CN109251179A - 1,2,4- triazines Growth of Gastric inhibitor and its preparation method and application - Google Patents
1,2,4- triazines Growth of Gastric inhibitor and its preparation method and application Download PDFInfo
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- CN109251179A CN109251179A CN201811267436.1A CN201811267436A CN109251179A CN 109251179 A CN109251179 A CN 109251179A CN 201811267436 A CN201811267436 A CN 201811267436A CN 109251179 A CN109251179 A CN 109251179A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a kind of 1,2,4- compound in triazine class, their preparation method and its applications in Growth of Gastric inhibitor, belong to anti-tumor drug chemical field.The present invention is simple and efficient, 1,2,4- compound in triazine class of environmentally protective synthesis.It has the following structure general formula:
Description
Technical field
The present invention relates to anti-tumor drug chemical fields, and in particular to 1,2,4- of one kind compound in triazine class, their system
Preparation Method and its application as a new class of anti-tumor drug lead compound.
Background technique
Gastric cancer (gastric carcinoma) is initiated by the malignant tumour of gastric epithelial, various pernicious swollen in China
Disease incidence ranks first in tumor, and incidence gastric cancer has apparent region gender gap, sends out in the northwest in China and coastal region in east China gastric cancer
Sick rate is evident as high than southern area.1,2,4- triazine gains great popularity as star's skeleton in field of medicinal chemistry.It can be used as
Pharmacology segment designs medicinal small molecule.
Summary of the invention
It is an object of that present invention to provide a kind of novel 1,2,4- triazines chemical combination of potent antitumor for being better than 5 FU 5 fluorouracil
Object.
It is another object of the present invention to provide one kind to be simple and efficient, environmentally protective 1,2,4- triazines chemical combination of synthesizing new
The method of object.
The novel 1,2,4- compound in triazine class of one kind of the present invention has following general formula:
R represents H, methoxyl group, C2-3 acyl group, C1-3 ester group, C1-3 amide groups, by C1-3 alkyl or the mono-substituted C1-3 acyl of amino
Amido and monosubstituted on phenyl ring in addition to methoxyl group.
It is preferred that: R represents H, methoxyl group, acetyl group, methyl acetate base, methyl formate base, and formamido is taken by methyl or amino list
The formamido in generation and monosubstituted on phenyl ring in addition to methoxyl group.
More preferable: R represents H, acetyl group, methyl acetate base, methyl formate base, and formamido is mono-substituted by methyl or amino
Formamido aligns monosubstituted on phenyl ring；R representation methoxy, 3,4,5 substitutions on phenyl ring.
The novel 1,2,4- compound in triazine class selects compound shown in formula (III):
Novel 1,2,4- compound in triazine class of the present invention is mainly made through the following steps:
(1) preparation method of compound (II):
In solvent, by compound I under alkaline condition with 3,4,5- trimethoxy-anilines react to obtain compound II, alkali used
Property compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, ten phosphate dihydrate sodium, potassium phosphate, bicarbonate
One of potassium, sodium bicarbonate；Solvent used is ethyl alcohol, methanol, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydro furan
It mutters, one of dioxane, methylene chloride, ethyl acetate or in which any two kinds of mixture；Reaction is between 60-120 DEG C
It carries out.
(2) lead to the preparation method of formula (III):
In solvent, compound (II), the aniline of different substituents under alkaline condition one pot reaction obtain compound IIIa~
IIIh, alkali compounds used are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, ten phosphate dihydrate sodium, phosphorus
One of sour potassium, saleratus, sodium bicarbonate；Solvent used is ethyl alcohol, methanol, N,N-dimethylformamide, dimethyl
One of sulfoxide, tetrahydrofuran, dioxane, methylene chloride, acetone or in which any two kinds of mixture；Reaction is in 80-140
It is carried out between DEG C.
The invention has the advantages that 1, such Compound ira vitro anticancer activity is experiments have shown that all have certain inhibition to kinds of tumor cells
Effect, especially to MGC803 cancer cell, such compound activity is better than anti-tumor drug 5 FU 5 fluorouracil, especially compound
IIIa, IIIc can be used as the candidate further developed or lead compound, be applied to the tumour medicines such as preparation anti-gastric cancer.2, it closes
It is simple and efficient at method, environmentally protective, high income, up to 76% or more.
Specific embodiment
It is as follows for embodiment for the present invention is better described:
The preparation of 1 compound of embodiment (II)
1,2,4- triaizine compounds I (1.1g, 6mmol) and Anhydrous potassium carbonate (0.69g, 5mmol) are mixed, the second of 10mL is added
Acetoacetic ester is added 3,4,5- trimethoxy-anilines (6mmol) in system, is warming up to 60 DEG C, the reaction was continued.TLC monitoring react into
Journey, to which distilled water after reaction, is added into system, then quenching reaction is extracted with ethyl acetate 3 times, then is eaten with saturation
Salt water is stripped ethyl acetate phase 3 times, each 20mL, and last organic phase is dry with anhydrous magnesium sulfate, filters out magnesium sulfate, filtrate decompression
Ethyl acetate is distilled off.Gained crude product silicagel column column chromatographic isolation and purification, petrol ether/ethyl acetate=10:1 elution,
It obtains compound (II).
Embodiment 2 leads to the preparation of formula (III)
By compound (II) (1.65g, 5mmol), the aniline (5mmol) of different substituents, potassium carbonate (0.69g, 5mmol), add
The acetone for entering 5mL, is stirred at room temperature.TLC monitors reaction process, to after reaction, distilled water be added into system, is quenched anti-
It answers, is then extracted with dichloroethanes, then be stripped dichloroethanes phase 3 times, each 5mL with saturated salt solution, last organic phase nothing
Water magnesium sulfate is dry, filters out magnesium sulfate, dichloroethanes is distilled off in filtrate decompression.Gained crude product silicagel column column chromatography for separation
Purifying, petrol ether/ethyl acetate=7:1 elution, obtains compound (III).
Compound IIIa:1H NMR(400MHz,DMSO-d6) δ 9.72 (s, 1H), 9.43 (s, 1H), 7.62 (d, J=8.1Hz,
2H), 7.18 (t, J=7.6Hz, 2H), 7.01-6.91 (m, 3H), 3.70 (d, J=11.6Hz, 9H), yield 76%.
Compound IIIb:1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),9.35(s,1H),7.01(s,2H),6.97
(s, 2H), 3.67 (d, J=3.4Hz, 9H), 3.61 (s, 3H), 3.57 (s, 6H), yield 80%.
Compound IIIc:1H NMR(400MHz,DMSO-d6) δ 10.12 (s, 1H), 9.58 (s, 1H), 7.77 (d, J=6.6Hz,
4H), 6.97 (s, 2H), 3.72 (d, J=11.4Hz, 9H), 2.50 (dd, J=4.6,3.0Hz, 3H), yield 82%.
Compound IIId:1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.58(s,1H),7.78(s,4H),6.98
(s, 2H), 3.81 (s, 3H), 3.75 (s, 6H), 3.72 (s, 3H), yield 83%.
Compound IIIe:1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H), 9.61 (s, 1H), 7.76 (d, J=2.0Hz,
4H), 6.95 (s, 2H), 4.26 (q, J=7.1Hz, 2H), 3.72 (d, J=10.1Hz, 9H), 1.37-1.22 (m, 3H), yield
85%.
Compound IIIf:1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),11.44(s,1H),9.48(s,1H),8.44
(s, 1H), 7.80 (d, J=47.6Hz, 3H), 7.13 (d, J=8.4Hz, 2H), 3.70 (dd, J=36.8,8.5Hz, 9H),
2.77 (d, J=3.9Hz, 3H), yield 88%.
Compound IIIg:1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),10.27(s,1H),9.49(s,1H),7.61
(d, J=8.2Hz, 2H), 7.13 (s, 2H), 6.58 (d, J=7.5Hz, 2H), 4.21-3.59 (m, 11H), yield 90%.
Compound IIIh:1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.37(s,1H),7.98(s,1H),7.92–
7.81 (m, 2H), 7.45 (d, J=7.7Hz, 1H), 7.25 (dd, J=17.4,9.4Hz, 2H), 7.02 (s, 2H), 3.70 (d, J
=13.0Hz, 9H), yield 92%.
The antitumor cytolytic activity of 3 above compound of embodiment:
Screening compound used therefor is to be synthesized by the present invention, purify and obtain；Stock sample solution: it weighs 1-2mg sample and is placed in 2mL
In EP pipe, solution then is configured to DMSO, and 4 DEG C of preservations are placed, and utilize culture medium dilution according to required concentration when experiment.It takes pair
The cell in number growth period after digestion counts, adjusts cell density with culture medium, is seeded to 96 holes with the 4000-5000 hole cell/
In plate, every 150 μ L of hole discards culture medium, drug (50 μ g/mL, 100 μ g/ that addition has been diluted with culture medium after culture for 24 hours
ML), each concentration sets 6 multiple holes, separately sets blank control group and negative control group.After drug effect 72h, 20 μ are added in every hole
LMTT continues after cultivating 4h, sucks liquid, be added the DMSO of 150mL, shaken well, the place microplate reader 490nm detection absorbance
Value calculates inhibiting rate, and calculation formula is as follows: inhibiting rate (%)=(1- administration group absorbance value/blank group absorbance value) ×
Inhibiting rate is greater than 50% sample when 100%, 50 μ g/mL, resets concentration and carries out dusting cover.Test result uses SPSS software
Calculate IC50Value and related coefficient.Experimental result is shown in Table 1.
The IC of 1 part of compounds of table inhibition tumor cell strain50Value
aEach numerical value indicates that variance analysis: p < 0.05.5-Fu:5- fluorine urine is phonetic with average value ± standard deviation (mean ± SD)
Pyridine.
Claims (6)
1.1,2,4- compound in triazine class, which is characterized in that there is structure shown in general formula III:
R represents H, methoxyl group, C2-3 acyl group, C1-3 ester group, C1-3 amide groups, by C1-3 alkyl or the mono-substituted C1-3 acyl of amino
Amido and monosubstituted on phenyl ring in addition to methoxyl group.
2. as described in claim 11,2,4- compound in triazine class, which is characterized in that R represents H, methoxyl group, acetyl group, second
Sour carbomethoxy, methyl formate base, formamido, in benzene by methyl or the mono-substituted formamido of amino and in addition to methoxyl group
It is monosubstituted on ring.
3. as claimed in claim 21,2,4- compound in triazine class, which is characterized in that R aligns monosubstituted, methoxy on phenyl ring
Base replaces at 3,4,5.
4. as described in claim 11,2,4- compound in triazine class, which is characterized in that select one of following compound:
5. 1 as described in one of claim 1-4, the application of 2,4- compound in triazine class in medicine preparation, feature
It is, it is used to prepare anti-gastric cancer tumour medicine as active constituent.
6. the method for preparing 1,2, the 4- compound in triazine class compounds as described in one of claim 1-4, feature exist
In, comprising the following steps:
(1) preparation method of compound (II):
In solvent, by compound I under alkaline condition with 3,4,5- trimethoxy-anilines react to obtain compound II, alkali used
Property compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, ten phosphate dihydrate sodium, potassium phosphate, bicarbonate
One of potassium, sodium bicarbonate；Solvent used is ethyl alcohol, methanol, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydro furan
It mutters, one of dioxane, methylene chloride, ethyl acetate or in which any two kinds of mixture；Reaction is between 60-120 DEG C
It carries out；
(2) lead to the preparation method of formula (III):
In solvent, compound (II), difference replace aniline under alkaline condition one pot reaction obtain compound IIIa~
IIIh, alkali compounds used are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, ten phosphate dihydrate sodium, phosphorus
One of sour potassium, saleratus, sodium bicarbonate；Solvent used is ethyl alcohol, methanol, N,N-dimethylformamide, dimethyl
One of sulfoxide, tetrahydrofuran, dioxane, methylene chloride, acetone or in which any two kinds of mixture；Reaction is in 80-140
It is carried out between DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811267436.1A CN109251179B (en) | 2018-10-29 | 2018-10-29 | 1,2, 4-triazine gastric cancer cell growth inhibitor and preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811267436.1A CN109251179B (en) | 2018-10-29 | 2018-10-29 | 1,2, 4-triazine gastric cancer cell growth inhibitor and preparation method and application thereof |
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| Publication Number | Publication Date |
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| CN109251179A true CN109251179A (en) | 2019-01-22 |
| CN109251179B CN109251179B (en) | 2021-04-13 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146478A (en) * | 2015-04-10 | 2016-11-23 | 山东轩竹医药科技有限公司 | Triazine derivatives species anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor |
| WO2018121650A1 (en) * | 2016-12-29 | 2018-07-05 | 南京明德新药研发股份有限公司 | Fgfr inhibitor |
-
2018
- 2018-10-29 CN CN201811267436.1A patent/CN109251179B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146478A (en) * | 2015-04-10 | 2016-11-23 | 山东轩竹医药科技有限公司 | Triazine derivatives species anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor |
| WO2018121650A1 (en) * | 2016-12-29 | 2018-07-05 | 南京明德新药研发股份有限公司 | Fgfr inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| PASCAL DAO等: "Synthesis of novel 1,2,4-triazine scaffold as FAK inhibitors with antitumor activity", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 侯玉辉: "《郑州大学专业硕士学位论文》", 1 May 2018 * |
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Inventor after: Zhang Yanbing Inventor after: Zhang Saiyang Inventor after: Fu Dongjun Inventor before: Fu Dongjun Inventor before: Shi Lei Inventor before: Song Jian Inventor before: Zhang Saiyang Inventor before: Zhang Yanbing |
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Granted publication date: 20210413 Termination date: 20211029 |