CN108675988A - A kind of pyridine compounds and their and application - Google Patents
A kind of pyridine compounds and their and application Download PDFInfo
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Abstract
A kind of pyridine compounds and their and application, based on VEGFR 2, EphB4, TIE 2 can compensatory activation discovery, using biphenyl aryl ureas as pilot object, the conservative conformation in three kinds of receptor active sites of analysis simultaneously finds general character structural domain；The drug design strategies hybridized using molecule, structure meet the compound library of general character structural domain conformational requirements, and more target inhibitor of three compensatory accesses of antagonism simultaneously are found by multilevel screening active ingredients.Kinases screening test shows most of all with preferable kinase inhibiting activity in pyridine compounds and their of the invention, cell proliferation test, which shows majority of compounds all, has stronger cell inhibitory effect activity, the novel drug effect segment that Structure-activity analysis is designed as more target inhibitor, can be used in preparing in anti-angiogenic medicaments.
Description
Technical field
The present invention relates to a kind of pyridine compounds and their and applications.
Background technology
Anti-angiogenesis is mainly used in the treatment of the various vascular proliferative diseases including malignant tumour.It is intended to drop
Low vessel density and inhibition angiogenesis.Assume initially that anti-angiogenesis inhibitor can evade typical drug resistance, because
Its target cell is the endothelial cell of inheritance stability.But the tumor invasiveness of a variety of angiogenic factors induction increase and with
The drug resistance obtained afterwards, so and not all patient all from antiangiogenesis therapy be benefited.
In order to preferably determine the resistance of cancer cell, more in-depth study is done, this allows them to overcome anti-blood
Pipe generation strategy.The acquired resistance of anti-angiogenesis inhibitor is mainly to be drawn by the compensatory activation of angiogenic factors
It rises.The compensatory of angiogenic factors activates the blocking for enabling tumour to evade single channel.Anti-angiogenesis inhibitor
Then induction of vascular normalization and the transmission of chemotherapeutics can be enhanced.Another mechanism is to reduce anoxic to obtain cancer cell maximum
The death of degree.The temporary increase oxygen of anti-angiogenic therapy closes and drug delivery.Clinical and experimental study it has been proved that
After treatment using anti-angiogenesis inhibitor, tumour is using compensatory angiogenesis approach and its continued propagation and transfer
Other Adaptive mechanisms.Therefore, the compensatory signal path of growth and metastasis of tumours is caused to become the intractable potential original of tumour
Cause.
The researchs such as Sato confirm：A variety of regulatory factors take part in angiogenesis jointly, after single target agent effect
The compensatory activation of other regulatory factors can be induced.Wang and Sawamiphak etc. has found to activate after EphB4 is suppressed
VEGFR-2 promotes angiogenesis as compensatory access.In addition, the activity of EphB4 also controllable VEGFR-2, in angiogenesis
The expression of the middle effect for playing total regulation and control person, EphB4 and VEGFR-2 is also in high consistency.Erber etc. has found that EphB4 is pressed down
It is capable of the expression of compensatory up-regulation Tie-2 and VEGFR-2 after system, and then promotes angiogenesis.Huang etc. confirms the rush of Tie-2
Angiogenesis function is VEGFR-2 dependences, and especially when VEGFR-2 is suppressed, Tie-2 can be used as alternative rush blood vessel
The factor is generated to be activated by compensatory.The activation of this three compensatory accesses can make the dynamic equilibrium of angiogenesis regulation and control once again
Imbalance causes blood vessel paraplasm again, and then shortens " time window " of simultaneously final plant closure blood vessel normalization.
Currently, although the research of anti-angiogenic medicaments achieves some innovative progress, asked there is also following
Topic：1. modulating vascular generation is a network, it is related to multiple signal paths, after single target agent effect, angiogenesis often goes out
Existing compensatory access, leads to the generation of drug resistance；2. it has been found that anti-angiogenic medicaments action targets selectivity it is not high, it is bad
React more；3. single target anti-angiogenic medicaments can only vasoactive generating process a link, angiogenesis it is more
Cytokine regulatory and its complexity directly limit the effect of single target agent.Although the research of anti-angiogenic medicaments is for clinic
Time do not grow, be scarcely out of swaddling-clothes, but for pathologic vessels generate relevant disease treatment have definite curative effect and
Good application prospect will become a kind of and also need to more basic research explorations applied to clinical maturation method.
Therefore, blood vessel normalization potentially contributes to during anti-angiogenic therapy, and have improves within some period
Cycle so that chemotherapeutics are more effective.The mechanism of anti-angiogenesis inhibitor resistance is alterable height, and depending on anti-
The difference of angiogenesis inhibitors and it is different.Angiogenic factors such as VEGFR-2, the compensatory of Tie-2, EphB4 and FGFR
Activation is possible to lead to the main mechanism of reactivity and drug resistance difference.
Invention content
The purpose of the present invention is to provide a kind of pyridine compounds and their and applications.
To achieve the above object, the present invention adopts the following technical scheme that：
The structural formula of a kind of pyridine compounds and their, the compound is：
Wherein, R1For Cl, F, H, CH3、CF3、NH2OrR2For-OCH3Or H.
The present invention, which further improves, to be, R1And R2It is specific as follows：
The present invention, which further improves, to be, R1For Cl, R2For-OCH3When, preparation process is as follows：
Synthesis to bromine Bian nitrine：Under condition of ice bath, bromine Bian bromine will be dissolved in anhydrous DMF, first part of nitrine is added dropwise
Change sodium water solution, be warmed to room temperature and second part of aqueous sodium azide is added dropwise again, after being added dropwise, reacts at room temperature 12h, decompression is steamed
It evaporates, with chromatography post separation, yellow oil is obtained, as to bromine Bian nitrine；
The synthesis of 1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles：It will be to bromine Bian nitrine, m-chloro phenylacetylene
It is dissolved in absolute ethyl alcohol, L-AA sodium and Salzburg vitriol is then added, water is then added, 12h is stirred at room temperature, depressurize
Distillation obtains white solid, as 1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles with chromatography post separation；
5- (4- (4- (3- chlorphenyls) -1H-1,2,3- triazole 1- yls) methyl) phenyl) -2 methoxypyridines synthesis：To
1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles, 2- methoxyl group -5- pyridine boronic acids, carbonic acid are added in reaction bulb
Potassium and [1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride, add Isosorbide-5-Nitrae-dioxane and water, under nitrogen protection in
100 DEG C of reaction 12h, are cooled to room temperature, by chromatographing post separation, obtain white solid, as 5- (4- (4- (3- chlorphenyls)-
1H-1,2,3- triazole 1- yls) methyl) phenyl) -2 methoxypyridines.
A kind of application of pyridine compounds and their in preparing anti-angiogenic medicaments.
The present invention, which further improves, to be, which, which has, inhibits VEGFR-2, Tie-2 and EphB4 kinase activity
Effect.
The present invention, which further improves, to be, which has the function of anti-vascular endothelial cell proliferation activity.
Compared with prior art, the device have the advantages that：
The present invention is based on VEGFR-2, EphB4, TIE-2 can compensatory activation discovery, with biphenyl aryl ureas be novel elder generation
Object is led, the conservative conformation in three kinds of receptor active sites is analyzed and finds general character structural domain；The drug design plan hybridized using molecule
Slightly, structure meets the compound library of general character structural domain conformational requirements, and three generations of antagonism simultaneously are found by multilevel screening active ingredients
More target inhibitor of repaying property access.Kinases screening test shows that majority of compounds all has preferable kinase inhibiting activity,
Middle R1For-Cl, R2For-OCH3When pyridine compounds and their and R1For-NH2, R2For-OCH3When pyridine compounds and their simultaneously
There is preferable inhibitory activity to three kinds of kinases.Cell proliferation test, which shows majority of compounds all, has the suppression of stronger cell Proliferation
System activity, Activity Results experiment confirm R1For-Cl, R2For-OCH3When pyridine compounds and their have very to Human umbilical vein endothelial cells
Strong inhibitory activity.Structure-activity analysis is found：Triazole structure segment plays an important roll the inhibitory activity of compound, hinge
The introducing of sequence heterocycle can improve small molecule and the affinity and inhibitory activity of receptor, more target inhibitor can be used as to design
Novel drug effect segment.
Further, it is respectively synthesized pyridines target compound using reactions such as acylation, Suzuki couplings, click chemistries,
The compound has the more target inhibitor of small molecule of brand new, and characterizes target compound by means such as HRMS, NMR
Structure.
Description of the drawings
Fig. 1 is the synthetic route chart of the present invention.
Specific implementation mode
The present invention is described in detail below in conjunction with the accompanying drawings.
Referring to Fig. 1, the structural formula of pyrazole compound of the invention is：
Wherein, R1For Cl, F, H, CH3、CF3、NH2OrR2For-OCH3Or H.Specifically refer to table 1.
The concrete structure of 1 the compound of the present invention of table
R in table 11In number be to indicate R1Position of the group on phenyl ring.
Referring to Fig. 1, specific preparation process of the invention is as follows：
Synthesis of the compound to bromine Bian nitrine (3)：It, will be molten to bromine Bian bromine (2) 2.00g (8.00mmol) under condition of ice bath
In 20mL anhydrous DMFs, the aqueous solution of sodium azide (amount of sodium azide is 0.78g (11.99mmol)) is slowly added dropwise, then
It is warmed to room temperature the aqueous solution that sodium azide (amount of sodium azide is 0.78g (11.99mmol)) is slowly added dropwise again, is added dropwise
Afterwards, ice bath is removed, room temperature reaction is stayed overnight, i.e. 12h.After reaction, be extracted with ethyl acetate 2~3 times, the organic phase of extraction according to
Secondary saturation NaHCO3Solution (60mL × 3), saturation NaCl washings (60mL × 3), anhydrous Na2SO4Dry, filtering, decompression steams
Solvent, with chromatography post separation (petroleum ether：Ethyl acetate volume ratio=40:1) yellow oil, is obtained, as to bromine Bian nitrine
(3) 1.45g, yield are about 85.1%.
The synthesis of compound 1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles (4)：In 100ml reaction bulbs
In, it is anhydrous that 1.20g (5.63mmol) is dissolved in 30ml to bromine Bian nitrine (3) and 0.78g (5.63mmol) m-chloro phenylacetylenes (1)
In ethyl alcohol, add after 0.45g (2.25mmol) L-AA sodium and 0.29g (1.13mmol) Salzburg vitriol is then added
Enter 3mL water, be stirred overnight at room temperature, is i.e. 12h.Vacuum distillation removes solvent, with chromatography post separation (petroleum ether：Ethyl acetate volume
Than=3:1) white solid, as 1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles (4) 1.31g, yield, are obtained
About 66.7%.
Compound 5- (4- (4- (3- chlorphenyls) -1H-1,2,3- triazole 1- yls) methyl) phenyl) -2 methoxypyridines
(BD1) synthesis and structure characterization：1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles are added into reaction bulb
(4) 1.20g (3.44mmol), 2- methoxyl group -5- pyridine boronic acids 0.68g (4.47mmol), potassium carbonate 1.43g (10.35mmol)
And [1,1'- bis- (diphenylphosphine) ferrocene] four kinds of reaction reagents of palladium chloride 0.25g (0.34mmol), and 30mL is added
Isosorbide-5-Nitrae-dioxane and 10mL water, under nitrogen protection overnight in 100 DEG C of reactions, i.e. 12h.It is cooled to room temperature, uses ethyl acetate
Extraction 3-4 times, the organic phase of extraction is successively with saturation NaHCO3Solution (60mL × 3), saturation NaCl washings (60mL × 3), nothing
Water Na2SO4It is dry, it is spin-dried for, by chromatographing post separation (petroleum ether：Ethyl acetate volume ratio=15:1) white solid, is obtained, i.e.,
For 5- (4- (4- (3- chlorphenyls) -1H-1,2,3- triazole 1- yls) methyl) phenyl) -2 methoxypyridines (BD1) 0.39g, yield
About 30%, m.p.=160-162 DEG C.HRMS(ESI)[M+H]+:M/z=376.1H NMR(400MHz,DMSO)δ10.87(s,
1H), 9.21 (s, 1H), 8.99 (s, 1H), 8.63 (d, J=2.2Hz, 1H), 8.14 (d, J=8.7Hz, 2H), 8.04 (m, J=
8.7,2.4Hz, 1H), 7.65 (t, J=8.3Hz, 4H), 7.58 (d, J=8.7Hz, 2H), 2.03 (t, J=12.3,8.6,
4.8Hz,1H),0.92–0.71(m,4H).13C NMR(101MHz,DMSO)δ163.62,145.82,145.20,138.01,
137.39,135.35,134.15,133.20,131.34,129.21,129.15,128.14,127.20,125.22,124.12,
122.80,111.09,53.74,53.25.
The synthesis of compound BD2~BD16 is same as above, 2- methoxyl group -5- pyridine boronic acids (5) and 5- pyridine boronic acids (6) with containing not
Intermediate 4 with substituent group obtains target compound by Suzuki coupling reactions.
Compound 5- (4- (4- (2- fluorophenyls) -1H-1,2,3- triazole 1- yls) methyl) phenyl) -2 methoxypyridines
(BD2) synthesis and structure characterization：Yield 33%, m.p.=122-124 DEG C.HRMS(ESI)[M+H]+:M/z=360.1H NMR
(400MHz,DMSO-d6) δ 8.16 (t, J=7.7Hz, 1H), 8.02 (dd, J=8.7,2.6Hz, 1H), 7.70 (d, J=
8.2Hz, 2H), 7.49 (d, J=8.2Hz, 1H), 7.45-7.31 (m, 3H), 6.93 (d, J=8.6Hz, 1H), 5.76 (s, 2H),
3.91(s,3H).13C NMR(101MHz,DMSO)δ163.67,160.20,157.75,145.26,140.45,138.06,
137.39,135.64,130.25,130.17,129.22,127.84,127.80,127.23,125.51,125.47,124.56,
124.45,118.89,118.76,116.64,116.43,111.13,53.79,53.08.
Compound 2- methoxyl groups -5- (4- (4- phenyl -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine (BD3)
Synthesis and structure characterizes：Yield 29%, m.p.=196-197 DEG C.HRMS(ESI)[M+H]+:M/z=342.1H NMR
(400MHz,DMSO-d6) δ 8.69 (s, 1H), 8.48 (d, J=2.3Hz, 1H), 8.01 (d, J=11.1Hz, 1H), 7.86 (d, J
=7.4Hz, 2H), 7.69 (d, J=8.1Hz, 2H), 7.45 (t, J=7.5Hz, 4H), 7.34 (d, J=7.3Hz, 1H), 6.91
(d, J=8.6Hz, 1H), 5.70 (s, 2H), 3.89 (s, 3H)13C NMR(101MHz,DMSO)δ163.64,147.18,
145.22,138.04,137.35,135.60,131.13,129.39,129.20,129.14,128.39,127.21,125.64,
122.06,111.12,53.77,53.17.
Compound 2- methoxyl groups -5- (4- (4- (p-methylphenyl) -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine
(BD4) synthesis and structure characterization：Yield 37%, m.p.=168-170 DEG C.HRMS(ESI)[M+H]+:M/z=356.1H NMR
(400MHz,DMSO-d6) δ 8.62 (s, 1H), 8.48 (s, 1H), 8.01 (d, J=8.6Hz, 1H), 7.74 (d, J=8.0Hz,
2H), 7.69 (d, J=8.1Hz, 2H), 7.45 (d, J=8.1Hz, 2H), 7.25 (d, J=7.9Hz, 2H), 6.91 (d, J=
8.6Hz,1H),5.68(s,2H),3.89(s,3H),2.33(s,3H).13C NMR(101MHz,DMSO)δ163.67,147.28,
145.25,138.06,137.71,137.38,135.65,129.96,129.24,129.18,128.40,127.24,125.61,
121.65,111.14,53.79,53.17,21.34.
Compound 2- methoxyl groups -5- (4- (4- (tolyl) -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine
(BD5) synthesis and structure characterization：Yield 38%, m.p.=158-160 DEG C.HRMS(ESI)[M+H]+:M/z=356.1H NMR
(400MHz,DMSO-d6) δ 8.65 (s, 1H), 8.49 (s, 1H), 8.01 (dd, J=8.7,2.6Hz, 1H), 7.69 (d, J=
8.2Hz, 3H), 7.65 (d, J=7.8Hz, 1H), 7.48-7.43 (m, 2H), 7.33 (t, J=7.6Hz, 1H), 7.15 (d, J=
7.7Hz, 1H), 6.92 (d, J=8.6Hz, 1H), 5.69 (s, 2H), 3.89 (s, 3H), 2.35 (s, 3H)13C NMR(101MHz,
DMSO)δ163.68,147.31,145.26,138.56,138.07,137.39,135.62,131.08,129.32,129.24,
129.21,129.06,127.25,126.24,122.83,122.01,111.15,53.80,53.20,21.55.
Compound 2- methoxyl groups -5- (4- (4- (4- (trifluoromethyl) phenyl) -1H-1,2,3- triazol-1-yls) methyl) benzene
Base) pyridine (BD6) synthesis and structure characterization：Yield 41%, m.p.=163-165 DEG C.HRMS(ESI)[M+H]+:M/z=
410.1H NMR(400MHz,DMSO-d6) δ 8.87 (s, 1H), 8.49 (d, J=2.2Hz, 1H), 8.09 (d, J=8.1Hz, 2H),
8.01 (dd, J=8.6,2.6Hz, 1H), 7.82 (d, J=8.3Hz, 2H), 7.70 (d, J=8.2Hz, 2H), 7.47 (d, J=
8.2Hz, 2H), 6.92 (d, J=8.6Hz, 1H), 5.73 (s, 2H), 3.89 (s, 3H)13C NMR(101MHz,DMSO)δ
163.68,145.84,145.27,138.06,137.47,135.40,135.13,129.27,129.21,127.27,126.44,
126.40,126.21,123.38,111.15,53.79,53.34.
Compound 3- (1- (4- (6- methoxypyridine -3- bases) benzyl) -1H-1,2,3- triazole-4-yls) aniline (BD7)
Synthesis and structure characterizes：Yield 34%, m.p.=156-158 DEG C.HRMS(ESI)[M+H]+:M/z=357.1H NMR
(400MHz,DMSO-d6) δ 8.49 (d, J=2.4Hz, 1H), 8.02 (dd, J=8.7,2.6Hz, 1H), 7.70 (d, J=
8.2Hz, 1H), 7.46 (d, J=8.2Hz, 2H), 7.15-7.05 (m, 2H), 6.98-6.89 (m, 2H), 6.54 (d, J=
7.9Hz,1H),5.68(s,2H),5.19(s,2H),3.90(s,3H).13C NMR(101MHz,DMSO)δ163.66,149.57,
147.88,145.25,138.06,137.35,135.73,131.61,129.86,129.25,129.17,127.22,121.62,
114.11,113.51,111.13,110.94,53.79,53.10.
Compound N-(3- (1- (4- (6- methoxypyridine -3- bases) benzyl) -1H-1,2,3- triazole-4-yls) phenyl) ring
The synthesis and structure of cyclopropane carboxamide (BD8) characterizes：Under condition of ice bath, by compound 3- (1- (4- (6- methoxypyridines -3-
Base) benzyl) -1H-1,2,3- triazole-4-yls) aniline (BD7) 0.2g (0.56mmol) is dissolved in 10ml anhydrous methylene chlorides, slowly
Anhydrous triethylamine 0.14ml (1.01mmol) is added dropwise, after stirring 30 minutes, is slow added into 0.11ml (1.12mmol) third first of ring
The dichloromethane solution of acyl chlorides, is added dropwise, and removes ice bath, and room temperature reaction is stayed overnight, i.e. 12h.It is extracted 3-4 times with dichloromethane,
The organic phase of extraction is successively with saturation NaHCO3Solution (60mL × 3), saturation NaCl washings (60mL × 3), anhydrous Na2SO4It is dry
It is dry, it is spin-dried for, by chromatographing post separation (petroleum ether：Ethyl acetate volume ratio=15:1) white solid (BD8) 0.19g, is obtained, is produced
Rate：80%, m.p.=218-220 DEG C.HRMS(ESI)[M+H]+:M/z=424.1H NMR(400MHz,DMSO-d6)δ8.51
(d, J=2.6Hz, 1H), 8.19 (s, 1H), 8.04 (d, J=8.5Hz, 1H), 7.71 (d, J=7.9Hz, 2H), 7.58 (d, J=
7.7Hz, 1H), 7.47 (t, J=4.4Hz, 3H), 7.37 (s, 1H), 6.94 (d, J=8.5Hz, 1H), 5.71 (s, 1H), 3.91
(s, 1H), 1.81 (s, 1H), 0.83 (d, J=8.0Hz, 4H)13C NMR(101MHz,DMSO)δ172.27,163.67,
147.16,145.27,140.41,138.08,137.40,135.63,131.59,129.84,129.25,127.25,122.09,
120.45,118.96,116.09,111.15,53.81,53.20,15.07,7.74.
Compound 3-4- (4- (3- chlorphenyl -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine (BD9) synthesizes and knot
Structure characterizes：Yield 33%, m.p.=140-142 DEG C.HRMS(ESI)[M+H]+:M/z=346.1H NMR(400MHz,DMSO-
d6) δ 8.90 (d, J=1.9Hz, 1H), 8.81 (s, 1H), 8.59 (dd, J=4.8,1.5Hz, 1H), 8.08 (d, J=8.0Hz,
1H), 7.94 (s, 1H), 7.86 (d, J=7.8Hz, 1H), 7.78 (d, J=8.3Hz, 2H), 7.54-7.47 (m, 4H), 7.40
(dd, J=7.6,1.5Hz, 1H), 5.74 (s, 2H)13C NMR(101MHz,DMSO)δ149.16,148.16,145.86,
137.49,136.22,135.46,134.63,134.18,133.22,131.36,129.28,128.17,127.85,125.26,
124.38,124.16,122.89,53.25.
Compound 3-4- (4- (2- fluorophenyl -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine (BD10) synthesis
With structural characterization：Yield 30%, m.p.=115-117 DEG C.HRMS(ESI)[M+H]+:M/z=344.1H NMR(400MHz,
DMSO-d6) δ 8.89 (s, 1H), 8.63-8.54 (m, 2H), 8.17-8.11 (m, 1H), 8.07 (d, J=8.1Hz, 1H), 7.76
(d, J=8.3Hz, 2H), 7.49 (dd, J=13.1,5.9Hz, 3H), 7.43-7.29 (m, 3H), 5.76 (s, 2H)13C NMR
(101MHz,DMSO)δ149.15,148.16,140.40,137.42,136.45,135.49,134.63,130.25,130.16,
129.24,127.82,125.46,124.61,124.49,124.37,116.62,116.41,53.00.
Compound 3- (4- (4- phenyl -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine (BD11) synthesis and knot
Structure characterizes：Yield 34%, m.p.=162-164 DEG C.HRMS(ESI)[M+H]+:M/z=312.1H NMR(400MHz,DMSO-
d6) δ 8.90 (s, 1H), 8.70 (s, 1H), 8.58 (s, 1H), 8.08 (d, J=8.1Hz, 1H), 7.92-7.86 (m, 2H), 7.77
(d, J=8.2Hz, 2H), 7.52-7.42 (m, 5H), 7.34 (t, J=7.4Hz, 1H)13C NMR(101MHz,DMSO)δ
149.17,148.18,147.23,137.45,136.46,135.51,134.65,131.15,129.42,129.22,128.43,
127.86,125.68,124.40,122.15,53.17.
Compound 3- (4- (4- (p-methylphenyl) -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine (BD12) conjunction
At with structural characterization：Yield 37%, m.p.=162-164 DEG C.HRMS(ESI)[M+H]+:M/z=326.1H NMR(400MHz,
DMSO-d6) δ 8.90 (d, J=2.1Hz, 1H), 8.66-8.63 (m, 1H), 8.59 (d, J=4.7Hz, 1H), 8.08 (d, J=
8.1Hz, 1H), 7.76 (t, J=7.7Hz, 4H), 7.49 (d, J=8.3Hz, 3H), 7.26 (d, J=8.0Hz, 2H), 5.71 (s,
2H),2.33(s,3H).13C NMR(101MHz,DMSO)δ149.18,148.19,147.29,137.72,137.44,136.49,
135.52,134.65,129.97,129.23,128.39,127.85,125.62,124.41,121.71,53.14,21.34.
Compound 3- (4- (4- (tolyl) -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine (BD13) conjunction
At with structural characterization：Yield 40%, m.p.=165-167 DEG C.HRMS(ESI)[M+H]+:M/z=326.1H NMR(400MHz,
DMSO-d6) δ 8.81 (d, J=1.9Hz, 1H), 7.61 (s, 2H), 7.57 (d, J=7.8Hz, 1H), 7.45-7.38 (m, 1H),
7.25 (t, J=7.6Hz, 1H)13C NMR(101MHz,DMSO)δ149.18,148.19,147.32,138.56,137.46,
136.46,135.52,134.66,131.07,129.32,129.26,129.08,127.86,126.25,124.41,122.83,
122.08,53.16,21.55.
Compound 3- (4- (4- (4- (trifluoromethyl) phenyl) -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine
(BD14) synthesis and structure characterization：Yield 40%, m.p.=173-175 DEG C.HRMS(ESI)[M+H]+:M/z=380.1H
NMR(400MHz,DMSO-d6) δ 8.90 (d, J=2.0Hz, 2H), 8.58 (d, J=6.0Hz, 1H), 8.09 (t, J=8.1Hz,
3H), 7.80 (dd, J=18.0,8.3Hz, 4H), 7.54-7.47 (m, 3H), 5.76 (s, 2H)13C NMR(101MHz,DMSO)δ
149.19,148.19,145.86,137.54,136.23,135.49,135.12,134.65,129.32,127.88,126.43,
126.39,126.21,126.11,124.39,123.44,53.30.
Compound 3- (4- (4- (3- (trifluoromethyl) phenyl) -1H-1,2,3- triazol-1-yls) methyl) phenyl) pyridine
(BD15) synthesis and structure characterization：Yield 19%, m.p.=110-112 DEG C.HRMS(ESI)[M+H]+:M/z=380.1H
NMR(400MHz,DMSO-d6) δ 8.90 (s, 2H), 8.64-8.56 (m, 1H), 8.21 (s, 2H), 8.08 (d, J=8.0Hz,
1H), 7.78 (d, J=8.2Hz, 2H), 7.71 (d, J=5.1Hz, 2H), 7.54-7.45 (m, 3H), 5.75 (s, 2H)13C NMR
(101MHz,DMSO)δ149.20,148.18,145.86,137.54,136.22,135.49,134.66,132.22,130.65,
129.46,129.34,127.89,124.93,124.89,124.41,123.15,122.04,122.01,53.32.
The synthesis of compound 3- (1- (4- (pyridin-3-yl) benzyl) -1H-1,2,3- triazole-4-yls) aniline (BD16) with
Structural characterization：Yield 36%, m.p.=189-191 DEG C.HRMS(ESI)[M+H]+:M/z=327.1H NMR(400MHz,DMSO-
d6) δ 8.90 (s, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.08 (d, J=8.1Hz, 1H), 7.76 (d, J=8.2Hz, 2H),
7.49 (t, J=7.0Hz, 3H), 7.14-7.03 (m, 2H), 6.94 (d, J=7.6Hz, 1H), 6.52 (d, J=9.3Hz, 1H),
5.69(s,2H),5.18(s,2H).13C NMR(101MHz,DMSO)δ149.57,149.17,148.18,147.89,137.41,
136.57,135.53,134.65,131.60,129.87,129.22,127.84,124.41,121.69,114.12,113.51,
110.94,53.06,39.79.
The inhibitory activity of VEGFR-2/Tie-2/EphB4：
2 pyridines series compound of table is to VEGFR-2/Tie-2/EphB4 inhibitory activity IC50(nM)
ND=undetermineds
As can be seen from Table 2, part of compounds has inhibiting effect simultaneously to VEGFR-2, Tie-2 and EphB4.It is right
For the inhibitory activity of VEGFR-2, inhibitory activity has 4 in 10nM compounds below, is BD1 (IC respectively50=1.63nM),
BD7(IC50=1.85nM) and BD8 (IC50=0.52nM) and BD13 (IC50=1.33nM), and compound BD8 (IC50=
Inhibitory activity 0.52nM) is suitable with the inhibitory activity of positive drug Sorafenib, chemical combination of the inhibitory activity between 10~50nM
Object has 4.For Tie-2, inhibitory activity has 6 in 10nM compounds below, is compound BD1 (IC respectively50=
0.36nM), BD4 (IC50=0.26nM), BD6 (IC50=0.30nM), BD7 (IC50=0.73nM), BD9 (IC50=0.28nM),
With BD13 (IC50=0.45nM), and compound BD1 (IC50=0.36nM), BD4 (IC50=0.26nM), BD6 (IC50=
0.30nM) and BD7 (IC50=0.73nM), BD9 (IC50=0.28nM) and BD13 (IC50=0.45nM) inhibitory activity with sun
Property medicine Sorafenib inhibitory activity it is suitable, wherein 4 compound inhibitory activity are higher than positive drug Sorafenib.EphB4 is come
It says, inhibitory activity has 2 in 10nM compounds below, is compound BD7 (IC respectively50=2.99nM) and BD12 (IC50=
0.44nM), and compound BD12 (IC50=0.44nM) inhibitory activity it is suitable with the inhibitory activity of positive drug Sorafenib.Change
It closes object BD1, BD7 and preferable inhibitory activity, BD1, BD7 hinge area bases is shown to tri- kinds of kinases of VEGFR-2/Tie-2/EphB4
Group is methoxyl group, and Activity Results are shown, substitution base type is Bu Tong all affected to bioactivity with position.
When substituent group is trifluoromethyl on phenyl ring in pyridines series compound, to the inhibitory activity of three kinds of kinases compared with
Difference, it is preferable to the inhibitory activity of VEGFR-2 when substituent group is methyl on aniline.
Anti-vascular endothelial cell proliferation activity：
3 pyridines series compound of table is to Human umbilical vein endothelial cells inhibitory activity IC50(μM)
Measure antiproliferative activity of the compound to Human umbilical vein endothelial cells (EA.hy926).From table 3 it can be seen that big portion
Divide compound that there is a degree of antiproliferation, part of compounds to have inhibitory activity more better than positive drug.Change
Close object BD10 (IC50=9.28 μM) and BD12 (IC50=6.49 μM) compared with Sorafenib have higher inhibitory activity, 4 chemical combination
Object inhibitory activity is suitable with Sorafenib inhibitory activity between 10~50 μM.Compound BD12 (IC50=6.49 μM) to cell
Antiproliferative activity it is most strong.
In the present invention compound BD7 to tri- kinds of kinases of VEGFR-2/Tie-2/EphB4 and EA.hy926 cells show compared with
Good inhibitory activity.
Claims (6)
1. a kind of pyridine compounds and their, which is characterized in that the structural formula of the compound is：
Wherein, R1For Cl, F, H, CH3、CF3、NH2OrR2For-OCH3Or H.
2. a kind of pyridine compounds and their according to claim 1, which is characterized in that R1And R2It is specific as follows：
3. a kind of pyridine compounds and their according to claim 1, which is characterized in that R1For Cl, R2For-OCH3When, it prepared
Journey is as follows：
Synthesis to bromine Bian nitrine：Under condition of ice bath, bromine Bian bromine will be dissolved in anhydrous DMF, first part of sodium azide is added dropwise
Aqueous solution is warmed to room temperature and second part of aqueous sodium azide is added dropwise again, after being added dropwise, reacts at room temperature 12h, is evaporated under reduced pressure, uses
Post separation is chromatographed, yellow oil is obtained, as to bromine Bian nitrine；
The synthesis of 1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles：Bromine Bian nitrine, m-chloro phenylacetylene will be dissolved in
In absolute ethyl alcohol, L-AA sodium and Salzburg vitriol is then added, water is then added, 12h is stirred at room temperature, decompression is steamed
It evaporates, with chromatography post separation, obtains white solid, as 1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles；
5- (4- (4- (3- chlorphenyls) -1H-1,2,3- triazole 1- yls) methyl) phenyl) -2 methoxypyridines synthesis：To reaction
Bottle in be added 1- (4- bromobenzyls) -4- (3- chlorphenyls) -1H-1,2,3- triazoles, 2- methoxyl group -5- pyridine boronic acids, potassium carbonate with
And [1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride, Isosorbide-5-Nitrae-dioxane and water are added, under nitrogen protection in 100
DEG C reaction 12h, is cooled to room temperature, and by chromatographing post separation, obtains white solid, as 5- (4- (4- (3- chlorphenyls) -1H-1,
2,3- triazole 1- yls) methyl) phenyl) -2 methoxypyridines.
4. a kind of pyridine compounds and their as described in any one of claim 1-2 answering in preparing anti-angiogenic medicaments
With.
5. application according to claim 4, which is characterized in that the compound, which has, inhibits VEGFR-2, Tie-2 and EphB4
The effect of kinase activity.
6. application according to claim 4, which is characterized in that the compound has anti-vascular endothelial cell proliferation activity
Effect.
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|---|---|---|---|---|
| CN102603660A (en) * | 2012-02-10 | 2012-07-25 | 浙江工业大学 | Preparation method of 1H-1,2,3-triazole compound |
| CN103275022A (en) * | 2013-06-08 | 2013-09-04 | 浙江工业大学 | 1-benzyl-1, 2, 3-triazole compound, as well as preparation method and application thereof |
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2018
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|---|---|---|---|---|
| CN102603660A (en) * | 2012-02-10 | 2012-07-25 | 浙江工业大学 | Preparation method of 1H-1,2,3-triazole compound |
| CN103275022A (en) * | 2013-06-08 | 2013-09-04 | 浙江工业大学 | 1-benzyl-1, 2, 3-triazole compound, as well as preparation method and application thereof |
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| CN111675696A (en) * | 2020-06-08 | 2020-09-18 | 西安交通大学 | Light affinity probe molecule based on triazole active molecule and preparation method and application thereof |
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