CN110128360A - Two thio 1,2,4- nitrogen triazole class compounds and its preparation method and application - Google Patents
Two thio 1,2,4- nitrogen triazole class compounds and its preparation method and application Download PDFInfo
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- CN110128360A CN110128360A CN201910571966.3A CN201910571966A CN110128360A CN 110128360 A CN110128360 A CN 110128360A CN 201910571966 A CN201910571966 A CN 201910571966A CN 110128360 A CN110128360 A CN 110128360A
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses two thio 1, 2, 4- nitrogen triazole class compounds and its preparation method and application, the compound is using ethyl alcohol as solvent, in the presence of acid binding agent, pass through 1 containing sulfydryl, 2, 4- nitrogen triazole class compounds are reacted with sulfydryl isothiuronium salts Barbiturates compound, preparation series two thio 1, 2, 4- nitrogen triazole class compounds, the invention has the advantages that according to new drug design theory and method, it is prepared for series two thio 1, 2, 4- nitrogen triazole class compounds, with CCK-8 method, by testing this kind of compound to human body cervical carcinoma cell Hela, the proliferation inhibition activity of human hepatoma cell SMMC-7721 and Human Lung Cancer cell A549, the result shows that: this kind of compound has preferable antitumor cell increment inhibitory activity, it is used to prepare including anti-cervical cancer Hel A, the drug of liver cancer SMMC-7721 and lung cancer A549, the anticancer drug to develop new open new approach.
Description
Technical field
The present invention relates to thio 1,2,4- nitrogen triazole class compounds of anticancer drug field, especially two and preparation method thereof and
Using.
Background technique
Cancer seriously threatens the health of the mankind.Currently, anti-tumor drug is many kinds of, especially using nitrogen triazole as parent
The compound of structure shows preferable anticancer activity in previous research and report.Many documents all report nitrogen
Heterocyclic compound is with anticancer activity pharmacophoric group.Substituted 1,2,4- nitrogen triazole class compounds are a kind of important structure bases
Sequence has extensive bioactivity, is applied to the fields such as organic synthesis, pharmaceutical chemistry and material science.
Triazole class compounds are because of its special biological activity, and antimycotic in antibacterial, anti-hypertension, analgesic is anti-oxidant,
Anti-inflammatory, treating tuberculosis, insecticide, herbicide is antiviral, and many aspects such as anticancer all have potential using value.In addition to this,
Disulfide compound has many-sided bioactivity, such as antibacterial, antimycotic, anti-tumor activity, HIV-resistant activity, and activity
Preferably.So as to cause the concern of various fields.In recent years, a kind of two pharmacophoric groups of combination and generate have additional bio
It learns the monomolecular molecule hybridizing method of characteristic and receives the favor of Pharmaceutical Chemist.These hybrids are by two in individual molecule
Bioactive molecule is combined together, it is therefore an objective to create a kind of chemical entities medically more more effective than single ingredient.Pass through this
Kind mode realizes synergy and the superposition of bioactivity of pharmacophoric group.Nitrogen triazole with broad-spectrum biological activity has become
It is wide that indispensable heterocyclic skeleton in drug development, the synthesis of nitrogen triazole derivative and the research of bioactivity have caused people
General concern.Referring to: document 1) Shen QK, Liu CF, Zhang HJ, et al., J.Bioor.Med.Chem.Let, 2017,
27,4871-4875；Document 2) LiuXH, Weng JQ, Wang BL, et al.J.Res Chem Intermed, 2014,40,
2605–2612；Document 3) MatthewM, Jorge F, A B,et al.J.Med.Chem.2015,58,6448-
6455；Document 4) Meti GY., Kamble AA., Kamble RR., et al.Eur.J.Med.Chem.2016,121,221-
231；Document 5) Zaki I, Ramadan M, Abdelrahman MH, et.al.Monatsh Chem.2017,148,1483-
1496；Document 6) Micheli F, Bernardelli A, Bianchi F, et.al.Bioorg.Med.Chem.2016,24,
1619–1636；Document 7) Papadopoulou MV, Bloomer DW, Rosenzweig H S,
et.al.Eur.J.Med.Chem.2016,123,895-904；Document 8) Kulabas N, Tatar E, Ozakpinar OB,
Eur.J.Med.Chem.2016,121,58-70；Document 9) Tabrizi MA, Baraldi PG, Ruggiero E,
et.al.Eur.J.Med.Chem.2016,113,11-27；Document 10) Chelamalla R, Akena V, Manda S.Med
Chem Res.2017,26,1359–1366。
In order to find that anti-cancer drugs, the present invention have done further two thio 1,2,4- nitrogen triazole class compounds class compounds
Research.It was found that realizing disulfide and 1 by chemical reaction, the splicing of 2,4- nitrogen triazole structures increases active group in organic molecule
The number of group measures the proliferation inhibition activity of such compound on tumor cell, using CCK-8 method then to realize drug effect base
The synergy of group and the superposition of bioactivity.
Summary of the invention
The purpose of the present invention is analyzing in view of the above technology, two thio 1 are provided, 2,4- nitrogen triazole class compounds and its preparation
Method.Such compound has anticancer activity, opens new way to develop new anticancer drug and abundant clinical application kind
Diameter.
Technical solution of the present invention:
Two thio 1,2,4- nitrogen triazole class compounds, chemical structural formula is as follows:
In structural formula: R1To can be one of a variety of substituent groups such as alkyl, amino, nitro, halogen atom, methoxyl group, institute
Stating halogen atom is fluorine, chlorine, bromine or iodine atom；R2For the aromatic group of C1-6 alkyl, C3-8 naphthenic base or C5-14, wherein
Aromatic group can replaced the group of 1-3 hydroxyl, nitro, halogen atom, cyano, C1-6 alkoxy or C1-6 alkyl,
Or replaced the amino replaced by one or two of C1-6 alkyl, C1-6 alkyl sulphonyl and C1-6 alkyl-carbonyl group.
Described two thio 1, the preparation method of 2,4- nitrogen triazole class compounds is being tied up using ethyl alcohol and methylene chloride as solvent
In the presence of sour agent, by 1 containing sulfydryl, 2,4- nitrogen triazole class compounds and sulfydryl isothiuronium salts Barbiturates compound are carried out instead
It should prepare, steps are as follows:
1) by 1- phenyl -5- (substituted-phenyl) -3- sulfydryl -1,2,4- nitrogen triazole, sulfydryl isothiuronium salts Barbiturates compound
It is mixed and stirred for uniformly with ethyl alcohol and methylene chloride mixed solvent, acid binding agent aqueous solution is instilled at 0-5 DEG C, is stirred to react 1-
2h obtains reaction solution；
2) it by above-mentioned reaction solution through adding water and methylene chloride to extract to obtain organic phase, is then concentrated under reduced pressure, is cooling, being precipitated solid
Body, column chromatography can be prepared by object.
The acid binding agent is sodium bicarbonate, anhydrous sodium acetate, pyridine or piperidines.
The sulfydryl isothiuronium salts Barbiturates compound and 1- phenyl -5- (substituted-phenyl) -3- sulfydryl -1,2,4- nitrogen triazole
Molar ratio be 1-1.2:1；The amount ratio of 1- phenyl -5- (substituted-phenyl) -3- sulfydryl -1,2,4- nitrogen triazole and solvent is
1mmol:6-9ml；The dosage molar ratio of acid binding agent and sulfydryl isothiuronium salts Barbiturates compound is 1.3-1.6:1.
The synthetic route of the preparation method is schematically as follows:
This kind of two thio 1,2,4- nitrogen triazole class compounds are used to prepare antitumor medicine composition, including anti-liver cancer and anti-,
Gastric cancer, lung cancer, breast cancer, prostate cancer, oophoroma, cervical carcinoma, cancer of pancreas, the carcinoma of the rectum, lymph cancer, cancer of the esophagus, carcinoma of mouth, nose
The pharmaceutical composition of pharynx cancer or cutaneum carcinoma.
The invention has the advantages that the present invention according to new drug design theory and method, is prepared for series two thio 1,2 for the first time,
4- nitrogen triazole class compounds are thin to Human Lung Cancer cell A549, Human Cervical by testing this kind of compound with CCK-8 method
The proliferation inhibition activity of born of the same parents Hela and human hepatoma cell SMMC-7721, the results showed that this kind of compound has very strong anticancer
Activity opens new approach to develop new anticancer drug and abundant clinical application kind；Preparation method simple process, easily
It is higher in implementation, yield, it is applicable to the production of scale.
Specific embodiment
In order to find good effect and have the anticancer drug of inhibitory activity to a variety of cancer cells, recognize in conjunction with to anticancer drug
Know, according to reported in literature and applicant laboratory many years research work achievement, has synthesized multiple compounds, and to the target of acquisition
Compound carries out Anticancer Activity in vitro primary dcreening operation pharmacological testing.It was found that this kind of two thio 1,2,4- nitrogen triazole class compounds have relatively by force
Anticancer activity, have exploitation be new anticancer drug prospect.
Embodiment 1:
Two thio 1, the preparation method of 2,4- nitrogen triazole class compounds, it is characterised in that: with ethyl alcohol and methylene chloride be molten
Agent, in the presence of acid binding agent, by 1- phenyl -5- (substituted-phenyl) -3- sulfydryl -1,2,4- nitrogen triazole and sulfydryl isothiourea hydrochloric acid
Salt compounds carry out reaction preparation.Specific method is: in flask, 1,5- diphenyl -3- sulfydryl -1,2,4- nitrogen three is added
Azoles, positive fourth sulfydryl isothiuronium salts hydrochlorate and ethyl alcohol and methylene chloride, stirring and dissolving instill appropriate sodium bicarbonate water at 0-5 DEG C
Solution after being stirred to react 2h, adds water and methylene chloride to extract to obtain organic phase, is then concentrated under reduced pressure, is cooling, solid, column layer is precipitated
Analysis purification, is eluted with petroleum ether-ethyl acetate (volume ratio 23:1), and object 1, two mercapto of 5- diphenyl -3- normal-butyl is made
Base -1,2,4- nitrogen triazole, yield 72.0% is oily liquids, and product obtained is a.
Embodiment 2:
Two thio 1, the preparation method of 2,4- nitrogen triazole class compounds, preparation method and condition are substantially the same manner as Example 1,
The difference is that: raw materials used is 1,5- diphenyl -3- sulfydryl -1,2,4- nitrogen triazole, isobutyl sulfydryl isothiuronium salts hydrochlorate, system
Obtaining object is 1,5- diphenyl -3- isobutyl group dimercapto -1,2,4- nitrogen triazole.Yield 76.3%, 64.5-65.7 DEG C of fusing point,
Product obtained is b.
Embodiment 3:
Two thio 1, the preparation method of 2,4- nitrogen triazole class compounds, preparation method and condition are substantially the same manner as Example 1,
The difference is that: raw materials used is 1,5- diphenyl -3- sulfydryl -1,2,4- nitrogen triazole, Zhong Ding sulfydryl isothiuronium salts hydrochlorate, system
Obtaining object is 1,5- diphenyl -3- sec-butyl dimercapto -1,2,4- nitrogen triazole.Yield 71.5% is oily liquids.It is obtained
Product is c.
Embodiment 4:
Two thio 1, the preparation method of 2,4- nitrogen triazole class compounds, preparation method and condition are substantially the same manner as Example 1,
The difference is that: it is raw materials used for 1- phenyl -5- (4 '-aminomethyl phenyl) -3- sulfydryl -1,2,4- nitrogen triazole, positive fourth sulfydryl it is different
Object 1- phenyl -5- (4 '-aminomethyl phenyl) -3- normal-butyl dimercapto -1,2,4- nitrogen triazole, yield is made in thiouronium hydrochloride
81.4%, 74.7-75.5 DEG C of fusing point.Product obtained is d.
Embodiment 5:
Two thio 1, the preparation method of 2,4- nitrogen triazole class compounds, preparation method and condition are substantially the same manner as Example 1,
The difference is that: it is raw materials used for 1- phenyl -5- (4 '-aminomethyl phenyl) -3- sulfydryl -1,2,4- nitrogen triazole, isobutyl sulfydryl it is different
Object 1- phenyl -5- (4 '-aminomethyl phenyl) -3- isobutyl group dimercapto -1,2,4- nitrogen triazole, yield is made in thiouronium hydrochloride
78.1%, 65.5-66.3 DEG C of fusing point.Product obtained is e.
Embodiment 6:
Two thio 1, the preparation method of 2,4- nitrogen triazole class compounds, preparation method and condition are substantially the same manner as Example 1,
The difference is that: it is raw materials used for 1- phenyl -5- (4 '-aminomethyl phenyl) -3- sulfydryl -1,2,4- nitrogen triazole, Zhong Ding sulfydryl it is different
Object 1- phenyl -5- (4 '-aminomethyl phenyl) -3- sec-butyl dimercapto -1,2,4- nitrogen triazole, yield is made in thiouronium hydrochloride
80.4%, it is oily liquids.Product obtained is f.
Anticancer Activity in vitro measurement:
Product anticancer activity body outer screening test obtained by above embodiments:
Product samples are dissolved with DMSO, and Test compound concentrations are 5 × 10-5Mol/L chemicals treatment 48 hours, is used
CCK-8 method measures series compound to human body cervical carcinoma cell Hela, human hepatoma cell SMMC-7721 and Human Lung Cancer cell
The proliferation inhibition rate of A549.
Testing result:
1) product1H-NMR data are as shown in table 1:
Table 1
2) product increment inhibiting rate is as shown in table 2:
Table 2
2 testing result of table shows: such compound on tumor cell proliferation has preferable inhibitory effect, has potential
Application prospect.
Above content is only representative embodiment of the present invention, is not intended to limit the invention in any way, all foundations
Technical spirit of the invention any simple modification, equivalent change and modification to the above embodiments, still fall within the present invention
In the range of technical solution.
Claims (5)
1. two thio 1,2,4- nitrogen triazole class compounds, which is characterized in that chemical structural formula is as follows:
In structural formula: R1 is one of alkyl, amino, nitro, halogen atom, a variety of substituent groups of methoxyl group, and the halogen atom is
Fluorine, chlorine, bromine or iodine atom；R2 is the aromatic group of C1-6 alkyl, C3-8 naphthenic base or C5-14, and wherein aromatic group can
Replaced the group of 1-3 hydroxyl, nitro, halogen atom, cyano, C1-6 alkoxy or C1-6 alkyl, or by C1-6 alkyl,
Replaced the amino that one or two of C1-6 alkyl sulphonyl and C1-6 alkyl-carbonyl group replace.
2. as described in claim 1 two thio 1, the preparation method of 2,4- nitrogen triazole class compounds is tiing up acid using ethyl alcohol as solvent
In the presence of agent, by 1 containing sulfydryl, 2,4- nitrogen triazole class compounds are reacted with sulfydryl isothiuronium salts Barbiturates compound
Preparation, steps are as follows:
1) by 1- phenyl -5- (substituted-phenyl) -3- sulfydryl -1,2,4- nitrogen triazole, sulfydryl isothiuronium salts Barbiturates compound and second
Alcohol and methylene chloride mixed solvent are mixed and stirred for uniformly, and acid binding agent aqueous solution is instilled at 0-5 DEG C, 1-2h is stirred to react, obtains
To reaction solution；
2) it by above-mentioned reaction solution through adding water and methylene chloride to extract to obtain organic phase, is then concentrated under reduced pressure, is cooling, solid, column is precipitated
Chromatography can be prepared by object.
3. two thio 1 according to claim 2, the preparation method of 2,4- nitrogen triazole class compounds, it is characterised in that: described to tie up
Sour agent is sodium bicarbonate, anhydrous sodium acetate, pyridine or piperidines.
4. two thio 1 according to claim 2, the preparation method of 2,4- nitrogen triazole class compounds, it is characterised in that: the mercapto
The molar ratio of base isothiuronium salts Barbiturates compound and 1- phenyl -5- (substituted-phenyl) -3- sulfydryl -1,2,4- nitrogen triazole is 1-
1.2:1；The amount ratio of 1- phenyl -5- (substituted-phenyl) -3- sulfydryl -1,2,4- nitrogen triazole and solvent is 1mmol:6-9ml；Tie up acid
The dosage molar ratio of agent and sulfydryl isothiuronium salts Barbiturates compound is 1.3-1.6:1.
5. as described in claim 1 two thio 1, the application of 2,4- nitrogen triazole class compounds, it is characterised in that: the chemical combination
Object is used to prepare the drug of anti-cervical cancer Hela, liver cancer SMMC-7721 and lung cancer A549 cell.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461625A (en) * | 2021-07-02 | 2021-10-01 | 天津理工大学 | Preparation method and application of disulfide compound based on 1,2, 4-azotriazole |
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| CN105061342A (en) * | 2015-09-08 | 2015-11-18 | 天津理工大学 | 1,2,4-triazole based disulfide compound and preparation method thereof |
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| CN113461625A (en) * | 2021-07-02 | 2021-10-01 | 天津理工大学 | Preparation method and application of disulfide compound based on 1,2, 4-azotriazole |
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