell carcinoma A431, the human lung adenocarcinoma cell NCI-H1975 of EGFR high expression level, human lung carcinoma cell PC-9 cell.
In sum, 4,6-pyrimidinediamine compounds of the present invention, can be used for broad spectrum and suppress EGFR kinase activity, the activity of the tumour cell that antagonism EGFR expresses.Described EGFR kinases is the EGFR kinases of wild-type or medicament-resistant mutation, for novel drugs screening provides the foundation.And the synthetic method providing 4,6-pyrimidinediamine compounds of the present invention, its synthesis technique is simple, is conducive to suitability for industrialized production.
Above-mentioned detailed description is the illustrating of possible embodiments for invention, and this embodiment is also not used to limit the scope of the claims of the present invention, does not allly depart from equivalence of the present invention and implements or change, and all should be contained in the scope of the claims of the present invention.
In addition, those skilled in the art also can make various amendments in other form and details, interpolation and replacement in the claims in the present invention scope of disclosure and spirit.Certainly, the changes such as these various amendments made according to the present invention's spirit, interpolation and replacement, all should be included within the present invention's scope required for protection.
Claims (8)
1. a pyrimidinediamine compounds, is characterized in that, has the structure of following general formula (I) or (II):
R1, R2, R3, R4 in formula (I) and formula (II) are respectively the alkyl of C1 ~ C4.
2. a kind of 4,6-pyrimidinediamine compounds according to claim 1, it is characterized in that, described R1, R2, R3, R4 are methyl.
3. prepare the method for 4,6-pyrimidinediamine compounds described in any one of claim 1 or 2 for one kind, it is characterized in that:
The method that preparation has the compound of the structure of described general formula (I) comprises the following steps:
Step one: prepare intermediate product: get 1g 4,6-dichloro pyrimidine and put into reaction flask and add 30mL ethanol, potassiumiodide, ultrasonic dissolution, magnetic agitation, 80 DEG C of reflux, get 2,5-dialkoxy aniline 1.275g is placed in another round-bottomed flask, and add 10mL dissolve with ethanol, with every 5 minutes 5 be added dropwise in 4,6-dichloro pyrimidine solution, drip off rear continuation backflow 1 ~ 2 hour, suction filtration, recrystallization obtains the chloro-N-of intermediate product 6-(2,5-dialkoxy phenyl)-pyrimidine-4-amine;
Step 2: preparation has the crude compound of the structure of described general formula (I): get the chloro-N-(2 of intermediate product 6-, 5-dialkoxy phenyl)-pyrimidine-4-amine 100mg puts into flask, and add 3-anisidine 120mg and 30mg p-methyl benzenesulfonic acid is dissolved in 30mL ethanol, stir, 80 DEG C of reflux 6 hours, extract reaction solution and carry out TLC race plate, under Ultraluminescence observing response completely after, cooling, suction filtration, recrystallization must have the crude compound of the structure of described general formula (I);
Step 3: purify: add saturated NaHCO
3, stir 1 hour, suction filtration, cross the compound that chromatography column obtains the structure of described general formula (I);
The method that preparation has the compound of the structure of described general formula (II) comprises the following steps:
Step one: preparation has the crude compound of the structure of described general formula (II): get 1g4,6-dichloro pyrimidine is put into reaction flask and is added 30mL ethanol, 0.5mol p-methyl benzenesulfonic acid, ultrasonic dissolution, put into magnetite, stirring, 80 DEG C of reflux, get 2mol 2,5-dialkoxy benzene amine solvent, magnetic agitation, 80 DEG C of reflux 6 hours, extract reaction solution and carry out TLC race plate, under Ultraluminescence, observing response is complete, and suction filtration, recrystallization must have the crude compound of the structure of described general formula (II).
Step 2: purify: prepare to described step one in the crude compound of the structure with described general formula (II) and add saturated NaHCO
3, stir 1 hour, suction filtration, cross the compound that chromatography column obtains the structure with described general formula (II);
Wherein, the alkoxyl group in described 2,5-dialkoxy aniline is the alkyl of C1 ~ C4, and the alkoxyl group in the chloro-N-of described 6-(2,5-dialkoxy phenyl)-pyrimidine-4-amine is the alkyl of C1 ~ C4.
4. the application of 4,6-pyrimidinediamine compounds described in any one of claim 1 or 2, is characterized in that, can be used for broad spectrum and suppresses EGFR kinase activity, the activity of the tumour cell that antagonism EGFR expresses.
5. the application of 4,6-pyrimidinediamine compounds according to claim 4, is characterized in that, described EGFR kinases is the EGFR kinases of wild-type or medicament-resistant mutation.
6. a pharmaceutical composition, is characterized in that, comprises 4,6-pyrimidinediamine compounds described in any one of claim 1 or claim 2 or its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material.
7. pharmaceutical composition according to claim 6, is characterized in that, its formulation can be any one in capsule, tablet, oral liquid, injection, pulvis, paste or external medicinal liquid.
8. the application of the pharmaceutical composition described in any one of claim 6 or 7, is characterized in that, described pharmaceutical composition can be used for treating any one in lung cancer, mammary cancer, intestinal cancer, ovarian cancer, kidney, bladder cancer, oral carcinoma, laryngocarcinoma, esophagus cancer, cancer of the stomach.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510179620.0A CN104844526B (en) | 2015-04-16 | 2015-04-16 | A kind of 4,6- pyrimidinediamines class compound and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510179620.0A CN104844526B (en) | 2015-04-16 | 2015-04-16 | A kind of 4,6- pyrimidinediamines class compound and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104844526A true CN104844526A (en) | 2015-08-19 |
| CN104844526B CN104844526B (en) | 2018-08-31 |
Family
ID=53844564
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510179620.0A Active CN104844526B (en) | 2015-04-16 | 2015-04-16 | A kind of 4,6- pyrimidinediamines class compound and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104844526B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111777592A (en) * | 2020-06-22 | 2020-10-16 | 温州医科大学 | N4- (2, 5-dimethoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof |
| CN111793035A (en) * | 2020-06-22 | 2020-10-20 | 温州医科大学 | N4- (3-methoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof |
| CN115160235A (en) * | 2022-08-10 | 2022-10-11 | 宜宾学院 | 2, 3-dihydroquinazoline-4 (1H) -ketone compound and ultrasonic synthesis method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995015952A1 (en) * | 1993-12-09 | 1995-06-15 | Zeneca Limited | 4,6-dianilino-pyrimidine derivatives, their preparation and their use as tyrosine kinase inhibitors |
| CN102791131A (en) * | 2010-01-13 | 2012-11-21 | 葛兰素史密斯克莱有限责任公司 | Compounds and methods |
| CN103483273A (en) * | 2013-09-12 | 2014-01-01 | 浙江工业大学 | 6-methyl-5-fluorine-2,4-pyrimidinediamine compound and preparation and application thereof |
| WO2014183300A1 (en) * | 2013-05-17 | 2014-11-20 | Suzhou Vivotide Biotechnologies Co., Ltd. | Vegfr tyrosine kinase inhibitors |
-
2015
- 2015-04-16 CN CN201510179620.0A patent/CN104844526B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995015952A1 (en) * | 1993-12-09 | 1995-06-15 | Zeneca Limited | 4,6-dianilino-pyrimidine derivatives, their preparation and their use as tyrosine kinase inhibitors |
| CN102791131A (en) * | 2010-01-13 | 2012-11-21 | 葛兰素史密斯克莱有限责任公司 | Compounds and methods |
| WO2014183300A1 (en) * | 2013-05-17 | 2014-11-20 | Suzhou Vivotide Biotechnologies Co., Ltd. | Vegfr tyrosine kinase inhibitors |
| CN103483273A (en) * | 2013-09-12 | 2014-01-01 | 浙江工业大学 | 6-methyl-5-fluorine-2,4-pyrimidinediamine compound and preparation and application thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111777592A (en) * | 2020-06-22 | 2020-10-16 | 温州医科大学 | N4- (2, 5-dimethoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof |
| CN111793035A (en) * | 2020-06-22 | 2020-10-20 | 温州医科大学 | N4- (3-methoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof |
| CN111777592B (en) * | 2020-06-22 | 2021-06-18 | 温州医科大学 | N4- (2, 5-dimethoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof |
| CN111793035B (en) * | 2020-06-22 | 2021-06-18 | 温州医科大学 | N4- (3-methoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof |
| CN115160235A (en) * | 2022-08-10 | 2022-10-11 | 宜宾学院 | 2, 3-dihydroquinazoline-4 (1H) -ketone compound and ultrasonic synthesis method thereof |
| CN115160235B (en) * | 2022-08-10 | 2023-12-15 | 宜宾学院 | 2, 3-dihydro-quinazoline-4 (1H) -ketone compound and ultrasonic synthesis method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104844526B (en) | 2018-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105461695B (en) | Pyrimidine or pyrrolotriazine derivatives and its production and use | |
| US9359370B2 (en) | Icotinib hydrochloride, synthesis, crystalline forms, pharmaceutical compositions, and uses thereof | |
| Liu et al. | 6-Bromoindirubin-3′-oxime inhibits JAK/STAT3 signaling and induces apoptosis of human melanoma cells | |
| CN103649074B (en) | Be used for the treatment of the azacyclo-of the replacement of cancer | |
| CN105832740A (en) | Aromatic amino purine derivative as well as preparation method and pharmaceutical application thereof | |
| WO2007076085A2 (en) | Fused pyrimidones and thiopyrimidones, and uses thereof | |
| Yang et al. | Virtual screening and synthesis of quinazolines as novel JAK2 inhibitors | |
| US8575143B2 (en) | 3-aryl-substituted quinazolones, and uses thereof | |
| CN104093714B (en) | As the tetrahydro-quinazolin ketone derivatives of TANK and PARP inhibitor | |
| MXPA97000883A (en) | Derivatives substituted from quinazol | |
| HU229078B1 (en) | Quinazolinones and pharmaceutical compositions containing them | |
| CN103533939A (en) | Multiple myeloma treatment | |
| WO2009002553A1 (en) | Methods of treating multiple myeloma and resistant cancers | |
| CN104844526A (en) | 4,6-pyrimidine diamine compound and preparing method and application thereof | |
| CN108774219A (en) | Inhibit the micromolecular compound and application thereof of PD-1/PD-L1 | |
| Liu et al. | Synthesis and antitumor activity of novel 6, 7, 8-trimethoxy N-aryl-substituted-4-aminoquinazoline derivatives | |
| CN102942529B (en) | 4-(4-substituted piperazine)-5,6,7-trialkoxy quinazoline type compound as well as preparation method and application of 4-(4-substituted piperazine)-5,6,7-trialkoxy quinazoline type compound | |
| Liu et al. | 4-Anilinoquinazoline derivatives with epidermal growth factor receptor inhibitor activity | |
| CN107362166A (en) | Tetrahydropyridine simultaneously application of (3) ketone compounds of [4,5] thieno [2,3] pyrimidine 4 in pharmacy | |
| CN107383014A (en) | A kind of 1H pyrazolos [3,4 d] pyrimidines and its preparation method and application | |
| EP1883403A2 (en) | Keratinocyte growth factor receptor - tyrosine specific inhibitors for the prevention of cancer metastatis | |
| Theodore et al. | Design, synthesis, molecular docking and biological evaluation of novel pyrazole derivatives bearing quinoxalinone moiety as multi-targeted anticancer agents | |
| CN105566329B (en) | A kind of pyrazoles [5,6-d] miazines EGFR inhibitor and its anti-tumor activity | |
| CN101120945B (en) | Application of 8-arylamine-3H-imidazole [4, 5-g] quinazoline derivatives | |
| Zhang et al. | Novel quinazoline-based dual EGFR/c-Met inhibitors overcoming drug resistance for the treatment of NSCLC: Design, synthesis and anti-tumor activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 325000 Zhejiang, Ouhai, South East Road, No. 38, Wenzhou National University Science Park Incubator Applicant after: Wenzhou Medical University Address before: 325035 Wenzhou college, Zhejiang, West Road, No. 82 Applicant before: Wenzhou Medical University |
|
| COR | Change of bibliographic data | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |