CN103113355A - 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
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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 the 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 a common leukemia of class, and the leukocyte disorder propagation that shows as in blood causes canceration.Chronic myelocytic leukemia (being called for short slow grain) is mainly produced by the 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 the Novartis development, it causes that by acting on target Bcr-Abl kinases thereby cancer cell-apoptosis reaches purpose (Quitas-Cardama, the A. that controls or treat chronic myelocytic leukemia; Cortes, J.Blood2009,113,1619-1630; Druker, B.J., et al Nature Med.1996,2,561-566).Although imatinib gets validity when begin treatment, yet a large amount of patients must resistance can occur after the time in medication, and chronic white corpuscle leukemia patient invalid or decline evident in efficacy to imatinib of 1/3 is approximately arranged.Patient at burst period (blast crisis), this situation is more outstanding, reason is that the dialogue chronic myeloid leukemia becomes the sick Bcr/Abl Tyrosylprotein kinase that plays 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 with the Bcr/Abl Tyrosylprotein kinase after suppressing 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, tool has very great significance in effective control chronic myelocytic leukemia.
Summary of the invention:
Goal of the invention: technical problem to be solved by this invention is, overcome the existing deficiency of controlling the Bcr/Abl Tyrosylprotein kinase of chronic myelocytic leukemia, provide a kind of and not only the Bcr/Abl Tyrosylprotein kinase is had obvious restraining effect, and to the Bcr/Abl Tyrosylprotein kinase after variation particularly the Bcr/Abl Tyrosylprotein kinase of T315I variation still have 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 and its application with Bcr/Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia.
Technical scheme: in order to realize above purpose, 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, above-described Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, wherein said X and Y are nitrogen (N).
As preferred version, above-described Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, described Ar is naphthyl, phenyl or pyridyl.
As preferred version, 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, above-described Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia, described R3 is cyclopropylamino, cyclopropyl methene amido or phenyl.
Method with Bcr/Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia provided by the invention, it comprises the following steps:
A, get 2,4-dichloro pyrimidine chemical compounds I under the cuprous iodide effect, at tetrahydrofuran (THF), obtain the intermediate II with the aryl ethane coupling in the triethylamine solvent, standby;
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, the heated and stirred aminolysis reaction obtains the end product compound VI.
As preferred version, above-described preparation method with Bcr/Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia, the described aryl ethane of its step a is naphthalene acetylene.
As preferred version, above-described preparation method with Bcr/Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia adds two (triphenylphosphine) palladium II complex compounds of dichloro as catalyzer in step a.
Reaction process with method of the Bcr/Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia provided by the invention can be as follows:
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 made tablet, Bcr/Abl tyrosine kinase inhibitor and carrier lactose or W-Gum having the treatment chronic myelocytic leukemia added magnesium stearate lubricant when needing, mix, and then compressing tablet is made tablet.
When the present invention makes capsule, mix whole grain, the then encapsulated capsule of making having the treatment Bcr/Abl tyrosine kinase inhibitor of chronic myelocytic leukemia and carrier lactose or W-Gum.
During granulation agent of the present invention, mix whole grain, drying, granulation agent having the treatment Bcr/Abl tyrosine kinase inhibitor of chronic myelocytic leukemia and thinner lactose or W-Gum.
When the present invention makes injection liquid, get the Bcr/Abl tyrosine kinase inhibitor with treatment chronic myelocytic leukemia and add solubilizing agent, stir, 80 ℃ were heated 30 minutes, filter, regulate pH value, be filtered to clear and bright with sintered glass funnel or other filter, can was made injection liquid in 30 minutes 100 to 115 ℃ of sterilizations.
The present invention carries out biological activity test to the target compound for preparing, vitro inhibition Bcr/Abl and the kinase whose activity of T315I variation Bcr/Abl to them are assessed by the vitro enzyme activity test, and compare with Apoptosis and Dasatinib (dasatinib).For the Bcr/Abl kinases that does not make 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 for preparing of the present invention can be used for treatment imatinib and s-generation Bcr/Abl tyrosine kinase inhibitor is had 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 for preparing, can not only effectively suppress the Bcr/Abl Tyrosylprotein kinase, and the Bcr/Abl Tyrosylprotein kinase after variation is still had fine restraining effect, is a kind of novel B cr/Abl tyrosine kinase inhibitor of effective treatment chronic myelocytic leukemia.And the experiment show, untoward reaction is low, medication is safer, and can be made into the multi-medicament formulation, facilitates clinical application.
2, the preparation method with Bcr/Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia provided by the invention, screen by great many of experiments, as shown in Figure 2, with 2, the 4-dichloro pyrimidine is starting raw material, through the aryl ethane coupling, and through the triple bond reduction, heating ammonia solution, aminolysis obtains target compound.
Description of drawings
Fig. 1 is the structural representation with Bcr/Abl tyrosine kinase inhibitor general formula for the treatment of chronic myelocytic leukemia of the present invention.
Fig. 2 is the reacting flow chart with Bcr/Abl tyrosine kinase inhibitor preparation method for the treatment of chronic myelocytic leukemia of the present invention.
Embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand, the described concrete material proportion of embodiment, processing condition and result thereof only are used for explanation the present invention, 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)-the 3-methyl)-the N6-(4-(2-(2-naphthalene vinyl)-preparation of 2-pyrimidyl-triaminopyrimidine (VIax1)
1, add 2,4-dichloro pyrimidine (14.5g, 97.5mmol) in the 500ml round-bottomed flask, two (triphenylphosphine) palladium (II) complex compound (1.3g of dichloro, 2.6mmol), cuprous iodide (25mg, 0.13mmol), tetrahydrofuran (THF) (250ml), triethylamine (34ml, 263mmol).After mixture heating up to 50 ℃, add tetrahydrofuran (THF) (100ml) solution of naphthalene acetylene (97.5mmol).After 5 hours, reaction solution is cooling, and with the methylene dichloride dilution, after washing with water, saturated common salt respectively after organic phase is separated 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, add IIa(16.0g in a tube sealing), saturated ammonia ethanolic soln (200ml).System stirring heating 24 hours.Open tube sealing after cooling, 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, add 2 in the 500ml round-bottomed flask, 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 the dilution of frozen water and methylene dichloride, after washing with water, saturated common salt respectively after organic phase is separated and with anhydrous sodium sulfate drying.Crude product after concentrated obtains product intermediate compound IV x9.5 gram by column chromatography purification.
4, then add IIIa(2.47g in the 100ml round-bottomed flask), IVx(2.18g), DMF(30ml), saleratus.Reaction mixture heated and stirred 6 hours, cooling rear thin up is separated out precipitation.Obtain intermediate Vax(R1=2-naphthyl after filtration drying, R3=encircles the third methyl) 3.8 grams.
5, add intermediate Vax(100mg in the 10ml round-bottomed flask), solvent (3ml), (1-methyl-Pyrrolidine base) methylamine (3 equivalent), reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.Obtain end product compound VI ax1(R1=2-naphthyl after filtration, purifying, R3=encircles the third methyl, the R2=methyl, and 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)-the 3-methyl)-the N6-(4-(2-(2-naphthalene vinyl)-preparation of 2-pyrimidyl-triaminopyrimidine (VIax2)
Add the intermediate Vax(100mg for preparing by embodiment 1 method in the 10ml round-bottomed flask), solvent (3ml), (1-phenyl-Pyrrolidine base) methylamine (3 equivalent), reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.Obtain end product compound VI ax2(R1=2-naphthyl after filtration, 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)-the N6-(4-(2-(2-naphthalene vinyl)-preparation of 2-pyrimidyl-triaminopyrimidine (VIax3)
Add the intermediate Vax(100mg for preparing by embodiment 1 method in the 10ml round-bottomed flask), solvent (3ml), (1-Boc-Pyrrolidine base) methylamine (3 equivalent), reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.The filtration drying after product is dissolved in the dichloromethane solution of 25%TFA, reacts after 4 hours concentrated, obtains end product compound VI ax3(R1=2-naphthyl after thick purifying products, 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)-the N6-(4-(2-(2-naphthalene vinyl)-preparation of 2-pyrimidyl-triaminopyrimidine (VIax4)
Add the intermediate Vax(100mg for preparing by embodiment 1 method in the 10ml round-bottomed flask), solvent (3ml), (1-Boc-piperidines)-4-methylamine (3 equivalent).Reaction mixture heated and stirred 18 hours, cooling rear thin up is separated out precipitation.The filtration drying after product is dissolved in the dichloromethane solution of 25%TFA, reacts after 4 hours concentrated, obtains end product compound VI ax4(R1=2-naphthyl after thick purifying products, 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)-the 3-methyl)-the N6-(4-(2-(2-naphthalene vinyl)-preparation of 2-pyrimidyl-triaminopyrimidine (VIay1)
Add 2,4,6-trichloropyrimidine (100mmol), methylene dichloride (250ml) in the 500ml round-bottomed flask, after solution is cooling with frozen water, slowly add cyclopropylamine (90mmol).Reaction is stirred half an hour in ice-water bath, adds the dilution of frozen water and methylene dichloride, after washing with water, saturated common salt respectively after organic phase is separated 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.
Add the IIIa(2.47g for preparing by embodiment 1 method in the 100ml round-bottomed flask), IVy(2.02g), DMF(30ml), saleratus.Reaction mixture heated and stirred 6 hours, cooling rear thin up is separated out precipitation.Obtain intermediate Vay(R1=2-naphthyl after filtration drying, R3=encircles the third methyl) 2.95 grams.
Add intermediate Vay(100mg in the 10ml round-bottomed flask), 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.Obtain end product compound VI ay1(R1=2-naphthyl, R3=cyclopropyl, R2=methyl, n=1) 57.10 milligrams after filtration, purifying.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)-the 3-methyl)-N6-(4-(2-(2-naphthalene ethyl)-preparation of 2-pyrimidyl-triaminopyrimidine (VIIax1)
Add the VIax1(30mg for preparing by embodiment 1 method in the 10ml tube sealing), solvent (3ml), Pd/C catalyzer (5mg).Reaction mixture pressure hydration 6 hours obtains end product compound VI Iax1(R1=2-naphthyl after filtration, 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)-the 3-methyl)-the N6-(4-(2-(2-naphthalene vinyl)-2-pyrimidyl-triaminopyrimidine (VIIay1)
Add the VIay1(30mg for preparing by embodiment 5 methods in the 10ml tube sealing), solvent (3ml), Pd/C catalyzer (5mg).Reaction mixture pressure hydration 6 hours obtains end product compound VI Iay1(R1=2-naphthyl, R3=cyclopropyl, R2=methyl, n=1) 22.20 milligrams after filtration, purifying.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)。
Embodiment 8Bcr/Abl Tyrosylprotein kinase and variation Bcr/Abl tyrosine-kinase enzymeinhibition active testing 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 Bcr/Abl tyrosine-kinase enzymeinhibition is active by the 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) were at room temperature hatched 1 to 2 hour.Obtain activity data with Perkin-Elmer Plate Reader after the reaction cancellation.
Experimental result: concrete experimental result is as shown in table 1:
Table 1Bcr/Abl Tyrosylprotein kinase and variation Bcr/Abl tyrosine-kinase enzymeinhibition active testing result 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 the Bcr/Abl tyrosine kinase activity, and the Bcr/Abl Tyrosylprotein kinase after variation is still had 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 such as Apoptosis, Dasatinib.Therefore Bcr/Abl tyrosine kinase inhibitor provided by the invention is expected to be developed further into the active drug into the treatment chronic myelocytic leukemia.
Above embodiment only is explanation technical conceive of the present invention and characteristics; its purpose is to allow the person skilled in the art understand content of the present invention and implemented; can not limit protection scope of the present 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 (9)
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, alkyl, aromatic base or halogeno-group;
R2 represents hydrogen, alkyl or aromatic base;
R3 represents hydrocarbon amino, two hydrocarbon amino, alkyl or aromatic base;
N=1,2 or 3;
Ar is aromatic base;
X and Y represent N or CH.
2. Bcr/Abl tyrosine kinase inhibitor according to claim 1, is characterized in that, described X and Y are N.
3. Bcr/Abl tyrosine kinase inhibitor according to claim 2, is characterized in that, described Ar is naphthyl, phenyl or pyridyl.
4. Bcr/Abl tyrosine kinase inhibitor according to claim 3, is characterized in that, described R2 is C
1~ C
5Alkyl or phenyl.
5. according to claim 3 or 4 described Bcr/Abl tyrosine kinase inhibitors, is characterized in that, described R3 is cyclopropylamino, cyclopropyl methene amido or phenyl.
6. method for preparing Bcr/Abl tyrosine kinase inhibitor claimed in claim 5 is characterized in that comprising the following steps:
A, get 2,4-dichloro pyrimidine chemical compounds I under the cuprous iodide effect, at tetrahydrofuran (THF), obtain the intermediate II with the aryl ethane coupling in the triethylamine solvent, standby;
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, the heated and stirred aminolysis reaction obtains the end product compound VI.
7. the preparation method of Bcr/Abl tyrosine kinase inhibitor according to claim 6, is characterized in that, the described aryl ethane of step a is naphthalene acetylene.
8. the application of the described Bcr/Abl tyrosine kinase inhibitor of claim 1 to 5 any one in preparation control chronic myelocytic leukemia medicine.
9. the application of Bcr/Abl tyrosine kinase inhibitor according to claim 8 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.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001203A (en) * | 2014-04-16 | 2015-10-28 | 成都大学 | Bcr-Abl amphiploid inhibitor and preparation method and application thereof |
| US9238644B2 (en) | 2012-08-17 | 2016-01-19 | Cancer Therapeutics Crc Pty Limited | VEGFR3 inhibitors |
| US9266864B2 (en) | 2012-08-17 | 2016-02-23 | Cancer Therapeutics Crc Pty Limited | VEGFR3 inhibitors |
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007116025A2 (en) * | 2006-04-07 | 2007-10-18 | Novartis Ag | Use of c-src inhibitors in combination with a pyrimidylaminobenzamide compound for the treatment of leukemia |
| 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 |
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Patent Citations (2)
| 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 |
| WO2007116025A2 (en) * | 2006-04-07 | 2007-10-18 | Novartis Ag | Use of c-src inhibitors in combination with a pyrimidylaminobenzamide compound for the treatment of leukemia |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9238644B2 (en) | 2012-08-17 | 2016-01-19 | Cancer Therapeutics Crc Pty Limited | VEGFR3 inhibitors |
| US9266864B2 (en) | 2012-08-17 | 2016-02-23 | Cancer Therapeutics Crc Pty Limited | VEGFR3 inhibitors |
| CN105001203A (en) * | 2014-04-16 | 2015-10-28 | 成都大学 | Bcr-Abl amphiploid inhibitor and preparation method and application thereof |
| 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 |
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