CN107474046B - A kind of pyrido 3-triazole compounds and its preparation method and application - Google Patents
A kind of pyrido 3-triazole compounds and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of pyrido 3-triazole compounds and its preparation method and application.Inventor is prepared for a kind of compound A with SMO target spot inhibitory activity by long-term further investigation01~A20, belong to a kind of pyrido 3-triazole compounds, tested by molecular docking, it can be seen that the compounds of this invention can form strong combination with target Protein S MO；And there is excellent inhibiting effect to kinds of tumors, be expected to be used for preparation SMO target spot inhibitor and anti-tumor drug.The compounds of this invention preparation method simple process, the used time is short, substantially reduces the cost of drug, is suitble to large-scale production.
Description
Technical field
The present invention relates to field of medicaments, relate more specifically to a kind of pyrido 3-triazole compounds and preparation method thereof and answer
With.
Background technique
As aging of population, ecological environment are increasingly severe and the reasons such as unhealthy life style increase, China's tumour
Disease incidence persistently rise, tumour has become the unavoidable one of the major reasons for seriously threatening life.This makes anti-swollen
The research and development of tumor medicine are the most active field of medicament research and development always.Traditional chemotherapeutics is substantially cell toxicity medicament, due to
Selectivity it is low, while killing tumor cell, cause normal tissue and cell to be also damaged.With to tumor development
Research is goed deep into, with the cutting edge technology of medicament research and development and life science such as genomics, proteomics, biochip, life
Object informatics is combined closely, and the new drug development of tumor area is increasingly turned to targeted drug from traditional chemotherapeutics.Institute
Meaning targeted drug is for the drug of MOLECULE DESIGN specific during tumor development, they are can selective killing tumour
Cell, the drug without involving the normal tissue around tumour, has many characteristics, such as highly selective, small toxicity.Targeted drug
Research and development have become one of the hot spot of current anti-tumor drug research and development.Wherein the hedgehog signal of abnormal activation is logical in many tumours
The research and development of crucial target spot inhibitor are increasingly taken seriously in road (Hedgehog, HH).
Hedgehog signal path is primarily involved in cell signalling, have it is well-conserved, be initially by Wieschaus
It is found when to drosophila progress mutant screening with Nusslein-Volhard, since Hedghog gene mutation will lead to fruit
There is the furcella of many frightened hedgehogs of likeness in form in fly larvae body, therefore is named as " hedgehog " gene (Hedgehog).Then it is goed deep into
The study found that there is also mainly by Hedgehog ligand, transmembrane protein receptor in mammals for Hedgehog signal path
Patched, Smoothened (SMO) albumen and downstream transcription factor Gli albumen composition.By showing its functional study
The abnormal activation of Hedgehog signal path plays significant role in many malignant tumour occurrence and development, therefore Hedgehog believes
The targeted inhibition agent of number access can be used for inhibiting the proliferation and transfer of malignant tumour.In Hh signal path, Hh ligand, SMO egg
White and Gli transcription factor can become the target spot of targeting anti-tumor small molecule compound, and wherein SMO albumen is in signal path
With pivotal role, druggability is best, so SMO albumen has become the popular target spot of small molecule compound.
Although SMO albumen target spot small-molecule compound layer goes out not poor, only genentech corp at present
The Vismodegib and Sonidegib of Novartis Co., Ltd is successfully listed and is used in the U.S. as the inhibitor of Hh access SMO albumen
Clinical neoplasm targeted therapy, but the two only SMO target spot inhibitor find to have in clinical application it is serious it is bad instead
It answers, and drug resistance occurs, there are no SMO target spot inhibitor with independent intellectual property rights to enter clinical research in China at present, because
This novel SMO target spot small molecule compound is simultaneously very important applied to clinic.
Summary of the invention
The purpose of the present invention is to provide a kind of pyrido 3-triazole compounds and its preparation method and application.
The technical solution used in the present invention is:
Pyrido 3-triazole compounds or its pharmaceutically acceptable salt, the pyrido 3-triazole compounds are selected from following
Any one structure:
The preparation method of pyrido 3-triazole compounds, includes the following steps:
(1) in phosphorus oxychloride solvent, by formula (III) compound and formula (IV) compound heating reflux reaction, preparation formula
(V) compound；
(2) in alcohol solvent, catalyst and reducing agent is added, by formula (V) compound heating reflux reaction, preparation formula
(II) compound；
(3) formula (II) compound is subjected to condensation acylation reaction with compound shown in R1~R20 respectively, obtains right respectively and wants
Compound A described in asking 101~A20；
Wherein, formula (II), (III), (IV), the structural formula difference of (V) are as follows:
The structural formula of compound shown in R1~R20 is as follows:
Further, above-mentioned preparation method specific steps are as follows:
(1) in phosphorus oxychloride solvent, under logical nitrogen protection, formula (III) compound and formula (IV) compound are heated back
Stream reaction 8~12 hours, heating temperature are 100~120 DEG C, isolate and purify product and obtain formula (V) compound；
(2) in alcohol solvent, catalyst and reducing agent is added, after mixing evenly, formula (V) compound is added, is heated to
70~90 DEG C, 3~5h of back flow reaction is isolated and purified after reaction, obtains formula (II) compound；
(3) in toluene solvant, compound shown in R1~R20 is heated to thionyl chloride respectively back flow reaction 2.5~
3.5 hours, acyl chlorides is obtained, it is spare；In dichloromethane solvent, formula (II) compound is added and catalyst adds after mixing evenly
Enter acyl chlorides, reaction is stirred at room temperature overnight, generates compound A respectively01~A20。
Further, in step (1), the concrete operations that isolate and purify are as follows: after reaction, phosphorus oxychloride solvent is evaporated off,
Reaction solution is poured into ice water under stirring, beige solid is precipitated, is filtered, drying.
Further, in step (2), catalyst is iron powder, and reducing agent is saturated aqueous ammonium chloride, the tool isolated and purified
Gymnastics conduct: after reaction, being evaporated off alcohol solvent, adds water, adjusts pH to 8.5~9.5, and methylene chloride extraction merges organic
Phase, washing, salt washing, dry filter are evaporated, and ethyl acetate rinse, filtering obtains field gray solid, are dried.
Further, in step (3), after back flow reaction, it is cooled to room temperature, revolving removes toluene solvant and dichloro is sub-
Sulfone dissolves acyl chlorides with methylene chloride, spare.
Further, in step (3), catalyst DIPEA, the A of generation01~A20Compound uses column chromatographic purifying.
Pyrido 3-triazole compounds and/or its pharmaceutically acceptable salt described above are in preparation SMO protein inhibitor
In application.
Pyrido 3-triazole compounds and/or its pharmaceutically acceptable salt described above are in preparing anti-tumor agent
Application.
Further, the tumour is colon cancer, breast cancer, non-small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, lung maxicell
Cancer.
The beneficial effects of the present invention are:
Inventor is prepared for a kind of A with SMO target spot inhibitory activity by long-term further investigation01~A20Shown structure
Compound belongs to a kind of pyrido 3-triazole compounds, is tested by molecular docking, it can be seen that the compounds of this invention can energy
Enough and target Protein S MO forms strong combination；And there is excellent inhibiting effect to kinds of tumors, be expected to be used for
Prepare SMO target spot inhibitor and anti-tumor drug.The compounds of this invention preparation method simple process, the used time is short, substantially reduces medicine
The cost of object is suitble to large-scale production.
Detailed description of the invention
Hydrogen bond action of the Fig. 1 between compound and SMO albumen, hollow arrow prompt are the amino acid on SMO albumen
Molecule；Filled arrows instruction is the molecular structure of compound；Dotted line is to be formed by hydrogen bond between compound and SMO albumen.
Specific embodiment
In the present invention, term " the compounds of this invention " refers to A01~A20Shown structural compounds, the term further include A01~
A20Various crystalline forms, optical isomer, pharmaceutically acceptable salt, hydrate or the solvate of compound.
In the present invention, term " SMO albumen " refers to smooth albumen (smoothened protein), is 7 transmembrane structures
Domain albumen is under the jurisdiction of g protein coupled receptor FZ/SMO super families member, is that tumour forms related transduction signal path
The crucial of Hedgehog signal path adjusts target spot.
In the present invention, the ingredient of term " pharmaceutically acceptable " refers to suitable for people and/or animal and without excessively bad
Side reaction (such as toxicity, stimulation and allergy) has the substance of reasonable benefit/risk ratio.
In the present invention, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use
Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid
The salt of formation.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic
Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
In the present invention, term " IC50" referring to half-inhibitory concentration, i.e., certain certain density drug-induced tumour cell withers
50% is died, which is known as IC50。
In the present invention, term " mtt assay " refers to a kind of method for detecting cell survival and growth, and testing principle is to live
The bluish violet that succinate dehydrogenase in cell mitochondrial can make exogenous MTT be reduced to water-insoluble crystallizes first a ceremonial jade-ladle, used in libation
(Formazan) it and is deposited in cell, and dead cell is without this function.Because bluish violet crystal production quantity and viable count at
Direct ratio utilizes enzyme-linked immunosorbent assay instrument pair by using the bluish violet crystal deposited in dimethyl sulfoxide (DMSO) dissolution cell
Solution absorbance value (OD) is measured, and can obtain corresponding cell viability situation.
Following embodiments are as an example, and be not intended to be limitation of the present invention in any way.Unless otherwise stated, part
Number is parts by weight, and pressure is or close to atmospheric pressure.All reagent raw materials used in the present invention are that commercial channel obtains.
The preparation method of embodiment 1, pyrido 3-triazole compounds
(1) 3- chloride-2-hydrazinopyridine (formula III) (20g) successively is put into dry reaction flask, the chloro- 5- nitro-benzene of 2-
Formic acid (formula IV) (30g), phosphorus oxychloride (400ml), nitrogen protection, heating (110 DEG C) to back flow reaction are stayed overnight, and trichlorine oxygen is evaporated off
Phosphorus pours into reaction solution in ice water under stirring, and beige solid is precipitated, and filters, and drying obtains the chloro- 3- of 8- (5- nitro -2- chlorobenzene
Base)-[1,2,4] triazole simultaneously [4,3-a] pyridine (formula V)；
(2) iron powder (10g) is put into reaction flask, saturated aqueous ammonium chloride (25ml), ethyl alcohol (25ml), stirring, then
The chloro- 3- of 8- (5- nitro -2- chlorphenyl)-[1,2,4] triazole simultaneously [4,3-a] pyridine (formula V) (11g) is added, heats (60 DEG C)
To back flow reaction 4h, ethyl alcohol is evaporated off, adds water, adjusts pH=9, methylene chloride extraction merges organic phase, washing, and salt is washed, dry
Filtering is evaporated, ethyl acetate rinse, filtering, obtain field gray solid, dry, obtain the chloro- 3- of 8- (5- amino -2- chlorphenyl)-[1,2,
4] the triazole simultaneously basic mother nucleus structure compound (formula II) of [4,3-a] pyridine；
(3) it is put into respectively into reaction flask one of 1~R20 of compound R (being shown in Table 1) (262mg), toluene (1ml), then
It is added thionyl chloride (0.55ml), heating (90 DEG C) was to back flow reaction 3 hours, and system dissolved clarification is cooled to room temperature, and revolving removes molten
Agent and excessive thionyl chloride are dissolved with methylene chloride and obtain solution of acid chloride, spare；The chloro- 3- of 8- is put into another reaction flask
(5- amino -2- chlorphenyl)-[1,2,4] triazole simultaneously [4,3-a] pyridine (formula II) (400mg), methylene chloride (15ml),
DIPEA (554mg), stirring, is added dropwise the solution of acid chloride (5.5ml) of above-mentioned preparation at room temperature, and reaction is stirred at room temperature overnight, reaction knot
Shu Hou carries out column chromatographic isolation and purification, obtains to obtain compound A respectively according to 1~R20 of compound R of investment01~A20, as
SMO protein inhibitor, A01~A20Structural formula be shown in Table 1.
Table 1 compound R 1~R20 and A01~A20Structure
The compound A that the present invention is prepared01~A20Progress nuclear magnetic resonance spectroscopy (1H-NMR it) analyzes, each compound
Structural characterization is as follows.
1. compound A01
1H-NMR(d6-DMSO):δ10.65(s,1H)；8.20(t,1H)；8.17(d,1H)；8.13(q,1H)；7.98(m,
2H)；7.76(d,1H)；7.70(d,1H)；7.62(m,1H)；7.55(m,2H)；7.06(t,1H).13C-NMR(d6-DMSO):δ
166.36,147.97,146.19,139.24,134.84,132.41,130.91,128.97,128.20,127.92,127.55,
125.60,124.52,124.39,124.13,120.65,114.88；
2. compound A02
1H-NMR(d6-DMSO):δ10.95(s,1H)；8.15(m,2H)；8.01(m,1H)；7.77(d,1H)；7.71(d,
1H)；7.62(m,2H)；7.51(m,2H)；7.06(t,1H).13C-NMR(d6-DMSO):δ165.78,148.00,146.16,
138.87,136.87,131.91,131.10,130.38,130.22,129.44,127.94,127.83,125.87,124.19,
123.86,123.76,120.63,114.86；
3. compound A03
1H-NMR(d6-DMSO):δ10.73(s,1H)；8.17(m,2H)；8.11(m,1H)；8.04(t,1H)；7.94(m,
1H)；7.78(d,1H)；7.70(m,2H)；7.60(t,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ164.86,
147.99,146.14,138.93,136.78,133.76,132.24,131.02,127.93,127.85,127.07,125.66,
124.65,124.49,124.15,120.65,114.89；
4. compound A04
1H-NMR(d6-DMSO):δ10.70(s,1H)；8.17(m,2H)；8.11(q,1H)；8.01(m,2H)；7.77(d,
1H)；7.71(q,1H)；7.65(m,2H)；7.06(t,1H).13C-NMR(d6-DMSO):δ165.22,147.98,146.15,
139.03,137.27,133.50,130.95,130.17,129.07,127.93,127.74,125.63,124.60,124.46,
124.14,120.65,114.89；
5. compound A05
1H-NMR(d6-DMSO):δ10.98(s,1H)；8.16(d,1H)；8.11(d,1H)；7.99(q,1H)；7.79(m,
2H)；7.70(m,2H)；7.59(m,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ164.86,148.00,146.12,
138.68,135.69,131.71,131.14,130.87,129.79,128.05,125.91,124.19,123.93,123.80,
120.63,114.87；
6. compound A06
1H-NMR(d6-DMSO):δ10.88(s,1H)；8.21~8.16 (m, 4H)；8.11(m,3H)；7.79(d,1H)；
7.71(q,1H)；7.06(t,1H)；3.31(s,3H).13C-NMR(d6-DMSO):δ165.13,148.00,146.12,
143.91,139.32,138.83,131.03,129.24,127.95,127.66,125.72,124.69,124.53,124.15,
120.65,114.90,43.73；
7. compound A07
1H-NMR(d6-DMSO):δ10.81(s,1H)；9.09(d,1H)；8.75(q,1H)；8.29(m,1H)；8.13(m,
2H)；8.08(m,1H)；7.74(d,1H)；7.66(d,1H)；7.55(m,1H)；7.02(t,1H).13C-NMR(d6-DMSO):δ
164.85,152.84,149.16,147.94,146.07,138.86,135.98,130.95,130.51,127.87,125.65,
124.55,124.42,124.07,123.99,120.62,114.85；
8. compound A08
1H-NMR(d6-DMSO):δ10.62(s,1H)；8.30(s,1H)；8.24(d,1H)；8.14(m,2H)；7.68(q,
2H)；7.01(t,1H)；2.73(s,3H).13C-NMR(d6-DMSO):δ166.97,159.87,149.30,147.89,
146.04,138.63,130.81,127.87,127.74,126.30,125.42,124.62,124.59,124.07,120.59,
114.84,19.26；
9. compound A09
1H-NMR(d6-DMSO):δ11.05(s,1H)；8.72(m,1H)；8.33(d,1H)；8.21(q,1H)；8.14(m,
2H)；8.05(m,1H)；7.73(d,1H)；7.66(m,2H)；7.02(t,1H).13C-NMR(d6-DMSO):δ163.49,
149.90,148.94,147.89,146.03,138.63,138.48,130.88,127.90,127.88,127.63,125.51,
124.59,124.56,124.06,123.06,120.60,114.84；
10. compound A10
1H-NMR(d6-DMSO):δ10.86(s,1H)；8.28(d,1H)；8.11(m,4H)；7.81(t,1H)；7.76(d,
1H)；7.67(d,1H)；7.02(t,1H).13C-NMR(d6-DMSO):δ164.74,147.95,146.07,141.64,
138.79,135.77,133.21,
130.97,130.62,130.34,127.98,127.89,126.58,125.67,124.78,124.61,
124.09,120.62,114.84,43.88；
11. compound A11
1H-NMR(d6-DMSO):δ11.08(s,1H)；8.12(m,2H)；8.06(d,1H)；7.98(m,2H)；7.90(d,
1H)；7.75(d,1H)；7.67(d,1H)；7.02(t,1H).13C-NMR(d6-DMSO):δ164.48,147.97,146.04,
143.68,141.08,138.43,131.38,131.17,130.41,128.58,128.19,127.90,126.41,125.95,
124.14,123.96,123.81120.59,114.82,43.52；
12. compound A12
1H-NMR(d6-DMSO):δ10.95(s,1H)；8.16(d,1H)；8.12(d,1H)；8.00(q,1H)；7.73(m,
3H)；7.63(q,1H)；7.39(m,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ164.98,164.12,161.63,
148.00,146.14,138.78,133.56,131.92,131.36,131.12,127.92,125.88,124.18,123.90,
123.78,120.63,117.69,115.11,114.87；
13. compound A13
1H-NMR(d6-DMSO):δ11.08(s,1H)；8.17(d,1H)；8.09(m,2H)；8.00(m,1H)；7.89(s,
2H)；7.79(d,1H)；7.71(d,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ164.61,148.01,146.10,
140.55,138.52,131.47,131.21,130.45,128.19,127.94,127.15,125.98,124.95,124.20,
123.99,123.84,120.64,114.87；
14. compound A14
1H-NMR(d6-DMSO):δ11.03(s,1H)；8.16(d,1H)；8.12(d,1H)；8.01(q,1H)；7.93(m,
2H)；7.78(m,2H)；7.70(d,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ162.43,160.35,157.85,
148.00,146.06,138.49,131.72,131.18,128.79,128.21,127.94,125.93,124.80,124.16,
124.12,123.98,122.14,120.64,114.87,114.59；
15. compound A15
1H-NMR(d6-DMSO):δ11.10(s,1H)；8.24(d,1H)；8.16(d,1H)；8.08(d,1H)；7.97(q,
1H)；7.78(m,2H)；7.71(d,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ163.46,150.28,148.02,
146.31,146.07,141.89,138.43,132.21,131.24,127.95,126.02,124.29,124.19,124.00,
123.84,120.64,114.87；
16. compound A16
1H-NMR(d6-DMSO):δ10.76(s,1H)；8.15(m,2H)；8.01(m,1H)；7.76(d,1H)；7.70(m,
1H)；7.55(d,1H)；7.45(d,1H)；7.40(m,1H)；7.06(t,1H)；2.40(s,3H).13C-NMR(d6-DMSO):δ
167.61,147.98,146.18,139.06,138.71,135.72,134.90,131.00,130.77,129.69,127.93,
127.64,126.14,125.75,124.15,124.00,123.90,120.64,114.87,19.55；
17. compound A17
1H-NMR(d6-DMSO):δ11.19(s,1H)；8.48(d,1H)；8.17(m,2H)；8.08(d,1H)；7.98(q,
1H)；7.81(d,1H)；7.71(d,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ163.20,148.03,147.61,
147.44,146.04,146.07,141.18,138.29,136.45,131.30,128.47,127.96,126.09,124.21,
124.05,123.88,122.31,121.09,120.64,114.87；
18. compound A18
1H-NMR(d6-DMSO):δ11.25(s,1H)；8.17(d,1H)；8.10(m,1H)；7.98(m,1H)；7.79(d,
1H)；7.70(d,1H)；7.58(q,1H)；7.49(d,1H)；7.42(t,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ
160.99,160.39,157.92,148.02,146.10,138.38,132.64,131.48,131.28,128.28,127.94,
126.15,126.09,125.87,124.28,123.81,123.65,120.61,115.42,114.82；
19. compound A19
1H-NMR(d6-DMSO):δ11.08(s,1H)；8.57(m,1H)；8.14(m,3H)；8.00(m,1H)；7.79(d,
1H)；7.71(m,1H)；7.60(m,1H)；7.06(t,1H).13C-NMR(d6-DMSO):δ164.41,151.32,148.01,
146.86,146.10,138.79,138.62,133.12,131.20,128.13,127.95,125.98,124.20,123.93,
123.79,123.73,120.63,114.87；
20. compound A20
1H-NMR(d6-DMSO):δ11.16(s,1H)；9.19(d,1H)；8.19(m,2H)；8.12(m,1H)；7.79(d,
1H)；7.71(d,1H)；7.06(m,2H).13C-NMR(d6-DMSO):δ162.43,158.45,158.02,147.99,
146.00,138.09,131.09,128.51,127.96,125.73,124.79,124.74,124.14,120.65,114.90,
105.13。
Embodiment 2, the compounds of this invention A01~A20Influence to tumor cell activity
Tumor cell activity is detected using mtt assay, specific experimental method is as follows: digestion logarithmic growth phase human tumor cells
(HT-29, SW620, RKO, A549, T47D, HCT-116, MDA-MB-231), adjustment cell number are 2 × 103A/hole, is inoculated into
96 porocyte culture plates (100 hole μ l/), 37 DEG C, 5%CO2It is cultivated in incubator for 24 hours, replaces complete medium, every group of addition is pressed
The gradient concentration compound (compound concentration is set to 1 μM, 3 μM, 10 μM, 30 μM, 100 μM) of setting is tested, every group 3 multiple
Hole, after cultivating 72h, 10 μ l MTT liquid are added in every hole, are incubated for 4h, terminate reaction, measure every hole OD value with enzyme-linked immunosorbent assay instrument
(wavelength 570nm).Experiment sets not inoculating cell and replaces compound group (blank group) and inoculating cell and use with complete medium
Complete medium replaces compound group (control group), by the inhibition journey for calculating you can get it compound on tumor cell vigor
Degree.
Inhibitory rate of cell growth is calculated according to the following formula:
Inhibiting rate=[(Ac-As)/(Ac-Ab)] × 100%
As: experimental port (containing cell culture medium, MTT, compound)
Ac: control wells (culture medium containing cell, MTT, without compound)
Ab: blank well (culture medium, MTT, without compound) without cell and compound
According to the inhibiting rate of drug cell proliferation at different dosages, calculated by 5 software of GraphPad Prism
IC50Value, the results are shown in Table 2.
2 the compounds of this invention A of table01~A20To the IC of different tumour cells50Value
Note: HT-29, SW620, RKO, HCT-116 are colon cancer cells；T47D, MDA-MB-231 are breast cancer cells；
A549 is non-small cell lung cancer cell.
This is the results showed that compound A01~A20Have to cancers such as colon cancer, breast cancer, non-small cell lung cancer cells
Different degrees of inhibiting effect can be applied to prepare anti-tumor drug.Wherein, compound A03Have to kinds of tumor cells preferably
Inhibitory effect, especially particularly evident to the cell inhibitory effect effect of HT-29 cell, IC50Value is 6.2 ± 1.5 μM.
Binding force detection between embodiment 3, the compounds of this invention and target proteins SMO albumen
In order to further study the compounds of this invention antineoplastic action mechanism, invention further contemplates the present inventionization
Close object A01~A20It whether there is combination between target proteins SMO albumen.Molecular docking is according to ligand and receptor acting
" lock-key principle ", simulate the interaction between smaller ligand and receptor biological macromolecular.Divided by software MVD 4.0
Analysis calculates binding pattern and affinity between smaller ligand and receptor biological macromolecular, evaluates ligand in conjunction with the targeting of receptor
Degree is to carry out drug design and screening.Combination between small molecule compound and target albumen mainly passes through the two
Between be formed by hydrogen bond action.Compound A03,A14,A15,A18Can preferable inhibitory effect be generated to kinds of tumor cells, especially
It is A03It is particularly evident to the cell inhibitory effect effect of HT-29 cell, IC50Value is 6.2 ± 1.5 μM.Choose compound
A03,A14,A15,A18Representative compound and SMO albumen as the invention series compound carry out molecular docking experiment, with inspection
It is strong and weak to survey binding force between series compound and the target proteins SMO of the present invention, and tie up Mo Diji be at present clinically by
Targeted inhibition SMO albumen and the drug for being used to treat basal cell tumor, choose it as positive control herein.
Testing result is as shown in Figure 1, A03,A14,A15,A18It can be formed therewith and forming multiple hydrogen bonds with SMO albumen
Strong binding pattern, and wherein A14,A15The number that hydrogen bond is formed between SMO is more than positive control medicine dimension not especially
It is lucky.Molecular docking the result shows that the invention series compound may be played by targeting in SMO albumen it is antitumor
Effect.
Claims (11)
1. pyrido 3-triazole compounds or its pharmaceutically acceptable salt, the pyrido 3-triazole compounds are selected from following
It anticipates a kind of structure:
2. the preparation method of pyrido 3-triazole compounds described in claim 1, characterized by the following steps:
(1) in phosphorus oxychloride solvent, by formula (III) compound and formula (IV) compound heating reflux reaction, preparation formula (V) is changed
Close object；
(2) in alcohol solvent, catalyst and reducing agent is added, by formula (V) compound heating reflux reaction, preparation formula (II)
Compound；
(3) formula (II) compound is subjected to condensation acylation reaction with compound shown in R1~R20 respectively, obtains claim 1 respectively
The compound A01~A20；
Wherein, formula (II), (III), (IV), the structural formula difference of (V) are as follows:
The structural formula of compound shown in R1~R20 is as follows:
3. preparation method according to claim 2, it is characterised in that: preparation method specific steps are as follows:
(1) in phosphorus oxychloride solvent, under logical nitrogen protection, formula (III) compound and formula (IV) compound are heated to reflux instead
It answers 8~12 hours, heating temperature is 100~120 DEG C, isolates and purifies product and obtains formula (V) compound；
(2) in alcohol solvent, catalyst and reducing agent is added, after mixing evenly, formula (V) compound is added, it is heated to 70~
90 DEG C, 3~5h of back flow reaction is isolated and purified after reaction, obtains formula (II) compound；
(3) in toluene solvant, it is small that compound shown in R1~R20 is heated to back flow reaction 2.5~3.5 with thionyl chloride respectively
When, acyl chlorides is obtained, it is spare；In dichloromethane solvent, formula (II) compound and catalyst is added, after mixing evenly, acyl is added
Chlorine is stirred at room temperature reaction overnight, generates compound A respectively01~A20。
4. preparation method according to claim 3, it is characterised in that: in step (1), the concrete operations that isolate and purify are as follows:
After reaction, phosphorus oxychloride solvent is evaporated off, pours into reaction solution in ice water under stirring, beige solid is precipitated, filters, dries
It is dry.
5. preparation method according to claim 3, it is characterised in that: in step (2), catalyst is iron powder, and reducing agent is
Saturated aqueous ammonium chloride, the concrete operations isolated and purified are as follows: after reaction, alcohol solvent is evaporated off, adds water, adjust pH to
8.5~9.5, methylene chloride extraction merges organic phase, washing, and salt is washed, and dry filter is evaporated, ethyl acetate rinse, filtering,
Obtain field gray solid, drying.
6. preparation method according to claim 3, it is characterised in that: in step (3), after back flow reaction, be cooled to
Room temperature, revolving remove toluene solvant and thionyl chloride, dissolve acyl chlorides with methylene chloride, spare.
7. preparation method according to claim 3, it is characterised in that: in step (3), catalyst DIPEA, the A of generation01
~A20Compound uses column chromatographic purifying.
8. pyrido 3-triazole compounds described in claim 1 and/or its pharmaceutically acceptable salt are in preparation SMO albumen suppression
Application in preparation.
9. pyrido 3-triazole compounds described in claim 1 and/or its pharmaceutically acceptable salt are preparing antitumor system
Application in agent.
10. application according to claim 9, it is characterised in that: the tumour is colon cancer, breast cancer, non-small cell lung
Cancer.
11. application according to claim 10, it is characterised in that: the non-small cell lung cancer is adenocarcinoma of lung, lung squamous cancer, lung
Large cell carcinoma.
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