CN102225925A - Compound with activity for resisting chronic cell leukemia and preparation method thereof - Google Patents
Compound with activity for resisting chronic cell leukemia and preparation method thereof Download PDFInfo
- Publication number
- CN102225925A CN102225925A CN2011100916917A CN201110091691A CN102225925A CN 102225925 A CN102225925 A CN 102225925A CN 2011100916917 A CN2011100916917 A CN 2011100916917A CN 201110091691 A CN201110091691 A CN 201110091691A CN 102225925 A CN102225925 A CN 102225925A
- Authority
- CN
- China
- Prior art keywords
- hydrogen
- hydroxyl
- compound
- preparation
- ethanoyl
- 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.)
- Pending
Links
- ZYXLQTUDYRTLOO-SNAWJCMRSA-N C/C=C/c(cc1)cc(OC(C)=O)c1OC(C)=O Chemical compound C/C=C/c(cc1)cc(OC(C)=O)c1OC(C)=O ZYXLQTUDYRTLOO-SNAWJCMRSA-N 0.000 description 1
- 0 Cc(ccc(NC(C=Cc1cc(*)c(*)c(C)c1)=O)c1)c1Nc1nc(-c2cnccc2)ccn1 Chemical compound Cc(ccc(NC(C=Cc1cc(*)c(*)c(C)c1)=O)c1)c1Nc1nc(-c2cnccc2)ccn1 0.000 description 1
Abstract
A compound with activity for resisting chronic cell leukemia is a phenyl allylamine derivative as shown in general formula (I), wherein R1, R2, R3 are selected from hydrogen, chlorine, hydroxyl, methyl, trifluoromethyl, methoxyl, carboxyl, dimethylamino or acetyl, etc; and at least one substituent is hydrogen.
Description
One, technical field
The present invention relates to a kind of medical compounds and preparation method thereof, exactly is a kind of anti-active hydrocinnamamide derivative of chronic chronic myeloid leukemia and preparation method thereof that has.
Two, background technology
Chronic chronic myeloid leukemia (CML) is a kind of common tumor disease.It is by No. 9 karyomit(e)s and No. 22 chromosome reciprocal translocation and form.Before the nineties in 20th century, CML mainly uses radiotherapy, chemotherapy (through base urine) and alpha-interferon means to be treated, though these methods can be killed and wounded cancer cell, makes patient's clinical symptom that certain alleviation be arranged, but also a large amount of injuring normal cells can not effectively prolong patient's survival time.After the nineties in 20th century, the appearance of imatinib (Imatinib) has brought Gospel to the patient.Yet, show that by the more than ten years clinical study resistance phenomenon has appearred in Imatinib.Its reason has: the P-glycoprotein that (1) is relevant with multidrug resistance is exceedingly expressed; (2) the BCR-ABL Tyrosylprotein kinase is exceedingly expressed; (3) the BCR-ABL gene unrestrictedly increases; (4) point mutation of BCR-ABL gene self.Therefore, seek the focus that new antitumor drug molecule becomes people's research.
At present, there are some research institutions to be engaged in the antitumor drug research that the BCR-ABL Tyrosylprotein kinase is a target both at home and abroad.Therefore, with the BCR-ABL protein research target, find the medicine of a kind of new anti-cell strain K562, so just can reach the purpose of the chronic chronic myeloid leukemia of treatment.
In nearest several years, have some effective micromolecular compounds and shown one's talent, and shown good inside and outside and clinical effectiveness.
After imatinib, Switzerland Novartis has researched and developed nilotinib (Nilotinib) again, and obtain drugs approved by FDA listing, clinical being used for the treatment of in October, 2007 to the invalid chronic myelocytic leukemia of imatinib mesylate (imatinib mesylate).Simultaneously, United States Patent (USP) (US 2007/0259869) has protected a series of aminopyridine derivatives (nilotinib analogue) as tyrosine kinase inhibitor.
According to (Bioorganic ﹠amp such as Tetsuo Asaki; Medicinal Chemistry Letters, 2006,16:1421-1425) Bao Dao NS-187 has good anti-chronic chronic myeloid leukemia activity by in vitro tests research, and NS-187 is in clinical experimental stage at present.
Three, summary of the invention
The present invention aims to provide a kind of medical compounds with anti-chronic chronic myeloid leukemia, and the technical problem of required solution is to select this compound and confirm that it has the activity of anti-chronic chronic myeloid leukemia.
The compound that the present invention selects is a kind of phenylallene amide derivatives, and following chemical formula (I) is arranged:
In the formula:
R1, R2, the substituting group of R3 representative is selected from: hydrogen, chlorine, hydroxyl, methyl, trifluoromethyl, methoxyl group, carboxyl, dimethylamino or ethanoyl etc.; Wherein at least one substituting group is a hydrogen.
Preferably:
(1) R1, R3 are hydrogen, and R2 is hydrogen, chlorine, hydroxyl, ethanoyl, methoxyl group or dimethylamino;
(2) R2 is a hydrogen, and R1, R3 are all methoxyl group or are all ethanoyl or are all hydroxyl; Perhaps one be hydroxyl, another for methoxyl group or for hydroxyl, another is ethanoyl.
Preparation method by the phenylallene amide derivatives shown in the formula (I), so that substituent phenyl aldehyde to be arranged is raw material, comprise the preparation of intermediate and synthesizing and separating of target product, washing and dry, the preparation that it is characterized in that described intermediate at first by raw material substituted benzaldehyde 1 and propanedioic acid in toluene solvant, have under pyridine and the aniline existence condition and obtained intermediate substituted benzene vinylformic acid 2 in 5-7 hour in 80-90 ℃ of reaction, intermediate 2 obtains intermediate substituted benzene acrylate chloride 3 with the chloride reagent reaction then, and last intermediate 3 and PYRIMITHAMINE 4 are in tetrahydrofuran solvent, there is under the pyridine existence condition stirring at room reaction be no less than 20 hours and obtains the target product shown in the formula (I).
Described substituent phenyl aldehyde 1 is arranged promptly is that R1, R2, the substituent phenyl aldehyde of R3 are arranged, and substituting group is selected from hydrogen, chlorine, hydroxyl, methyl, trifluoromethyl, methoxyl group, carboxyl, dimethylamino or ethanoyl etc., and wherein at least one substituting group is a hydrogen.
Described PYRIMITHAMINE 4 chemical names are 2-[N-(2-methyl-5-aminophenyl) amino]-4-(3-pyridyl) pyrimidine, be the intermediate of preparation imatinib, concrete preparation method is referring to patent US 5,521,184 and WO 03/066613.
Reaction process is as follows:
The concrete operations step is as follows:
Steps A: the acrylic acid preparation of intermediate 2 substituted benzenes
Raw material substituted benzaldehyde 1 and propanedioic acid in toluene solvant, have under pyridine and the aniline existence condition in 80-90 ℃ of reaction 5-7 hour, reaction is used K after finishing
2CO
3Solution is transferred reacting liquid pH value 9-10, standing demix, and the water intaking phase, with hydrochloric acid adjust pH 6, separating out yellow solid is intermediate 2, filtration, washing and dry.
Step B: the preparation of intermediate 3 substituted benzene acrylate chlorides
Intermediate 2 obtains intermediate 3 with chloride reagent through the acyl chloride reaction of classics.
Step C: target product synthetic
Intermediate 3 and PYRIMITHAMINE 4 have under the pyridine existence condition stirring at room reaction spend the night in tetrahydrofuran solvent, add water after reaction finishes and stir target product is separated out, after filtration, washing, drying.
Four, description of drawings
Fig. 1 is that this compound is to K562 cell 503nhibiting concentration IC
50Test-results figure.
Five, embodiment
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1 ((E)-3-(4-(dimethylamino phenyl)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) acrylamide)
Synthetic route:
Steps A: the preparation of intermediate 2 (4-(dimethylamino) cinnamic acid)
Take by weighing the 4-dimethylaminobenzaldehyde (7.5g, 0.05mol), propanedioic acid (8.1g 0.075mol), adds toluene 30mL, pyridine 10mL, aniline 0.4mL (preventing the p-Hydroxybenzaldehyde oxidation), in 85 ℃ of following reacting by heating 6h, stopped reaction is used K
2CO
3Solution stirring transfers reaction solution to PH=9～10, stirs 15min, separatory, and the water intaking layer transfers to about PH=6 with the hydrochloric acid of 4mol/L, has a large amount of yellow solids to separate out.Filter washing, drying obtains yellow solid 7.0g, fusing point: 238～240 ℃, and yield 82.3%.
1HNMR(DMSO-d
6)δ：12.0(s，1H)，7.5(m，3H)，6.7(d，2H)，6.2(d，1H)，3.0(s，6H)。Step B: the preparation of intermediate 3 (4-(dimethylamino) acryloyl chloride)
Take by weighing 4-(dimethylamino) cinnamic acid (2.87g 0.015mol), adds the 10mL thionyl chloride, drips 3 DMF, 60 ℃ of heated and stirred 1.5h, stopped reaction removes excessive thionyl chloride under reduced pressure, is directly used in the next step.
Step C: the target product (preparation of (E)-3-(4-(dimethylamino phenyl)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) acrylamide)
(4.0g 0.014mol) is dissolved in the 40mL tetrahydrofuran (THF), adds pyridine 4mL to take by weighing PYRIMITHAMINE 4, after being dissolved in the 20mL tetrahydrofuran (THF), 4-(dimethylamino) acryloyl chloride that step B is made pours PYRIMITHAMINE solution into, stirred overnight at room temperature, stopped reaction stirs 2h (having more solid to separate out) to wherein adding water, filter, drying adds silica gel mixed sample and crosses the column purification separated product, obtains the 4.2g orange/yellow solid, fusing point: 258-260 ℃, yield: 66.7%.
1H?NMR(DMSO-d
6)δ：9.9(s，1H)，9.3(s，1H)，8.9(s，1H)，8.7(d，1H)，8.5(m，2H)，8.0(s，1H)，7.5(d，2H)，7.5(m，6H)，7.2(d，1H)，6.8(d，2H)，6.6(d，1H)，3.0(s，6H)，2.2(s，3H)。
Embodiment 2 (N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) cinnamide)
Operation steps is used phenyl aldehyde with embodiment 1 in steps A.End product is the off-white color solid, fusing point 187-189 ℃.
1HNMR(CDCl
3-d
6)δ：10.2(s，1H)，9.3(s，1H)，8.7(d，1H)，8.5(m，2H)，8.0(s，1H)，7.7-7.5(m，4H)，7.4(m，5H)，7.2(d，1H)，6.8(d，1H)，2.2(s，3H)。
Embodiment 3 ((E)-3-(4-chloro-phenyl-)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino)) acrylamide)
Operation steps is used 4-chloro-benzaldehyde with embodiment 1 in steps A.End product is the off-white color solid, fusing point: 273-275 ℃.
1H?NMR(DMSO-d
6)δ：10.2(s，1H)，9.3(s，1H)，9.0(s，1H)，8.7(d，1H)，8.5(m，2H)，8.0(s，1H)，7.7(d，2H)，7.5(m，4H)，7.4(m，2H)，7.2(d，1H)，6.8(d，1H)，2.2(s，3H)。
Embodiment 4 ((E)-3-(4-hydroxyphenyl)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) acrylamide)
Operation steps is used p-Hydroxybenzaldehyde with embodiment 1 in steps A.End product is a yellow solid, fusing point: 267-269 ℃.
1H?NMR(DMSO-d
6)δ：10.1(s，1H)，9.9(s，1H)，9.3(s，1H)，9.0(s，1H)，8.7(d，1H)，8.5(m，2H)，8.0(s，1H)，7.4-7.6(m，6H)，7.2(d，1H)，6.8(d，1H)，6.6(d，1H)，2.2(s，3H)。
Embodiment 5 ((E)-4-(3-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) anilino)-3-oxygen-1-thiazolinyl) phenylacetate)
Operation steps is used acetylbenzene formaldehyde in steps A with embodiment 1.End product is a yellow solid, fusing point: 216-218 ℃.
1H?NMR(DMSO-d
6)δ：10.5(s，1H)，9.5(s，1H)，9.2(s，1H)，9.1(d，1H)，8.9(d，1H)，8.6(d，1H)，8.2(s，1H)，8.0(m，1H)，7.8-7.6(m，4H)，7.5(m，1H)，7.2(m，3H)，6.9(d，1H)，2.3(s，3H)，2.2(s，3H)。
Embodiment 6 ((E)-3-(4-methoxyphenyl 1)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) acrylamide)
Operation steps is used aubepine with embodiment 1 in steps A.End product is off-white color solid 0.5g, fusing point: 202-204 ℃.
1HNMR(DMSO-d
6)δ：10.0(s，1H)，9.3(s，1H)，9.0(s，1H)，8.7(s，1H)，8.5(m，2H)，8.0(s，1H)，7.5(m，4H)，7.2(m，3H)，7.0(d，1H)，6.7(d，1H)，3.8(s，3H)，2.2(s，3H)。
Embodiment 7 ((E)-3-(3, the 4-dihydroxyphenyl)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) acrylamide)
Operation steps uses 3 with embodiment 1 in steps A, the 4-Dihydroxy benzaldehyde.End product is the khaki color solid, fusing point: 273-275 ℃.
1H?NMR(DMSO-d
6)δ：10.0(s，1H)，9.6(s，1H)，9.2(d，2H)，9.0(s，1H)，8.7(s，1H)，8.6(m，2H)，8.0(s，1H)，7.6(s，1H)，7.3(m，3H)，7.2(m，1H)，7.0(s，1H)，6.9(d，1H)，6.8(d，1H)，6.6(d，1H)，2.2(s，3H)。
Embodiment 8 ((E)-3-(3,4-phenylacetate base)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) acrylamide)
Operation steps uses 3 with embodiment 1 in steps A, 4-diacetyl phenyl aldehyde.End product is an off-white color, fusing point: 224-227 ℃.
1H?NMR(DMSO-d
6)δ：10.2(s，1H)，9.3(s，1H)，9.0(s，1H)，8.7(d，1H)，8.5(m，2H)，8.0(s，1H)，7.6(m，4H)，7.4(m，3H)，7.2(m，1H)，6.8(d，1H)，2.3(s，6H)，2.2(s，3H)。
Embodiment 9 ((E)-3-(4-hydroxyl-3-methoxyphenyl)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) acrylamide)
Operation steps is used 3-methoxyl group-4-hydroxy benzaldehyde with embodiment 1 in steps A.End product is a faint yellow solid, fusing point: 252-255 ℃.
1HNMR(DMSO-d
6)δ：10.0(s，1H)，9.5(s，1H)，9.3(s，1H)，9.0(s，1H)，8.7(d，1H)，8.5(m，2H)，8.0(s，1H)，7.5(m，4H)，7.2(s，2H)，7.1(d，1H)，7.0(s，1H)，6.8(d，1H)，6.6(d，1H)，3.8(s，3H)，2.2(s，3H)。
Embodiment 10 ((E)-2-methoxyl group-4-(3-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) aniline)-3-oxygen-1-thiazolinyl) phenylacetate)
Operation steps is used 3-methoxyl group-4-acetylbenzene formaldehyde with embodiment 1 in steps A.End product is the off-white color solid, fusing point: 258-259 ℃.
1HNMR(DMSO-d
6)δ：10.2(s，1H)，9.3(s，1H)，8.9(s，1H)，8.8(s，1H)，8.6(m，2H)，8.0(s，1H)，7.7(m，2H)，7.5(m，3H)，7.2(m，3H)，6.8(d，1H)，2.3(s，3H)，3.8(s，3H)，2.2(s，3H)。
Embodiment 11 ((E)-3-(3, the 4-dimethoxy phenyl)-N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2-amino) phenyl) acrylamide)
Operation steps uses 3 with embodiment 1 in steps A, the 4-dimethoxy benzaldehyde.White solid, fusing point: 236-240 ℃.
1HNMR(DMSO-d
6)δ：10.1(s，1H)，9.3(s，1H)，9.0(s，1H)，8.7(d，1H)，8.5(m，2H)，8.0(s，1H)，7.5(m，4H)，7.2(m，3H)，7.0(d，1H)，6.7(d，1H)，3.8(s，6H)，2.2(s，3H)。
The pharmacological research of The compounds of this invention
Antitumor shaker test is tested with human chronic myelogenous leukemia's cell line k562, adopts mtt assay.
Being mixed with concentration behind the K562 cell centrifugation with logarithmic phase is 1 * 10
5ML
-1Cell suspension, be inoculated in 96 orifice plates, every hole 100 μ L, behind 37 ℃ of cultivation 24h, divide into groups according to experiment, every group of medicine 10 μ L that add different concns, establishing not administration group is the blank group, establish 3 parallel holes for every group, after continuing to cultivate 72h, every hole adds the freshly prepared 5gL of containing of 20 μ L
-1The serum free medium of MTT continues to cultivate 4h, promptly has the hyacinthine crystallisate to generate, and in certain cell count scope, the growing amount of crystallisate is directly proportional with cell count.Every hole adds acidifying SDS100 μ L, puts into CO
2Spend the night in the incubator.With the microoscillator mixing that vibrates, detect optical density value (OD value) under wavelength 492nm condition with microplate reader.
Inhibiting rate/%=(control group average absorption degree value-administration group average absorption degree value)/control group average absorption degree value.Calculate the inhibiting rate of medicine with above formula, and calculate IC with improvement bandit formula method to tumour cell
50
Experimental result and conclusion: experimental result is seen Fig. 1, and embodiment 2,3,4,5 and 6 compound have the good restraining effect to the K562 cell, and embodiment 1 and 11 compound have obvious restraining effect to the K562 cell.Show that most compound of the present invention has significant inhibitory effect to the K562 cell.
Claims (3)
1. one kind has the anti-active compound of chronic chronic myeloid leukemia, and it is characterized in that: this compound is the phenylallene sulfonamide derivatives shown in the following chemical formula (I):
In the formula:
R1, R2, the substituting group of R3 representative is selected from: hydrogen, chlorine, hydroxyl, methyl, trifluoromethyl, methoxyl group, carboxyl, dimethylamino or ethanoyl; Wherein at least one substituting group is a hydrogen.
2. compound according to claim 1 is characterized in that described compound is:
(1) R1, R3 are hydrogen, and R2 is hydrogen, chlorine, hydroxyl, ethanoyl, methoxyl group or dimethylamino;
(2) R2 is a hydrogen, and R1, R3 are all methoxyl group or are all ethanoyl or are all hydroxyl; Perhaps one be hydroxyl, another for methoxyl group or for hydroxyl, another is ethanoyl.
3. the preparation method with anti-active compound of chronic chronic myeloid leukemia as claimed in claim 1, so that substituent R 1 to be arranged, R2, R3, wherein at least one substituting group is that the substituted benzaldehyde (1) of hydrogen is a raw material, comprise the preparation of intermediate and synthesizing and separating of target product, washing and dry, it is characterized in that: at first by substituted benzaldehyde (1) and propanedioic acid in toluene solvant, have under pyridine and the aniline existence condition and obtained intermediate substituted benzene vinylformic acid (2) in 5-7 hour in 80-90 ℃ of reaction, intermediate (2) obtains intermediate substituted benzene acrylate chloride (3) with the chloride reagent reaction then, and last intermediate (3) and PYRIMITHAMINE (4) are in tetrahydrofuran solvent, there is under the pyridine existence condition stirring at room reaction be no less than 20 hours and obtains the target product shown in the formula (I).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100916917A CN102225925A (en) | 2011-04-13 | 2011-04-13 | Compound with activity for resisting chronic cell leukemia and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100916917A CN102225925A (en) | 2011-04-13 | 2011-04-13 | Compound with activity for resisting chronic cell leukemia and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102225925A true CN102225925A (en) | 2011-10-26 |
Family
ID=44806934
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100916917A Pending CN102225925A (en) | 2011-04-13 | 2011-04-13 | Compound with activity for resisting chronic cell leukemia and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102225925A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103121990A (en) * | 2013-01-23 | 2013-05-29 | 安徽安生生物化工科技有限责任公司 | Cinnamyl amide imatinib ramification as well as preparation method and application thereof |
| CN106187995A (en) * | 2015-05-05 | 2016-12-07 | 天津国际生物医药联合研究院 | Amide bond heterocycle compound and its preparation method and application |
| CN106986821A (en) * | 2017-06-08 | 2017-07-28 | 安徽星宇化工有限公司 | A kind of aminomethyl pyridine analog derivative and its production and use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900073A (en) * | 2006-07-12 | 2007-01-24 | 浙江省医学科学院 | Process for preparing N-phenyl-2-pyrimidyl amine derivative |
| CN101417995A (en) * | 2008-11-21 | 2009-04-29 | 陈依军 | Phenoxy pyrimidine derivates and its production and use |
| CN101503402A (en) * | 2009-03-10 | 2009-08-12 | 沈阳药科大学 | 2-aniline pyrimidine derivative, as well as preparation and uses thereof |
-
2011
- 2011-04-13 CN CN2011100916917A patent/CN102225925A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900073A (en) * | 2006-07-12 | 2007-01-24 | 浙江省医学科学院 | Process for preparing N-phenyl-2-pyrimidyl amine derivative |
| CN101417995A (en) * | 2008-11-21 | 2009-04-29 | 陈依军 | Phenoxy pyrimidine derivates and its production and use |
| CN101503402A (en) * | 2009-03-10 | 2009-08-12 | 沈阳药科大学 | 2-aniline pyrimidine derivative, as well as preparation and uses thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103121990A (en) * | 2013-01-23 | 2013-05-29 | 安徽安生生物化工科技有限责任公司 | Cinnamyl amide imatinib ramification as well as preparation method and application thereof |
| CN106187995A (en) * | 2015-05-05 | 2016-12-07 | 天津国际生物医药联合研究院 | Amide bond heterocycle compound and its preparation method and application |
| CN106986821A (en) * | 2017-06-08 | 2017-07-28 | 安徽星宇化工有限公司 | A kind of aminomethyl pyridine analog derivative and its production and use |
| CN106986821B (en) * | 2017-06-08 | 2019-07-02 | 安徽星宇化工有限公司 | A kind of aminomethyl pyridine analog derivative and its preparation method and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104822267B (en) | The inhibitor and its application method that hepatitis b virus covalence closed cyclic DNA is formed | |
| JP7110232B2 (en) | Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compound | |
| CN101906076B (en) | Naphthaline amide derivative serving as protein kinase inhibitor and histone deacetylase inhibitor and preparation method and application thereof | |
| JP4895806B2 (en) | TIE-2 modulator and usage | |
| CN103354809B (en) | A kind of aryl urea compounds, its intermediate and application thereof | |
| CN104829610B (en) | A kind of novel cloth Shandong tyrosine kinase inhibitor | |
| CN102977014B (en) | New quinoline compounds and uses thereof | |
| CN104844566B (en) | A kind of kinase inhibitor of new structure | |
| CN105579457B (en) | The substituted acetyl-amino benzamide of N biphenyl 3 and N [3 (acetyl-amino) phenyl] dibenzoyl amine and its it is used as WNT signal pathway inhibitor purposes | |
| CN106831569A (en) | Quinolines and preparation method thereof and the purposes as lithate transporter inhibitors class medicine | |
| CN105980377B (en) | Substituted pyrimidines as EGFR-T790M kinase inhibitors | |
| CN105669564A (en) | Urea compound and preparation method, medicine composition, intermediate and application thereof | |
| CN108752322A (en) | A kind of novel Tepotinib derivatives and preparation method and its application in antitumor drug | |
| CN105705493A (en) | Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof | |
| CN104955826A (en) | Spiro-quinazolinone derivatives useful for the treatment of neurological diseases and conditions | |
| CN102225925A (en) | Compound with activity for resisting chronic cell leukemia and preparation method thereof | |
| CN101503402A (en) | 2-aniline pyrimidine derivative, as well as preparation and uses thereof | |
| JP2017526668A (en) | Quinazoline derivatives | |
| CN102421754B (en) | Acrylamide derivative and use thereof in manufacture of medicament | |
| CN103113355B (en) | Bcr/Abl tyrosine kinase inhibitor as well as preparation method and application thereof in treating chronic granulocytic leukemia | |
| CN106117182A (en) | Quinazoline N phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application | |
| CN107286140A (en) | Substituted aromatic amines base heteroaromatic class compound and its application as antineoplastic | |
| CN109456279A (en) | Thiazoleamino benzamide acetic ester derivative and application thereof | |
| CN103664876A (en) | Quinoline derivative and usage thereof | |
| CN107501283B (en) | Preparation of substituted arylmethyl hetero-substituted anilino ethylene glycol ether cycloquinazoline and application of tumor treatment drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20111026 |