CN105646454B - The 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid and preparation and application - Google Patents
The 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid and preparation and application Download PDFInfo
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- CN105646454B CN105646454B CN201610034632.9A CN201610034632A CN105646454B CN 105646454 B CN105646454 B CN 105646454B CN 201610034632 A CN201610034632 A CN 201610034632A CN 105646454 B CN105646454 B CN 105646454B
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- amino
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- pyrimidine
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- 239000002253 acid Substances 0.000 title claims abstract description 25
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000012634 fragment Substances 0.000 title claims abstract description 16
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- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- -1 aryl amine pyridine derivatives Chemical class 0.000 claims abstract description 15
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 13
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 13
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- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims abstract description 9
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229960002584 gefitinib Drugs 0.000 claims abstract description 9
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 7
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- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 77
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 16
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical class ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
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- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims description 4
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- KZVYALGJGCJPLQ-UHFFFAOYSA-N n-fluoro-3-nitroaniline Chemical class [O-][N+](=O)C1=CC=CC(NF)=C1 KZVYALGJGCJPLQ-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- YAQLSKVCTLCIIE-UHFFFAOYSA-M 2-bromobutanoate Chemical compound CCC(Br)C([O-])=O YAQLSKVCTLCIIE-UHFFFAOYSA-M 0.000 claims description 2
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 2
- 229910021502 aluminium hydroxide Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 2
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- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical class OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical class NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 claims 1
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- SPIFDSWFDKNERT-UHFFFAOYSA-N nickel;hydrate Chemical compound O.[Ni] SPIFDSWFDKNERT-UHFFFAOYSA-N 0.000 description 1
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides 2 aryl amine pyridine derivatives of two kinds of fragments containing hydroxamic acid as shown in formula I, II, and mainly using the 2 arylamine yl pyrimidines containing carboxy fragment as parent nucleus, target compound is obtained by the condensation of one step of azanol and relevant modification protected with THP.Experiment proves; the series compound is in cellular level pair and the relevant tumour cell of EGFR tyrosine kinase activities (the people's epidermis cancer cell line A431, the human lung adenocarcinoma cell line H1975 drug resistant to Gefitinib that are overexpressed EGFR) and pair has inhibited proliferation with the relevant tumour cell of HDAC acetylation of histone enzymatic activitys (human cervical carcinoma cell lines Hela, HepG2 cell lines, the early young grain acute leukemia cells strain HL60 of people, human mouth epidermoid carcinoma cell line KB, human colon cancer cell strain SW620), can prepare corresponding antitumor cell medicine.General structure is as follows：
Description
Technical field
The invention belongs to pharmaceutical field, and in particular to a kind of 2- arylamine pyrimidine derivatives of fragment containing hydroxamic acid, its system
Preparation Method, intermediate and its application.
Background technology
Protein tyrosine kinase plays an important role during signal transduction, participates in the growth of regulating cell, increases
Grow and the bioprocess such as apoptosis.Its unconventionality expression can cause cell functional disorders.EGF-R ELISA (EGFR) is typical case
The acceptor with tyrosine kinase activity, be epidermal growth factor (ErbB/HER) family a member.Current study show that
The excessive expression or mutation of EGFR is present in lung cancer, spongioblastoma (brain tumor), breast cancer, colorectal cancer, stomach cancer, neck
In a variety of entity tumors such as cancer and cancer of pancreas.EGFR, which is overexpressed, can make downstream signaling pathway signal enhancing.EGFR and tumour cell
Angiogenesis, tumor invasion, transfer and apoptosis have relation, existing lot of documents report, suppresses EGFR tyrosine kinase
Activity can effectively suppress the growth of tumour.Small molecule EGFR tyrosine kinase inhibitor is competed with ATP, is attached to EGFR intracellular regions
Phosphorylation site, EGFR can be suppressed from process phosphoric acid and block downstream signaling pathway, achieve the purpose that suppress tumour cell.Root
According to inhibitor and the binding mechanism of EGFR, small molecule EGFR inhibitor can be divided into first generation reversible EGFR tyrosine-kinases at present
The non-reversible type EGFR tyrosine kinase inhibitors of enzyme inhibitor, the second generation and the non-reversible type Catastrophic selection EGFR junket ammonia of the third generation
Acid kinase inhibitor.
First generation reversible EGFR inhibitor including Gefitinib has Patients with Non-small-cell Lung preferable treatment
Effect, however, acquired resistance occurs in Clinical practice in first generation EGFR inhibitor.The gain mutation of EGFR is 40%-
The major impetus of the malignant progression of 45% Patients with Non-small-cell Lung, and EGFRT790MMutation is more typical mutation.Can not
The therapeutic strategy of inverse EGFR inhibitor targeting EGFR T790M obtains certain achievement.The irreversible EGFR inhibitor pair of the second generation
People's epidermis cancer cell A431 of EGFR high expressionWT,overexpression, the drug resistant Non-small cell lung carcinoma cell lines of Gefitinib
H1975L858R/T790MBetween inhibited proliferation selectivity it is not strong.Because the first generation and second generation inhibitor are to skin and enteron aisle
Wild type EGFR have stronger inhibitory action, so trigger dermatitis, the side effect such as diarrhea, patient receiving treatment is lived matter
Amount declines.This promotes researchers' research more preferable EGFR inhibitor of selectivity between Wild type EGFR and T790M saltant types.
The non-reversible Catastrophic selection type EGFR inhibitor tower gires of the third generation researched and developed by Astrazeneca AB (AstraZeneca)
(Tagrisso) the NSCLC patient being mutated to existing EGFR-TKI resistances and T790M has good therapeutic effect.AZD9291 pairs
The IC50 of EGFR, EGFRT790M/L858R, EGFRWT that exons 19 lacks are respectively 12.92nM, 11.4nM and 493.8nM,
Compared with Wild type EGFR, it has very strong inhibited proliferation in EGFR cell lines are mutated.In In vivo study, AZD9291
(5mg/kg, p.o.) can cause whole EGFRm+(PC90) and EGFRm+Tumour in/T790M (H1975) tumor model significantly disappears
Move back, and internal EGFR phosphorylations and downstream key signal path (AKT, ERK etc.) can be significantly inhibited.It is controlled clinical stage
Therapeutic effect is obvious.[] U.S. FDA with November, 2015 approved AZD9291 list.Research reports NSCLC patient recently
New C797S mutation are found in EGFR extron 20s in using the irreversible EGFR inhibitor therapeutic process of the third generation.Drug resistance is asked
Topic has become the problem that must be solved.
Traditional chemotherapy combined medication clinically obtains certain effect, compared with single target drug, is controlled in clinic
The combination therapies therapeutic effect of several target spots is more preferable in treatment.But drug combination may be because drug interaction and cause
Adverse drug reaction.The more target agents rationally designed can improve curative effect, while reduce Drug-resistant incidence, more target medicines
Thing is as one of countermeasure of overriding resistance.Hdac inhibitor can influence cell cycle progression, Apoptosis, differentiation and tumour blood
Pipe occurs, therefore all inhibited to kinds of tumors.Controlled in clinical hdac inhibitor for solid tumor with hemopathic
Treat, many clinical researches now are intended to HDACIs and other antitumor drugs being combined, to obtain more preferable therapeutic effect.
Hdac inhibitor directly acts on and nucleosome, and very strong Proliferation Ability ability is suffered to kinds of tumor cells.Hdac inhibitor
Also widely studied with being used in combination for other tyrosine kinase inhibitors.CUDC-101 is studied into clinicalⅰstage
EGFR/HER2/HDAC Mutiple Targets inhibitor, XiongCai et al. are in distress by the EGFR inhibitor listed using appropriate linker
Lip river is attached for the hydroxamic acid fragment of Buddhist nun and hdac inhibitor SAHA.They have synthesized a series of compounds, and to its into
Row structure activity study.In experiment in vitro, to EGFR enzymes, the IC50 values of HER2 enzymes and HDAC enzymes are respectively the series compound
2.4nM, 15.7nM, 4.4nM.Propagation strain inhibitory activity ratios of the CUDC-101 to Tarceva sensitivity and cells of resistant tumors
SAHA, Tarceva, Lapatinib, SAHA and Tarceva drug combination, SAHA and lapatinib in combination medication are strong.Clinic is ground
Study carefully the result shows that, HDACIs can with other tyrosine kinase inhibitors produce be added or act synergistically, strengthen medicine treatment imitate
Fruit, and be conducive to overcome drug resistance.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of 2- arylamine pyridine derivatives of fragment containing hydroxamic acid,
It is a kind of with the entirely different pyridine derivatives of the prior art, there is preferable antitumor activity, while there is EGFR/HDAC
Inhibitory activity.
A kind of 2- arylamine pyridine derivatives structural formulas of fragment containing hydroxamic acid provided by the invention are 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 formulas of fragment containing hydroxamic acid provided by the invention are as shown in formula II：
Wherein：R1For hydrogen atom or chlorine atom.
The type I compound is following any compound：
N1The fluoro- 5- of -2- ((4- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) phenyl)-N4- hydroxyl Malaysia acyl
Amine hydrochlorate (compound 1)；
N1- 5- ((4- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) phenyl)-N4- hydroxyl maleic amide salt
Hydrochlorate (compound 2)；
N1- (2- (dimethylamino) -5- ((4- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) phenyl)-N4-
Hydroxyl maleic amide hydrochloride (compound 3)；
N1- 5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) -2- (dimethylamino) benzene
Base)-N4- hydroxyl maleic amide hydrochloride (compound 4)；
N1The fluoro- 5- of -2- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) phenyl)-N4- hydroxyl
Maleic amide hydrochloride (compound 5).
II compound of formula is following any compound：
4- (4- (2- acryloyl groups-amino -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine radicals -2- bases) amino) benzene
Base) piperazine -1- bases)-N- hydroxybutyramide hydrochlorides (compound 6)；
4- (4- (2- acryloyl groups-amino -4- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine radicals -2- bases) ammonia
Base) phenyl) piperazine -1- bases)-N- hydroxybutyramide hydrochlorides (compound 7).
It is a further object to provide the preparation method of the type I compound, realized by following steps：
With 2,4- dichloro pyrimidine A and 1- methyl indol for starting material, life is reacted under the conditions of 1,2- dichloroethanes, 80 DEG C
Into 3- (2- chlorine pyrimidine-4-yl) -1- methyl isophthalic acid-H- indoles B, intermediate B is with the fluoro- 3- nitroanilines of 4- in sec-butyl alcohol, 1N HCl
Reaction obtains 2- (3- nitrobenzophenones) -4- (N- methyl indols) -2- aminopyrimidine C under catalytic condition, and intermediate C is in reducing condition
Lower nitro reduction generation 2- (3- aminophenyls) -4- (N- methyl indols) -2- aminopyrimidine D, intermediate D and maleic anhydride
4- oxo -2- butenoic acid E are generated under the conditions of dichloromethane, intermediate E is condensed with O- (tetrahydrochysene -2H- pyrans -2- bases) hydroxylamine
Generate compound F, last F and take off protection group generation target compound I in acid condition；Reagent and reaction condition：A) it is anhydrous
Aluminium chloride, dichloroethanes, 80 DEG C, 2 it is small when；B) sec-butyl alcohol, reflux, 4 it is small when；C) sodium borohydride, Nickel dichloride hexahydrate, dichloromethane
Alkane:Methanol=4：1,0 DEG C-room temperature, 30 minutes；D) dichloromethane, room temperature, when 3-5 is small；E) 1- (3- dimethylamino-propyls) -3-
Ethyl-carbodiimide hydrochloride, 1- hydroxy benzo triazoles, dichloromethane:N,N-dimethylformamide=2:5 DEG C of Isosorbide-5-Nitrae, 5 is small
When；F) 1M ethereal HCIs solution, 30 minutes；Reaction equation is：
Wherein substituent R1And R2It is as defined above described.
It is also another object of the present invention to provide the preparation method of the compound ii, realized by following steps：
With 2,4- dichloro pyrimidine a and 1- methyl indol for starting material, life is reacted under the conditions of 1,2- dichloroethanes, 80 DEG C
Into the fluoro- 3- nitroanilines of 3- (2- chlorine pyrimidine-4-yl) -1- methyl isophthalic acid-H- indoles b, intermediate b and 4- in sec-butyl alcohol, 1N hydrochloric acid
Reaction obtains 2- (the fluoro- 3- nitrobenzophenones of 4-) -4- (N- methyl indols) -2- aminopyrimidine c, intermediate c and N- under catalytic condition
Boc piperazines react to obtain d in alkaline conditions, and d takes off protection group and obtains intermediate e, e and bromobutyrate in acid condition
Reaction obtains f under the conditions of acetone reflux, and nitro reduction generates g, intermediate g and acryloyl chloride to intermediate f under the reducing conditions
Reaction obtains h.Intermediate h hydrolyzes generation i, i and O- (tetrahydrochysene -2H- pyrans -2- bases) hydroxylamine (THP) contracting in alkaline conditions
Into compound j, last j takes off protection group generation target compound II in acid condition for symphysis.Reagent and reaction condition：1) nothing
Water aluminium chloride, dichloroethanes, 80 DEG C, 2 it is small when；2) sec-butyl alcohol, reflux, 4 it is small when；3) dimethyl sulfoxide (DMSO), potassium carbonate, 90 DEG C, 3 is small
When；4) trifluoroacetic acid, dichloromethane, 30 minutes；5) acetone, potassium carbonate, reflux, 5 it is small when；6) sodium borohydride, six chloride hydrates
Nickel, dichloromethane:Methanol=4:1,0 DEG C to room temperature, 30 minutes；7) dichloromethane, triethylamine, -5 DEG C, 30 minutes；8) hydroxide
Aluminium, tetrahydrofuran：Water=1:1, room temperature, 3 it is small when；9) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 1- hydroxyls
Base benzotriazole, n,N-Dimethylformamide:Dichloromethane=1:2,45 DEG C, 5 it is small when；10) 1M ethereal HCIs solution, 0 DEG C,
30 minutes to 1 it is small when.Wherein, the definition of each group is as described above.Reaction equation is as follows：
Raw material and intermediate according to the present invention, the literature method system that can directly buy or be referred to according to embodiment part
It is standby.
II compound of formula I and formula described in preparation method of the present invention, can use organic synthesis and medicinal chemistry art or skill
Known to art personnel prepared by a variety of methods, and method described above can be used to prepare the compound of the present invention, allusion quotation can be used
Type or preferable process condition (i.e. reaction temperature, time, the molar ratio of reactant and solvent etc.), can also use
Other process conditions, unless otherwise indicated.Optimum reaction condition can change with specific reactant or solvent used, but
These conditions should be determined by those skilled in the art by routine optimization process.In general, above-mentioned reaction road can be used
Line and technique prepare the compounds of this invention, but are not limited to the reagent in reaction condition and solvent.
Fourth object of the present invention is to provide a kind of 2- arylamine pyridine derivatives of fragment containing hydroxamic acid
Application in antitumor drug is prepared, the tumour cell refer to the people's epidermis cancer cell line A431, right for being overexpressed EGFR
The drug resistant human lung adenocarcinoma cell line H1975 of Gefitinib, pair with the relevant tumour cell of acetylation of histone enzyme (HDAC) activity
(human cervical carcinoma cell lines Hela, human mouth epidermoid carcinoma cell line KB, the early young grain acute leukemia cells strain HL60 of people, people liver
Cancer cell line HepG2, human colon cancer cell strain SW620).Its pharmacodynamics embodiment experimental data shows that it is in cellular level pair
There is significant inhibited proliferation with EGFR, the relevant tumour cell of HDAC activity, corresponding antitumor drug can be prepared.
The present invention provides a kind of brand-new 2- arylamine pyridine derivatives, hydroxamic acid fragment therein can be used as HDAC
Zinc Ions Chelated group.Its pharmacodynamics embodiment experimental data is shown, in cellular level pair and the relevant tumour cells of EGFR
People's epidermis cancer cell line A431, the human lung adenocarcinoma cell line H1975 drug resistant to Gefitinib of EGFR (be overexpressed) and pair and group
Histone acetylation enzyme (HDAC) activity relevant tumour cell (human cervical carcinoma cell lines Hela, human mouth epidermoid carcinoma cell line
KB, the early young grain acute leukemia cells strain HL60 of people, HepG2 cell lines, human colon cancer cell strain SW620) with aobvious
The inhibited proliferation of work.Particularly there is preferable inhibition to drug-resistant cell strain H1975, can be that design is new overcomes
The double target spot inhibitor of the drug resistant EGFR/HDAC of Gefitinib provide may.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
The experimental method of actual conditions is not specified among applying a scope, in the following example, according to conventional methods and conditions, or according to business
Product specification selects.
1 N of embodiment1The fluoro- 5- of -2- ((4- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) phenyl)-N4- hydroxyl
Base maleic amide hydrochloride (compound 1)
Reagent and reaction condition：1) dichloromethane, room temperature, when 3-5 is small；2) 1- (3- dimethylamino-propyls) -3- ethyl carbon
Diimmonium salt hydrochlorate, 1- hydroxy benzo triazoles, dichloromethane:N,N-dimethylformamide=2:5 DEG C of Isosorbide-5-Nitrae, 5 it is small when；3)1M
Ethereal HCI solution, 30 minutes.
Step 1:(Z) -4- ((the fluoro- 5- of 2- ((4- (N- methyl -3- indyls) -2- pyrimidines) amino) phenyl) amino) -4-
The preparing raw material 1 of oxo -2- butenoic acids：2- (the fluoro- 3- aminophenyls of 4-) -4- (N- methyl indols) -2- aminopyrimidines according to
It is prepared by the method for J.Med.Chem.2014,57,8249-8267.
By 2- (the fluoro- 3- aminophenyls of 4-) -4- (N- methyl indols) -2- aminopyrimidines (1mmol) and maleic anhydride
(1.2mmol) is dissolved in 15mL dichloroethanes, when reaction 3-5 is small.After reaction, decompression is spin-dried for.Can with acetone recrystallization
Obtain brown solid.
Yellow solid；m.p.:236.1–236.7℃；1HNMR(500MHz,DMSO-d6)δ10.28(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.for C23H19FN5O3[M+H]+=432.1466, found 432.1468.
Step 2：N1The fluoro- 5- of -2- ((4- (N- methyl -3- indyls) -2- pyrimidine radicals) amino) phenyl)-N4- ((tetrahydrochysene-
2H- pyrans -2- bases) oxo) Malaysia acid diamine preparation
By Z) -4- ((the fluoro- 5- of 2- ((4- (N- methyl -3- indyls) -2- pyrimidines) amino) phenyl) amino) -4- oxos -
2- butenoic acids (1mmol), O- (tetrahydrochysene -2H- pyrans -2- bases) azanol (1.2mmol) be dissolved into be dissolved in 12mL dichloroethanes and
In 4mL n,N-Dimethylformamide mixed solutions, it is sub- that 1- (3- dimethylamino-propyls) -3- ethyls carbon two is added into reaction solution
Amine hydrochlorate (1.32mmol), 1- hydroxy benzo triazoles (1.32mmol), be placed in 40 DEG C stirring reaction 4 it is small when.Reaction terminates
Afterwards, 30mL water is added into reaction solution, with the extraction of 20mL dichloromethane three times, merges organic phase, organic phase is spin-dried for, pure through column chromatography
(mobile phase is ethyl acetate for change：Petroleum ether=10:1) solid of yellow is obtained.
Yellow solid；m.p.:181.3–181.6℃；1H NMR(500MHz,DMSO-d6)δ11.65(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.for
C28H28FN6O4[M+H]+=513.2245, found 513.2245.
Step 3：N1The fluoro- 5- of -2- ((4- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) phenyl)-N4- hydroxyl
The preparation of maleic amide hydrochloride
By N1The fluoro- 5- of -2- ((4- (N- methyl -3- indyls) -2- pyrimidine radicals) amino) phenyl)-N4- ((tetrahydrochysene -2H- pyrroles
Mutter -2- bases) oxo) Malaysia acid diamine (1mmol) is added in 25mL three-necked flasks, and adds the dichloroethanes of 8mL.Ice bath bar
Ether (3.4mL) solution of 1M hydrochloric acid is instilled under part, when low-temp reaction 1 is small.There is solid precipitation after the completion of reaction, decompression filters,
Obtain yellow solid.
Yellow solid；m.p.:181.3–181.6℃；1H NMR(500MHz,DMSO-d6)δ11.65(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.for
C28H28FN6O4[M+H]+=531.2151, found 531.2158.
According to 1 same procedure of embodiment, using different material, following compound is prepared.
2 N of embodiment1- 5- ((4- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) phenyl)-N4- hydroxyl horse
Carry out amide hydrochloride
Its structural formula is：
Yellow solid；m.p.:181.0-181.4℃；1HNMR(500MHz,DMSO-d6)δ11.73(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)δ169.1,167.0,158.1,157.6,157.3,156.4,137.1,
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.for C23H21N6O3[M+H]+=429.1670, found 429.1670.
3 N of embodiment1- (2- (dimethylamino) -5- ((4- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino)
Phenyl)-N4- hydroxyl maleic amide hydrochloride
Its structural formula is：
Yellow solid；m.p.:217.9–218.3℃；1H NMR(500MHz,DMSO-d6)δ10.31(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.for C25H26N7O3[M+H]+=472.2092, found 472.2095.
4 N of embodiment1- 5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) -2- (diformazan ammonia
Base) phenyl)-N4- hydroxyl maleic amide hydrochloride
Its structural formula is：
Yellow solid；m.p.:180.4–180.7℃；1H NMR(500MHz,DMSO-d6)δ10.30(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.for C25H25ClN7O3[M+H]+=506.1702, found 506.1709.
5 N of embodiment1The fluoro- 5- of -2- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases)-pyrimidine -2-base) amino) benzene
Base)-N4- hydroxyl maleic amide hydrochloride
Its structural formula is：
Yellow solid；m.p.:128.2–128.5℃；1H NMR(500MHz,DMSO-d6)δ12.55(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.for C23H19ClFN6O3[M+H]+=481.1186, found 481.1188.
6 4- of embodiment (4- (2- acryloyl groups-amino -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine radicals -2- bases)
Amino) phenyl) piperazine -1- bases)-N- hydroxybutyramide hydrochlorides
Reaction equation：
Reagent and reaction condition:1) acetone, potassium carbonate, reflux, 5 it is small when；2) sodium borohydride, Nickel dichloride hexahydrate, dichloro
Methane:Methanol=4:1,0 DEG C to room temperature, 30 minutes；3) dichloromethane, triethylamine, -5 DEG C, 30 minutes；4) aluminium hydroxide, tetrahydrochysene
Furans:Water=1:1, room temperature, 3 it is small when；5) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 1- hydroxy benzos
Triazole, n,N-Dimethylformamide:Dichloromethane=1:2,45 DEG C, 5 it is small when；6) 1M ethereal HCIs solution, 0 DEG C, 30 minutes
To 1 it is small when.
Step 1：Ethyl 4- (4- (4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- nitrobenzenes
Base) piperazine -1- bases) ethyl propionate preparation：
Raw material 1：4- (1- Methyl-1H-indole -3- bases)-N- (3- nitros -4- (piperazine -1- bases) phenyl) pyrimidine -2- amine is pressed
According to Bioorg.Med.Chem.Lett., 2008,18 (12), prepared by 3513-3516. the methods.
By 4- (1- Methyl-1H-indole -3- bases)-N- (3- nitros -4- (piperazine -1- bases) phenyl) pyrimidine -2- amine
(1.0mmol) and ethyl bromide (1.0mmol) are added in 50mL three-necked flasks, and add the acetone of 10mL, are heated to reflux, are made
When mixture stirring reaction 5 is small.Room temperature is cooled to after reaction, 20mL water is added into reaction solution, is extracted with 20mL dichloromethane
Take three times, merge organic phase, organic phase is spin-dried for, and obtains yellow solid.
Yellow solid；m.p.:106.1–106.5℃；1H NMR(500MHz,DMSO-d6)δ10.28(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.for C29H34N7O4[M+H]+=544.2667, found 544.2668.
Step 2：Ethyl 4- (4- (2- amino -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) benzene
Base) piperazine -1- bases) ethyl propionate preparation
By ethyl 4- (4- (4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- nitrobenzophenones) piperazines
Piperazine -1- bases) ethyl propionate (0.5mmol) is dissolved in 5mL methanol and 20mL dichloromethane mixed solutions, add six water nickel chlorides
After mixing, sodium borohydride (2.0mmol) is added portionwise in (1.0mmol), system under condition of ice bath, reacts 30min, transfer
To room temperature, continue stirring reaction 30 minutes.After reaction, 10mL water is added into system, is stirred 15 minutes, filters, uses second
Acetoacetic ester washing filter cake 3-4 times, collects filtrate, and filtrate is extracted with ethyl acetate, and collects ethyl acetate layer.By ethyl acetate layer
Decompression is spin-dried for, and obtains brown solid.
Yellow solid；m.p.:117.3–117.5℃；1H NMR(500MHz,DMSO-d6)δ10.28(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.for C29H36N7O2[M+H]+=514.2925, found
514.2925。
Step 3：Ethyl 4- (4- (2- acrylamides -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino)
Phenyl) piperazine -1- bases) ethyl propionate preparation
By ethyl 4- (4- (2- amino -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) piperazines
Piperazine -1- bases) ethyl propionate (1.0mmol) is added in 25mL three-necked flasks, and adds the two of triethylamine (4.0mmol) and 10mL
Chloromethanes, reaction bulb is placed in -5 DEG C to -10 DEG C of ice bath.Treat that interior temperature control system at -5 DEG C to -10 DEG C, is slow added into propylene
Acyl chlorides (1.0mmol), makes mixture stirring reaction 30 minutes.After reaction, 20mL water is added into reaction solution, with 20mL dichloros
Methane extracts three times, merges organic phase, and organic phase is spin-dried for, and obtains yellow solid.
Yellow solid；m.p.:117.3–117.5℃；1H NMR(500MHz,DMSO-d6)δ10.28(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.for C32H38N7O3[M+H]+=568.3031, found 568.3031.
Step 4：Ethyl 4- (4- (2- acrylamides -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino)
Phenyl) piperazine -1- bases) butyric acid preparation
By ethyl 4- (4- (2- acrylamides -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) benzene
Base) piperazine -1- bases) ethyl propionate (1.0mmol) and lithium hydroxide (10mmol) are added in 25mL three-necked flasks, and are added
The tetrahydrofuran of 8mL and the water of 8mL, when reaction 1 is small.After the reaction was complete, reaction system PH is adjusted to 7 or so with hydrochloric acid, is separated out
Faint yellow yellow solid.
Yellow solid；m.p.:117.3–117.5℃；1H NMR(500MHz,DMSO-d6)δ10.28(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.for
C30H34N7O3[M+H]+=540.2718, found 540.2719.
Step 5：4- (4- (2- acrylamides -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) benzene
Base) piperazine -1- bases)-N- ((tetrahydrochysene -2H- pyrans -2- bases) oxo) butyramide preparation
By ethyl 4- (4- (2- acrylamides -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) benzene
Base) piperazine -1- bases) butyric acid (1mmol) and O- (tetrahydrochysene -2H- pyrans -2- bases) azanol (1.2mmol) be dissolved into and be dissolved in 12mL
Dichloroethanes and 4mLN, in dinethylformamide mixed solution, 1- (3- dimethylamino-propyls) -3- second is added into reaction solution
Base carbodiimide hydrochloride (1.32mmol), 1- hydroxy benzo triazoles (1.32mmol), be placed in 40 DEG C stirring reaction 4 it is small when.
After reaction, 30mL water is added into reaction solution, with the extraction of 20mL dichloromethane three times, merges organic phase, organic phase is spin-dried for, and is passed through
(mobile phase is dichloromethane for column chromatography purifying:Methanol=90:1) solid of yellow is obtained.
Yellow solid；m.p.:117.3–117.5℃；1H NMR(500MHz,DMSO-d6)δ10.28(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.for C35H43N8O4[M+H]+=639.3402, found 639.3404.
Step 5：4- (4- (2- acryloyl groups-amino -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine radicals -2- bases) ammonia
Base) phenyl) piperazine -1- bases) and-N- hydroxybutyramide hydrochlorides preparation
By 4- (4- (2- acrylamides -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) piperazines
Piperazine -1- bases) butyramide (1mmol) is added in 25mL three-necked flasks-N- ((tetrahydrochysene -2H- pyrans -2- bases) oxo), and is added
The dichloroethanes of 8mL.Ether (3.4mL) solution of 1M hydrochloric acid is instilled under condition of ice bath, when low-temp reaction 1 is small.After the completion of reaction
There is solid precipitation, decompression filters, and obtains yellow solid.
Yellow solid；m.p.:165.3–166.1℃；1H NMR(500MHz,DMSO-d6)δ9.07(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.for C30H35N8O3[M+H] +=555.2827, found 555.2829.
According to 5 same procedure of embodiment, using different material, following compound is prepared.
Embodiment 7：4- (4- (2- acryloyl groups-amino -4- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine radicals -
2- yls) amino) phenyl) piperazine -1- bases)-N- hydroxybutyramide hydrochlorides
Its structural formula is：
Yellow solid；m.p.:114.3–114.9℃；1H NMR(500MHz,DMSO-d6)δ9.19(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.for C30H34ClN8O3[M+H]+=589.2437, found 589.2440.
Embodiment 8：Compound is to A431, H1975, HeLa cell inhibitory effect determination of activity
This example is thin for EGFR wild type overexpression cell line A431, T790M point mutation for measuring the compounds of this invention
Born of the same parents' strain H1975, the proliferation inhibition activity of human cervical carcinoma cell lines Hela, the inhibitory activity of compound on intracellular propagation are pressed down with half
Concentration IC processed50To represent.Testing program is as follows：EGFR wild type overexpression cell line A431, T790M point mutation cell lines
H1975 cells and human cervical carcinoma cell lines Hela are purchased from ATCC, with suitable cell concentration (A431：20000 cell/ml
Culture medium；H1975：15000 cells/ml culture mediums) by cell inoculation on 96 well culture plates of white clear；Afterwards will be thin
Born of the same parents are positioned over 37 DEG C, 5%CO2Environment in cultivated, 24 it is small when after, added into the cell culture medium of culture a series of dense
Spend gradient medicine, be typically chosen 10 concentration, cell is put back in former culture environment afterwards continue culture 48 it is small when, press afterwards
According to the method for CellTiter-Glo Luminescent Cell Viability Assay, measure test-compound to A431 and
The influence of H1975, HeLa cell Proliferation, and the inhibitory activity of the compound on intracellular propagation of various concentrations is calculated,
CellTiter-Glo Luminescent Cell Viability Assay detection reagents are purchased from Promega.Afterwards to difference
A431, H1975, HeLa cell inhibitory effect activity carry out four parameter fittings, test-compound of the present invention under the compound of concentration
IC50 data be shown in Table 1.
Table 1
Embodiment 9：Part of compounds is to SW620, KB, HepG2, HL60 cell inhibitory effect determination of activity
This example be used for measure the compounds of this invention 10 for HepG2 cell lines, human colon cancer cell strain SW620,
Human mouth epidermoid carcinoma cell line KB, the proliferation inhibition activity of people in loop strain HL60, compound on intracellular increase
The inhibitory activity grown half-inhibition concentration IC50To represent.Testing program such as embodiment 8.Part test-compound of the present invention
IC50Data such as table 2 below.
Table 2
Conclusion：There is novelty in the compounds of this invention structure, first introduce the pharmacophore fragment hydroxamic acid of SAHA
Onto the 2- arylamine yl pyrimidines parent nucleus of third generation EGFR inhibitor AZD9291, the 2- arylamine pyrimidines of the fragment containing hydroxamic acid are synthesized
Class compound.Bioactivity evaluation result is shown at the same time, and compound of the invention is thin to the people's epidermal carcinoma for being overexpressed EGFR
Born of the same parents' strain A431, human lung adenocarcinoma cell line H1975 drug resistant to Gefitinib and Human cervical carcinoma cell line HeLa have obvious suppression
Proliferation activity processed, part of compounds are suitable with positive WZ4002 and SAHA.Overcome Gefitinib drug resistances EGFR/ for design is new
The double target spot inhibitor of HDAC provide mentality of designing.
Claims (8)
1. a kind of 2- aryl amine pyridine derivatives of fragment containing hydroxamic acid as shown in formula I, its general structure are：
Wherein：
R1For hydrogen atom or chlorine atom.
R2For hydrogen atom, fluorine atom orN,N- dimethyl.
2. a kind of 2- aryl amine pyridine derivatives of fragment containing hydroxamic acid as shown in formula II, its general structure are：
Wherein：R1For hydrogen atom or chlorine atom.
3. the 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid as claimed in claim 1, it is characterised in that described
Type I compound is following any compound：
N 1The fluoro- 5- of -2- ((4- (1- methyl isophthalic acidsH- indol-3-yl)-pyrimidine -2-base) amino) phenyl)-N 4- hydroxyl maleic amide salt
Hydrochlorate；
N 1 - 5- ((4- (1- methyl isophthalic acidsH- indol-3-yl)-pyrimidine -2-base) amino) phenyl)-N 4 - hydroxyl maleic amide hydrochloride；
N 1 - (2- (dimethylamino) -5- ((4- (1- methyl isophthalic acidsH- indol-3-yl)-pyrimidine -2-base) amino) phenyl)-N 4 - hydroxyl
Maleic amide hydrochloride；
N 1 - 5- ((5- chloro- 4- (1- methyl isophthalic acidsH- indol-3-yl)-pyrimidine -2-base) amino) -2- (dimethylamino) phenyl) -N 4 -
Hydroxyl maleic amide hydrochloride；
N 1 The fluoro- 5- of -2- ((5- chloro- 4- (1- methyl isophthalic acidsH- indol-3-yl)-pyrimidine -2-base) amino) phenyl)-N 4 - hydroxyl Malaysia
Amide hydrochloride.
4. the 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid as claimed in claim 2, it is characterised in that described
II compound of formula is following any compound：
4- (4- (2- acryloyl groups-amino -4- ((4- (1- methyl isophthalic acidsH- indol-3-yl) pyrimidine radicals -2- bases) amino) phenyl) piperazine
Piperazine -1- bases) -N- hydroxybutyramide hydrochloride；
4- (4- (2- acryloyl groups-amino -4- ((5- chloro- 4- (1- methyl isophthalic acidsH- indol-3-yl) pyrimidine radicals -2- bases) amino) benzene
Base) piperazine -1- bases) -N- hydroxybutyramide hydrochloride.
5. the preparation method of the type I compound according to claim 1 or 3, it is characterised in that realized by following steps：
With substituted 2,4- dichloro pyrimidine A and 1- methyl indol for starting material, reacted under the conditions of 1,2- dichloroethanes, 80 DEG C
Generate intermediate B, intermediate B and 4- R2Substituted 3- nitroanilines react under sec-butyl alcohol, 1N HCl catalytic conditions to be obtained
Nitro reduction generates intermediate D under the reducing conditions by intermediate C, intermediate C, and intermediate D is with maleic anhydride in dichloromethane
Generate intermediate E under the conditions of alkane, intermediate E withO- (tetrahydrochysene -2H- pyrans -2- bases) hydroxylamine condensation generation compound F, finally
Compound F takes off protection group generation target compound I in acid condition；Reagent and reaction condition：a）Anhydrous Aluminum chloride, dichloro
Ethane, 80 DEG C, 2 it is small when；b）Sec-butyl alcohol, reflux, 4 it is small when；c）Sodium borohydride, Nickel dichloride hexahydrate, dichloromethane:Methanol=4：
1,0 DEG C-room temperature, 30 minutes；d）Dichloromethane, room temperature, when 3-5 is small；e）1- (3- dimethylamino-propyls) -3- ethyl carbodiimides
Hydrochloride, 1- hydroxy benzo triazoles, dichloromethane:N,N- dimethylformamide=2:5 DEG C of Isosorbide-5-Nitrae, 5 it is small when；f）1M hydrochloric acid second
Ethereal solution, 30 minutes；Reaction equation is：
Wherein substituent R1And R2Definition with claim 1.
6. the preparation method of II compound of formula according to claim 2 or 4, it is characterised in that realized by following steps：
With substituted 2,4- dichloro pyrimidine a and 1- methyl indol for starting material, reacted under the conditions of 1,2- dichloroethanes, 80 DEG C
The generation fluoro- 3- nitroanilines of intermediate b, intermediate b and 4- react under sec-butyl alcohol, 1N HCl catalytic conditions obtains intermediate c,
Intermediate c withN- Boc piperazines react to obtain compound d in alkaline conditions, and compound d takes off protection group and obtains in acid condition
To intermediate e, intermediate e is reacted with bromobutyrate under the conditions of acetone reflux obtains intermediate f, and intermediate f is in reduction bar
Nitro reduction generation intermediate g, intermediate g react to obtain intermediate h with acryloyl chloride under part, and intermediate h is in alkaline conditions
Hydrolysis generation compound i, compound i withO- (tetrahydrochysene -2H- pyrans -2- bases) hydroxylamine condensation generation compound j, last chemical combination
Thing j takes off protection group generation target compound II in acid condition；Reagent and reaction condition：1）Anhydrous Aluminum chloride, two chloroethenes
Alkane, 80 DEG C, 2 it is small when；2）Sec-butyl alcohol, reflux, 4 it is small when；3）Dimethyl sulfoxide (DMSO), potassium carbonate, 90 DEG C, 3 it is small when；4）Trifluoroacetic acid,
Dichloromethane, 30 minutes；5）Acetone, potassium carbonate, reflux, 5 it is small when；6）Sodium borohydride, Nickel dichloride hexahydrate, dichloromethane:First
Alcohol=4:1,0 DEG C to room temperature, 30 minutes；7）Dichloromethane, triethylamine, -5 DEG C, 30 minutes；8）Aluminium hydroxide, tetrahydrofuran：Water=
1:1, room temperature, 3 it is small when；9）1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 1- hydroxy benzo triazoles,N, N- dimethylformamide:Dichloromethane=1:2,45 DEG C, 5 it is small when； 10）1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 it is small when；
Reaction equation is：
Wherein R1Definition with claim 2.
7. antitumor cell and targeting EGFR/HDAC are being prepared according to any formulas I of claim 1-4 or II compound of formula
Application in medicine, it is characterised in that wherein described tumour cell refers to the people's epidermis cancer cell line A431, right for being overexpressed EGFR
The drug resistant human lung adenocarcinoma cell line H1975 of Gefitinib and the relevant tumour cell of HDAC acetylation of histone enzymatic activitys.
8. apply according to claim 7, it is characterised in that the described and relevant tumour of HDAC acetylation of histone enzymatic activitys
Cell is Human cervical carcinoma cell line HeLa, human mouth epidermoid carcinoma cell line KB, the early young grain acute leukemia cells strain HL60 of people,
HepG2 cell lines or human colon cancer cell strain SW620.
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| CN106243044A (en) * | 2016-06-30 | 2016-12-21 | 浙江大学 | Pyridine derivatives containing halo acrylamide side chain and preparation 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 |
| CN113354622B (en) * | 2020-03-06 | 2022-11-01 | 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 |
| CN114380806B (en) * | 2022-03-24 | 2022-06-10 | 中国药科大学 | 2-amino-4-indolyl pyrimidine compound and 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 |
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| CN104844580A (en) * | 2015-04-17 | 2015-08-19 | 中国药科大学 | Miazines compound, preparation method and medical application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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