CN102924450A - 6-(5-pyridyl)-1,2,4-triazolopyridine compound, and preparation method and application thereof - Google Patents
6-(5-pyridyl)-1,2,4-triazolopyridine compound, and preparation method and application thereof Download PDFInfo
- Publication number
- CN102924450A CN102924450A CN2012104308046A CN201210430804A CN102924450A CN 102924450 A CN102924450 A CN 102924450A CN 2012104308046 A CN2012104308046 A CN 2012104308046A CN 201210430804 A CN201210430804 A CN 201210430804A CN 102924450 A CN102924450 A CN 102924450A
- Authority
- CN
- China
- Prior art keywords
- pyridyl
- preparation
- triazolopyridine compounds
- compounds
- triazolopyridine
- 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
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 6-(5-pyridyl)-1,2,4-triazolopyridine compound, and a preparation method and application thereof. The medical compound is novel in structure, and the synthesis method is easy to realize. The compound has obvious antineoplastic activity and can be used for antineoplastic preparation. Determination of antineoplastic activity on cell proliferation indicates that the synthesized compound has obvious inhibiting action on the proliferation of human colon cancer cells HCT116 and human brain glioma cells U87.
Description
Technical field
The invention belongs to the antineoplastic compound technical field, relate to 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds and its production and use.
Background technology
Tumour is one of malignant disease of serious threat human health.Over nearly 20 years, the M ﹠ M of China's malignant tumour constantly rises, and tumor incidence is about 2,00/,100,000 people, and annual new cases reach more than 2,200,000 people, and is dead approximately more than 160 ten thousand, controlling more than patient 6,000,000 people.
The treatment means of tumour remains traditional operative treatment, radiotherapy and pharmacological agent at present, but is still to a great extent take pharmacological agent as main.Therefore, the new antitumor drug of research and development is significant.
In recent years, along with the oncomolecularbiology progress of research, tumor invasion mechanism there has been more understanding, found the novel targets of many antitumor drug effects, make the development of antitumor drug obtain many new achievements, such as topoisomerase enzyme inhibitor, kinases inhibitor, PI3K inhibitor, mTOR inhibitors etc.
In the most tumors cell, some kinases present high expression level or excessive activation.For these characteristics, the kinase whose antitumor drugs of target such as Gefitinib, imatinib, erlotinib, Conmana, Xarelto, Sutent and lapatinibditosylate have been developed.But it is not efficient high in clinical rear discovery in some medicinal application, and some medicine that acts on single target spot easily produces resistance.Therefore, the new antitumor drug of research and development or to act on simultaneously the antitumor drug of a plurality of target spots significant.
Document J.Med.Chem.2011; 54; the 1789-1811 report; 2-acetylaminohydroxyphenylarsonic acid 5-(3-pyridyl) benzothiazole compound has the activity of good inhibition kinases PI3K and mTOR; experimentation on animals proves that it has good anti-tumor activity; but its 2-position ethanoyl is unstable in vivo, and facile hydrolysis descends the activity of compound.In addition, benzothiazole compound has certain toxicity.
Document J.Med.Chem.2011,54,5174-5184 report replaces benzothiazole with Imidazopyridazine, when synthetic compound has good anti-tumor activity, also has good internal metabolism stability.But, the synthetic difficulty of Imidazopyridazine derivative, production cost is high, and solvability is also bad.
Summary of the invention
The problem that the present invention solves is to provide 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds and its production and use.This compounds has obvious anti-tumor activity, can be applicable to antineoplastic preparation, and its synthesis material is easy to get, synthetic method easily realizes.
The present invention is achieved through the following technical solutions:
A kind of 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds, the structural formula of this compounds is:
Wherein, R
1Be hydrogen or acyl group; R
2Be methoxyl group or chlorine; R
3Be cyclopropyl or substituted-phenyl.
Further, described R
1Be hydrogen, ethanoyl or cyclopropane carbonyl, R
2Be methoxyl group or chlorine.
Described substituted-phenyl is single the replacement or two replacement, and substituting group is halogen or methyl.
A kind of 6-(5-pyridyl)-1,2, the preparation method of 4-Triazolopyridine compounds may further comprise the steps:
Intermediate A and intermediate B are carried out suzuki reaction and are obtained 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds, and its reaction formula is as follows:
Wherein, R
1Be hydrogen or acyl group; R
2Be methoxyl group or halogen; R
3Be cyclopropyl or substituted-phenyl.
Concrete its preparation method is, at PdCl
2(pddf) under the catalysis; intermediate A, intermediate B are mixed in solvent with an alkali metal salt; wherein the mol ratio of intermediate A and intermediate B is 1:1～1.3; then stirring and refluxing is reacted 1～5h under nitrogen protection; steam solvent; from reaction mixture, separate and obtain 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds.
Described intermediate A is 2-methoxyl group-3-sulfoamido-5-bromopyridine or 2-chloro-3-sulfoamido-5-bromopyridine, and described intermediate B is 2-ethanoyl (or cyclopropane carbonyl)-6-[1,2,4-triazole [1,5-α] and pyridyl] pinacol borate.
Described solvent is one or more in tetrahydrofuran (THF), dioxane, glycol dimethyl ether, dimethyl formamide, the water.
Described an alkali metal salt is yellow soda ash, salt of wormwood, cesium carbonate or sodium-acetate, and the mol ratio of itself and intermediate A is 1:1～5:1.
Described 1 mole intermediate A joins in the solvent of 5～10L reacts.
Described 6-(5-pyridyl)-1,2, the application of 4-Triazolopyridine compounds in the preparation antitumor drug.
6-(5-pyridyl)-1,2,4-Triazolopyridine compounds adds auxiliary material and makes tablet, capsule, soft capsule or injection, wherein every or a preparation in contain the 6-(5-pyridyl)-1 of 10～500mg, 2,4-Triazolopyridine compounds;
Described auxiliary material comprises one or more in additive, stablizer, solubilizing agent, lubricant, the disintegrating agent.
Compared with prior art, the present invention has following useful technique effect:
6-provided by the invention (5-pyridyl)-1,2,4-Triazolopyridine compounds is to 2-acetylaminohydroxyphenylarsonic acid 5-(3-pyridyl) transformation of benzothiazole compound structure: the present invention is with 1,2,4-triazole [1,5-α] and pyridine replacement benzothiazole ring or Imidazopyridazine ring, can obtain new antineoplastic compound 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds, itself and 2-acetylaminohydroxyphenylarsonic acid 5-(3-pyridyl) benzothiazole compound has identical pharmacophore, also have the activity and the anti-tumor activity that suppress kinases PI3K and mTOR, and its synthesis material is easy to get, synthetic method easily realizes.
6-provided by the invention (5-pyridyl)-1,2,4-Triazolopyridine compounds has the activity of obvious inhibition human colon cancer cell HCT-116 and human glioma cell U87 propagation, and wherein the activity of the activity of part of compounds and positive drug quite or better.Amino such as compound 5(2-acetylaminohydroxyphenylarsonic acid 6-[2-methoxyl group-3-(4-Methyl benzenesulfonyl)-the 5-pyridyl]-1,2,4-triazole [1,5-α] and pyridine are 10 μ MolL in concentration
-1The time, the proliferation inhibition rate of HCT116 cell is reached 82.4%; And under the same concentrations, the inhibiting rate of positive drug is 80.2%.Compound 5 is 10 μ MolL in concentration
-1The time, the proliferation inhibition rate of U87 cell is reached 73.2%; And under the same concentrations, the inhibiting rate of positive drug is 52.0%.
6-provided by the invention (5-pyridyl)-1,2,4-Triazolopyridine compounds can be used in the preparation anti-tumor medicinal preparation, wherein every or this pharmaceutical preparation in contain this compounds 10-500mg.When the active compound that utilizes the present invention to provide prepares anti-tumor medicinal preparation, this medicine can be made tablet, capsule, soft capsule or injection.These pharmaceutical preparations can be made according to the conventional preparation technology of various preparations.For tablet or capsule, preferred content is 20-200mg.And can contain pharmaceutical excipient in the oral preparations that the present invention relates to, comprise additive, stablizer, solubilizing agent, lubricant, disintegrating agent etc., such as starch, dextrin, glucose, lactose, Mierocrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pectin, cyclodextrin, twen-80, polyvinyl alcohol, Magnesium Stearate, talcum powder etc.
Description of drawings
Fig. 1 is that detection of drugs concentration is 1 * 10
-5MolL
-1The time to the proliferation inhibition rate of HCT116 cell;
Fig. 2 is that detection of drugs concentration is 1 * 10
-5MolL
-1The time to the proliferation inhibition rate of U87 cell.
Embodiment
The invention provides 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds and its production and use, with 1,2,4-triazole [1,5-α] and pyridine replacement benzothiazole ring or Imidazopyridazine ring, can obtain new antineoplastic compound 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds.The below further specifies this compound.Should be noted that, following examples are used for explanation of the present invention and also unrestricted the present invention.Although with preferred embodiment the present invention is had been described in detail, those of ordinary skill in the art should be appreciated that and can make amendment, be out of shape the present invention under not departing from the scope of the present invention or be equal to replacement, all belongs to protection scope of the present invention.
A kind of 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds, the structural formula of this compounds is:
Wherein, R
1Be hydrogen or acyl group; R
2Be methoxyl group or halogen; R
3Be cyclopropyl or substituted-phenyl.
Further, described R
1Be hydrogen, ethanoyl or cyclopropane carbonyl, R
2Be methoxyl group or chlorine; Described substituted-phenyl is single the replacement or two replacement, and substituting group is halogen or methyl.
The below provides some representative compounds numbering and structural formulas (seeing Table 1).The structure warp of target compound
1The H-NMR spectrum is determined (solvent DMSO-d
6).The synthetic method of the compound in the table 1 is:
Carry out suzuki reaction with intermediate A and intermediate B and obtain 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds 1-9, its reaction formula is as follows:
Perhaps, carry out suzuki reaction with intermediate C and intermediate D and obtain 6-(5-pyridyl)-1,2,4- Triazolopyridine compounds 10 and 11, its reaction formula is as follows:
Wherein, R
1Be hydrogen or acyl group; R
2Be methoxyl group or halogen; R
3Be cyclopropyl or substituted-phenyl.
Table 1. some representational compound number and structural formulas
The below provides the synthetic example of above-claimed cpd.
Intermediate A: 2-chloro-3-(4-fluorobenzene sulfonamido)-preparation of 5-bromopyridine (1A)
Reference J.Med.Chem.2011,54,4735 – 4751 are synthetic.
Intermediate B: 2-ethanoyl-6-[1,2,4-triazole [1,5-α] and pyridyl] preparation of pinacol borate (1B).
Reference WO 2009068482A1 is synthetic.
Synthesizing of compound 1:
In the 50mL round-bottomed flask, add 2-chloro-3-(4-fluorobenzene sulfonamido)-5-bromopyridine (0.19g), 2-ethanoyl-6-[1,2,4-triazole [1,5-α] and pyridyl] pinacol borate (0.16g), PdCl
2(pddf) (25mg); yellow soda ash (0.08g); glycol dimethyl ether (7.0mL); water (2.0mL), ethanol (3.0mL), mixture is stirring and refluxing 1h under nitrogen protection; decompression steams solvent; (chloroform: methyl alcohol=30:1), product gets Off-white solid 0.15g with ethyl alcohol recrystallization to residue, productive rate 65.2% with the silica gel column chromatography separation.
1H-NMR:δ10.90(s,1H,NH),10.56(s,1H,NH),9.39(s,1H,Ar-H),8.71(s,1H,Ar-H),8.18(s,1H,Ar-H),7.97(d,J=9.2Hz,1H,Ar-H),7.85(m,3H,Ar-H),7.43(m,2H,Ar-H),2.17(s,3H,CH).
Embodiment 2 2-acetylaminohydroxyphenylarsonic acid 6-[2-chloro-3-(4-Methyl benzenesulfonyls are amino)-the 5-pyridyl]-1,2, the preparation of 4-triazole [1,5-α] and pyridine (2)
Reference J.Med.Chem.2011, the synthetic 2-chloro-3-(4-Methyl benzenesulfonyl of 54,4735-4751 is amino)-the 5-bromopyridine.
Amino with 2-chloro-3-(4-Methyl benzenesulfonyl)-5-bromopyridine replacement 2-chloro-3-(4-fluorobenzene sulfonamido)-the 5-bromopyridine, other are synthetic with compound 1 among the embodiment 1.Productive rate 57.4%.
1H-NMR:δ10.89(s,1H,NH),10.39(s,1H,NH),9.34(s,1H,Ar-H),8.68(s,1H,Ar-H),8.10(s,1H,Ar-H),7.91(d,J=9.2Hz,1H,Ar-H),7.82(d,J=9.2Hz,1H,Ar-H),7.65(d,J=8.0Hz,2H,Ar-H)7.38(d,J=7.6Hz,2H,Ar-H),2.39(s,3H,CH
3),2.16(s,3H,CH
3).
Reference WO 2008157191A2 synthesizes 2-methoxyl group-3-(4-fluorobenzene sulfonamido)-the 5-bromopyridine.
With 2-methoxyl group-3-(4-fluorobenzene sulfonamido)-5-bromopyridine replacement 2-chloro-3-(4-fluorobenzene sulfonamido)-the 5-bromopyridine, other are synthetic with compound 1 among the embodiment 1.Productive rate 70.4%.
1H-NMR:δ10.84(s,1H,NH),10.08(s,1H,NH),9.23(s,1H,Ar-H),8.40(s,1H,Ar-H),8.00(s,1H,Ar-H),7.90(d,J=9.2Hz,1H,Ar-H),7.81(m,3H,Ar-H),7.41(m,2H,Ar-H),3.64(s,3H,OCH
3),2.16(s,3H,CH
3).
Embodiment 4 2-acetylaminohydroxyphenylarsonic acid 6-[2-methoxyl group-3-(4-chlorobenzene sulfonamidos)-and the 5-pyridyl]-1,2, the preparation of 4-triazole [1,5-α] and pyridine (4)
Reference WO 2008157191A2 synthesizes 2-methoxyl group-3-(4-chlorobenzene sulfonamido)-the 5-bromopyridine.
With 2-methoxyl group-3-(4-chlorobenzene sulfonamido)-5-bromopyridine replacement 2-chloro-3-(4-fluorobenzene sulfonamido)-the 5-bromopyridine, other are synthetic with compound 1 among the embodiment 1.Productive rate 55.6%.
1H-NMR:δ10.84(s,1H,NH),10.15(s,1H,NH),9.23(s,1H,Ar-H),8.41(s,1H,Ar-H),8.00(s,1H,Ar-H),7.90(d,J=9.2Hz,1H,Ar-H),7.76(m,3H,Ar-H),7.65(d,J=8.0Hz,2H,Ar-H),3.64(s,3H,OCH
3),2.16(s,3H,CH
3).
It is amino that reference WO 2008157191A2 synthesizes 2-methoxyl group-3-(4-Methyl benzenesulfonyl)-the 5-bromopyridine.
Amino with 2-methoxyl group-3-(4-Methyl benzenesulfonyl)-5-bromopyridine replacement 2-chloro-3-(4-fluorobenzene sulfonamido)-the 5-bromopyridine, other are synthetic with compound 1 among the embodiment 1.Productive rate 66.8%.
1H-NMR:δ10.84(s,1H,NH),9.94(s,1H,NH),9.18(s,1H,Ar-H),8.35(s,1H,Ar-H),7.93(s,1H,Ar-H),7.85(d,J=9.2Hz,1H,Ar-H),7.77(d,J=9.2Hz,1H,Ar-H),7.66(d,J=7.6Hz,2H,Ar-H),7.36(d,J=8.0Hz,2H,Ar-H),3.67(s,3H,OCH
3),2.36(s,3H,CH
3),2.16(s,3H,CH
3).
Reference WO 2008157191A2 synthesizes 2-methoxyl group-3-cyclopropyl-phenyl sulfonamido-5-bromopyridine.
With synthesizing of compound 1 among the embodiment 1.Replace 2-chloro-3-(4-fluorobenzene sulfonamido with 2-methoxyl group-3-cyclopropyl-phenyl sulfonamido-5-bromopyridine)-the 5-bromopyridine.Productive rate 47.0%.
1H-NMR:δ10.83(s,1H,NH),9.43(s,1H,NH),9.28(s,1H,Ar-H),8.42(s,1H,Ar-H),8.00(s,1H,Ar-H),7.94(d,J=9.2Hz,1H,Ar-H),7.70(d,J=9.2Hz,1H,Ar-H),3.99(s,3H,OCH
3),2.87(m,1H,CH),2.16(s,3H,CH
3),0.95(m,4H,CH
2).
Embodiment 7 2-acetylaminohydroxyphenylarsonic acid 6-[2-methoxyl group-3-(2,4-difluorobenzene sulfonamido)-the 5-pyridyl]-1,2, the preparation of 4-triazole [1,5-α] and pyridine (7)
Reference WO 2008157191 A2 synthesize 2-methoxyl group-3-(2,4-difluorobenzene sulfonamido)-the 5-bromopyridine.
With synthesizing of compound 1 among the embodiment 1.With 2-methoxyl group-3-(2,4-difluoro sulfonamido)-5-bromopyridine replacement 2-chloro-3-(4-fluorobenzene sulfonamido)-the 5-bromopyridine.Productive rate 50.0%.
1H-NMR:δ10.85(s,1H,NH),10.35(s,1H,NH),9.26(s,1H,Ar-H),8.45(s,1H,Ar-H),8.03(s,1H,Ar-H),7.93(d,J=9.2Hz,1H,Ar-H),7.76(m,2H,Ar-H),7.59(m,1H,Ar-H),7.20(m,1H,Ar-H),3.64(s,3H,OCH
3),2.16(s,3H,CH
3).
The synthetic 2-of reference WO 2009068482A1 encircles the third formamido group-6-[1,2,4-triazole [1,5-α] and pyridyl] pinacol borate.
With synthesizing of compound 3 among the embodiment 3.Encircle the third formamido group-6-[1 with 2-, 2,4-triazole [1,5-α] and pyridyl] pinacol borate replacement 2-ethanoyl-6-[1,2,4-triazole [1,5-α] and pyridyl] pinacol borate.Productive rate 56.7%.
1H-NMR:δ11.12(s,1H,NH),10.09(s,1H,NH),9.21(s,1H,Ar-H),8.40(s,1H,Ar-H),8.00(s,1H,Ar-H),7.86(m,4H,Ar-H),7.41(m,2H,Ar-H),3.64(s,3H,OCH
3),2.07(m,1H,CH),0.85(s,4H,CH
2).
Embodiment 9 2-encircle the third formamido group-6-[2-chloro-3-(4-fluorobenzene sulfonamido)-the 5-pyridyl]-1,2, the preparation of 4-triazole [1,5-α] and pyridine (9)
With synthesizing of compound 8 among the embodiment 8.With 2-chloro-3-(4-fluorine sulfonamido)-5-bromopyridine replacement 2-methoxyl group-3-(4-fluorobenzene sulfonamido)-the 5-bromopyridine.Productive rate 48.9%.
1H-NMR:δ11.12(s,1H,NH),10.56(s,1H,NH),9.37(s,1H,Ar-H),8.71(s,1H,Ar-H),8.18(s,1H,Ar-H),7.97(d,J=9.2Hz,1H,Ar-H),7.82(d,J=8.4Hz,3H,Ar-H),7.43(m,2H,Ar-H),2.06(m,1H,CH),0.85(d,J=5.6Hz,4H,CH
2).
Intermediate C:2-methoxyl group-3-(4-Methyl benzenesulfonyl is amino)-preparation of 5-pyridyl pinacol borate (1C)
Reference J.Med.Chem.2011,54,4735 – 4751 are synthetic.
Intermediate D:2-amino-6-bromo-1,2, the preparation of 4-triazole [1,5-α] and pyridine (1D)
Reference WO 2009068482A1 is synthetic.
Synthesizing of compound 10:
In the 50mL round-bottomed flask, add 2-methoxyl group-3-(4-Methyl benzenesulfonyl amino)-5-pyridyl pinacol borate (0.12g), 2-amino-6-bromo-1,2,4-triazole [1,5-α] and pyridine ((0.06g), PdCl
2(pddf) (15mg); yellow soda ash (0.07g); glycol dimethyl ether (7mL); water (2mL) ethanol (3mL); mixture is stirring and refluxing 1h under nitrogen protection, and decompression steams solvent, and residue separates (chloroform: methyl alcohol=25:1) with silica gel column chromatography; product gets Off-white solid 0.06g with ethyl alcohol recrystallization, productive rate 49.8%.
1H-NMR:δ9.92(s,1H,NH),8.84(s,1H,Ar-H),8.29(s,1H,Ar-H),7.86(s,1H,Ar-H),7.64(s,3H,Ar-H),7.44(d,J=7.6Hz,1H,Ar-H),7.36(d,J=6.0Hz,2H,Ar-H),6.10(s,2H,NH
2),3.65(s,3H,OCH
3),2.36(s,3H,CH
3).
Reference J.Med.Chem.2011,54,4735 –, 4751 synthetic 2-methoxyl group-3-(4-chlorobenzene sulfonamidos)-5-pyridyl pinacol borate.
With synthesizing of compound 10 among the embodiment 10.With 2-methoxyl group-3-(4-chlorobenzene sulfonamido)-methoxyl group-the 3-(4-Methyl benzenesulfonyl is amino for 5-pyridyl pinacol borate replacement 2-)-5-pyridyl pinacol borate.Productive rate 57.1%.
1H-NMR:δ10.13(s,1H,NH),8.84(s,1H,Ar-H),8.89(s,1H,Ar-H),8.35(s,1H,Ar-H),7.75(d,J=7.6Hz,2H,Ar-H),7.66(t,J
1=8.4Hz,J
2=8.0Hz,3H,Ar-H),7.45(d,J=8.8Hz,1H,Ar-H),6.11(s,2H,NH
2),3.62(s,3H,OCH
3).
Embodiment 12 2-acetylaminohydroxyphenylarsonic acid 6-[2-chloro-3-(4-fluorobenzene sulfonamidos)-and the 5-pyridyl]-1,2, the preparation of 4-triazole [1,5-α] and pyridine (1)
With embodiment 1.Replace yellow soda ash with salt of wormwood.Productive rate 55.5%.
Embodiment 13 2-acetylaminohydroxyphenylarsonic acid 6-[2-chloro-3-(4-fluorobenzene sulfonamidos)-and the 5-pyridyl]-1,2, the preparation of 4-triazole [1,5-α] and pyridine (1)
With embodiment 1.Replace glycol dimethyl ether with dioxane.Productive rate 60.2%.
Embodiment 14 2-acetylaminohydroxyphenylarsonic acid 6-[2-chloro-3-(4-fluorobenzene sulfonamidos)-and the 5-pyridyl]-1,2, the preparation of 4-triazole [1,5-α] and pyridine (1)
With embodiment 1.Replace glycol dimethyl ether with tetrahydrofuran (THF).Productive rate 59.8%.
The checking of anti-tumor activity
In order to verify 6-(5-pyridyl)-1,2, the anti-tumor activity of 4-Triazolopyridine compounds, specifically with 4-morpholinyl-6-[2-chloro-3-(4-fluorobenzene sulfonamido)-the 5-pyridyl] quinoline (document J.Med.Chem.2011,54, the active best compound of 4735 –, 4751 reports) positive contrast medicine adopts external mtt assay to measure the growth-inhibiting effect of 1～11 couple of human colon cancer cell HCT-116 of compound and human glioma cell U87.
Verification method:
Two kinds of tumour cells are cultivated respectively in containing the RPMI1640 substratum of 10% calf serum, contained penicillin 100UmL
-1, Streptomycin sulphate 100 μ gmL
-1, in 37 ℃, 5%CO
2The cultivation of going down to posterity in the incubator.
Get the adherent tumour cell of 0.3% trysinization, contain the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 6 * 10
3Individual cells/ml.Every hole is inoculated 200 μ L(and is approximately contained 1000 tumour cells in 96 well culture plates), cultivate 24h for 37 ℃.Medicine dissolves with DMSO, and is diluted to 10
-3MolL
-1Administration group (compound 1～11, and positive drug) adds medicine, and it is 10 that every kind of medicine is set its final concentration
-5MolL
-1, each concentration is established 5 parallel holes.Control group adds and the isopyknic solvent of administration, places 37 ℃, 5%CO
2Discard nutrient solution after cultivating 48h in the incubator, every hole adds 20 μ L 5mgmL
-1MTT solution, hatch 4h after, abandoning supernatant, every hole adds DMSO 150 μ L, measures optical density value (OD) with microplate reader under 570nm behind the gentle agitation.
The result calculates:
The tumour cell of processing take solvent control asks medicine to the inhibiting rate of tumour cell as control group according to following formula.
The result:
Above-mentioned test-results as depicted in figs. 1 and 2.Can see that compound 1～11 is 1 * 10 in concentration
-5MolL
-1The time propagation of human colon cancer cell HCT116 and human glioma cell U87 had obvious restraining effect.
This shows 6-(5-pyridyl)-1,2, and 4-Triazolopyridine compounds can be used in the preparation anti-tumor medicinal preparation, this medicine can be made tablet, capsule, soft capsule or injection.
Wherein every or this pharmaceutical preparation in contain this compounds 10-500mg, these pharmaceutical preparations can be made according to the conventional preparation technology of various preparations.For tablet or capsule, preferred content is 20-200mg.And can contain pharmaceutical excipient in the oral preparations that the present invention relates to, comprise additive, stablizer, solubilizing agent, lubricant, disintegrating agent etc., such as starch, dextrin, glucose, lactose, Mierocrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pectin, cyclodextrin, twen-80, polyvinyl alcohol, Magnesium Stearate, talcum powder etc.
Claims (10)
1. a 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds is characterized in that, the structural formula of this compounds is:
Wherein, R
1Be hydrogen or acyl group; R
2Be methoxyl group or halogen; R
3Be cyclopropyl or substituted-phenyl.
2. 6-as claimed in claim 1 (5-pyridyl)-1,2,4-Triazolopyridine compounds is characterized in that, described R
1Be hydrogen, ethanoyl or cyclopropane carbonyl, R
2Be methoxyl group or chlorine.
3. 6-as claimed in claim 1 (5-pyridyl)-1,2,4-Triazolopyridine compounds is characterized in that, and described substituted-phenyl is single the replacement or disubstituted phenyl, and substituting group is halogen or methyl.
4. a 6-(5-pyridyl)-1,2, the preparation method of 4-Triazolopyridine compounds is characterized in that, may further comprise the steps:
Intermediate A and intermediate B obtain 6-(5-pyridyl)-1,2 by suzuki reaction, 4-Triazolopyridine compounds, and its reaction formula is as follows:
Wherein, R
1Be hydrogen or acyl group; R
2Be methoxyl group or halogen; R
3Be cyclopropyl or substituted-phenyl.
5. 6-as claimed in claim 4 (5-pyridyl)-1,2, the preparation method of 4-Triazolopyridine compounds is characterized in that, at PdCl
2(pddf) under the catalysis, intermediate A, intermediate B are mixed in solvent with an alkali metal salt, wherein the mol ratio of intermediate A and intermediate B is 1:1～1.3, then stirring and refluxing is reacted 1～5h under nitrogen protection, steam solvent, from reaction mixture, separate and obtain 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds;
Described intermediate A is 2-methoxyl group-3-sulfoamido-5-bromopyridine or 2-chloro-3-sulfoamido-5-bromopyridine; Described intermediate B is 2-ethanoyl-6-[1,2,4-triazole [1,5-α] and pyridyl] pinacol borate or 2-cyclopropane carbonyl-6-[1,2,4-triazole [1,5-α] and pyridyl] pinacol borate.
6. 6-as claimed in claim 5 (5-pyridyl)-1, the preparation method of 2,4-Triazolopyridine compounds is characterized in that, described an alkali metal salt is yellow soda ash, salt of wormwood, cesium carbonate or sodium-acetate, and the mol ratio of itself and intermediate A is 1:1～5:1.
7. 6-as claimed in claim 5 (5-pyridyl)-1,2, the preparation method of 4-Triazolopyridine compounds is characterized in that, described solvent is one or more in tetrahydrofuran (THF), dioxane, glycol dimethyl ether, dimethyl formamide, ethanol, the water.
8. 6-as claimed in claim 5 (5-pyridyl)-1,2, the preparation method of 4-Triazolopyridine compounds is characterized in that, described 1 mole intermediate A joins in the solvent of 5～10L reacts.
9. 6-claimed in claim 1 (5-pyridyl)-1,2, the application of 4-Triazolopyridine compounds in the preparation antitumor drug.
10. application as claimed in claim 7, it is characterized in that, 6-(5-pyridyl)-1,2,4-Triazolopyridine compounds adds auxiliary material and makes tablet, capsule, soft capsule or injection, wherein every or preparation in contain the 6-(5-pyridyl)-1,2 of 10～500mg, 4-Triazolopyridine compounds;
Described auxiliary material comprises one or more in additive, stablizer, solubilizing agent, lubricant, the disintegrating agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104308046A CN102924450A (en) | 2012-11-01 | 2012-11-01 | 6-(5-pyridyl)-1,2,4-triazolopyridine compound, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104308046A CN102924450A (en) | 2012-11-01 | 2012-11-01 | 6-(5-pyridyl)-1,2,4-triazolopyridine compound, and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102924450A true CN102924450A (en) | 2013-02-13 |
Family
ID=47639406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012104308046A Pending CN102924450A (en) | 2012-11-01 | 2012-11-01 | 6-(5-pyridyl)-1,2,4-triazolopyridine compound, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102924450A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175411A (en) * | 2015-05-06 | 2015-12-23 | 西安交通大学 | Synthesis method and application of urea compound and salt compound thereof |
| US9573953B2 (en) | 2013-02-21 | 2017-02-21 | Calitor Sciences, Llc | Heteroaromatic compounds as PI3 kinase modulators and methods of use |
| CN107245075A (en) * | 2017-08-04 | 2017-10-13 | 西安交通大学 | Simultaneously [3,4 d] pyrimidines and its salt and the application of 2,4,6 3 substituted pyridines |
| CN109053556A (en) * | 2018-09-13 | 2018-12-21 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Pyridyl group bridging-phenyl-amino pyridine compounds and their, complex and its synthesis and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101952285A (en) * | 2007-11-27 | 2011-01-19 | 塞尔卓姆有限公司 | Amino triazoles as PI3K inhibitors |
-
2012
- 2012-11-01 CN CN2012104308046A patent/CN102924450A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101952285A (en) * | 2007-11-27 | 2011-01-19 | 塞尔卓姆有限公司 | Amino triazoles as PI3K inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| KATHRYN BELL, ET AL.: "SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 22, 23 June 2012 (2012-06-23), pages 5257 - 5263, XP028932801, DOI: doi:10.1016/j.bmcl.2012.06.049 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9573953B2 (en) | 2013-02-21 | 2017-02-21 | Calitor Sciences, Llc | Heteroaromatic compounds as PI3 kinase modulators and methods of use |
| CN105175411A (en) * | 2015-05-06 | 2015-12-23 | 西安交通大学 | Synthesis method and application of urea compound and salt compound thereof |
| CN107245075A (en) * | 2017-08-04 | 2017-10-13 | 西安交通大学 | Simultaneously [3,4 d] pyrimidines and its salt and the application of 2,4,6 3 substituted pyridines |
| CN109053556A (en) * | 2018-09-13 | 2018-12-21 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Pyridyl group bridging-phenyl-amino pyridine compounds and their, complex and its synthesis and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI772291B (en) | Substituted pyrrolopyrimidine CDK inhibitors, pharmaceutical compositions containing the same and uses thereof | |
| CN106883213B (en) | Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) | |
| JP6404717B2 (en) | Amidospirocyclic amide and sulfonamide derivatives | |
| CN114269735A (en) | Dihydro or tetrahydro quinazoline compound and intermediate, preparation method and application thereof | |
| KR20140048968A (en) | Inhibitors of bruton's tyrosine kinase | |
| CN106008511A (en) | Pteridinone derivatives and application of pteridinone derivatives as EGFR (epidermal growth factor receptor tyrosine kinase), BLK (B lymphocyte tyrosine kinase) and FLT3 (FMS-like tyrosine kinase 3) inhibitors | |
| CN101878218A (en) | Icotinib hydrochloride, synthesis, crystallographic form, medical combination, and uses thereof | |
| CN107245075B (en) | 2,4, 6-trisubstituted pyrido [3,4-d ] pyrimidine compound and salt and application thereof | |
| CN103044395B (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| CN105985342A (en) | Pyrimido pyrimidine dione derivative as EGFR inhibitor and application thereof | |
| CN103421010A (en) | Pteridinone derivative as EGFR inhibitor and application thereof | |
| AU2013318672B2 (en) | Means and method for treating solid tumours | |
| CN102924450A (en) | 6-(5-pyridyl)-1,2,4-triazolopyridine compound, and preparation method and application thereof | |
| CN113087671B (en) | Cyano-substituted pyridine and cyano-substituted pyrimidine compounds, and preparation methods and applications thereof | |
| CN115109036B (en) | Quinazoline compound, composition and application thereof | |
| CN102746241B (en) | 2, 3, 5-trisubstituted benzamide compound, and preparation method and application thereof | |
| CN103864765A (en) | Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative | |
| CN110845476B (en) | High-selectivity CSF1R inhibitor, preparation method and pharmaceutical application thereof | |
| CN107474043A (en) | Nicotinic acid derivates and preparation method thereof and purposes | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN104402875A (en) | Synthesis method and application N-(2-aminoethyl)-N'-(6-substituted-2-benzothiazolyl)urea and salt compounds thereof | |
| CN109942566A (en) | Isonicotinic acid derivatives and its preparation method and application | |
| CN104926804A (en) | Compounds with anti-tumor effect, and preparation method and application of compounds | |
| CN104341407A (en) | Quinazoline compounds, preparation method and applications thereof | |
| CN115894486B (en) | Hydrogenated pyridoquinazoline compound, composition and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C05 | Deemed withdrawal (patent law before 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130213 |