CN109666024A - 2- oxygen pyrimidines and its preparation method and application - Google Patents

2- oxygen pyrimidines and its preparation method and application Download PDF

Info

Publication number
CN109666024A
CN109666024A CN201810227357.1A CN201810227357A CN109666024A CN 109666024 A CN109666024 A CN 109666024A CN 201810227357 A CN201810227357 A CN 201810227357A CN 109666024 A CN109666024 A CN 109666024A
Authority
CN
China
Prior art keywords
oxygen
pyrimidines
compound
preparation
milligrams
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201810227357.1A
Other languages
Chinese (zh)
Inventor
韩志坚
边泓竹
亓树建
李阳冰
杨璐西
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nantong Norwich Medical Technology Co Ltd
Lanzhou University
Original Assignee
Nantong Norwich Medical Technology Co Ltd
Lanzhou University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nantong Norwich Medical Technology Co Ltd, Lanzhou University filed Critical Nantong Norwich Medical Technology Co Ltd
Priority to CN201810227357.1A priority Critical patent/CN109666024A/en
Publication of CN109666024A publication Critical patent/CN109666024A/en
Pending legal-status Critical Current

Links

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
    • 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
    • C07D403/14—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 three or more hetero rings

Abstract

The present invention provides a kind of 2- oxygen pyrimidines, structure is shown in formula I:

Description

2- oxygen pyrimidines and its preparation method and application
Technical field
The present invention relates to a kind of 2- oxygen pyrimidines and its preparation method and application, belong to medicine synthesis technique neck Domain.
Background technique
With the development of targeted drug, the treatment of non-small cell lung cancer (NSCLC) has obtained incremental advances.Wherein, for The drug of EGFR target spot is continuously developed out in recent years.Targeted drug structural formula from the first generation to the third generation is as follows:
Its corresponding general formula is shown below:
The first generation and second generation inhibitor molecules are 4- aminopyridine derivatives, and third generation inhibitor is that 2- aminopyrimidine spreads out Biology.Obviously, the structural commonality of this three generations's inhibitor is that they have the basic structure of aminopyrimidine.This also sufficiently shows This basic structure plays very important effect in drug molecule activity.
AZD9291 is targeted as the third generation lung cancer that efficient selective EGFR mutant inhibitor is AstraZeneca exploitation Drug (WO2013014448A1, WO2015195228A1), molecular structure is as follows:
In order to develop new targeted drug, the isostere oxygen atom of this patent nitrogen-atoms replaces 2- aminopyrimidine Amino nitrogen atom in basic structure inhibits to successfully synthesize novel 2- oxygen pyrimidines as EGFR mutant Agent.
Summary of the invention
For existing known structure, the object of the present invention is to provide a kind of novel 2- oxygen pyrimidines and its preparations Method and purposes.
The present invention is achieved by the following technical solutions:
A kind of 2- oxygen pyrimidines, structure are shown in formula I:
X is various amidos and aminoderivative group.Preferably, the X group comprises the following structure:
A kind of preparation method of 2- oxygen pyrimidines as the aforementioned, according to following reaction route:
A kind of EGFR mutant inhibitor, it includes the 2- oxygen pyrimidines or 2- oxygen above-mentioned of effective dose are phonetic The medically acceptable salt and compound of pyridine class compound.
Compared with prior art, the present invention have it is following the utility model has the advantages that
The present invention provides a kind of new construction 2- oxygen pyrimidines, provide newly for the inhibitor of EGFR mutant Optional compound.
Specific embodiment
The present invention is described in detail combined with specific embodiments below.Following embodiment will be helpful to the technology of this field Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the common skill of this field For art personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to this The protection scope of invention.
Experimental method used in following embodiments is conventional method unless otherwise specified.
Experimental material used in following embodiments, reagent unless otherwise specified, obtain for commercial sources.
The preparation of embodiment compound 1:
The synthetic route of compound 1:
Embodiment 1
The synthesis of intermediate 4- [(2- dimethylaminoethyl)-methylamino] -2- methoxyl group -5- nitrophenols
Under nitrogen protection, by 1.0 grams of starting material tert-butyls (the fluoro- 2- methoxyl group -5- nitrobenzene phenolic group of 4-) dimethyl-silicon (CAS 1164273-87-3,3.32 mMs) is dissolved in 5 milliliters of anhydrous n,N-Dimethylformamide, and 339 millis are then added Gram N1, N1, N2- trimethylethyl -1,2- diamines (3.32 mMs) and 858 milligrams of N, N- diisopropyl ethyl amine (6.64 millis Mole).Reaction solution reacts 4 hours at 85 DEG C to be finished to consumption of raw materials.Reaction solution is concentrated to dryness, residue silica gel Column chromatographic purifying (mobile phase: DCM/MeOH=10/1) obtains 500 milligrams of dark red solid products, yield 56%.
1HNMR(400MHz,DMSO-d6) δ ppm:7.28 (s, 1H), 6.78 (s, 1H), 3.87 (s, 3H), 3.11 (t, J= 6.8Hz, 2H), 2.74 (s, 3H), 2.40 (t, J=6.8Hz, 2H), 2.14 (s, 6H)；
m/z:ES+,MH+,270.1。
Embodiment 2
Intermediate N { 5- methoxyl group -4- [4- (1- Methyl-1H-indole -3- base)-pyrimidine -2- oxygroup] -2- nitro-benzene Base }-N, the synthesis of N', N'- trimethyl-ethylene -1,2- diamines
Under nitrogen protection, 500 milligrams of 4- [(2- dimethylaminoethyl)-methylamino] -2- first is sequentially added in reaction flask Oxygroup -5- nitrophenols (1.86 mMs), 452 milligrams of 3- (2- chlorine pyrimidine-4-yl) -1- methyl indol (CAS 1032452- 86-0,1.86 mMs), 727 milligrams of cesium carbonates (2.23 mMs) and 20 milliliters of anhydrous n,N-Dimethylformamide.Mixing Object stirs 5 hours under 100 degrees Celsius to be terminated to reaction.Reaction solution is cooled to room temperature, and filtering, filtrate is spin-dried for, and residue is through silicon Gel column chromatography eluting (eluant, eluent: DCM/MeOH=10/1) obtains 620 milligrams of yellow solids, yield 70%.
1HNMR(400MHz,CDCl3) δ ppm:8.38 (d, J=5.6Hz, 1H), 8.01 (m, 1H), 7.94 (s, 1H), 7.82 (s, 1H),7.26-7.32(m,3H),7.16(m,1H),6.77(s,1H),6.65(s,1H),3.82(s,3H),3.81(s, 3H), 3.46 (t, J=6.8Hz, 2H), 2.95 (s, 3H), 2.86 (t, J=6.8Hz, 2H), 2.43 (s, 6H)；
m/z:ES+,MH+,477.2。
Embodiment 3
Intermediate N2- (2- dimethyl amido-ethyl) -4- methoxyl group-N2- methyl -5- [4- (1- Methyl-1H-indole -3- Base)-pyrimidine-2-yloxy]-benzene -1,2- diamines synthesis
By 641 milligrams of intermediate Ns { 5- methoxyl group -4- [4- (1- Methyl-1H-indole -3- base)-pyrimidine -2- oxygroup] -2- Nitro-phenyl }-N, N', N'- trimethyl-ethylene -1,2- diamines (1.34 mMs) is dissolved in 20 ml methanols, is added 200 Milligram 10%Pd/C.Reaction solution 1 atmospheric pressure nitrogen atmosphere and at room temperature stir 2 hours, until TLC shows that end of reaction is Only.Diatomite filtering, filtrate are spin-dried for, and obtain 600 milligrams of white solids, yield 100%.Crude product is directly used in the next step.
1HNMR(400MHz,DMSO-d6) δ ppm:8.40 (m, 2H), 7.88 (d, J=8.0Hz, 1H), 7.47 (m, 2H), 7.18 (t, J=8.0Hz, 1H), 6.96 (t, J=8.0Hz, 1H), 6.86 (s, 1H), 6.54 (s, 1H), 3.84 (s, 3H), 3.53 (s, 3H), 3.02 (t, J=6.8Hz, 2H), 2.73 (t, J=6.8Hz, 2H), 2.65 (s, 3H), 2.38 (s, 6H)；
m/z:ES+,MH+,447.2。
Embodiment 4
Intermediate N { 2- [(2- dimethylarnino-ethyl)-Methyl-amino] -4- methoxyl group -5- [4- (1- methyl-1 H- Indoles -3- base)-pyrimidine-2-yloxy]-phenyl-acrylamide synthesis
Under nitrogen protection, 400 milligrams of intermediate N2- (2- dimethyl amido-ethyl) -4- methoxyl group-N2- methyl -5- [4- (1- Methyl-1H-indole -3- base)-pyrimidine-2-yloxy]-benzene -1,2- diamines (0.896 mM) be dissolved in 10 milliliters it is anhydrous In methylene chloride, system is as cold as 0~5 degree Celsius by ice-water bath, and 150 milligrams of N, N- diisopropyl ethyl amine is then added 98 milligrams of acryloyl chloride (1.075 mMs) is then added dropwise in (1.146 mMs).Add rear reaction solution at 5 c Stirring 3 hours.TLC is shown after reaction, and reaction solution is spin-dried for, and residue is through silica gel column purification (eluant, eluent: DCM/MeOH =10/1) 290 milli off-white powder products, yield 64.6% are obtained.
1HNMR(400MHz,CDCl3) δ ppm:10.20 (brs, 1H), 8.61 (s, 1H), 8.39 (d, J=5.2Hz, 1H), 8.06 (d, J=8.0Hz, 1H), 7.85 (s, 1H), 7.2~7.35 (m, 3H), 7.10 (m, 1H), 6.96 (s, 1H), 6.20~ 6.50(m, 2H),5.70(m,1H),3.82(s,3H),3.74(s,3H),2.96(m,2H),2.81(s,3H),2.41(m, 2H),2.31(s, 6H).
13CNMR(400MHz,CDCl3)δppm:165.1,163.9,163.1,158.1,147.8,139.4,139.2, 137.6, 131.7,129.2,126.0,125.8,122.3,122.0,120.9,115.3,113.0,110.3,109.4, 106.9,57.2,56.6, 56.2,45.4,42,7
m/z:ES+,MH+,501.2。
Using with the identical synthetic method of compound 1, following compound 2~4 can be obtained:
Embodiment 5
(i.e. the 858th amino acids are by leucine for 1~4 pair of EGFR wild type of compound and EGFRL858R single mutation kinases Sport arginic epidermal growth factor) and the bis- mutant kinases of EGFRL858R/T790M (i.e. simultaneous with 858 bit aminos Acid sports arginine by leucine and the 790th amino acids are sported the epidermal growth factor of methionine by threonine) Inhibitory activity.This test uses Kinase-Glo Plus luminescence kinase assay kit detection examination Agent box (Promega#V3772).The test is sharp to detect by remaining ATP content in solution after quantitative analysis enzymatic reaction Enzymatic activity.Fluorescence signal and ATP content in test are positively correlated and negatively correlated with kinase activity.Specific steps are as follows: configuration The reaction solution of 50uL, including 40mM Tris, pH 7.4,10mM MgCl2, 0.1mg/ml BSA, 1mM DTT, 10uM ATP, With respective kinase substrate.Untested compound is made into 10%DMSO solution, takes 5uL to be diluted in the above-mentioned reaction solution of 50uL and obtains The reaction solution that final DMSO concentration is 1%.All enzymic catalytic reactions carry out 40 minutes all at 30 DEG C.30 minutes are incubated in advance The reaction of change, enzyme first hatch 30 minutes with inhibitor, ATP then are added and substrate starts to react.After enzymic catalytic reaction, 50uL Kinase-Glo Plus Luminescence Kinase Assay solution is added in reaction solution, continues in incubation at room temperature 5 minutes.Fluorescence signal is measured by BioTek company Synergy 2Microplate Reader.IC50 is to use GraphPadPrism5.0 (this base of a fruit equation of four parameter logistics) is calculated.Data are that embodiment 1-4 corresponds to compound in following table Biological test data, measure with the method described above.
Compound 1-4 has inhibitory activity to two kinds of enzymes it can be seen from the data in table, wherein compound 1 for EGFRL858R/T790MThere is better choice.
Embodiment 6
The proliferation inhibition activity of 1~4 pair of H1975 and A431 cell of compound is tested.
Using Sulforhodamine B (Sulforhodamine B, SRB) reagent detection compound to H1975 cell (human lung cancer EGFRL858R/T790MDouble mutational cell lines) and A431 (EGFR wild-type cell system) inhibited proliferation.A431 and H1975 are thin Born of the same parents system is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences.Specific step is as follows for operation: the culture of A431 and H1975 cell line is being prepared Culture solution in (DMEM 90%, FBS 10%), when cell covering 80% or so when, with 0.25% pancreatin (EDTA) digestion blow It plants after dissipating into 96 orifice plates (A431 4000cells/well；H1975 10000cells/well), 37 DEG C are placed in, 5%CO2 It is cultivated 24 hours in incubator.By medicine ordinance at the stock solution of 500uM, 3uM to 8 of 1nM concentration are diluted to culture medium Gradient.Remove the culture medium in 96 orifice plates after 24 hours, every hole is added the culture medium that 100uL contains respective concentration, is placed on 37 DEG C, 5%CO2It is cultivated in incubator 72 hours, SRB reagent 20uL is added in every hole later, mixes, and is read with microplate reader in 540nm Light absorption value.The cell activity value finally measured is as follows:
As can be seen from the data in the table, compound 1-4 has inhibitory activity to two kinds of cell lines, the inhibition of compound 1 is living Property is most strong, has better choice for double mutational cell line H1975.
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited to above-mentioned Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow Ring substantive content of the invention.

Claims (4)

1. a kind of 2- oxygen pyrimidines, which is characterized in that structure is shown in formula I:
2. 2- oxygen pyrimidines as described in claim 1, which is characterized in that the X be various amidos and
Aminoderivative group.
3. a kind of preparation method of 2- oxygen pyrimidines as described in claim 1, which is characterized in that according to following reaction Route:
4. a kind of EGFR mutant inhibitor, which is characterized in that the 2- oxygen miazines described in claim 1 comprising effective dose The medically acceptable salt and compound of compound or 2- oxygen pyrimidines.
CN201810227357.1A 2018-03-20 2018-03-20 2- oxygen pyrimidines and its preparation method and application Pending CN109666024A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810227357.1A CN109666024A (en) 2018-03-20 2018-03-20 2- oxygen pyrimidines and its preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810227357.1A CN109666024A (en) 2018-03-20 2018-03-20 2- oxygen pyrimidines and its preparation method and application

Publications (1)

Publication Number Publication Date
CN109666024A true CN109666024A (en) 2019-04-23

Family

ID=66141973

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810227357.1A Pending CN109666024A (en) 2018-03-20 2018-03-20 2- oxygen pyrimidines and its preparation method and application

Country Status (1)

Country Link
CN (1) CN109666024A (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002102783A1 (en) * 2001-06-19 2002-12-27 Merck & Co., Inc. Tyrosine kinase inhibitors
US20110046370A1 (en) * 2009-08-20 2011-02-24 Korea Institute Of Science And Technology 1,3,6-substituted indole derivatives having inhibitory activity for protein kinase
US20130345219A1 (en) * 2007-03-27 2013-12-26 Synta Pharmaceuticals Corp. Triazinone and diazinone derivatives useful as hsp90 inhibitors
CN103702990A (en) * 2011-07-27 2014-04-02 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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002102783A1 (en) * 2001-06-19 2002-12-27 Merck & Co., Inc. Tyrosine kinase inhibitors
US20130345219A1 (en) * 2007-03-27 2013-12-26 Synta Pharmaceuticals Corp. Triazinone and diazinone derivatives useful as hsp90 inhibitors
US20110046370A1 (en) * 2009-08-20 2011-02-24 Korea Institute Of Science And Technology 1,3,6-substituted indole derivatives having inhibitory activity for protein kinase
CN103702990A (en) * 2011-07-27 2014-04-02 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R.B.西尔弗曼: "《有机药物化学》", 31 January 2008 *

Similar Documents

Publication Publication Date Title
Carmi et al. 5-Benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity
KR100832593B1 (en) Quinazoline derivatives as an signal trnasduction inhibitor and method for the preparation thereof
Kim et al. Synthesis and biological evaluations of pyrazolo [3, 4-d] pyrimidines as cyclin-dependent kinase 2 inhibitors
RU2704445C2 (en) Human ezh2 inhibitors and methods for use thereof
Mont et al. A three-component synthesis of pyrido [2, 3-d] pyrimidines
Garofalo et al. Impact of aryloxy-linked quinazolines: A novel series of selective VEGFR-2 receptor tyrosine kinase inhibitors
Gupta et al. Synthesis and bio-evaluation of indole-chalcone based benzopyrans as promising antiligase and antiproliferative agents
CN105646454B (en) The 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid and preparation and application
Liu et al. Design, synthesis and anti-HIV evaluation of novel diarylnicotinamide derivatives (DANAs) targeting the entrance channel of the NNRTI binding pocket through structure-guided molecular hybridization
EP2896620A1 (en) Alkynyl heteroaromatic ring compound and application thereof
Zhou et al. Design, synthesis and pharmacological evaluation of 6, 7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents
Qu et al. Design, synthesis and biological evaluation of sulfonamide-substituted diphenylpyrimidine derivatives (Sul-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with antitumor activity
Zhang et al. Synthesis and anticancer activities of 5, 6, 7-trimethoxy-N-phenyl (ethyl)-4-aminoquinazoline derivatives
Zhang et al. Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents
Wang et al. Discovery of 7H-pyrrolo [2, 3-d] pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study
Qin et al. Design, synthesis and biological evaluation of 2, 3-dihydro-[1, 4] dioxino [2, 3-f] quinazoline derivatives as EGFR inhibitors
Liu et al. New acrylamide-substituted quinazoline derivatives with enhanced potency for the treatment of EGFR T790M-mutant non-small-cell lung cancers
Li et al. Discovery of potent EGFR inhibitors with 6-arylureido-4-anilinoquinazoline derivatives
Li et al. Design, synthesis, and antiproliferative evaluation of novel longifolene-derived tetraline pyrimidine derivatives with fluorescence properties
Gan et al. Discovery of novel 4-arylamino-quinazoline derivatives as EGFRL858R/T790M inhibitors with the potential to inhibit the non-small cell lung cancers
Li et al. Design, synthesis and antitumor evaluation of a new series of N‐substituted‐thiourea derivatives 1
CN106565612B (en) Diphenylethyllene pyrimidines, composition and application thereof
CN109666024A (en) 2- oxygen pyrimidines and its preparation method and application
Wang et al. Design, synthesis and biological evaluation of novel 4-anlinoquinazoline derivatives as EGFR inhibitors with the potential to inhibit the gefitinib-resistant nonsmall cell lung cancers
CN109053594A (en) 1- (3,5- Dimethoxyphenyl) -3- (substituted pyrimidines -4- base) carbamide compounds and its preparation and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20190423

RJ01 Rejection of invention patent application after publication