CN103113355B - Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia - Google Patents
Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia Download PDFInfo
- Publication number
- CN103113355B CN103113355B CN201310063042.5A CN201310063042A CN103113355B CN 103113355 B CN103113355 B CN 103113355B CN 201310063042 A CN201310063042 A CN 201310063042A CN 103113355 B CN103113355 B CN 103113355B
- Authority
- CN
- China
- Prior art keywords
- bcr
- tyrosine kinase
- kinase inhibitor
- abl tyrosine
- obtains
- 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.)
- Expired - Fee Related
Links
Abstract
The invention discloses a Bcr/Abl tyrosine kinase inhibitor capable of treating chronic granulocytic leukemia and a preparation method thereof. The Bcr/Abl tyrosine kinase inhibitor capable of treating chronic granulocytic leukemia obtained by a large number of experimental screenings not only can effectively inhibit Bcr/Abl tyrosine kinase, and still has a good inhibitory effect to mutated Bcr/Abl tyrosine kinase, so that the Bcr/Abl tyrosine kinase inhibitor is a novel Bcr/Abl tyrosine kinase inhibitor for effectively treating chronic granulocytic leukemia.
Description
Technical field
The present invention relates to biological medicine research field, be specifically related to a kind of Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, and its preparation method and application.
Background technology
Chronic myelocytic leukemia (CML) is the common leukemia of a class, and the leukocyte disorder propagation showing as in blood causes canceration.Chronic myelocytic leukemia (being called for short slow grain) is mainly produced by karyomit(e) mutation.Whole world patient ratio is that in 100,000 people, one to two people falls ill, the slow grain leukemia people of China about 20,000 left and right.
The medicine imatinib (Imatinib) for the treatment of chronic myelocytic leukemia is sold by Novartis development; it causes that by acting on target Bcr-Abl kinases thereby cancer cell-apoptosis reaches the object (Quitas-Cardama, the A. that control or treat chronic myelocytic leukemia; Cortes, J.Blood2009,113,1619-1630; Druker, B.J., et al Nature Med.1996,2,561-566).Although imatinib obtains validity in the time of begin treatment, but must can there is resistance in medication in a large amount of patients after the time, approximately have chronic white corpuscle leukemia patient invalid or decline evident in efficacy to imatinib of 1/3.At the patient of burst period (blast crisis), this situation is more outstanding, reason is that dialogue chronic myeloid leukemia becomes the sick Bcr/Abl Tyrosylprotein kinase playing a decisive role to undergo mutation, and this medicine is lost activity to it, common sudden change has Q252H, Y253F, E255K, T315I, M351T, and H396P.For these variations, people are constantly designing new drug molecule to suppress the Bcr/Abl Tyrosylprotein kinase after these variations, thereby reach the treatment to chronic myelocytic leukemia, but these inhibitor are inoperative to mutation T 315I.Therefore, necessary on the basis of prior art, work out can mutation inhibiting the new inhibitor of T315I Bcr/Abl Tyrosylprotein kinase, in effective control chronic myelocytic leukemia, tool has very great significance.
Summary of the invention:
Goal of the invention: technical problem to be solved by this invention is, overcome the deficiency of the existing Bcr/Abl Tyrosylprotein kinase of controlling chronic myelocytic leukemia, provide one not only Bcr/Abl Tyrosylprotein kinase to be had to obvious restraining effect, and the Bcr/Abl Tyrosylprotein kinase that particularly T315I makes a variation of the Bcr/Abl Tyrosylprotein kinase after variation is still had to fine restraining effect, can effectively treat the Bcr/Abl tyrosine kinase inhibitor of chronic myelocytic leukemia.Another object of the present invention is to provide such preparation method with the Bcr/Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and its application.
Technical scheme: in order to realize above object, the general formula of the Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia provided by the invention is as follows:
In general formula
Wherein R1 represents hydrogen, alkyl, aromatic base or halogeno-group;
R2 represents hydrogen, alkyl or aromatic base;
R3 represents hydrocarbon amino, two hydrocarbon amino, alkyl or aromatic base;
R4 represents CH
2, CH
2cH
2, HC=CH or C ≡ C;
Ar is aromatic base;
N=1,2 or 3
As preferred version, the above-described Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, wherein said X and Y are nitrogen (N).
As preferred version, the above-described Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, described Ar is naphthyl, phenyl or pyridyl.
As preferred version, the above-described Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, described R2 is C
1~ C
5alkyl or phenyl, the most more preferably scheme, R2 is methyl, ethyl, propyl group or phenyl.
As preferred version, the above-described Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, described R3 is cyclopropylamino, cyclopropyl methene amido or phenyl.
The method of the Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia provided by the invention, it comprises the following steps:
A, get 2,4-dichloro pyrimidine chemical compounds I under cuprous iodide effect, at tetrahydrofuran (THF), in triethylamine solvent, obtain intermediate II with aryl ethane coupling, for subsequent use;
B, get intermediate II that step a obtains in saturated ammonia ethanolic soln heating ammonia solution to intermediate III;
C, first get 2,4,6-trichloropyrimidine, dichloromethane solution cooling with frozen water after, slowly add cyclopropylamine, ring the third methylamine or benzene, reaction stirring reaction in ice-water bath obtains intermediate compound IV; Then getting intermediate compound IV and step b obtains intermediate III heated and stirred reaction under DMF and saleratus effect and obtains intermediate V;
D, get the intermediate V that step c obtains and add (1-methyl-Pyrrolidine base) methylamine, (1-ethyl-Pyrrolidine base) methylamine, (1-methyl-hexahydropyridine base) methylamine or (1-ethyl-hexahydropyridine base) methylamine, heated and stirred aminolysis reaction obtains end product compound VI.
As preferred version, the above-described preparation method of Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, the aryl ethane described in its step a is naphthalene acetylene.
As preferred version, the preparation method of the above-described Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, adds two (triphenylphosphine) palladium II complex compounds of dichloro as catalyzer in step a.
The reaction process of the method for the Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia provided by the invention can be as follows:
The Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia provided by the invention can be prepared into pharmaceutically acceptable carrier the medicine of the formulations such as tablet, capsule, granule, injection liquid, pill.
When the present invention makes tablet, Bcr/Abl tyrosine kinase inhibitor and carrier lactose or the W-Gum with treatment chronic myelocytic leukemia, add magnesium stearate lubricant while needs, mix, then compressing tablet is made tablet.
When the present invention makes capsule, mix whole grain, the then encapsulated capsule of making thering is the treatment Bcr/Abl tyrosine kinase inhibitor of chronic myelocytic leukemia and carrier lactose or W-Gum.
When granulation agent of the present invention, mix thering is the treatment Bcr/Abl tyrosine kinase inhibitor of chronic myelocytic leukemia and thinner lactose or W-Gum, whole grain, dry, granulation agent.
When the present invention makes injection liquid, get have treatment chronic myelocytic leukemia Bcr/Abl tyrosine kinase inhibitor add solubilizing agent, stir, 80 DEG C are heated 30 minutes, filter, regulate pH value, be filtered to clear and bright with sintered glass funnel or other filter, filling, within 30 minutes, make injection liquid 100 to 115 DEG C of sterilizings.
The present invention carries out biological activity test to the target compound preparing, vitro inhibition Bcr/Abl to them and the kinase whose activity of T315I variation Bcr/Abl are assessed by vitro enzyme activity test, and compare with Apoptosis and Dasatinib (dasatinib).For the Bcr/Abl kinases not making a variation, the target compound activity that the present invention prepares is between 0.8-520nM, suitable with Apoptosis and Dasatinib, for T315I variation Bcr/Abl kinases, the target compound that the present invention prepares still shows good inhibition active (1.2-650nM), and Apoptosis and Dasatinib have lost activity.Therefore the target compound that the present invention prepares can be used for treatment imatinib and s-generation Bcr/Abl tyrosine kinase inhibitor is had to drug-fast chronic myelocytic leukemia.
Beneficial effect: provided by the invention have the treatment Bcr/Abl tyrosine kinase inhibitor of chronic myelocytic leukemia and prior art now than having the following advantages:
1, series provided by the invention has the Bcr/Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia, screen by great many of experiments, the Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia preparing, can not only effectively suppress Bcr/Abl Tyrosylprotein kinase, and the Bcr/Abl Tyrosylprotein kinase after variation is still had to fine restraining effect, is a kind of novel B cr/Abl tyrosine kinase inhibitor of effective treatment chronic myelocytic leukemia.And test and show, untoward reaction is low, and medication is safer, and can be made into multi-medicament formulation, facilitates clinical application.
2, the preparation method of the Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia provided by the invention, screen by great many of experiments, as shown in Figure 2, with 2,4-dichloro pyrimidine is starting raw material, through aryl ethane coupling, and through triple bond reduction, heating ammonia solution, aminolysis obtains target compound.
Brief description of the drawings
Fig. 1 is the structural representation of the Bcr/Abl tyrosine kinase inhibitor general formula with treatment chronic myelocytic leukemia of the present invention.
Fig. 2 is the Bcr/Abl tyrosine kinase inhibitor preparation method's with treatment chronic myelocytic leukemia of the present invention reacting flow chart.
Embodiment
According to following embodiment, the present invention may be better understood.But, those skilled in the art will readily understand, the described concrete material proportion of embodiment, processing condition and result thereof be only for the present invention is described, and should also can not limit the present invention described in detail in claims.
Embodiment 1(E)-N2-(encircles the third methyl)-N4-((1-methyl-Pyrrolidine base)-3-methyl)-N6-(4-(2-(2-naphthalene vinyl) preparation of-2-pyrimidyl-triaminopyrimidine (VIax1)
1, in 500ml round-bottomed flask, add 2,4-dichloro pyrimidine (14.5g, 97.5mmol), two (triphenylphosphine) palladium (II) complex compound (1.3g of dichloro, 2.6mmol), cuprous iodide (25mg, 0.13mmol), tetrahydrofuran (THF) (250ml), triethylamine (34ml, 263mmol).Mixture is heated to after 50 DEG C, adds tetrahydrofuran (THF) (100ml) solution of naphthalene acetylene (97.5mmol).After 5 hours, reaction solution is cooling, and with methylene dichloride dilution, after organic phase is washed with water, saturated common salt respectively after separating and with anhydrous magnesium sulfate drying.Crude product after concentrated obtains product intermediate II a(R1=2-naphthyl by column chromatography purification) 18.5 grams.
2, in a tube sealing, add IIa(16.0g), saturated ammonia ethanolic soln (200ml).System stirring heating 24 hours.After cooling, open tube sealing, with nitrogen, ammonia is blown away, solution adds water, and product is separated out, and obtains intermediate III a(R1=2-naphthyl after filtration drying) 13.2 grams.
3, in 500ml round-bottomed flask, add 2,4,6-trichloropyrimidine (100mmol), methylene dichloride (250ml), after solution is cooling with frozen water, slowly add ring the third methylamine (90mmol), reaction is stirred half an hour in ice-water bath, adds frozen water and methylene dichloride dilution, after organic phase is washed with water, saturated common salt respectively after separating and with anhydrous sodium sulfate drying.Crude product after concentrated obtains product intermediate compound IV x9.5 gram by column chromatography purification.
4, then in 100ml round-bottomed flask, add IIIa(2.47g), IVx(2.18g), DMF(30ml), saleratus.Reaction mixture heated and stirred 6 hours, cooling rear thin up is separated out precipitation.After filtration drying, obtain intermediate Vax(R1=2-naphthyl, R3=encircles the third methyl) 3.8 grams.
5, in 10ml round-bottomed flask, add intermediate Vax(100mg), solvent (3ml), (1-methyl-Pyrrolidine base) methylamine (3 equivalent), reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.Filter, obtain end product compound VI ax1(R1=2-naphthyl after purifying, R3=encircles the third methyl, R2=methyl, n=1) 52.15 milligrams, structural formula is as follows.
Gained compound spectroscopic data is: LCMS m/z=507(M+H)
1H-NMR(DMSO-d6,400MHz):δ8.30(d,1H),7.30-8.05(m,7H),7.10(d,1H),7.01(d,1H),6.85(d,1H).
Embodiment 2(E)-N2-(encircles the third methyl)-N4-((1-phenyl-Pyrrolidine base)-3-methyl)-N6-(4-(2-(2-naphthalene vinyl) preparation of-2-pyrimidyl-triaminopyrimidine (VIax2)
In 10ml round-bottomed flask, add the intermediate Vax(100mg preparing by embodiment 1 method), solvent (3ml), (1-phenyl-Pyrrolidine base) methylamine (3 equivalent), reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.Filter, obtain end product compound VI ax2(R1=2-naphthyl after purifying, R3=encircles the third methyl, R2=phenyl, n=1) 59.85 milligrams.Its structural formula is as follows.
Gained compound spectroscopic data is:
LCMS?m/z=569（M+H）;1H-NMR(DMSO-d6,400MHz):δ8.30(d,1H),7.30-8.15(m,7H),6.80-7.30(d,7H)。
Embodiment 3(E)-N2-(encircles the third methyl)-N4-Pyrrolidine base-3-methyl)-N6-(4-(2-(2-naphthalene vinyl) preparation of-2-pyrimidyl-triaminopyrimidine (VIax3)
In 10ml round-bottomed flask, add the intermediate Vax(100mg preparing by embodiment 1 method), solvent (3ml), (1-Boc-Pyrrolidine base) methylamine (3 equivalent), reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.Filtration drying after product is dissolved in the dichloromethane solution of 25%TFA, reacts after 4 hours concentrated, after thick purifying products, obtains end product compound VI ax3(R1=2-naphthyl, and R3=encircles the third methyl, R2=H, n=1) 32.55 milligrams.Its structural formula is as follows
Gained compound spectroscopic data is:
LCMS?m/z=493（M+H）；1H-NMR(DMSO-d6,400MHz):δ8.30(d,1H),7.30-8.05(m,7H),7.10(d,1H),7.01(d,1H),6.85(d,1H).
Embodiment 4(E)-N2-(encircles the third methyl)-N4-piperidines-4-methyl)-N6-(4-(2-(2-naphthalene vinyl) preparation of-2-pyrimidyl-triaminopyrimidine (VIax4)
In 10ml round-bottomed flask, add the intermediate Vax(100mg preparing by embodiment 1 method), solvent (3ml), (1-Boc-piperidines)-4-methylamine (3 equivalent).Reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.Filtration drying after product is dissolved in the dichloromethane solution of 25%TFA, reacts after 4 hours concentrated, after thick purifying products, obtains end product compound VI ax4(R1=2-naphthyl, and R3=encircles the third methyl, R2=H, n=2) 31.45 milligrams.Its structural formula is as follows.
Gained compound spectroscopic data is:
LCMS?m/z=507（M+H）;1H-NMR(DMSO-d6,400MHz):δ8.25(d,1H),8.10(dd,2H),7.30-7.80(m,5H),6.96(m,2H)。
Embodiment 5(E)-N2-(encircles the third methyl)-N4-((1-methyl-Pyrrolidine base)-3-methyl)-N6-(4-(2-(2-naphthalene vinyl) preparation of-2-pyrimidyl-triaminopyrimidine (VIay1)
In 500ml round-bottomed flask, add 2,4,6-trichloropyrimidine (100mmol), methylene dichloride (250ml), after solution is cooling with frozen water, slowly add cyclopropylamine (90mmol).Reaction is stirred half an hour in ice-water bath, adds frozen water and methylene dichloride dilution, after organic phase is washed with water, saturated common salt respectively after separating and with anhydrous sodium sulfate drying.Crude product after concentrated obtains product intermediate compound IV y(R3=cyclopropyl by column chromatography purification) 7.5 grams.
In 100ml round-bottomed flask, add the IIIa(2.47g preparing by embodiment 1 method), IVy(2.02g), DMF(30ml), saleratus.Reaction mixture heated and stirred 6 hours, cooling rear thin up is separated out precipitation.After filtration drying, obtain intermediate Vay(R1=2-naphthyl, R3=encircles the third methyl) 2.95 grams.
In 10ml round-bottomed flask, add intermediate Vay(100mg), solvent (3ml), (1-methyl-Pyrrolidine base)-3-methylamine (3 equivalent).Reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.Filter, obtain end product compound VI ay1(R1=2-naphthyl, R3=cyclopropyl, R2=methyl, n=1 after purifying) 57.10 milligrams.Its structural formula is as follows:
Gained compound spectroscopic data is:
LCMS?m/z=493（M+H）；1H-NMR(DMSO-d6,400MHz)δ8.30(d,1H),7.30-8.05(m,7H),7.10(d,1H),7.01(d,1H),6.85(d,1H)。
Embodiment 6(E)-N2-(encircles the third methyl)-N4-((1-methyl-Pyrrolidine base)-3-methyl)-N6-(4-(2-(2-naphthalene ethyl) preparation of-2-pyrimidyl-triaminopyrimidine (VIIax1)
In 10ml tube sealing, add the VIax1(30mg preparing by embodiment 1 method), solvent (3ml), Pd/C catalyzer (5mg).Reaction mixture pressure hydration 6 hours, filters, obtains end product compound VI Iax1(R1=2-naphthyl after purifying, and R3=encircles the third methyl, R2=methyl, n=1) 20.25 milligrams.Its structural formula as:
Gained compound spectroscopic data is:
LCMS?m/z=509（M+H）；1H-NMR(DMSO-d6,400MHz)δ8.20(d,1H),720-8.05(m,7H),6.85(d,1H)。
Embodiment 7(E)-N2-(encircles the third methyl)-N4-((1-methyl-Pyrrolidine base)-3-methyl)-N6-(4-(2-(2-naphthalene vinyl)-2-pyrimidyl-triaminopyrimidine (VIIay1)
In 10ml tube sealing, add the VIay1(30mg preparing by embodiment 5 methods), solvent (3ml), Pd/C catalyzer (5mg).Reaction mixture pressure hydration 6 hours, filters, obtains end product compound VI Iay1(R1=2-naphthyl, R3=cyclopropyl, R2=methyl, n=1 after purifying) 22.20 milligrams.Its structural formula is as follows:
Gained compound spectroscopic data is:
LCMS?m/z=495（M+H）；1H-NMR(DMSO-d6,400MHz)δ8.20(d,1H),720-8.05(m,7H),6.85(d,1H)。
The inhibition active testing of embodiment 8Bcr/Abl Tyrosylprotein kinase and variation Bcr/Abl Tyrosylprotein kinase thereof
Given the test agent: the compound that the embodiment of the present invention 1 to 7 prepares: VIax1, VIax2, VIax3, VIax4, VIay1, VIIax1 and VIIay1.
Reference substance: Apoptosis and Dasatinib.
Experimental technique: the inhibitor that the embodiment of the present invention 1 to 7 prepares shifts standardization (TR-FRET) mensuration to the inhibition of Bcr/Abl Tyrosylprotein kinase is active by time resolved fluorescence resonance energy.Or the Bcr/Abl Tyrosylprotein kinase that test makes a variation with the good Bcr/Abl Tyrosylprotein kinase T315I of purifying respectively, substrate is fluorescently-labeled phosphokinase substrate polypeptide, kinase reaction is containing 0.1mg/ml BSA, 1mM ATP, 10mM MgCl2,0.41mM DTT, carries out in LANCE kinase buffer solution (LKB) medium of 20mM NaHEPES pH7.4.The inhibitor solution that the embodiment of the present invention 1 to 7 prepares and Tyrosylprotein kinase (40pM), substrate (50nM) are at room temperature hatched 1 to 2 hour.After reaction cancellation, obtain activity data with Perkin-Elmer Plate Reader.
Experimental result: specific experiment result is as shown in table 1:
The inhibition active testing result of table 1Bcr/Abl Tyrosylprotein kinase and variation Bcr/Abl Tyrosylprotein kinase thereof
Shown by above table 1 experimental result, compare with control group, the Bcr/Abl tyrosine kinase inhibitor of Fig. 1 general formula provided by the invention can not only effectively suppress Bcr/Abl tyrosine kinase activity, and the Bcr/Abl Tyrosylprotein kinase after variation is still had to fine restraining effect, is that a kind of effective treatment chronic myelocytic leukemia particularly has the novel B cr/Abl tyrosine kinase inhibitor of drug-fast chronic myelocytic leukemia to existing targeted drug as Apoptosis, Dasatinib.Therefore Bcr/Abl tyrosine kinase inhibitor provided by the invention is expected to be developed further into the active drug into treatment chronic myelocytic leukemia.
Above embodiment is only explanation technical conceive of the present invention and feature; its object is to allow person skilled in the art understand content of the present invention and implemented; can not limit the scope of the invention with this; all equivalences that spirit is done according to the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (4)
1.Bcr/Abl tyrosine kinase inhibitor, is characterized in that, they are to have the compound shown in following general formula:
Wherein R1 represents hydrogen;
R2 represents hydrogen, methyl or phenyl;
R3 represents cyclopropyl methene amido;
R4 represents vinylidene or ethylidene;
N=1 or 2;
Ar is naphthyl;
X and Y represent N.
2. prepare a method for Bcr/Abl tyrosine kinase inhibitor claimed in claim 1, it is characterized in that comprising the following steps:
A, get 2,4-dichloro pyrimidine chemical compounds I under cuprous iodide effect, at tetrahydrofuran (THF), in triethylamine solvent, obtain intermediate II with aryl ethane coupling, for subsequent use;
B, get intermediate II that step a obtains in saturated ammonia ethanolic soln heating ammonia solution to intermediate III;
C, first get 2,4,6-trichloropyrimidine, dichloromethane solution cooling with frozen water after, slowly add ring the third methylamine, reaction stirring reaction in ice-water bath obtains intermediate compound IV; Then getting intermediate compound IV and step b obtains intermediate III heated and stirred reaction under DMF and saleratus effect and obtains intermediate V;
D, get the intermediate V that step c obtains and add (1-methyl-Pyrrolidine base) methylamine, heated and stirred aminolysis reaction obtains end product compound VI;
The structural formula of described intermediate II is:
The structural formula of described intermediate III is:
The structural formula of described intermediate compound IV is:
The structural formula of described intermediate V is:
Aryl ethane described in step a is naphthalene acetylene.
3. the application of Bcr/Abl tyrosine kinase inhibitor claimed in claim 1 in preparation control chronic myelocytic leukemia medicine.
4. the application of Bcr/Abl tyrosine kinase inhibitor according to claim 3 in preparation control chronic myelocytic leukemia medicine, it is characterized in that, Bcr/Abl tyrosine kinase inhibitor and pharmaceutically acceptable carrier are prepared into the medicine of tablet, capsule, granule, injection liquid or pill formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310063042.5A CN103113355B (en) | 2013-02-27 | 2013-02-27 | Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310063042.5A CN103113355B (en) | 2013-02-27 | 2013-02-27 | Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103113355A CN103113355A (en) | 2013-05-22 |
| CN103113355B true CN103113355B (en) | 2014-08-13 |
Family
ID=48411774
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310063042.5A Expired - Fee Related CN103113355B (en) | 2013-02-27 | 2013-02-27 | Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103113355B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2885292A4 (en) | 2012-08-17 | 2015-07-01 | Cancer Therapeutics Crc Pty Ltd | Vegfr3 inhibitors |
| CN104736533B (en) | 2012-08-17 | 2016-12-07 | 癌症治疗合作研究中心有限公司 | Vegfr3 inhibitor |
| CN105001203B (en) * | 2014-04-16 | 2017-03-01 | 成都大学 | A kind of Bcr Abl amphiploid inhibitor and its production and use |
| WO2023051681A1 (en) * | 2021-09-30 | 2023-04-06 | 江苏豪森药业集团有限公司 | Four-membered fused ring compound and preparation method and use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101410108A (en) * | 2006-03-30 | 2009-04-15 | 内尔维阿诺医学科学有限公司 | Use of a kinase inhibitor for the treatment of particular resistant tumors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0710675A2 (en) * | 2006-04-07 | 2011-08-23 | Novartis Ag | use of c-src inhibitors in combination with a pyrimidylaminobenzamide compound for the treatment of leukemia |
-
2013
- 2013-02-27 CN CN201310063042.5A patent/CN103113355B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101410108A (en) * | 2006-03-30 | 2009-04-15 | 内尔维阿诺医学科学有限公司 | Use of a kinase inhibitor for the treatment of particular resistant tumors |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103113355A (en) | 2013-05-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105237515B (en) | Deuterated pyrimidines, its preparation method, pharmaceutical composition and purposes | |
| CN102341108B (en) | Phosphoinositide 3-kinase inhibitors with zinc binding moiety | |
| CN107556317B (en) | Imidazole pyrazinamine phenyl derivative and application thereof | |
| CN102245604A (en) | Anti-viral compounds | |
| CN105473588B (en) | Compound and composition as mek inhibitor | |
| CN102264737A (en) | Anti-viral compounds | |
| CN103113355B (en) | Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia | |
| TW200413331A (en) | Small molecule PI 3-kinase inhibitors and methods of their use | |
| TW200417546A (en) | New compounds | |
| CN102548990A (en) | Inhibitors of phosphatidylinositol 3-kinase | |
| CN101497601B (en) | Process for synthesizing imatinib | |
| CN106478605A (en) | Pyrimidines, its preparation method and medical usage | |
| CN103864793A (en) | Substituted purin-9-acetamino isohydroxamic acid histone deacetylase inhibitor and preparation method and application thereof | |
| JP2023544431A (en) | Small molecule compounds and their uses as JAK kinase inhibitors | |
| CN107417628A (en) | Diaryl quianzolinones, its preparation method and its medical usage and the pharmaceutical composition comprising such compound | |
| CN102083826A (en) | Inhibitors of phosphatidylinositol 3-kinase | |
| CN102336686A (en) | Preparation method of 2-(7-methoxy-1-naphthyl) acetonitrile | |
| WO2024040768A1 (en) | 5-pyridine-1h-indazole compound, pharmaceutical composition, and use | |
| CN104955826A (en) | Spiro-quinazolinone derivatives useful for the treatment of neurological diseases and conditions | |
| MX2015006437A (en) | Comt inhibitors. | |
| CN102993093A (en) | N,N'-2-substitubted-diphenylthiourea compound, as well as preparation method and applications thereof | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN1248254A (en) | Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for treatment of neurodegenerative and CNS-trauma related conditions | |
| AU2023282201A1 (en) | Chromene derivatives as inhibitors of TCR-Nck interaction | |
| CN105153143A (en) | Thiouracil derivatives containing oxadiazole/thiadiazole and preparation method and application of thiouracil derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140813 Termination date: 20170227 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |