CN107474046A - 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 inhibitory action to kinds of tumors, be expected to be used for preparing SMO target spots inhibitor and antineoplastic.The compounds of this invention preparation method technique is simple, and the used time is short, substantially reduces the cost of medicine, is adapted to large-scale production.
Description
Technical field
The present invention relates to field of medicaments, relates more specifically to a kind of pyrido 3-triazole compounds and preparation method thereof and answers
With.
Background technology
As aging population, ecological environment are increasingly severe and the reason such as unhealthy life style increases, China's tumour
The incidence of disease persistently rise, tumour has become one of major reason of unavoidable serious threat life.This causes anti-swollen
The research and development of tumor medicine are the most active field of medicament research and development all the time.Traditional chemotherapeutics is substantially cell toxicity medicament, due to
Selectivity it is low, while killing tumor cell, cause normal structure and cell also to suffer damage.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
Thing 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 to be directed to during tumor development the specifically medicine of MOLECULE DESIGN, and they are can selective killing tumour
Cell, the medicine without involving the normal structure around tumour, there is the features such as high selectivity, small toxicity.Targeted drug
Research and development have become one of focus of current antineoplastic research and development.The hedgehog signal of abnormal activation leads to wherein in many tumours
The research and development of crucial target spot inhibitor are increasingly taken seriously in road (Hedgehog, HH).
Hedgehog signal paths are primarily involved in cell signalling, have it is well-conserved, be initially by Wieschaus
The discovery when carrying out screening mutant to drosophila with Nusslein-Volhard, because Hedghog gene mutations can cause 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
Research finds that there is also mainly by Hedgehog parts, transmembrane protein acceptor in mammal for Hedgehog signal paths
Patched, Smoothened (SMO) albumen and downstream transcription factor Gli albumen composition.By showing its functional study,
The abnormal activation of Hedgehog signal paths plays significant role in many malignant tumour occurrence and development, therefore Hedgehog believes
The targeted inhibition agent of number path can be used for propagation and the transfer for suppressing malignant tumour.In Hh signal paths, Hh parts, SMO eggs
White and Gli transcription factors can turn into the target spot of targeting anti-tumor micromolecular 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 micromolecular compound.
Although SMO albumen target spot small-molecule compound layers go out not poor, only Genentech company 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 path SMO albumen
Clinical neoplasm targeted therapy, but the two only SMO target spots inhibitor finds to have in clinical practice it is serious it is bad instead
Should, and there is resistance, China also enters clinical research without the SMO target spots inhibitor with independent intellectual property right at present, because
This new SMO target spots micromolecular compound and applied to clinic be very important.
The content of the invention
It is an object of the invention 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, comprises the following steps：
(1) in POCl3 solvent, by formula (III) compound and formula (IV) compound heating reflux reaction, formula
(V) compound；
(2) in alcohol solvent, catalyst and reducing agent are added, by formula (V) compound heating reflux reaction, formula
(II) compound；
(3) formula (II) compound is subjected to condensation acylation reaction with compound shown in R1~R20 respectively, obtaining right respectively will
Seek the compound A described in 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 concretely comprises the following steps：
(1) in POCl3 solvent, under the protection of logical nitrogen, formula (III) compound and formula (IV) compound are heated back
Stream reaction 8~12 hours, heating-up temperature is 100~120 DEG C, isolates and purifies product and obtains formula (V) compound；
(2) in alcohol solvent, catalyst and reducing agent are added, after stirring, formula (V) compound is added, is heated to
70~90 DEG C, 3~5h of back flow reaction, reaction isolates and purifies after terminating, and 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 standby；In dichloromethane solvent, formula (II) compound and catalyst are added, after stirring, is added
Enter acyl chlorides, reaction is stirred at room temperature overnight, generates compound A respectively01~A20。
Further, in step (1), the concrete operations isolated and purified are：After reaction terminates, POCl3 solvent is evaporated off,
Reaction solution is poured into frozen water under stirring, separates out beige solid, 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 terminates, alcohol solvent is evaporated off, adds water, adjusts pH to 8.5~9.5, dichloromethane extraction, merges organic
Phase, washing, salt washing, dry filter are evaporated, and ethyl acetate rinse, filtering, are obtained field gray solid, are dried.
Further, in step (3), after back flow reaction terminates, room temperature is cooled to, revolving removes toluene solvant and dichloro is sub-
Sulfone, acyl chlorides is dissolved with dichloromethane, it is standby.
Further, in step (3), catalyst DIPEA, the A of generation01~A20Compound is purified using column chromatography.
Pyrido 3-triazole compounds and/or its pharmaceutically acceptable salt described above are preparing SMO protein inhibitors
In application.
Pyrido 3-triazole compounds described above and/or its pharmaceutically acceptable salt are in anti-tumor agent is prepared
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 invention are as follows：
Inventor is prepared for a kind of A with SMO target spot inhibitory activity by long-term further investigation01~A20Shown structure
Compound, belong to a kind of pyrido 3-triazole compounds, 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 inhibitory action to kinds of tumors, be expected to be used for
Prepare SMO target spots inhibitor and antineoplastic.The compounds of this invention preparation method technique is simple, and the used time is short, substantially reduces medicine
The cost of thing, it is adapted to large-scale production.
Brief description of the drawings
Hydrogen bond actions of the Fig. 1 between compound and SMO albumen, hollow arrow prompting for the amino acid on SMO albumen
Molecule；The molecular structure for compound of filled arrows instruction；Dotted line is the hydrogen bond that is formed between compound and SMO albumen.
Embodiment
In the present invention, term " the compounds of this invention " refers to A01~A20Shown structural compounds, the term also 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, it is under the jurisdiction of g protein coupled receptor FZ/SMO super families members, is that tumour forms related transduction signal path
The crucial regulation target spot of Hedgehog signal paths.
In the present invention, the composition of term " pharmaceutically acceptable " refers to suitable for people and/or animal and without excessively bad
Side reaction (such as toxicity, stimulation and allergy), that is, have rational benefit/risk than material.
In the present invention, term " pharmaceutically acceptable salt " refers to the suitable use that the compounds of this invention is formed with acid or alkali
Make the salt of medicine.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferable 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, butanedioic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
The organic acids such as picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzene sulfonic acid；And the acidic amino acid such as aspartic acid, glutamic acid.
In the present invention, term " IC50" referring to half-inhibition concentration, i.e., certain certain density drug-induced tumour cell withers
50% is died, the concentration is referred to as IC50。
In the present invention, term " mtt assay " refers to a kind of method for detecting cell survival and growth, and its Cleaning Principle is work
Succinate dehydrogenase in cell mitochondrial can make exogenous MTT be reduced to water-insoluble bluish violet crystallization first a ceremonial jade-ladle, used in libation
(Formazan) and it is deposited in cell, and dead cell is without this function.Because bluish violet crystal growing amount and viable count into
Direct ratio, the bluish violet crystal deposited in cell is dissolved by using dimethyl sulfoxide (DMSO), utilizes enzyme-linked immunosorbent assay instrument pair
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 indicated, 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-hydrazinopyridines (formula III) (20g), the chloro- 5- nitros-benzene of 2- are put into dry reaction bulb successively
Formic acid (formula IV) (30g), POCl3 (400ml), nitrogen protection, heating (110 DEG C) are stayed overnight to back flow reaction, and trichlorine oxygen is evaporated off
Phosphorus, reaction solution is poured into frozen water under stirring, separate out beige solid, filtered, drying, obtain the chloro- 3- of 8- (5- nitro -2- chlorobenzenes
Base)-[1,2,4] triazole simultaneously [4,3-a] pyridine (formula V)；
(2) iron powder (10g) is put into reaction bulb, saturated aqueous ammonium chloride (25ml), ethanol (25ml), is stirred, then
8- chloro- 3- (5- nitro -2- chlorphenyls)-[1,2,4] triazole simultaneously [4,3-a] pyridine (formula V) (11g) is added, is heated (60 DEG C)
To back flow reaction 4h, ethanol is evaporated off, adds water, adjusts pH=9, dichloromethane extraction, merges organic phase, washing, salt washing, dry
Filtering is evaporated, ethyl acetate rinse, filtering, obtain field gray solid, dry, obtain the chloro- 3- of 8- (5- amino -2- chlorphenyls)-[1,2,
4] the triazole simultaneously basic mother nucleus structure compound (formula II) of [4,3-a] pyridine；
(3) one kind (262mg) put into respectively into reaction bulb in 1~R20 of compound R (being shown in Table 1), toluene (1ml), then
Thionyl chloride (0.55ml), heating (90 DEG C) to back flow reaction 3 hours are added, system dissolved clarification is cooled to room temperature, and revolving removes molten
Agent and excessive thionyl chloride, dissolved with dichloromethane and obtain solution of acid chloride, it is standby；The chloro- 3- of 8- are put into another reaction bulb
(5- amino -2- chlorphenyls)-[1,2,4] triazole simultaneously [4,3-a] pyridine (formula II) (400mg), dichloromethane (15ml),
DIPEA (554mg), stirring, the solution of acid chloride (5.5ml) of above-mentioned preparation is added dropwise at room temperature, reaction is stirred at room temperature overnight, reaction knot
Shu Hou, column chromatographic isolation and purification is carried out, compound A is obtained to obtain according to 1~R20 of compound R of input respectively01~A20, it is
SMO protein inhibitors, A01~A20Structural formula be shown in Table 1.
Table 1 compound R 1~R20 and A01~A20Structure
The compound A prepared to the present invention01~A20Progress proton nmr spectra (1H-NMR) analyze, 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 experiment method is as follows：Digest exponential phase human tumor cells
(HT-29, SW620, RKO, A549, T47D, HCT-116, MDA-MB-231), adjustment cell number are 2 × 103Individual/hole, is inoculated into
96 porocyte culture plates (100 μ l/ holes), 37 DEG C, 5%CO224h is cultivated in incubator, changes 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 per hole, be incubated 4h, terminating reaction, determined with enzyme-linked immunosorbent assay instrument per hole OD values
(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), and the suppression journey of compound on tumor cell vigor can be drawn by calculating
Degree.
Inhibitory rate of cell growth is calculated by following equation：
Inhibiting rate=[(Ac-As)/(Ac-Ab)] × 100%
As:Experimental port (culture medium, MTT containing cell, compound)
Ac:Control wells (culture medium, MTT containing cell, without compound)
Ab:Blank well (culture medium, MTT without cell and compound, without compound)
According to the inhibiting rate of medicine cell proliferation at different dosages, calculated by the softwares of GraphPad Prism 5
IC50Value, as a result as shown in table 2.
The compounds of this invention A of table 201~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 test result indicates that：Compound A01~A20Have to cancers such as colon cancer, breast cancer, non-small cell lung cancer cells
Different degrees of inhibitory action, it can be applied to prepare antineoplastic.Wherein, compound A03Have to kinds of tumor cells preferably
Inhibition, especially particularly evident to the cell inhibitory effect effect of HT-29 cells, its IC50It is worth for 6.2 ± 1.5 μM.
Adhesion detection between embodiment 3, the compounds of this invention and target proteinses SMO albumen
In order to further study the compounds of this invention antineoplastic action mechanism, invention further contemplates the present inventionization
Compound A01~A20It whether there is combination between target proteinses SMO albumen.Molecular docking is according to part and receptor acting
" lock-key principle ", simulate the interaction between smaller ligand and receptor biological macromolecular.Divided by software MVD 4.0
Analysis calculates the binding pattern and affinity between smaller ligand and receptor biological macromolecular, and evaluation part is combined with the targeting of acceptor
Degree is so as to carrying out drug design and screening.Combination between micromolecular compound and target albumen is mainly it by both
Between the hydrogen bond action that is formed.Compound A03,A14,A15,A18Can preferable inhibition be produced to kinds of tumor cells, especially
It is A03It is particularly evident to the cell inhibitory effect effect of HT-29 cells, its IC50It is worth for 6.2 ± 1.5 μM.Choose compound
A03,A14,A15,A18Representative compound as the invention series compound carries out molecular docking experiment with SMO albumen, with inspection
It is strong and weak to survey adhesion between series compound and the target proteinses SMO of the present invention, and tie up Mo Diji be at present clinically by
Targeted inhibition SMO albumen and be used for the medicine for treating basal cell tumor, choose it herein as positive control.
Testing result is as shown in figure 1, A03,A14,A15,A18Can be by forming multiple hydrogen bonds with SMO albumen to be formed therewith
Strong binding pattern, and wherein A14,A15The number that hydrogen bond is formed between SMO is tieed up not more than positive control medicine especially
It is lucky.It is antitumor that the result of molecular docking shows that the invention series compound may be played in SMO albumen by targeting
Effect.
Claims (10)
1. pyrido 3-triazole compounds or its pharmaceutically acceptable salt, the pyrido 3-triazole compounds are selected from following
Anticipate a kind of structure：
2. the preparation method of pyrido 3-triazole compounds described in claim 1, it is characterised in that：Comprise the following steps：
(1) in POCl3 solvent, by formula (III) compound and formula (IV) compound heating reflux reaction, formula (V) is changed
Compound；
(2) in alcohol solvent, catalyst and reducing agent are added, by formula (V) compound heating reflux reaction, formula (II)
Compound；
(3) formula (II) compound is subjected to condensation acylation reaction with compound shown in R1~R20 respectively, obtains claim 1 respectively
Described 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 concretely comprises the following steps：
(1) in POCl3 solvent, under the protection of logical nitrogen, formula (III) compound and formula (IV) compound are heated to reflux instead
Answer 8~12 hours, heating-up temperature is 100~120 DEG C, isolates and purifies product and obtains formula (V) compound；
(2) in alcohol solvent, catalyst and reducing agent are added, after stirring, adds formula (V) compound, it is heated to 70~
90 DEG C, 3~5h of back flow reaction, reaction isolates and purifies after terminating, and 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 standby；In dichloromethane solvent, formula (II) compound and catalyst are added, after stirring,
Acyl chlorides is added, reaction is stirred at room temperature overnight, generates compound A respectively01~A20。
4. preparation method according to claim 3, it is characterised in that：In step (1), the concrete operations isolated and purified are：
After reaction terminates, POCl3 solvent is evaporated off, pours into reaction solution in frozen water under stirring, separate out beige solid, filter, dry
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：After reaction terminates, alcohol solvent is evaporated off, adds water, regulation pH to
8.5~9.5, dichloromethane extraction, merge organic phase, washing, 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 terminates, it is cooled to
Room temperature, revolving remove toluene solvant and thionyl chloride, dissolve acyl chlorides with dichloromethane, standby.
7. preparation method according to claim 3, it is characterised in that：In step (3), catalyst DIPEA, the A of generation01
~A20Compound is purified using column chromatography.
8. the pyrido 3-triazole compounds and/or its pharmaceutically acceptable salt described in claim 1 are preparing the suppression of SMO albumen
Application in preparation.
9. the pyrido 3-triazole compounds and/or its pharmaceutically acceptable salt described in claim 1 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, adenocarcinoma of lung, lung squamous cancer, large cell lung cancer.
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| CN104470902A (en) * | 2012-07-19 | 2015-03-25 | 南京英派药业有限公司 | N-(3-heteroarylaryl)-4-arylarylcarboxamtdes and analogs as hedgehog pathway inhibitors and use thereof |
| WO2015154039A2 (en) * | 2014-04-04 | 2015-10-08 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
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| CN104470902A (en) * | 2012-07-19 | 2015-03-25 | 南京英派药业有限公司 | N-(3-heteroarylaryl)-4-arylarylcarboxamtdes and analogs as hedgehog pathway inhibitors and use thereof |
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