CN109776513A - A kind of 4- phenyl -1,3,5- triazine -2- amine antitumoral compounds and preparation method thereof - Google Patents
A kind of 4- phenyl -1,3,5- triazine -2- amine antitumoral compounds and preparation method thereof Download PDFInfo
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- CN109776513A CN109776513A CN201910204352.1A CN201910204352A CN109776513A CN 109776513 A CN109776513 A CN 109776513A CN 201910204352 A CN201910204352 A CN 201910204352A CN 109776513 A CN109776513 A CN 109776513A
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Abstract
It is about a kind of 4-(2- substituted benzyl amino with anti-tumor activity the present invention relates to pharmaceutical technology field) phenyl-N- substituted-phenyl -1,3,5-triazines -2- amine antitumoral compounds specified chemical structure and preparation method thereof.Specific preparation are as follows: the chloro- 1,3,5- triazine of 2,4- bis- and substituted aniline react obtained compound (I)；The chloro- N- substituted-phenyl -1,3,5- triazine -2- amine (I) of 4- occurs Suzuki with adjacent amino phenyl boric acid and reacts to obtain compound (II)；4-(2- aminophenyl)-N- substituted-phenyl -1,3,5- triazine -2- amine (II) and substituted benzaldehyde occur reduction amination and obtain 4-(2- substituted benzyl amino) phenyl-N- substituted-phenyl -1,3,5- triazine -2- aminated compounds (III).The compound of the present invention has good anti-tumor activity, has obvious inhibiting effect especially for A549 cell.
Description
Technical field
It is about a kind of 4- (2- substituted benzyl amino) benzene with anti-tumor activity the present invention relates to pharmaceutical technology field
The specified chemical structure and preparation method thereof of base-N- substituted-phenyl -1,3,5- triazine -2- amine antitumoral compounds.
Background technique
Malignant tumour is common serious harm human health, threatens the disease of human life.According to the World Health Organization and
The data statistics of Union Against Cancer, in recent years, the cancer patient of global kainogenesis are more than 14,000,000 people, die of cancer more than 8,200,000 people
Disease.It therefore, is that countries in the world cannot be neglected social concern for the prevention and treatment of tumour, research, exploitation are effective anti-swollen
Tumor medicine is always the great research topic of various countries' medical field.
Although there are many antineoplastic species of current clinical application, traditional anti-tumor drug belongs to cell toxicant mostly
Class drug.This kind of drug is restricted its application since there are poor selectivity, toxicity is big, is also easy to produce the problems such as drug resistance.Cause
This, developing specific height, small toxicity, patient's tolerance, good anti-tumor drug becomes the key issues that various countries are studied.
Summary of the invention
It is an object of that present invention to provide 4- (2- substituted benzyl amino) phenyl-N- substituted-phenyl -1,3,5- triazine -2- amines
Antitumoral compounds and application thereof, the present invention prepared by compound have the function of inhibition tumor cell proliferation.
In order to achieve the above object, the present invention takes following technical scheme:
4- (the 2- substituted benzyl amino) phenyl-N- substituted-phenyl -1,3,5-triazines -2- amine and its salt, structure are logical
Formula is as follows:
Wherein: R1Substituent group is located at 2 of phenyl, and 3,4,5 or 6；R1Substituent group is monosubstituted or takes more
Generation；R1Substituent group is selected from any of following type:
(1)H；
(2) halogen；
The straight chain or branched paraffin of (3) 1~6 carbon atoms；
Wherein the straight chain of 1~6 carbon atom or branched paraffin are selected from any of following type: methyl, trifluoroalkyl,
Propyl, isopropyl, butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl；
(4) hydrophilic,
Specially hydroxyl；
(5) electron-withdrawing substituent or electron substituent group is pushed away,
Specially cyano, formic acid esters, alkoxy or amino；
(6) 2,3- ethylene oxygroup, 3,4- ethylene oxygroup, 2,3- methylenedioxy or 3,4- methylene dioxy
Base；
Wherein: R2Substituent group is located at 2 of phenyl, and 3,4,5 or 6, R2Substituent group is monosubstituted or takes more
Generation；R2Substituent group is selected from any of following type:
(1)H；
(2) halogen；
The straight chain or branched paraffin of (3) 1~6 carbon atoms；
Wherein the straight chain of 1~6 carbon atom or branched paraffin are selected from any of following type: methyl, trifluoroalkyl,
Propyl, isopropyl, butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl；
(4) hydrophilic,
Specially hydroxyl；
(5) electron-withdrawing substituent or electron substituent group is pushed away, specially cyano, formic acid esters, alkoxy or amino；
(6) 2,3- ethylene oxygroup, 3,4- ethylene oxygroup, 2,3- methylenedioxy or 3,4- methylene dioxy
Base；
R1And R2Group makees following collocation:
The present invention include such compound the preparation method is as follows:
1, synthetic route
2, specific operation process are as follows:
(1) the chloro- 1,3,5- triazine of 2,4- bis- and substituted aniline react obtained compound (I)；
(2) the chloro- N- substituted-phenyl -1,3,5- triazine -2- amine (I) of 4- is reacted with adjacent amino phenyl boric acid generation Suzuki
It obtains compound (II)；
(3) 4- (2- aminophenyl)-N- substituted-phenyl -1,3,5- triazine -2- amine (II) is restored with substituted benzaldehyde
Amination obtains 4- (2- substituted benzyl amino) phenyl-N- substituted-phenyl -1,3,5- triazine -2- aminated compounds (III).
Remarkable advantage of the invention is: the compound of the present invention has good anti-tumor activity, especially for
A549 cell has obvious inhibiting effect
Specific embodiment
Following example is to specific descriptions of the invention, but embodiment is not construed as limitations on the scope of the invention.
Embodiment 1: intermediate 4- (2- aminophenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxane -6- base) -1,
The preparation of 3,5- triazine -2- amine
Adjacent amino phenyl boric acid (1.9g, 14mmol), the chloro- N- substituted-phenyl of 4- -1,3,5-triazines -2- amine are added in reaction flask
I (3.0g, 10mmol), solid sodium carbonate (5.3g, 50mmol), dioxane (30ml) and water (15ml), under nitrogen protection,
It is added triphenylphosphine palladium chloride (0.35g, 0.5mmol).The insulated and stirred 1hr in 90 DEG C of oil baths, after being cooled to room temperature, liquid separation,
Water phase is extracted with ethyl acetate (100ml × 2), merges organic phase, and anhydrous sodium sulfate is dry.Organic phase obtains brown after being concentrated under reduced pressure
Dope obtains brown solid (1.2g) with 200~300 mesh silicagel column elutions.
Embodiment 2: target compound 4- (2- ((4- (tert-butyl) benzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b]
[1,4] dioxane -6- base) -1,3,5- triazine -2- amine preparation (compound 1 in table one)
The round-bottomed flask of 25ml is taken, 4- (2- aminophenyl)-N- substituted-phenyl -1,3,5-triazines -2- is added inside
Amine (200mg) and p-t-Butylbenzaldehyde (180mg).6ml1 is added, 2 dichloroethanes make compound ii suspend in a solvent.It is past
800mg sodium triacetoxy borohydride is added in reaction solution, stirring at normal temperature, overnight, TLC monitors reaction process for reaction.Reaction knot
40ml methylene chloride, organic phase saturation NaHCO is added in Shu Hou3Aqueous solution washes twice.Water phase is extracted with dichloromethane.It closes
And organic phase, organic phase are washed with saturated common salt, subsequent organic layer is dried, filtered with anhydrous sodium sulfate, is evaporated.Gained crude product,
Through 200~300 mesh silicagel column elutions (solvent: petroleum ether is than ethyl acetate), yellow solid (67mg) is obtained.
The present invention has synthesized and has been proven to have part 4- (the 2- substituted benzyl amino) phenyl-N- substitution of anti-tumor activity
The chemical structure of phenyl -1,3,5- triazine -2- aminated compounds is shown in Table 1.
4- (2- substituted benzyl amino) phenyl-N- substituted-phenyl -1,3,5-triazines -2- aminated compounds, structural formula:
Structural characterization and the hydrogen spectrum of 1 part of compounds of table, mass spectrum
Remaining target compound in table 1 uses corresponding substrate, and the step repeated in embodiment 2 can synthesize.Eachization
The Chinese for closing object is as follows:
Compound 2:4- (2- (benzylamino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxane -6- base) -1,
3,5- triazine -2- amine
Compound 3:4- (2- ((4- chlorobenzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxane -6-
Base) -1,3,5- triazine -2- amine
Compound 4:N- (2,3- dihydrobenzo [b] [1,4] dioxin -6- base) -4- (2- ((4- trifluoromethyl) benzyl) ammonia
Base) phenyl) -1,3,5- triazine -2- amine
Compound 5:4- (2- ((4- methylbenzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxane-
6- yl) -1,3,5- triazine -2- amine
Compound 6:4- (2- ((2- luorobenzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxane -6-
Base) -1,3,5- triazine -2- amine
Compound 7:4- (2- ((2- chlorobenzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxane -6-
Base) -1,3,5- triazine -2- amine
Compound 8:4- (2- ((4- luorobenzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxane -6-
Base) -1,3,5- triazine -2- amine
Compound 9:4- (2- ((2- bromobenzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxane -6-
Base) -1,3,5- triazine -2- amine
Compound 10:N- (2,3- dihydrobenzo [b] [1,4] dioxin -6- base) -4- (2- ((pyridin-4-yl methyl) ammonia
Base) phenyl) -1,3,5- triazine -2- amine
Compound 11:4- (2- ((4- hydroxybenzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxy six
Ring -6- base) -1,3,5- triazine -2- amine
Compound 12:4- (2- ((2- methylbenzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxy six
Ring -6- base) -1,3,5- triazine -2- amine
Compound 13:4- (2- ((2,4- dichloro benzyl) amino) phenyl)-N- (2,3- dihydrobenzo [b] [1,4] dioxy six
Ring -6- base) -1,3,5- triazine -2- amine
Embodiment 3, the cell toxicity test of the compounds of this invention
Test tumor strain: A549, HCT116, MDA-MB-231 cell are as screening object, by Chinese Academy of Sciences's Shanghai cell bank
It provides.
Culture solution and test equipment:
Sample preparation: after DMSO (Merck) dissolution, PBS (-) is added and is made into 1000 μM of solution or is uniformly suspended
Liquid, then with PBS (-) dilution containing DMSO.Final concentration of 100,10,1,0.1,0.01,0.001 μ g/ml.Culture solution: DMEM+
10%FBS+ is dual anti-
Other materials: all-wave length multi-function microplate reader；Model: Varioskan Flash；Production firm: Thermo
scientific；96 well culture plate of import etc..
Test method:
Mtt assay: it is 100 μ l of 4-5 × 104/ml cell suspension that concentration, which is added, in the every hole of 96 orifice plates, sets 37 DEG C, 5%CO2
In incubator.After for 24 hours, addition sample liquid, 10 holes μ l/, if duplicate hole, 37 DEG C, 5%CO2Act on 72h.5mg/ml is added in every hole
20 μ l of MTT solution, act on 4h after lysate is added, 100 holes μ l/ are set in incubator, after dissolution use all-wave length multifunctional enzyme mark
Instrument surveys 570nm OD value.And cell inhibitory rate is calculated, negative control is made with corresponding solvent.
The inhibiting rate of table 2, compound on tumor cell proliferation
In conclusion the compounds of this invention 4- (2- substituted benzyl amino) phenyl-N- substituted-phenyl -1,3,5-triazines -2-
Aminated compounds is the compound with anti-tumor activity of a kind of brand new, this is further further investigation and develops newly
Anti-tumor drug opens new approach and direction.
Claims (5)
1.4-(2- substituted benzyl amino) phenyl-N- substituted-phenyl -1,3,5-triazines -2- amine antitumoral compounds, feature
Be: general structure is as follows:
Wherein: R1Substituent group is located at 2 of phenyl, and 3,4,5 or 6；R1Substituent group is monosubstituted or polysubstituted；
R1Substituent group is selected from any one or several of following type:
(1) H；
(2) halogen；
The straight chain or branched paraffin of (3) 1 ~ 6 carbon atoms；
(4) hydrophilic,
Specially hydroxyl；
(5) electron-withdrawing substituent or electron substituent group is pushed away；
(6) 2,3- ethylene oxygroup, 3,4- ethylene oxygroup, 2,3- methylenedioxy or 3,4- methylenedioxy；
Wherein: R2Substituent group is located at 2 of phenyl, and 3,4,5 or 6, R2Substituent group is monosubstituted or polysubstituted；
R2Substituent group is selected from any one or several of following type:
(1) H；
(2) halogen；
The straight chain or branched paraffin of (3) 1 ~ 6 carbon atoms；
(4) hydrophilic,
Specially hydroxyl；
(5) electron-withdrawing substituent or electron substituent group is pushed away；
(6) 2,3- ethylene oxygroup, 3,4- ethylene oxygroup, 2,3- methylenedioxy or 3,4- methylenedioxy.
2. 4-(2- substituted benzyl amino according to claim 1) phenyl-N- substituted-phenyl -1,3,5- triazine -2- amine
Antitumoral compounds, it is characterised in that: the wherein any of straight chain or branched paraffin selected from following type of 1 ~ 6 carbon atom
Kind: methyl, trifluoroalkyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl.
3. 4-(2- substituted benzyl amino according to claim 1) phenyl-N- substituted-phenyl -1,3,5- triazine -2- amine
Antitumoral compounds, it is characterised in that: the electron-withdrawing substituent pushes away electron substituent group, specially cyano, formic acid esters, alcoxyl
Base or amino.
4. a kind of prepare such as the described in any item 4-(2- substituted benzyl amino of claim 1 ~ 3) substituted-phenyl -1,3 phenyl-N-,
The method of 5- triazine -2- amine antitumoral compounds, it is characterised in that: the reaction equation of the compound preparation is as follows:
；
Detailed process are as follows:
(1) the chloro- 1,3,5- triazine of 2,4- bis- and substituted aniline react obtained compound (I)；
(2) the chloro- N- substituted-phenyl -1,3,5- triazine -2- amine (I) of 4- reacts to obtain compound with adjacent amino phenyl boric acid generation Suzuki
(II)；
(3) 4-(2- aminophenyl) reduction amination occurs for-N- substituted-phenyl -1,3,5- triazine -2- amine (II) and substituted benzaldehyde
Obtain 4-(2- substituted benzyl amino) phenyl-N- substituted-phenyl -1,3,5- triazine -2- aminated compounds (III).
5. it is a kind of such as the described in any item 4-(2- substituted benzyl amino of claim 1 ~ 3) phenyl-N- substituted-phenyl -1,3,5- three
Piperazine -2- amine antitumoral compounds are preparing the application on anti-tumor drug.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001025220A1 (en) * | 1999-10-07 | 2001-04-12 | Amgen Inc. | Triazine kinase inhibitors |
| WO2005004818A2 (en) * | 2003-07-09 | 2005-01-20 | Imclone Systems Incorporated | Heterocyclic compounds and their use as anticancer agents |
| US20100099658A1 (en) * | 2007-07-06 | 2010-04-22 | Astellas Pharma Inc. | Di(arylamino)aryl compound |
| CN102933561A (en) * | 2010-03-22 | 2013-02-13 | 利德发现中心有限责任公司 | Pharmaceutically active disubstituted triazine derivatives |
| CN106715419A (en) * | 2014-09-26 | 2017-05-24 | 吉利德科学公司 | Aminotriazine derivatives useful as TANK-binding kinase inhibitor compounds |
| US20170368069A1 (en) * | 2015-01-13 | 2017-12-28 | Bayer Pharma Aktiengesellschaft | Use of 4-(4-fluoro-2-methoxyphenyl)-n--1,3,5-triazin-2-amine for treating leukemias |
-
2019
- 2019-03-18 CN CN201910204352.1A patent/CN109776513A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001025220A1 (en) * | 1999-10-07 | 2001-04-12 | Amgen Inc. | Triazine kinase inhibitors |
| WO2005004818A2 (en) * | 2003-07-09 | 2005-01-20 | Imclone Systems Incorporated | Heterocyclic compounds and their use as anticancer agents |
| US20100099658A1 (en) * | 2007-07-06 | 2010-04-22 | Astellas Pharma Inc. | Di(arylamino)aryl compound |
| CN102933561A (en) * | 2010-03-22 | 2013-02-13 | 利德发现中心有限责任公司 | Pharmaceutically active disubstituted triazine derivatives |
| CN106715419A (en) * | 2014-09-26 | 2017-05-24 | 吉利德科学公司 | Aminotriazine derivatives useful as TANK-binding kinase inhibitor compounds |
| US20170368069A1 (en) * | 2015-01-13 | 2017-12-28 | Bayer Pharma Aktiengesellschaft | Use of 4-(4-fluoro-2-methoxyphenyl)-n--1,3,5-triazin-2-amine for treating leukemias |
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