CN107445979B - 6- methYl-thiazol and triazole -5- carboxamides derivatives and application - Google Patents
6- methYl-thiazol and triazole -5- carboxamides derivatives and application Download PDFInfo
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
R the invention discloses the 6- methYl-thiazol of general formula I simultaneously [3,2-b] [1,2,4]-triazole -5- carboxamides derivatives or its pharmaceutically acceptable hydrate, salt, including its stereoisomer or tautomer, in Formulas I1For hydrogen, methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono, nitro or alkoxy；Pyrrole radicals, piperidyl, morpholinyl, N methyl piperazine, N-(4- bromophenyl are formed together with the nitrogen-atoms that the independent alkyl or R2 and R3 selected from C1-C6 of R2 and R3 is connected with them) piperazine.Simultaneously [3,2-b] [1,2,4]-triazole -5- carboxamides derivatives are as vascular endothelial growth factor receptor tyrosine kinase inhibitor for 6- methYl-thiazol of the invention, for treating and preventing the purposes of various cancers.
Description
Technical field
The invention belongs to pharmaceutical technology field more particularly to 6- methYl-thiazol simultaneously [3,2-b] [1,2,4]-triazole -5-
Carboxamides derivatives and preparation method thereof with as vascular endothelial growth factor receptor tyrosine kinase inhibitor, for treating
With the purposes for preventing various cancers.
Background technique
Malignant tumour is one of the principal disease that today's society threatens human health, and 1971, Folkman proposed tumour
Generation, development are closely related with angiogenesis.The growth of tumour and transfer are dependent on oxygen provided by angiogenesis and necessary
Nutriment.Entity tumor there is no angiogenesis at the beginning of being formed, and the nutrition of tumour cell is mainly obtained by disperse, when cell away from
When from 200 μm of capillary or more, nutrition will be unable to arrive at tumour cell by dispersion, when the cell number of tumour reaches 1
× 107After a, the nutrition that disperse obtains has been unable to satisfy the needs of tumor survival and growth, at this time as again without new blood vessel
It generates, tumor tissues will degenerate.Over more than 30 years, a large amount of clinical practice and experimental study confirm: angiogenesis is tumour
The general character of the prerequisite and all malignant tumours of growth and transfer, the angiogenesis for inhibiting tumour to mediate can be effectively
Inhibit the growth and transfer of tumour.
Angiogenesis be one by it is numerous adjust, regulatory factor adjust complex physiologic, pathologic process, at present it is separated and
It has been purified into more than 20 kinds of angiogenesis factors and correlation factor, at least 15 kinds of angiogenesis inhibitors.Its Endothelial Cell
Growth factor (vascular endothet ial growth factor, VEGF) is in core status, is to be currently known activity
Most strong, the highest angiogenesis factor of specificity.Vascular endothelial growth factor receptor (Vascular Endothelial
Growth Gactor Receptor, VEGFR) be VEGF specificity membrane receptor, have high-affinity.Currently, consistent see
Method is the main agencies factor that sexually revises of mitogenesis, Angiogensis and infiltration that VEGFR-2 is VEGF.In addition,
VEGFR-2 is almost only specifically expressed on endothelial cell, and endothelial cell membrane is not easy to be mutated because stable, passes through inhibition
VEGFR-2 can it is exclusive, effectively inhibit tumour cell angiogenesis, and be not likely to produce drug resistance.Therefore, using new vessels as target
Point is treated the research hotspot also become in recent years to tumour.
Summary of the invention
The purpose of the present invention is to provide a kind of 6- methYl-thiazol simultaneously [3,2-b] [1,2,4]-triazole -5- benzamide types
Derivative, with good anti-tumor activity.
Above-mentioned purpose of the invention is achieved by the following technical solution:
A kind of VEGFR-2 tyrosine kinase inhibitor, have anti-tumor activity, it is characterised in that: the compound be with
The 6- methYl-thiazol of general formula I simultaneously [3,2-b] [1,2,4]-triazole -5- carboxamides derivatives or its pharmaceutically acceptable water
Close object, salt, including its stereoisomer or tautomer；
Wherein, the R in Formulas I1For hydrogen, methyl, halogen, hydroxyl, methoxyl group, acetyl group, propiono, nitro or alkoxy；R2
And R3Independent alkyl or R selected from C1-C62And R3Pyrrole radicals, piperidyl, morpholine are formed together with the nitrogen-atoms being connected with them
Base, N methyl piperazine, N- (4- bromophenyl piperazine).
The term " halogen " applied in the present invention includes fluorine, chlorine or bromine.
The present invention also provides the purposes that above compound is used to prepare anti-tumor drug.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining type I compound, and with suitable non-toxic
The conventional acid addition salts or base addition salts that organic or inorganic acid or organic or inorganic alkali are formed.The example of acid-addition salts includes acetic acid
Salt, adipate, alginates, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphor
Hydrochlorate, camsilate, cipionate, digluconate, lauryl sulfate, esilate, fumarate, Portugal heptan
Sugar lime, glycerophosphate, Hemisulphate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2- hydroxyl second
Sulfonate, lactate, maleate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oxalates, pamoate, pectin ester
Hydrochlorate, persulfate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate,
Rhodanate, toluene fulfonate and undecylate.Alkali salt includes ammonium salt, alkali metal salt, such as sodium and sylvite, alkali salt,
Such as calcium and magnesium salts, the salt of organic base, such as dicyclohexyl amine salt, the salt of N- methyl-D-glucamine salt and amino acid, such as essence
Propylhomoserin, lysine etc., moreover, Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as first
The chlorine of base, ethyl, propyl and butyl, bromine and iodide；Dialkyl sulfate, such as dimethyl suflfate, diethylester, dibutyl ester and two
Pentyl ester；The chlorine of long chain halide, such as decyl, lauryl, myristyl and stearyl, bromine and iodide；Aralkyl halide,
The bromide of such as benzyl and phenethyl.It is preferred for generating the acid of acid-addition salts including hydrochloric acid and acetic acid.
The present invention also provides the preparation method of above-mentioned compound of Formula I, this method sees below formula.
Present system is studied and illustrates the structure and preparation of the compound, and the compound is as a new class of
VEGFR-2 tyrosine kinase inhibitor, structure type are novel, provide completely new direction and wide for exploitation new type antineoplastic medicine
Wealthy platform.
Specific embodiment
Embodiment 1
The preparation of 2- (4- chlorphenyl) -6- methYl-thiazol [3,2-b] [1,2,4] triazole -5- formic acid
The addition thiosemicarbazide 0.1mo1 in 250mL there-necked flask, methylene chloride 100mL, ice-water bath stirring and dissolving, then plus
Enter 0.13mo1 pyridine.4- chlorobenzoyl chloride 0.13mo1 is slowly added dropwise at 0-5 DEG C, 20min is added dropwise, 15 DEG C of reaction 2h, knot
Shu Fanying.System has a large amount of white solids to occur, filtering.Gained white solid is dissolved in the hydrogen-oxygen of 80mL mass fraction 5%
Change in sodium solution, be heated to reflux 2h, be down to room temperature, with the dilute hydrochloric acid tune pH to 5-6 of mass fraction 3.65%, has a large amount of light yellow
Solid is precipitated, and filters, and recrystallization obtains 5- (4- chlorphenyl) -3- sulfydryl -1,2,4- triazole 18.3g, yield 86.7%,
ESI-MS(m/z):212.3(M+H)+。
By 0.06mol5- (4- chlorphenyl) -3- sulfydryl -1,2,4- triazole is added in the KOH solution of 10mL10%, so
It is added dropwise 0.06mol2- chloroacetyl acetacetic ester afterwards, after heating reaction 1h, ice water dilution there are a large amount of crystal to be precipitated, dry 2- [3-
(4- chlorphenyl) -1H-1,2,4- triazole -5- sulfenyls]-ethyl 3-oxobutanoate, yield 42%.
0.02mol2- [3- (4- chlorphenyl) -1H-1,2,4- triazole -5- sulfenyl]-ethyl 3-oxobutanoate is added to
In 120 DEG C of 85%PPA, 1h is reacted, is cooled to room temperature after reaction, ice water is added, there are a large amount of solids to be precipitated, filtered, it is anhydrous
Ethyl alcohol recrystallization obtains 2- (4- chlorphenyl) -6- methYl-thiazol simultaneously [3,2-b] [1,2,4] triazole -5- Ethyl formate, yield
39%.
By 0.01mol2- (4- chlorphenyl) -6- methYl-thiazol, simultaneously [3,2-b] [1,2,4] triazole -5- Ethyl formate adds
Enter into the NaOH of 2mol/L, add 20mL methanol, reacts at room temperature 2h, methanol is removed under reduced pressure, with concentrated hydrochloric acid tune pH=2, has
A large amount of solids are precipitated, and filter, and dehydrated alcohol recrystallizes to obtain buff powder 2- (4- chlorphenyl) -6- methYl-thiazol [3,2-b]
[1,2,4] triazole -5- formic acid, yield 56%, ESI-MS (m/z): 294.1 (M+H)+。
Embodiment 2
N, N- dimethyl -2- (4- chlorphenyl) -6- methYl-thiazol simultaneously [3,2-b] [1,2,4] triazole -6- base } -5- first
The preparation 10mmol dimethylamine hydrochloride of amide (L1), 10mmol2- (4- chlorphenyl) -6- methYl-thiazol [3,2-b] [1,2,4]
Triazole -5- formic acid, 20mL methylene chloride are added in round-bottomed flask, then add 12mmolEDCI, 12mmolHOBt and
Triethylamine 10mmol, after reacting at room temperature 12h, reaction solution successively uses 5%HCl, 5%NaHCO3, saturation NaCl solution is washed, after dry
Column chromatography for separation obtains white solid, yield 34%；1H-NMR (300MHz, DMSO), δ (ppm): 7.42 (2H, d, J=8.7Hz),
7.26 (2H, d, J=8.7Hz), 3.96 (3H, s), 3.02 (3H, s), 2.60 (3H, s)；ESI-MS (m/z): 321.2 (M+
H)+。
Embodiment 3
N, N- diethyl -2- (4- chlorphenyl) -6- methYl-thiazol simultaneously [3,2-b] [1,2,4] triazole -5- formamide
(L2) preparation
Dimethylamine hydrochloride is replaced with diethylamine, synthetic method is referring to embodiment 2, yield 36%.
1H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d, J=9.0Hz), 7.37 (2H, d, J=9.0Hz),
3.98 (2H,m),3.32(2H,m),2.30(3H,s),1.18(3H,t),1.05(3H,t)；ESI-MS(m/z):349.1(M+
H)+。
Embodiment 4
2- (4- chlorphenyl) -6- methyl -5- (1- piperidines -1- carbonyl)-thiazole simultaneously [3,2-b] [1,2,4] triazole (L3)
Preparation
Dimethylamine hydrochloride is replaced with piperidines, synthetic method is referring to embodiment 2, yield 37%；1H-NMR (300MHz,
DMSO), δ (ppm): 7.52 (2H, d, J=8.4Hz), 7.32 (2H, d, J=8.4Hz), 3.45 (2H, m), 3.41 (2H, m),
2.31(3H,s), 1.60(2H,m),1.55(2H,m),1.45(2H,m)；ESI-MS(m/z):361.2(M+H)+。
Embodiment 5
2- (4- chlorphenyl) -6- methyl -5- (1- morpholine -1- carbonyl)-thiazole simultaneously [3,2-b] [1,2,4] triazole (L4)
Preparation
Dimethylamine hydrochloride is replaced with morpholine, synthetic method is referring to embodiment 2, yield 36%；1H-NMR (300MHz,
DMSO), δ (ppm): 7.49 (2H, d, J=8.4Hz), 7.18 (2H, d, J=8.4Hz), 3.75 (4H, br), 3.68 (4H, q),
2.34(3H,s)； ESI-MS(m/z):363.1(M+H)+。
Embodiment 6
2- (4- chlorphenyl) -6- methyl -5- [1- (4- methyl piperazine) -1- carbonyl]-thiazole simultaneously [1,2,4] three [3,2-b]
The preparation of nitrogen azoles (L5)
Dimethylamine hydrochloride is replaced with N methyl piperazine, synthetic method is referring to embodiment 2, yield 32%；1H-NMR
(300MHz, DMSO), δ (ppm): 7.50 (2H, d, J=8.4Hz), 7.28 (2H, d, J=8.4Hz), 3.65 (4H, dt),
2.45(5H,t),2.39 (3H,d),2.32(3H,s)；ESI-MS(m/z):375.0(M+H)+。
Embodiment 7
2- (4- chlorphenyl) -6- methyl -5- [1- pyrrolidines -1- carbonyl]-thiazole simultaneously [3,2-b] [1,2,4] triazole
(L6) preparation
Dimethylamine hydrochloride is replaced with nafoxidine, synthetic method is referring to embodiment 2, yield 29%；1H-NMR
(300MHz, DMSO), δ (ppm): 7.52 (2H, d, J=8.4Hz), 7.28 (2H, d, J=8.4Hz), 3.48 (4H, s), 2.36
(3H, s), 1.87 (4H, m)；ESI-MS(m/z):347.0(M+H)+。
Embodiment 8
2- (4- chlorphenyl) -6- methyl-N, N- di-n-butyl-thiazole simultaneously [3,2-b] [1,2,4] triazole -5- formamide
(L7) preparation
Dimethylamine hydrochloride is replaced with di-n-butyl, synthetic method is referring to embodiment 2, yield 52%；1H-NMR
(300MHz, DMSO), δ (ppm): 7.52 (2H, d, J=9.0Hz), 7.25 (2H, d, J=9.0Hz), 3.41 (4H, m), 2.41
(3H,s),1.62 (4H,m),1.32(4H,m),0.96(6H,m)；ESI-MS(m/z):405.3(M+H)+。
Embodiment 9
2- (4- chlorphenyl) -6- methyl -5- [1- (4- (4- bromophenyl) piperazine) -1- carbonyl]-thiazole simultaneously [3,2-b] [1,
2,4] preparation of triazole (L8)
Dimethylamine hydrochloride 1- (4- bromophenyl) piperazine is replaced, synthetic method is referring to embodiment 2, yield 32%；1H-
NMR (300MHz, DMSO), δ (ppm): 7.48 (2H, d, J=8.4Hz), 7.40 (2H, d, J=8.7Hz), 7.01 (2H, d, J
=8.7Hz), 6.95 (2H, d, J=8.4Hz), 3.57 (4H, t), 3.22 (4H, t), 2.48 (3H, s)；ESI-MS(m/z):
516.0(M+H)+。
Embodiment 10
The test of mtt assay antitumor cytolytic activity
1. the preparation of material:
Reagent: the RPMl640 culture solution containing 10% fetal calf serum, 0.25% tryptic digestive juice, PBS (0.01mol/
L, pH7.4), DMSO (analysis is pure), MTT solution；
Cell strain: human cervical carcinoma Hela cell's strain.
2. method:
(1) inoculating cell: by the Hela cell of logarithmic growth phase, with 0.25% trypsin digestion, with containing, 10% tire is small
1640 culture mediums of cow's serum are made into individual cells suspension, with every hole 104A cell inoculation is to 96 orifice plates, every pore volume
100mL；
(2) it cultivates cell: culture plate is put into CO2 incubator, at 37 DEG C, 100% relative humidity contains 5%CO2,95% sky
It is cultivated for 24 hours in the incubator of gas；
(3) it prepares 5mg/mLMTT solution: weighing 250mg MTT, be put into small beaker, add 50mL PBS solution, electromagnetism stirs
30min is mixed, with 0.22 μm of miillpore filter degerming, is saved backup in 4 DEG C, is used in l weeks；
(4) it is administered: aseptically, by target compound 10-7The suspension of mol/L is added to 96 holes with 100 holes μ L/
In culture plate, every kind of compound sets 3 in parallel, and 3 blank control wells are set on every culture plate.It places in CO2 incubator in item of the same race
Continue to cultivate under part；
(5) colour generation: after culture for 24 hours, every hole adds 10 μ LMTT solution, in culture 4h, terminates culture, carefully inhales to abandon in hole and train
Supernatant is supported, is inhaled again after suspension cell centrifugation and abandons culture supernatant in hole.Every hole adds 150 μ LDMSO, vibrates 10min, Shi formazan
Sufficiently dissolution；
(6) colorimetric: selection 570nm wavelength measures each hole absorbance value (OD value) on enzyme linked immunological monitor；
Growth of tumour cell inhibiting rate is calculated according to following formula:
Inhibitory rate of cell growth=(1- experimental group OD value/control group OD value) x100%.
3. result: experiment shows that above compound of the invention has inhibiting effect to tumour cell, is shown in Table 1.
The inhibitory activity of 1 compound Hela cell of table
Claims (2)
1. a kind of VEGFR-2 tyrosine kinase inhibitor has anti-tumor activity, it is characterised in that: the compound is with logical
The 6- methYl-thiazol of Formulas I simultaneously [3,2-b] [1,2,4]-triazole -5- carboxamides derivatives；
Specifically: 2- (4- chlorphenyl) -6- methyl -5- (1- pyrrolidines -1- carbonyl)-thiazole simultaneously [3,2-b] [1,2,4] three nitrogen
Azoles.
2. the purposes that compound described in claim 1 is used to prepare anti-tumor drug.
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| CN115197244B (en) * | 2022-09-03 | 2023-07-07 | 石家庄学院 | [1,2,4] triazino [3,2-b ] [1,3,5] thiadiazine derivatives and application thereof |
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Non-Patent Citations (2)
| Title |
|---|
| "One pot synthesis and reactions of novel 5-amino[1,3]thiazolo[3,2-b][1,2,4]triazoles";Hassan A. H. El-Sherief et al.;《ARKIVOC》;20111231;第73页 |
| "Synthesis of Some Functionalized Thiazolo[3,2-b][1,2,4]triazoles";A. DAVOODNIA et al.;《Asian Journal of Chemistry》;20111231;第23卷(第8期);第3707-3709页 |
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