CN114773320A - 1,3,5-triazine compound, preparation method and application thereof - Google Patents
1,3,5-triazine compound, preparation method and application thereof Download PDFInfo
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- CN114773320A CN114773320A CN202210614452.3A CN202210614452A CN114773320A CN 114773320 A CN114773320 A CN 114773320A CN 202210614452 A CN202210614452 A CN 202210614452A CN 114773320 A CN114773320 A CN 114773320A
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- -1 1,3,5-triazine compound Chemical class 0.000 title claims abstract description 16
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- 238000000034 method Methods 0.000 claims description 7
- GSSCQXYNRDFGAV-UHFFFAOYSA-N 2,4-dichloro-6-[6-(trifluoromethyl)pyridin-2-yl]-1,3,5-triazine Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(Cl)N=C(Cl)N=2)=N1 GSSCQXYNRDFGAV-UHFFFAOYSA-N 0.000 claims description 6
- JBXAKQJKSGOFNP-UHFFFAOYSA-N 6-[6-(trifluoromethyl)pyridin-2-yl]-1h-1,3,5-triazine-2,4-dione Chemical compound FC(F)(F)C1=CC=CC(C=2NC(=O)NC(=O)N=2)=N1 JBXAKQJKSGOFNP-UHFFFAOYSA-N 0.000 claims description 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a 1,3,5-triazine compound, a preparation method and application thereof. The 1,3,5-triazine compound provided by the invention has better activity of inhibiting TGF beta R1 kinase through detection, can be used as an antitumor lead compound, is used as a basis for further developing antitumor drugs, and has potential and wide application prospects in the field of tumor treatment. Meanwhile, the preparation method is simple and convenient for industrial production.
Description
Technical Field
The invention relates to the technical field of research and development of new drugs, and particularly relates to a 1,3,5-triazine compound and a preparation method and application thereof.
Background
Small Molecule Kinase Inhibitors (SMKIs) have made significant progress in the precise targeted treatment of cancer as an important class of drugs in the field of oncology. In 2020, the total number of cancer death cases is 996 ten thousand in all over the world, and the number of cancer deaths in China reaches 300 ten thousand, which accounts for 30% of the total number of cancer deaths in all over the world, so that the research and development and application of the anti-cancer drug have wide domestic and foreign markets. Cancer is the deterioration of a tumor. Tumor production depends on the ability of tumor cells to form and regulate the tumor microenvironment in which cancer-associated cytokines such as IL-2, TNF α, CXCR4, and TGF β are present. Among them, TGF β signals can promote invasion and spread of fibroblasts, endothelial cells and pericytes within the tumor microenvironment and reduce sensitivity to anticancer drugs. In addition, the TGF beta signal influences the structure of cancer cells and inhibits the activity of protective immune cells to remodel extracellular matrix, thereby interfering the physiological functions of various immune cells such as T cells, natural killer cells and the like and weakening the inhibition of cancer cell metastasis by the immune cells. Meanwhile, the TGF beta inhibitor can treat diseases such as fibrosis, inflammation and congenital defects, so the research of the TGF beta inhibitor has wide application value. In the TGF beta signal conduction pathway, TGF beta RI is a key node, and the action mechanism is as follows: inhibiting the combination of TGF beta RI and substrates Smad2/Smad3 and preventing the phosphorylation of Smad2/Smad3 can effectively block the conduction of TGF beta signals to the nucleus.
1,3,5-triazines are the core backbone of many biologically active compounds, such as insecticides, pesticides, herbicides, antimalarials, anticancer antibiotics, antiviral drugs, and the like. In addition, 1,3,5-triazine is also widely used in organic dyes, liquid crystals, fluorescent whitening agents, electroluminescent materials, gas generating agents, solid propellants, pyrotechnics, and the like. Based on this, the application of 1,3,5-triazine compounds has attracted people's attention.
In recent years, researchers at home and abroad have been dedicated to The construction of 1,3,5-triazines, such as Abhishek R.Tiwari, etc., using benzyl alcohol and benzamidine hydrochloride with different substituents, adding nickel sulfide as a catalyst, cesium carbonate as a base, DMSO as a solvent, reacting for 16h at 100 ℃, and finally obtaining 1,3,5-triazines with different substituents through cyclization (refer to Abhishek R.Tiwa ri, NIS-Ca solubilized oxidized substituted cyclization of alcohols with amines: A Simple and Efficient, Transition-Metal Free Method for The Synthesis of 1,3,5-triazines. org. biomol. chem.2015,13 (10973), (10976)).
Disclosure of Invention
In a first aspect, the present invention provides a 1,3,5-triazine compound or a pharmaceutically acceptable salt thereof.
Except for special description, the parts are parts by weight, and the percentages are mass percentages.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a 1,3,5-triazine compound or a pharmaceutically acceptable salt thereof, wherein the 1,3,5-triazine compound has a chemical structure represented by formula a below:
the above 1,3,5-triazine compound may be a hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, phosphate, formate, propionate, oxalate, malonate, succinate, fumarate, maleate, malate, tartrate, citrate, picrate, methanesulfonate or ethanesulfonate as a pharmaceutically acceptable salt.
In a second aspect, the present invention provides a process for producing the above-mentioned 1,3,5-triazine compound (compound of formula a).
The preparation method of the compound of the formula A is characterized in that the compound of the formula A is synthesized by the compound of the formula 3, 3-fluoropyridine-4-amine and 1-amino-2-methylpropane-2-ol;
reacting 2, 4-dichloro-6- (6- (trifluoromethyl) pyridine-2-yl) -1,3, 5-triazine (a compound shown in a formula 3) and 3-fluoropyridine-4-amine in a solvent THF at a reaction temperature of-5 ℃ for 2-6 h under an alkaline condition, adding 1-amino-2-methylpropane-2-ol, and stirring at room temperature for reaction for 10-15 h to prepare the compound shown in the formula A.
The alkali is selected from sodium bicarbonate or sodium carbonate.
From a compound of formula 2, PCl5And POCl3Synthesizing a compound of formula 3; the synthetic route is as follows:
reacting 6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione with PCl5Adding POCl3And reacting for 1-3 h at 80-120 ℃ to obtain the compound shown in the formula 3.
Synthesizing a compound of formula 2 from a compound of formula 1 and biuret; the synthetic route is as follows:
and refluxing the 6-trifluoromethyl picolinic acid methyl ester and the biuret for 0.5-2 h under the action of sodium ethoxide to prepare the compound shown in the formula 2.
In a third aspect, the invention provides an application of the compound of formula A in preparing a medicament for preventing or treating antitumor drugs.
Has the beneficial effects that:
the invention provides a 1,3,5-triazine compound (a compound shown in a formula A), which is an excellent anti-tumor lead compound, is used as a basis for further developing anti-tumor medicaments, and has potential and wide application prospect in the field of tumor treatment. Meanwhile, the preparation method is simple and convenient for industrial production.
Description of the drawings:
FIG. 1 is a graph showing the results of in vitro enzymatic inhibitory activity of Compound A.
Detailed Description
The present invention is described in detail below with reference to specific examples, which are given for the purpose of further illustrating the invention and are not to be construed as limiting the scope of the invention, and the invention may be modified and adapted by those skilled in the art in light of the above disclosure. The raw materials and reagents used in the invention are all commercial products.
Example 1
Synthesis of 6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione (2)
Na (384mg, 16.70mmol) and ethanol (50ml) were prepared as a fresh NaOEt solution to which were added methyl 6-trifluoromethylpicolinate (3.30g, 16.09mmol) and biuret (848mg, 8.22 mol). The mixture was stirred under reflux for 1h and then concentrated. The residue was poured into water and saturated NaHCO was used3(aq.) treatment, pH adjusted to 7. The precipitated solid was collected by filtration and dried under vacuum to give the desired compound 2(2.39g, yield 58%) as a white solid.
2-HNMR:1H NMR(400MHz,DMSO-d6)δ9.67(br,1H),8.38(d,J＝8.0Hz,1H),8.14(t,J＝7.6Hz,1H),7.93(d,J＝7.6Hz,1H).
2-LCMS:LC-MS:m/z for C9H6F3N4O2(M+H)+Calc μ lated 259.04; found 259.1, example 2
Synthesis of 2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (3)
6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione (2.05g, 7.94mmol) and PCl5(13.80g, 66.27mmol) was added POCl3(29ml) the mixture was stirred at 100 ℃ for 2h and concentrated. The crude product was dissolved in EtOAc and saturated NaHCO was used3Washing with water solution and extracting. Anhydrous Na for organic layer2SO4Drying, and concentrating under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether: EtOAc ═ 5:1) to give compound 3(900mg, yield 38%) as a white solid.
3-HNMR:1H NMR(400MHz,CDCl3)δ8.75(d,J＝7.6Hz,1H),8.16(t,J＝8.0Hz,1H),7.96(dd,J＝8.0,0.8Hz,1H).
LC-MS:m/z for C9H4Cl2F3N4(M+H)+:calcμlated 294.98；found 295.1.
Example 3
Synthesis of 1- ((4- ((3-fluoropyridin-4-yl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2-methylpropanol (A)
2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (88mg, 0.30mmol) and NaHCO3(50mg, 0.60mmol) were added to a solution of 3-fluoropyridin-4-amine (34mg, 0.30mmol) in dry THF (10mL) and reacted at 0 deg.C for 4 h. 1-amino-2-methylpropan-2-ol (27mg, 0.30mol) was then added to the above mixture, and the reaction was stirred at room temperature for 12 h. At the end of the reaction, the mixture was diluted with EtOAc-water (30mL:10 mL). After extraction, the organic layer was washed with saturated brine (10mL) and anhydrous Na2SO4Drying, and concentrating under reduced pressure. The resulting residue was purified by Prep-HPLC to give compound a (8mg, yield 38%) as a white solid.
1H NMR(400MHz,DMSO-d6,333K)δ9.55(br,1H),8.53-8.57(m,1H),8.46(s,1H),8.24-8.43(m,3H),8.03(d,J＝7.6Hz,1H),7.50-7.59(m,1H)4.32-4.44(m,1H),3.36-3.45(m,2H),1.14(s,6H).
LC-MS:m/z for C18H18F4N7O(M+H)+:calcμlated 424.15；found 424.2.
Example 4 Compound A in vitro TGF β R1(ALK5) kinase Activity assessment
1. Reagents and instrumentation:
the instruments include a centrifuge (Eppendorf, Cat.No.5430), a microplate Reader (Perkin Elmer: Cat.No. Caliper EZ Reader II), and Echo 550(Labcyte, Cat.No. Echo 550).
2. Experimental method
2.1. Preparing 1 time kinase buffer solution
50mM Tris,pH 7.5，0.001％BSA，200mM NaCl，10mM MgCl2，1mM DTT。
2.2 preparation of the Compounds
2.2.1 dilution of Compounds
2.2.1.1 Compound A of the present invention was prepared as 1mM working solution in DMSO, and diluted to 1.000mM, 0.333mM, 0.111mM, 0.0370mM,0.0123mM,0.00411mM,0.00137mM in a 3-fold dilution gradient in this order using DMSO to obtain 7 concentrations of working solution.
2.2.1.2 transfer of 50nl of compound solution to a 384 well plate using echo to give 7 sample final concentration solutions of 10.00. mu.M, 3.33. mu.M, 1.11. mu.M, 0.370. mu.M, 0.123. mu.M, 0.0411. mu.M, 0.0137. mu.M.
2.3 kinase reaction
50nl of 100% DMSO were already present in 384 well plates to dissolve the compounds. To the compound wells and the positive wells of the 384-well plate, 2.5. mu.l of 2-fold kinase solution was added, respectively, to the negative control wells, 2.5. mu.l of 1-fold kinase buffer was added, and the mixture was centrifuged at 1000rpm for 30 seconds and incubated at room temperature for 10 min. 2.5. mu.l of 2-fold substrate solution was added to the 384-well plate, centrifuged at 1000rpm for 30s, shaken well mixed and incubated at room temperature for 120 min. Add 5. mu.l ADP-Glo R1 solution, centrifuge at 1000rpm for 30s, mix well with shaking and incubate at room temperature for 180 min. Add 10. mu.l ADP-Glo R2 solution, centrifuge at 1000rpm for 30s, mix well with shaking and incubate at room temperature for 60 min.
2.4 data reading
The luminescence values of the samples were read on Envision.
2.5 fitting of curves
2.5.1 data of luminescence readings were copied from the Envision program.
2.5.2 the luminescence values are converted into percent inhibition by a formula.
Wherein: conversion% _ sample is the Conversion reading for the sample; conversion% _ min: negative control well mean, representing conversion readings without enzyme live wells; conversion% _ max: positive control well mean, representing conversion readings for wells without compound inhibition.
2.5.3 fitting dose-response curves
Data were imported into GraphPad Prism 5 software, using the log of concentration as the X-axis and the percent inhibition as the Y-axis, and using the analysis software, log (inhibitor) vs. response-Variable slope of GraphPad Prism 5 to fit the dose-effect curves, thereby obtaining the IC40 value of the compound for enzyme activity.
The TGF beta R1 kinase inhibitory activity of Compound A of the present invention was determined by the above experimental methods and the in vitro enzymatic inhibitory activity of Compound A was determined as shown in FIG. 1: IC of TGF beta R140About 10.00. mu. mol.
And (4) conclusion: the compound has certain inhibition effect on TGF beta R1 kinase, and can be further researched as a lead compound for inhibiting TGF beta R1.
Claims (10)
1. A 1,3,5-triazine compound or a pharmaceutically acceptable salt thereof, wherein the 1,3,5-triazine compound has a chemical structure represented by formula a below:
2. the 1,3,5-triazine compound according to claim 1, wherein the pharmaceutically acceptable salt thereof is selected from the group consisting of hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, phosphate, formate, propionate, oxalate, malonate, succinate, fumarate, maleate, malate, tartrate, citrate, picrate, methanesulfonate and ethanesulfonate.
3. A process for the preparation of a compound of formula a as claimed in claim 1 or 2, wherein a compound of formula a is synthesized from a compound of formula 3 with 3-fluoropyridin-4-amine and 1-amino-2-methylpropan-2-ol; the synthetic route is as follows:
4. the method of claim 3, wherein: reacting 2, 4-dichloro-6- (6- (trifluoromethyl) pyridine-2-yl) -1,3, 5-triazine (a compound shown in a formula 3) and 3-fluoropyridine-4-amine in a solvent THF at a reaction temperature of-5 ℃ for 2-6 h under an alkaline condition, adding 1-amino-2-methylpropane-2-ol, and stirring at room temperature for 10-15 h to obtain a compound shown in a formula A.
5. The method of claim 4, wherein: the alkali is selected from sodium bicarbonate or sodium carbonate.
6. The production method according to any one of claims 3 to 5, characterized in that: from a compound of formula 2, PCl5And POCl3Synthesizing a compound of formula 3; the synthetic route is as follows:
7. the method of claim 6, wherein: mixing 6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione and PCl5Adding POCl3And reacting for 1-3 h at 80-120 ℃ to obtain the compound shown in the formula 3.
8. The production method according to claim 6 or 7, characterized in that: synthesizing a compound of formula 2 from a compound of formula 1 and biuret; the synthetic route is as follows:
9. the method of claim 8, wherein: refluxing 6-trifluoromethyl picolinic acid methyl ester and biuret for 0.5-2 h under the action of sodium ethoxide to prepare the compound shown in the formula 2.
10. The use of a compound of formula a as claimed in claim 1 or 2 for the preparation of a medicament for the prophylactic or therapeutic treatment of an antineoplastic agent.
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