CN105646454A - 2-arylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application - Google Patents
2-arylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application Download PDFInfo
- Publication number
- CN105646454A CN105646454A CN201610034632.9A CN201610034632A CN105646454A CN 105646454 A CN105646454 A CN 105646454A CN 201610034632 A CN201610034632 A CN 201610034632A CN 105646454 A CN105646454 A CN 105646454A
- Authority
- CN
- China
- Prior art keywords
- base
- compound
- pyrimidine
- amino
- indole
- 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
- 0 Cc1c(-c2c[n](C)c3c2cccc3)c(I)cnc1*c1cc(NC(C=CC(NO)=O)=O)c(*)cc1 Chemical compound Cc1c(-c2c[n](C)c3c2cccc3)c(I)cnc1*c1cc(NC(C=CC(NO)=O)=O)c(*)cc1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides 2-arylamine pyrimidine derivatives containing hydroxamic acid fragments shown in the formulas I and II. 2-arylamine pyrimidine containing carboxyl fragments is mainly used as a parent nucleus and is subjected to single-step condensation and related modification with hydroxylamine protected by THP to obtain a target compound. An experiment proves that the derivatives has the remarkable anti-proliferative effect on tumor cells (an overexpression EGFR human epidermal carcinoma cell line A431 and a human pulmonary carcinoma cell line H1975 resisting Gefitinib) related to EGFR tyrosine kinase activity on the cellular level, and tumor cells (a human cervical carcinoma cell line Hela, a human hepatoma cell line HepG2, a human promyelocytic acute leukemia cell line HL60, a human oral epidermoid carcinoma cell line KB, a human colon cancer cell line SW620) related to the HDAC histone acetylase activity, and the corresponding medicine for resisting cancer cells can be prepared. The general structural formula is shown in the description.
Description
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of 2-arylamine pyrimidine derivatives, its preparation method, intermediate containing hydroxamic acid fragment and apply.
Background technology
Protein tyrosine kinase plays an important role in signal transduction process, participates in the bioprocesss such as the growth of regulating cell, propagation and apoptosis. Its unconventionality expression may result in cell functional disorders. EGF-R ELISA (EGFR) is the receptor typically with tyrosine kinase activity, is a member of epidermal growth factor (ErbB/HER) family. Current study show that, high expressed or the sudden change excessively of EGFR are present in the multiple entity tumors such as pulmonary carcinoma, glioblastoma (cerebroma), breast carcinoma, colorectal carcinoma, gastric cancer, head and neck cancer and cancer of pancreas. EGFR process LAN can make downstream signaling pathway signal strengthen. EGFR has relation with the angiogenesis of tumor cell, tumor invasion, transfer and apoptosis, existing lot of documents report, it is suppressed that the activity of EGFR tyrosine kinase can effectively suppress the growth of tumor. Small molecule EGFR tyrosine inhibitors of kinases and ATP competition, be attached to the phosphorylation site of EGFR intracellular region, EGFR can be suppressed from process phosphoric acid and to block downstream signaling pathway, reach to suppress the purpose of tumor cell. Binding mechanism according to inhibitor Yu EGFR, can be divided into first generation reversible EGFR tyrosine kinase inhibitor, the second filial generation non-reversible type EGFR tyrosine kinase inhibitor and the third generation non-reversible type Catastrophic selection EGFR tyrosine kinase inhibitor at present by small molecule EGFR inhibitor.
Patients with Non-small-cell Lung is had good curative effect by the first generation reversible EGFR inhibitor including gefitinib, but, there is acquired drug-resistance in Clinical practice in first generation EGFR inhibitor. The gain mutation of EGFR is the major impetus of the malignant progression of 40%-45% Patients with Non-small-cell Lung, and EGFRT790MSudden change is sudden change more typically. The therapeutic strategy of irreversible EGFR inhibitor targeting EGFR T790M obtains certain achievement. The second filial generation irreversible EGFR inhibitor people epidermal carcinoma cell A431 to EGFR high expressedWT,overexpression, Gefitinib drug resistance Non-small cell lung carcinoma cell strain H1975L858R/T790MBetween inhibited proliferation selectivity not strong.Because the Wild type EGFR of skin and intestinal is had stronger inhibitory action by the first generation and second filial generation inhibitor, so causing the side effect such as dermatitis, diarrhoea, making to connect subject patients ' life quality and declining. This promotes researcheres to study the better EGFR inhibitor of selectivity between Wild type EGFR and T790M saltant type. The NSCLC patient that existing EGFR-TKI resistance and T790M are suddenlyd change by the third generation non-reversible Catastrophic selection type EGFR inhibitor tower gires (Tagrisso) researched and developed by Astrazeneca AB (AstraZeneca) has good therapeutic effect. AZD9291 IC50 respectively 12.92nM, 11.4nM and 493.8nM to EGFR, EGFRT790M/L858R, EGFRWT that exon 19 lacks, compared with Wild type EGFR, it has very strong inhibited proliferation in sudden change EGFR cell line. In In vivo study, AZD9291 (5mg/kg, p.o.) can cause whole EGFRm+And EGFRm (PC90)+Tumor in/T790M (H1975) tumor model significantly disappears, and can significantly inhibit internal EGFR phosphorylation and downstream key signal path (AKT, ERK etc.). It is obvious at the therapeutic effect of clinical stage. [] U.S. FDA with in November, 2015 approved AZD9291 listing. Research recently reports NSCLC patient and finds new C797S sudden change in using the third generation irreversible EGFR inhibitor therapeutic process in EGFR extron 20. Resistance problems has become as the difficult problem that must solve.
Traditional chemotherapy combined medication obtains certain effect clinically, and compared with single target drug, on clinical treatment, the combination therapies therapeutic effect of several target spots is better. But drug combination probably due to drug interaction and cause adverse effect. Many target agents of appropriate design can improve curative effect, reduces Drug-resistant incidence rate, one of many target agents countermeasure becoming overriding resistance simultaneously. Hdac inhibitor can affect cell cycle progression, apoptosis, differentiation and tumor vessel and occur, therefore that kinds of tumors is all inhibited. Being in clinical hdac inhibitor for solid tumor and hemopathic treatment, a lot of clinical researches now trend towards the HDACIs antitumor drug coupling with other, to obtain better therapeutic effect. Hdac inhibitor directly acts on and nucleosome, and kinds of tumor cells suffers from very strong Proliferation Ability ability. Hdac inhibitor and being used in combination of other tyrosine kinase inhibitors are also studied widely. CUDC-101 is the EGFR/HER2/HDAC Mutiple Targets inhibitor entering clinical?stage research, and XiongCai et al. uses the suitable base that connects the hydroxamic acid fragment of the EGFR inhibitor Erlotinib listed and hdac inhibitor SAHA to be attached. They have synthesized a series of compound, and it is carried out structure activity study. In experiment in vitro, this series compound is to EGFR enzyme, IC50 value respectively 2.4nM, 15.7nM, the 4.4nM of HER2 enzyme and HDAC enzyme. Erlotinib is sensitive and cells of resistant tumors the propagation strain inhibitory activity of CUDC-101 is stronger than SAHA, Erlotinib, Lapatinib, SAHA and Erlotinib drug combination, SAHA and lapatinib in combination medication. Clinical study results shows, HDACIs can produce to be added or synergism with other tyrosine kinase inhibitors, strengthens the therapeutic effect of medicine, and is conducive to overcoming drug resistance.
Summary of the invention
The technical problem to be solved is to provide a kind of 2-arylamine pyridine derivatives containing hydroxamic acid fragment, is a kind of and the diverse pyridine derivatives of prior art, has preferably anti-tumor activity, have EGFR/HDAC inhibitory activity simultaneously.
A kind of 2-arylamine pyridine derivatives structural formula containing hydroxamic acid fragment provided by the invention is such as shown in formula I:
Wherein:
R1For hydrogen atom or chlorine atom,
R2For hydrogen atom, fluorine atom or N, N-dimethyl.
A kind of 2-arylamine pyridine derivatives structural formula containing hydroxamic acid fragment provided by the invention is such as shown in formula II:
Wherein: R1For hydrogen atom or chlorine atom.
Described type I compound is following arbitrary compound:
N1The fluoro-5-of-2-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 1);
N1-5-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 2);
N1-(2-(dimethylamino)-5-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 3);
N1-5-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino)-2-(dimethylamino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 4);
N1The fluoro-5-of-2-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 5).
Described formula II compound is following arbitrary compound:
4-(4-(2-acryloyl group-amino-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine radicals-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 6);
4-(4-(2-acryloyl group-amino-4-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base) pyrimidine radicals-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 7).
The preparation method that it is a further object to provide described type I compound, is realized by following steps:
With 2, 4-dichloro pyrimidine A and 1-methylindole are initiation material, 1, 2-dichloroethanes, under 80 DEG C of conditions, reaction generates 3-(2-chloropyrimide-4-base)-1-methyl isophthalic acid-H-indole B, intermediate B and the fluoro-3-nitroaniline of 4-are at sec-butyl alcohol, 2-(3-nitrobenzophenone)-4-(N-methylindole)-2-aminopyrimidine C it is obtained by reacting under 1NHCl catalytic condition, intermediate C nitroreduction under the reducing conditions generates 2-(3-aminophenyl)-4-(N-methylindole)-2-aminopyrimidine D, intermediate D and maleic anhydride generate 4-oxo-2-butylene acid E when dichloromethane, intermediate E generates compound F with O-(tetrahydrochysene-2H-pyrans-2-base) hydroxylamine condensation, last F takes off protection base in acid condition and generates target compound I, reagent and reaction condition: a) anhydrous Aluminum chloride, dichloroethanes, 80 DEG C, 2 hours, b) sec-butyl alcohol, backflow, 4 hours, c) sodium borohydride, Nickel dichloride hexahydrate, dichloromethane: methanol=4:1,0 DEG C-room temperature, 30 minutes, d) dichloromethane, room temperature, 3-5 hour, e) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, dichloromethane: DMF=2:1,45 DEG C, 5 hours, f) 1M ethereal HCI solution, 30 minutes, reaction equation is:
Wherein substituent R1And R2As defined above described in.
The preparation method that it is also another object of the present invention to provide described compound ii, is realized by following steps:
With 2, 4-dichloro pyrimidine a and 1-methylindole are initiation material, 1, 2-dichloroethanes, under 80 DEG C of conditions, reaction generates 3-(2-chloropyrimide-4-base)-1-methyl isophthalic acid-H-indole b, the fluoro-3-nitroaniline of intermediate b and 4-is at sec-butyl alcohol, 2-(the fluoro-3-nitrobenzophenone of 4-)-4-(N-methylindole)-2-aminopyrimidine c it is obtained by reacting when 1N hydrochloric acid catalysis, intermediate c and N-Boc piperazine are obtained by reacting d in the basic conditions, d takes off protection base in acid condition and obtains intermediate e, e and bromobutyrate are obtained by reacting f when acetone reflux, intermediate f nitroreduction under the reducing conditions generates g, intermediate g and acryloyl chloride are obtained by reacting h.Intermediate h is hydrolyzed generation i, i and O-(tetrahydrochysene-2H-pyrans-2-base) hydroxylamine (THP) condensation generation compound j, last j in the basic conditions and takes off protection base generation target compound II in acid condition. Reagent and reaction condition: 1) anhydrous Aluminum chloride, dichloroethanes, 80 DEG C, 2 hours; 2) sec-butyl alcohol, backflow, 4 hours; 3) dimethyl sulfoxide, potassium carbonate, 90 DEG C, 3 hours; 4) trifluoroacetic acid, dichloromethane, 30 minutes; 5) acetone, potassium carbonate, backflow, 5 hours; 6) sodium borohydride, Nickel dichloride hexahydrate, dichloromethane: methanol=4:1,0 DEG C to room temperature, 30 minutes; 7) dichloromethane, triethylamine ,-5 DEG C, 30 minutes; 8) aluminium hydroxide, oxolane: water=1:1, room temperature, 3 hours; 9) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, DMF: dichloromethane=1:2,45 DEG C, 5 hours; 10) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour. Wherein, described in the definition of each group all ditto. Reaction equation is as follows:
Raw material involved in the present invention and intermediate, can directly buy or prepared by the literature method mentioned according to embodiment part.
Formula I described in preparation method of the present invention and formula II compound, prepared by available organic synthesis and medicinal chemistry art or multiple method known by the technical staff, method described above can be used to prepare the compound of the present invention, typical or preferred process condition (i.e. the mol ratio and solvent etc. of reaction temperature, time, reactant) can be used, other process conditions can also be used, except as otherwise noted. Optimum reaction condition can change with concrete reactant used or solvent, but these conditions should be determined by routine optimization process by those skilled in the art. Generally, above-mentioned reaction scheme and technique can be used to prepare the compounds of this invention, but be not limited to the reagent in reaction condition and solvent.
4th purpose of the present invention is to provide the application in preparing antitumor drug of the described a kind of 2-arylamine pyridine derivatives containing hydroxamic acid fragment, and described tumor cell refers to the people epidermal carcinoma cell strain A431 of process LAN EGFR, to the human lung adenocarcinoma cell line H1975 of Gefitinib drug resistance, to the tumor cell (human cervical carcinoma cell lines Hela, human mouth epidermoid carcinoma cell strain KB, people early young grain acute leukemia cells strain HL60, HepG2 cell lines, human colon cancer cell strain SW620) relevant to acetylation of histone enzyme (HDAC) activity. Its pharmacodynamics embodiment experimental data shows, it has significant inhibited proliferation at cellular level pair and EGFR, tumor cell that HDAC activity is relevant, can prepare corresponding antitumor drug.
The invention provides the 2-arylamine pyridine derivatives that a class is brand-new, hydroxamic acid fragment therein can as the Zinc Ions Chelated group of HDAC. Its pharmacodynamics embodiment experimental data shows, has significant inhibited proliferation at the cellular level pair tumor cell (the people epidermal carcinoma cell strain A431 of process LAN EGFR, the human lung adenocarcinoma cell line H1975 to Gefitinib drug resistance) relevant to EGFR with to the tumor cell (human cervical carcinoma cell lines Hela, human mouth epidermoid carcinoma cell strain KB, people early children grain acute leukemia cells strain HL60, HepG2 cell lines, human colon cancer cell strain SW620) relevant with acetylation of histone enzyme (HDAC) activity. Particularly drug-resistant cell strain H1975 there is good inhibition, it is possible to provide possible for designing the novel double; two target spot inhibitor of EGFR/HDAC overcoming Gefitinib drug resistance.
Detailed description of the invention
Mode by the examples below further illustrates the present invention, but therefore do not limit the present invention among described scope of embodiments, the experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1N1The fluoro-5-of-2-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 1)
Reagent and reaction condition: 1) dichloromethane, room temperature, 3-5 hour; 2) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, dichloromethane: DMF=2:1,45 DEG C, 5 hours; 3) 1M ethereal HCI solution, 30 minutes.
Step 1:(Z) acid of-4-((the fluoro-5-of 2-((4-(N-methyl-3-indyl)-2-pyrimidine) amino) phenyl) amino)-4-oxo-2-butylene prepare raw material 1:2-(the fluoro-3-aminophenyl of 4-)-4-(N-methylindole)-2-aminopyrimidine according to J.Med.Chem.2014, prepared by the method for 57,8249-8267.
2-(the fluoro-3-aminophenyl of 4-)-4-(N-methylindole)-2-aminopyrimidine (1mmol) is dissolved in 15mL dichloroethanes with maleic anhydride (1.2mmol), reacts 3-5 hour. After reaction terminates, decompression is spin-dried for. Brown solid can be obtained with acetone recrystallization.
Yellowsolid; M.p.:236.1 236.7 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.28 (s, 1H), 9.60 (s, 1H), 8.56 8.40 (m, 3H), 8.33 (s, 1H), 7.263-7.52 (m, 4H) 7.29 7.20 (m, 4H), 6.59 (d, J=12.2Hz, 1H), 6.38 (d, J=12.2Hz, 1H), 6.26 (s, 3H), 3.88 (s, 3H), 2.09 (s, 2H) .HRMS (ESI) calcd.forC23H19FN5O3[M+H]+=432.1466, found432.1468.
Step 2:N1The fluoro-5-of-2-((4-(N-methyl-3-indyl)-2-pyrimidine radicals) amino) phenyl)-N4The preparation of-((tetrahydrochysene-2H-pyrans-2-base) oxo) maleic acid diamidogen
By Z)-4-((the fluoro-5-of 2-((4-(N-methyl-3-indyl)-2-pyrimidine) amino) phenyl) amino)-4-oxo-2-butylene acid (1mmol), O-(tetrahydrochysene-2H-pyrans-2-base) azanol (1.2mmol) is dissolved into and is dissolved in 12mL dichloroethanes and 4mLN, in dinethylformamide mixed solution, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.32mmol) is added in reactant liquor, 1-hydroxy benzo triazole (1.32mmol), is placed in 40 DEG C of stirring reactions 4 hours. Reaction adds 30mL water after terminating in reactant liquor, with 20mL dichloromethane extraction three times, merges organic facies, and organic facies is spin-dried for, through column chromatography purification (mobile phase is ethyl acetate: petroleum ether=10:1) the solid of yellow.
Yellowsolid; M.p.:181.3 181.6 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.65 (s, 1H), (10.99 s, 1H), 9.51 (d, J=10.8Hz, 1H), 8.68 8.48 (m, 2H), 8.43 (s, 1H), 8.33 (d, J=5.3Hz, 1H), 7.65 7.51 (m, 3H), 7.29 7.18 (m, 4H), 6.48 (d, J=12.6Hz, 1H), 6.27 (d, J=12.6Hz, 1H), 5.77 (s, 2H), 4.91 (s, 1H), 3.88 (s, 5H), 1.65 (s, 3H), 1.50 (s, 3H) .HRMS (ESI) calcd.forC28H28FN6O4[M+H]+=513.2245, found513.2245.
Step 3:N1The fluoro-5-of-2-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4The preparation of-hydroxyl maleic amide hydrochlorate
By N1The fluoro-5-of-2-((4-(N-methyl-3-indyl)-2-pyrimidine radicals) amino) phenyl)-N4-((tetrahydrochysene-2H-pyrans-2-base) oxo) maleic acid diamidogen (1mmol) joins in 25mL there-necked flask, and adds the dichloroethanes of 8mL.Ether (3.4mL) solution of 1M hydrochloric acid, low-temp reaction 1 hour is instilled under condition of ice bath. Having solid to precipitate out after having reacted, reduce pressure sucking filtration, obtains yellow solid.
Yellowsolid; M.p.:181.3 181.6 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.65 (s, 1H), (10.99 s, 1H), 9.51 (d, J=10.8Hz, 1H), 8.68 8.48 (m, 2H), 8.43 (s, 1H), 8.33 (d, J=5.3Hz, 1H), 7.65 7.51 (m, 2H), 7.29 7.18 (m, 4H), 6.48 (d, J=12.6Hz, 1H), 6.27 (d, J=12.6Hz, 1H), 5.77 (s, 2H), 4.91 (s, 1H), 3.88 (s, 5H), 1.65 (s, 3H), 1.50 (s, 3H) .HRMS (ESI) calcd.forC28H28FN6O4[M+H]+=531.2151, found531.2158.
According to embodiment 1 same procedure, adopt different material, prepare following compound.
Embodiment 2N1-5-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:181.0-181.4 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.73 (s, 1H), 10.98 (s, 1H), 10.36 (s, 1H), 8.85 (s, 1H), 8.30 (d, J=6.6Hz, 2H), 8.07 (s, 1H), 7.61 (d, J=8.3Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.48 7.45 (m, 2H), 7.39 7.23 (m, 3H), 7.17 (t, J=7.4Hz, 1H), 6.38 (d, J=12.1Hz, 1H), 6.24 (d, J=12.1Hz, 1H), 3.93 (s, 3H).
13CNMR(125MHz,DMSO-d6)��169.1,167.0,158.1,157.6,157.3,156.4,137.1,136.6,135.3,135.2,131.9,130.0,126.5,123.3,122.7,121.2,116.0,115.8,115.4,110.2,109.6,33.2.HRMS(ESI)calcd.forC23H21N6O3[M+H]+=429.1670, found429.1670.
Embodiment 3N1-(2-(dimethylamino)-5-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:217.9 218.3 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.31 (s, 3H), 7.65 (d, J=7.8Hz, 1H), 7.47 7.39 (m, 6H), 7.24 7.18 (m, 3H), 6.99 (s, 1H), 6.78 (d, J=12.1Hz, 1H), 6.28 (d, J=12.1Hz, 1H), 3.81 (s, 3H), 3.80 (s, 1H), 2.08 2.01 (m, 6H), 1.91 (s, 1H) .HRMS (ESI) calcd.forC25H26N7O3[M+H]+=472.2092, found472.2095.
Embodiment 4N1-5-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino)-2-(dimethylamino) phenyl)-N4-hydroxyl maleic amide hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:180.4 180.7 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.30 (s, 3H), 7.47 7.40 (m, 6H), 7.24 7.19 (m, 3H), 6.99 (s, 1H), 6.78 (d, J=12.0Hz, 1H), 6.28 (d, J=12.0Hz, 1H), 3.81 (s, 3H), 3.80 (s, 1H), 2.08 2.01 (m, 6H), 1.91 (s, 1H) .HRMS (ESI) calcd.forC25H25ClN7O3[M+H]+=506.1702, found506.1709.
Embodiment 5N1The fluoro-5-of-2-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:128.2 128.5 DEG C;1HNMR (500MHz, DMSO-d6) �� 12.55 (s, 1H), (10.98 s, 1H), 10.37 (s, 1H), 8.85 (s, 1H), 8.27 (t, J=17.1Hz, 2H), 7.61 7.59 (m, 1H), 7.47 7.42 (m, 2H), 7.39 7.27 (m, 3H), 7.16 (t, J=7.4Hz, 1H), 6.31 (d, J=7.4Hz, 2H), 3.92 (s, 3H) .HRMS (ESI) calcd.forC23H19ClFN6O3[M+H]+=481.1186, found481.1188.
Embodiment 64-(4-(2-acryloyl group-amino-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine radicals-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride
Reaction equation:
Reagent and reaction condition: 1) acetone, potassium carbonate, backflow, 5 hours;2) sodium borohydride, Nickel dichloride hexahydrate, dichloromethane: methanol=4:1,0 DEG C to room temperature, 30 minutes; 3) dichloromethane, triethylamine ,-5 DEG C, 30 minutes; 4) aluminium hydroxide, oxolane: water=1:1, room temperature, 3 hours; 5) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, DMF: dichloromethane=1:2,45 DEG C, 5 hours; 6) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour.
Step 1: the preparation of ethyl 4-(4-(4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino)-2-nitrobenzophenone) piperazine-1-base) ethyl propionate:
Raw material 1:4-(1-Methyl-1H-indole-3-base)-N-(3-nitro-4-(piperazine-1-base) phenyl) pyrimidine-2-amine is according to Bioorg.Med.Chem.Lett., 2008,18 (12), described in 3513-3516. prepared by method.
4-(1-Methyl-1H-indole-3-base)-N-(3-nitro-4-(piperazine-1-base) phenyl) pyrimidine-2-amine (1.0mmol) and ethyl bromide (1.0mmol) are added in 50mL there-necked flask, and add the acetone of 10mL, it is heated to reflux, makes mixture stirring reaction 5 hours. Reaction is cooled to room temperature after terminating, and adds 20mL water in reactant liquor, with 20mL dichloromethane extraction three times, merges organic facies, and organic facies is spin-dried for, and obtains yellow solid.
Yellowsolid; M.p.:106.1 106.5 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.28 (s, 1H), 9.60 (s, 1H), 8.56 8.40 (m, 3H), 8.33 (s, 1H), 7.26 7.52 (m, 3H), 7.29 7.20 (m, 1H), 3.92 (s, 3H), 3.37 3.30 (m, 4H), 3,15 3.10 (m, 4H), 2.48 (t, J=8.2Hz, 4H), 1.69 1.64 (m, 2H) .HRMS (ESI) calcd.forC29H34N7O4[M+H]+=544.2667, found544.2668.
Step 2: the preparation of ethyl 4-(4-(2-amino-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino) phenyl) piperazine-1-base) ethyl propionate
Ethyl 4-(4-(4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino)-2-nitrobenzophenone) piperazine-1-base) ethyl propionate (0.5mmol) is dissolved in 5mL methanol and 20mL dichloromethane mixed solution, add six water Nickel dichloride .s (1.0mmol), after system mix homogeneously, sodium borohydride (2.0mmol) it is dividedly in some parts under condition of ice bath, reaction 30min, it is transferred to room temperature, continues stirring reaction 30 minutes. After reaction terminates, in system, add 10mL water, stir 15 minutes, sucking filtration, with ethyl acetate washing leaching cake 34 times, collect filtrate, and be extracted with ethyl acetate filtrate, collection ethyl acetate layer. Ethyl acetate layer decompression is spin-dried for, obtains brown solid.
Yellowsolid; M.p.:117.3 117.5 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.28 (s, 1H), 9.60 (s, 1H), 8.56 8.40 (m, 3H), 8.33 (s, 1H), 7.26 7.52 (m, 3H), 7.29 7.20 (m, 1H), 5.02 (s, 1H), 4.94 (s, 2H), 3.92 (s, 3H), 3.37 3.34 (m, 4H), 3.15 3.10 (m, 4H), 2.48 (t, J=8.2Hz, 4H), 1.69 1.62 (m, 2H) .HRMS (ESI) calcd.forC29H36N7O2[M+H]+=514.2925, found514.2925.
Step 3: the preparation of ethyl 4-(4-(2-acrylamide-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino) phenyl) piperazine-1-base) ethyl propionate
Ethyl 4-(4-(2-amino-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino) phenyl) piperazine-1-base) ethyl propionate (1.0mmol) is joined in 25mL there-necked flask, and add the dichloromethane of triethylamine (4.0mmol) and 10mL, reaction bulb is placed in the ice bath of-5 DEG C to-10 DEG C.Treat that interior temperature control is at-5 DEG C to-10 DEG C, is slow added into acryloyl chloride (1.0mmol), makes mixture stirring reaction 30 minutes. Reaction adds 20mL water after terminating in reactant liquor, with 20mL dichloromethane extraction three times, merges organic facies, and organic facies is spin-dried for, and obtains yellow solid.
Yellowsolid; M.p.:117.3 117.5 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.28 (s, 1H), (10.08 s, 1H), 9.60 (s, 1H), 8.56 8.40 (m, 3H), 8.33 (s, 1H), 7.26 7.52 (m, 3H), 7.29 7.20 (m, 1H), 6.59 (d, J=2.4Hz, 1H), 6.48 (d, J=2.4Hz, 1H), 6.26 (s, 1H) 5.02 (s, 1H), 3.92 (s, 3H), 3.37 3.34 (m, 4H), 3.15 3.11 (m, 4H), 2.48 (t, J=8.2Hz, 4H), 1.69 1.62 (m, 2H) .HRMS (ESI) calcd.forC32H38N7O3[M+H]+=568.3031, found568.3031.
Step 4: the preparation of ethyl 4-(4-(2-acrylamide-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino) phenyl) piperazine-1-base) butanoic acid
Ethyl 4-(4-(2-acrylamide-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino) phenyl) piperazine-1-base) ethyl propionate (1.0mmol) and Lithium hydrate (10mmol) are joined in 25mL there-necked flask, and add the oxolane of 8mL and the water of 8mL, react 1 hour. After reacting completely, with hydrochloric acid, reaction system PH is adjusted to about 7, precipitates out faint yellow yellow solid.
Yellowsolid; M.p.:117.3 117.5 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.28 (s, 1H), (10.08 s, 1H), 10.01 (s, 1H), 9.60 (s, 1H), 8.56 8.40 (m, 3H), 8.33 (s, 1H), 7.52 7.26 (m, 3H), 7.29 7.20 (m, 1H), 6.59 (d, J=2.4Hz, 1H), 6.48 (d, J=2.4Hz, 1H), 6.26 (s, 1H), 5.02 (s, 1H), 3.37 3.29 (m, 4H), 3.15 3.09 (m, 4H), 2.48 (t, J=8.2Hz, 4H) .HRMS (ESI) calcd.forC30H34N7O3[M+H]+=540.2718, found540.2719.
The preparation of step 5:4-(4-(2-acrylamide-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino) phenyl) piperazine-1-base)-N-((tetrahydrochysene-2H-pyrans-2-base) oxo) butyramide
Ethyl 4-(4-(2-acrylamide-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino) phenyl) piperazine-1-base) butanoic acid (1mmol) and O-(tetrahydrochysene-2H-pyrans-2-base) azanol (1.2mmol) are dissolved into and are dissolved in 12mL dichloroethanes and 4mLN, in dinethylformamide mixed solution, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.32mmol) is added in reactant liquor, 1-hydroxy benzo triazole (1.32mmol), is placed in 40 DEG C of stirring reactions 4 hours. Reaction adds 30mL water after terminating in reactant liquor, with 20mL dichloromethane extraction three times, merges organic facies, and organic facies is spin-dried for, through column chromatography purification (mobile phase is dichloromethane: methanol=90:1) the solid of yellow.
Yellowsolid; M.p.:117.3 117.5 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.28 (s, 1H), 10.08 (s, 1H), 9.60 (s, 1H), 8.56 8.40 (m, 3H), 8.33 (s, 1H), 7.26 7.52 (m, 3H), 7.29 7.20 (m, 1H), 6.59 (d, J=2.4Hz, 1H), 6.48 (d, J=2.4Hz, 1H), 6.26 (s, 1H), 5.71 5.62 (m, 1H), 5.02 (s, 1H), 3.67 3.62 (m, 2H), 3.37 3.26 (m, 4H), 3.15 3.09 (m, 4H), 2.48 (t, J=8.2Hz, 4H) 1.75 (m, 6H) .HRMS (ESI) calcd.forC35H43N8O4[M+H]+=639.3402, found639.3404.
The preparation of step 5:4-(4-(2-acryloyl group-amino-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine radicals-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride
4-(4-(2-acrylamide-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base) amino) phenyl) piperazine-1-base)-N-((tetrahydrochysene-2H-pyrans-2-base) oxo) butyramide (1mmol) is joined in 25mL there-necked flask, and adds the dichloroethanes of 8mL. Ether (3.4mL) solution of 1M hydrochloric acid, low-temp reaction 1 hour is instilled under condition of ice bath. Having solid to precipitate out after having reacted, reduce pressure sucking filtration, obtains yellow solid.
Yellowsolid; M.p.:165.3 166.1 DEG C;1HNMR (500MHz, DMSO-d6) �� 9.07 (s, 1H), 8.93 (s, 1H), 8.45 (s, 1H), 8.34 (d, J=5.3Hz, 1H), 8.22 (d, J=7.6Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.32 7.26 (m, 5H), 7.15 7.09 (m, 2H), 6.42 (dd, J=16.9, 1.3Hz, 1H), 6.32 (dd, J=16.9, 1.1Hz, 1H), 5.79 (dd, J=10.1, 1.2Hz, 1H), 3.93 (s, 3H), 3.74 3.67 (m, 4H), 2.90 (t, J=4.4Hz, 4H), 2.63 (s, 1H), 2.46 (d, J=7.4Hz, 2H), 2.40 (t, J=7.3Hz, 2H), 1.89 1.86 (m, 2H) .HRMS (ESI) calcd.forC30H35N8O3[M+H] +=555.2827, found555.2829.
According to embodiment 5 same procedure, adopt different material, prepare following compound.
Embodiment 7:4-(4-(2-acryloyl group-amino-4-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base) pyrimidine radicals-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Yellowsolid; M.p.:114.3 114.9 DEG C;1HNMR (500MHz, DMSO-d6) �� 9.19 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 8.12 (d, J=7.7Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.30 7.22 (m, 5H), 7.15 7.12 (m, 2H), 6.42 (dd, J=16.9, 1.3Hz, 1H), 6.32 (dd, J=16.1, 1.3Hz, 1H), 5.81 (dd, J=16.1, 1.2Hz, 1H), 3.91 (s, 3H), 3.74 3.67 (m, 4H), 2.90 (t, J=4.4Hz, 4H), 2.634 (s, 1H), 2.46 (d, J=7.4Hz, 2H), 2.42 (t, J=7.3Hz, 2H), 1.89 1.86 (m, 2H) .HRMS (ESI) calcd.forC30H34ClN8O3[M+H]+=589.2437, found589.2440.
Embodiment 8: compound is to A431, H1975, HeLa cell inhibitory effect determination of activity
This example is used for measuring the compounds of this invention proliferation inhibition activity for EGFR wild type overexpression cell line A431, T790M point mutation cell strain H1975, human cervical carcinoma cell lines Hela, the inhibitory activity half-inhibition concentration IC of compound on intracellular propagation50Represent. Testing program is as follows: EGFR wild type overexpression cell line A431, T790M point mutation cell strain H1975 cell and human cervical carcinoma cell lines Hela are all purchased from ATCC, with suitable cell concentration (A431:20000 cell/ml culture medium; H1975:15000 cell/ml culture medium) cell is inoculated on 96 well culture plates of white clear; Afterwards cell is positioned over 37 DEG C, 5%CO2Environment in cultivate, after 24 hours, the medicine of a series of Concentraton gradient is added in cultured cells culture medium, it is typically chosen 10 concentration, afterwards cell is put back to and former culture environment continues cultivate 48 hours, afterwards according to the method for CellTiter-GloLuminescentCellViabilityAssay, measure the test-compound impact on A431 and H1975, HeLa cell proliferation, and the inhibitory activity that the compound on intracellular calculating variable concentrations is bred, CellTiter-GloLuminescentCellViabilityAssay detectable is purchased from Promega.Afterwards A431, H1975, HeLa cell inhibitory effect activity under the compound of variable concentrations being carried out four parameter fittings, the IC50 data of test-compound of the present invention are in Table 1.
Table 1
Embodiment 9: part of compounds is to SW620, KB, HepG2, HL60 cell inhibitory effect determination of activity
This example for measure the compounds of this invention 10 for HepG2 cell lines, human colon cancer cell strain SW620, human mouth epidermoid carcinoma cell strain KB, people in loop strain HL60 proliferation inhibition activity, compound on intracellular propagation inhibitory activity half-inhibition concentration IC50Represent. Testing program is embodiment 8 such as. The IC of part test-compound of the present invention50Data are table 2 below such as.
Table 2
Conclusion: have novelty in the compounds of this invention structure, is incorporated on the 2-aryl amine pyrimidine parent nucleus of third generation EGFR inhibitor AZD9291 by the pharmacophore fragment hydroxamic acid of SAHA first, the synthesis 2-arylamine pyrimidines containing hydroxamic acid fragment. Bioactivity evaluation result shows simultaneously, the compound of the present invention people epidermal carcinoma cell strain A431 to process LAN EGFR, the human lung adenocarcinoma cell line H1975 to Gefitinib drug resistance and Human cervical carcinoma cell line HeLa have obvious Inhibit proliferaton activity, and part of compounds is suitable with positive WZ4002 and SAHA. Mentality of designing is provided for designing the double; two target spot inhibitor of the novel Gefitinib of overcoming drug resistance EGFR/HDAC.
Claims (8)
1. the 2-aryl amine pyridine derivatives containing hydroxamic acid fragment as shown in formula I, its general structure is:
Wherein:
R1For hydrogen atom or chlorine atom.
R2For hydrogen atom, fluorine atom or N, N-dimethyl.
2. the 2-aryl amine pyridine derivatives containing hydroxamic acid fragment as shown in formula II, its general structure is:
Wherein: R1For hydrogen atom or chlorine atom.
3. the 2-aryl amine pyridine derivatives containing hydroxamic acid fragment as claimed in claim 1, it is characterised in that described type I compound is following arbitrary compound:
N1The fluoro-5-of-2-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 1);
N1-5-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 2);
N1-(2-(dimethylamino)-5-((4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 3);
N1-5-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino)-2-(dimethylamino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 4);
N1The fluoro-5-of-2-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 5).
4. the 2-aryl amine pyridine derivatives containing hydroxamic acid fragment as claimed in claim 2, it is characterised in that described formula II compound is following arbitrary compound:
4-(4-(2-acryloyl group-amino-4-((4-(1-Methyl-1H-indole-3-base) pyrimidine radicals-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 6);
4-(4-(2-acryloyl group-amino-4-((the chloro-4-of 5-(1-Methyl-1H-indole-3-base) pyrimidine radicals-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 7).
5. the preparation method of the type I compound according to claim 1 or 3, it is characterized in that, realized by following steps: with 2, 4-dichloro pyrimidine A and 1-methylindole are initiation material, 1, 2-dichloroethanes, under 80 DEG C of conditions, reaction generates 3-(2-chloropyrimide-4-base)-1-methyl isophthalic acid-H-indole B, intermediate B and the fluoro-3-nitroaniline of 4-are at sec-butyl alcohol, 2-(3-nitrobenzophenone)-4-(N-methylindole)-2-aminopyrimidine C it is obtained by reacting under 1NHCl catalytic condition, intermediate C nitroreduction under the reducing conditions generates 2-(3-aminophenyl)-4-(N-methylindole)-2-aminopyrimidine D, intermediate D and maleic anhydride generate 4-oxo-2-butylene acid E when dichloromethane, intermediate E generates compound F with O-(tetrahydrochysene-2H-pyrans-2-base) hydroxylamine condensation, last F takes off protection base in acid condition and generates target compound I,Reagent and reaction condition: a) anhydrous Aluminum chloride, dichloroethanes, 80 DEG C, 2 hours; B) sec-butyl alcohol, backflow, 4 hours; C) sodium borohydride, Nickel dichloride hexahydrate, dichloromethane: methanol=4:1,0 DEG C-room temperature, 30 minutes; D) dichloromethane, room temperature, 3-5 hour; E) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, dichloromethane: DMF=2:1,45 DEG C, 5 hours; F) 1M ethereal HCI solution, 30 minutes; Reaction equation is:
Wherein substituent R1And R2Definition with claim 1.
6. the preparation method of the formula II compound according to claim 2 or 4, it is characterised in that realized by following steps:
With 2, 4-dichloro pyrimidine a and 1-methylindole are initiation material, 1, 2-dichloroethanes, under 80 DEG C of conditions, reaction generates 3-(2-chloropyrimide-4-base)-1-methyl isophthalic acid-H-indole b, the fluoro-3-nitroaniline of intermediate b and 4-is at sec-butyl alcohol, 2-(the fluoro-3-nitrobenzophenone of 4-)-4-(N-methylindole)-2-aminopyrimidine c it is obtained by reacting under 1NHCl catalytic condition, intermediate c and N-Boc piperazine are obtained by reacting d in the basic conditions, d takes off protection base in acid condition and obtains intermediate e, e and bromobutyrate are obtained by reacting intermediate f when acetone reflux, f nitroreduction under the reducing conditions generates intermediate g, g and acryloyl chloride are obtained by reacting intermediate h, h is hydrolyzed generation i in the basic conditions, i and O-(tetrahydrochysene-2H-pyrans-2-base) hydroxylamine condensation generates compound j, last j takes off protection base in acid condition and generates target compound II, reagent and reaction condition: 1) anhydrous Aluminum chloride, dichloroethanes, 80 DEG C, 2 hours, 2) sec-butyl alcohol, backflow, 4 hours, 3) dimethyl sulfoxide, potassium carbonate, 90 DEG C, 3 hours, 4) trifluoroacetic acid, dichloromethane, 30 minutes, 5) acetone, potassium carbonate, backflow, 5 hours, 6) sodium borohydride, Nickel dichloride hexahydrate, dichloromethane: methanol=4:1,0 DEG C to room temperature, 30 minutes, 7) dichloromethane, triethylamine ,-5 DEG C, 30 minutes, 8) aluminium hydroxide, oxolane: water=1:1, room temperature, 3 hours, 9) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, DMF: dichloromethane=1:2,45 DEG C, 5 hours, 10) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour, reaction equation is:
Wherein R1Definition with claim 2.
7. according to the arbitrary described formula I of claim 1-4 or the application in preparing antitumor cell and targeting EGFR/HDAC medicine of the formula II compound; it is characterized in that, wherein said tumor cell refers to the people epidermal carcinoma cell strain A431 of process LAN EGFR, the tumor cell that human lung adenocarcinoma cell line H1975 and the HDAC acetylation of histone enzymatic activity of Gefitinib drug resistance is relevant.
8. apply according to claim 6; it is characterized in that, the described tumor cell relevant to HDAC acetylation of histone enzymatic activity is Human cervical carcinoma cell line HeLa, human mouth epidermoid carcinoma cell strain KB, people early children grain acute leukemia cells strain HL60, HepG2 cell lines or human colon cancer cell strain SW620.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610034632.9A CN105646454B (en) | 2016-01-19 | 2016-01-19 | The 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid and preparation and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610034632.9A CN105646454B (en) | 2016-01-19 | 2016-01-19 | The 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid and preparation and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105646454A true CN105646454A (en) | 2016-06-08 |
| CN105646454B CN105646454B (en) | 2018-05-08 |
Family
ID=56487684
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610034632.9A Expired - Fee Related CN105646454B (en) | 2016-01-19 | 2016-01-19 | The 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid and preparation and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105646454B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106243044A (en) * | 2016-06-30 | 2016-12-21 | 浙江大学 | Pyridine derivatives containing halo acrylamide side chain and preparation and application |
| CN107793413A (en) * | 2016-09-05 | 2018-03-13 | 天津滨江药物研发有限公司 | Pyrimidine heterocyclic compound and its preparation method and application |
| US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| CN111057073A (en) * | 2019-12-26 | 2020-04-24 | 浙江工业大学 | 4-indole-2-arylamino pyrimidine compound and application thereof in inflammation treatment |
| CN113354622A (en) * | 2020-03-06 | 2021-09-07 | 沈阳药科大学 | P-phenylenediamine LSD1 inhibitor and preparation method thereof |
| CN115872971A (en) * | 2021-09-29 | 2023-03-31 | 四川大学 | Preparation method of aromatic seven-membered cyclic lactone monomer and recyclable polyester |
| CN116751187A (en) * | 2023-06-07 | 2023-09-15 | 西南交通大学 | Indolyl pyrimidine dual-targeting inhibitor, preparation method and application thereof |
| WO2023178928A1 (en) * | 2022-03-24 | 2023-09-28 | 中国药科大学 | 2-amino-4-indolyl pyrimidine compounds, preparation method therefor and uses thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20140118575A (en) * | 2013-03-29 | 2014-10-08 | 한미약품 주식회사 | Novel hydroxamate derivative |
| CN104109161A (en) * | 2011-07-27 | 2014-10-22 | 阿斯利康(瑞典)有限公司 | 2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN104761544A (en) * | 2014-01-03 | 2015-07-08 | 南京波尔泰药业科技有限公司 | Selectivity inhibitor of EGFR tyrosine kinase clinic important mutant |
| CN104844580A (en) * | 2015-04-17 | 2015-08-19 | 中国药科大学 | Miazines compound, preparation method and medical application thereof |
-
2016
- 2016-01-19 CN CN201610034632.9A patent/CN105646454B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104109161A (en) * | 2011-07-27 | 2014-10-22 | 阿斯利康(瑞典)有限公司 | 2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| KR20140118575A (en) * | 2013-03-29 | 2014-10-08 | 한미약품 주식회사 | Novel hydroxamate derivative |
| CN104761544A (en) * | 2014-01-03 | 2015-07-08 | 南京波尔泰药业科技有限公司 | Selectivity inhibitor of EGFR tyrosine kinase clinic important mutant |
| CN104844580A (en) * | 2015-04-17 | 2015-08-19 | 中国药科大学 | Miazines compound, preparation method and medical application thereof |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| US11098030B2 (en) | 2016-05-26 | 2021-08-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| CN106243044A (en) * | 2016-06-30 | 2016-12-21 | 浙江大学 | Pyridine derivatives containing halo acrylamide side chain and preparation and application |
| CN107793413A (en) * | 2016-09-05 | 2018-03-13 | 天津滨江药物研发有限公司 | Pyrimidine heterocyclic compound and its preparation method and application |
| CN107793413B (en) * | 2016-09-05 | 2021-09-28 | 上海科州药物研发有限公司 | Pyrimidine heterocyclic compound and preparation method and application thereof |
| CN111057073A (en) * | 2019-12-26 | 2020-04-24 | 浙江工业大学 | 4-indole-2-arylamino pyrimidine compound and application thereof in inflammation treatment |
| CN113354622A (en) * | 2020-03-06 | 2021-09-07 | 沈阳药科大学 | P-phenylenediamine LSD1 inhibitor and preparation method thereof |
| WO2021175079A1 (en) * | 2020-03-06 | 2021-09-10 | 沈阳药科大学 | P-phenylenediamine lsd1 inhibitor and preparation method therefor |
| CN115872971A (en) * | 2021-09-29 | 2023-03-31 | 四川大学 | Preparation method of aromatic seven-membered cyclic lactone monomer and recyclable polyester |
| WO2023178928A1 (en) * | 2022-03-24 | 2023-09-28 | 中国药科大学 | 2-amino-4-indolyl pyrimidine compounds, preparation method therefor and uses thereof |
| CN116751187A (en) * | 2023-06-07 | 2023-09-15 | 西南交通大学 | Indolyl pyrimidine dual-targeting inhibitor, preparation method and application thereof |
| CN116751187B (en) * | 2023-06-07 | 2024-03-19 | 西南交通大学 | Indolyl pyrimidine dual-targeting inhibitor, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105646454B (en) | 2018-05-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105646454A (en) | 2-arylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application | |
| CN106008511A (en) | Pteridinone derivatives and application of pteridinone derivatives as EGFR (epidermal growth factor receptor tyrosine kinase), BLK (B lymphocyte tyrosine kinase) and FLT3 (FMS-like tyrosine kinase 3) inhibitors | |
| CN105985342B (en) | As the pyrimido-pyrimidine derovatives of EGFR inhibitor and its application | |
| WO2013064128A1 (en) | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof | |
| Zhai et al. | Design, synthesis and biological evaluation of novel 4-phenoxy-6, 7-disubstituted quinolines possessing (thio) semicarbazones as c-Met kinase inhibitors | |
| CN107383004A (en) | 2 aminooimidazoles and pyridine derivatives and preparation and application | |
| JP2011515421A (en) | Polymorphs of 4-phenylaminoquinazoline derivatives, methods for their preparation and uses thereof | |
| CN107129506B (en) | As pyrimido [4,5-d] [1,3] oxazines -2- ketone derivatives of EGFR inhibitor and its application | |
| Yu et al. | Structure-based design and synthesis of pyrimidine-4, 6-diamine derivatives as Janus kinase 3 inhibitors | |
| CN106243044A (en) | Pyridine derivatives containing halo acrylamide side chain and preparation and application | |
| CN105646371A (en) | 2,4-diarylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application | |
| CN102688234B (en) | Indolone derivatives is as the Synthesis and application of RSK2 inhibitor | |
| CN106892922B (en) | As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application | |
| CN106045980B (en) | A kind of quinazoline derivant and preparation method thereof | |
| WO2014063631A1 (en) | Tyrosine kinase irreversible inhibitor and preparation method and applications thereof | |
| TW201731837A (en) | Bis-pyridazine compounds and their use in treating cancer | |
| CN106467540A (en) | Pteridine ketone derivatives are as the application of FLT3 inhibitor | |
| JP2011111433A (en) | Uracil compound having ureide structure or salt thereof | |
| CN110724137B (en) | Thiophene derivative and preparation method and application thereof | |
| CN110283165B (en) | 4-phenoxy quinoline alpha-acyloxy amide compound and preparation method and application thereof | |
| CN107513040A (en) | Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine | |
| CN107235994B (en) | Simultaneously [3,2-a] pyrimidine -3- acetamide derivative and the application of 5,7- diphenyl -5H- thiazole | |
| CN102372675B (en) | 6-chlorine-4-iodine indazole, preparation method and application thereof | |
| WO2019119481A1 (en) | Carbazole derivative kinase inhibitor | |
| CN106536519A (en) | Crystal of azole benzene derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180508 Termination date: 20190119 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |