CN104059062B - Fused ring compound and its application containing benzothiazole and the double heterocycles of triazole - Google Patents
Fused ring compound and its application containing benzothiazole and the double heterocycles of triazole Download PDFInfo
- Publication number
- CN104059062B CN104059062B CN201410249790.7A CN201410249790A CN104059062B CN 104059062 B CN104059062 B CN 104059062B CN 201410249790 A CN201410249790 A CN 201410249790A CN 104059062 B CN104059062 B CN 104059062B
- Authority
- CN
- China
- Prior art keywords
- compound
- triazole
- formula
- reaction
- prepared
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 C*(CC*(C(c(cc1)c2c3cccc2c1N)=O)*3=O)CC=C(CNC1=C(*)Cc(cccc2)*2N1)*=C Chemical compound C*(CC*(C(c(cc1)c2c3cccc2c1N)=O)*3=O)CC=C(CNC1=C(*)Cc(cccc2)*2N1)*=C 0.000 description 2
- DLPJVVKWGUAKMK-UHFFFAOYSA-N CC(C(CCBr)CC(c(c1c2cc3)cccc1c3N1CCCCC1)=O)C2=O Chemical compound CC(C(CCBr)CC(c(c1c2cc3)cccc1c3N1CCCCC1)=O)C2=O DLPJVVKWGUAKMK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Fused ring compound the present invention relates to contain benzothiazole and the double heterocycles of triazole, the structure with formula Y.The present invention is connected to 4 of naphthalimide in the cyclic amine with bioactivity, and maintain the imines position triazole nitrogen-atoms that is connected with side chain of nitrogen-atoms of naphthalimide and be separated by two structures of carbon, sulfur heterocyclic ring benzothiazole is also introduced by molecule by the link of triazole, expand the diversity of naphthalimide derivative, the bioactivity of naphthalimide is improved, the identification to DNA and embedded ability is improve；Such compound has good inhibiting effect to the normal growth of the tumour cell of various different tissue sources such as cervical carcinoma, liver cancer, breast cancer.
Description
Technical field
The present invention relates to the double heterocycle naphthalimides of benzothiazole and triazole in biological organic synthesis field
Compound, its preparation method and its application.
Background technology
Most molecules containing naphthalimide precursor structure have fluorescence and compound shows extensive bioactivity,
Such as cancer therapy drug, antitrypanosomal agent is antiviral, local anaesthesia, anodyne, thrombocytin 5-HT3 and 5-HT4 Antibodies Against
Agent, chemical sensor etc..Cancer therapy drug with naphthalimide as parent as pacify how Fitow (Amonafide), mitonafide
(Mitonafide) and UNBS5162 etc. also into different phase clinical test, but Amonafide and mitonafide are due to its poison
Side effect inhibits further research.To 1973,Deng report first 3- nitros naphthalimide derivative have it is anti-
Tumor promotion, then by the modification different degrees of to naphthalimide precursor structure, having synthesized many has antitumor activity
Naphthoyl imide compounds.It is a kind of new Reconstruc-tion policy to naphthalimide that aromatic rings is bonded in the form of " non-naphtho- ",
The antitumor activity of naphthalimide is improve to a certain extent.
In the recent period, Amonafide has been enter into phase III clinical trial for the treatment of secondary myelogenous leukemia, and this is more inspired
Research of the scientific research personnel using naphthalimide derivative as potential cancer therapy drug.
Benzothiazole is twin nuclei, while being also that many has ocean and the land native compound structure of bioactivity
A part.Due to its extensive pharmacological activity, with benzothiazole as core be medicament research and development an important thinking.Reporting
In the document led, benzothiazole derivant is effective antitumor and anticancer agent, LTD4 receptor antagonists, Alzheimer's amyloid
Albumen preparation, anticonvulsant, antiseptic, antidiabetic, muscarinic receptor antagonist, antispasmodic etc..2- (4- aminobenzenes
Base) benzothiazole and its derivative, 2- (4- aminophenyls) -5- fluoro benzothiazoles are that institute of oncology of Univ Nottingham UK grinds
Hair, the medicine series have the cytotoxicity of high selection, IC to breast cancer50Value is up to nM grades.The Schiff base of benzothiazole
With certain antitumor curative effect, IC50Value is up to μM level.Ott etc. introduces mercaptobenzothiazoler in naphthalimide parent, obtains
The series derivates of sulfur-bearing substitution, the series mainly with topoisomerase enzyme effect and show phototoxicity.
Triazole class compounds have an extensive pharmacological activity, such as antibacterial, analgesia, anti-inflammatory, local anaesthesia, antiviral, anti-pernicious
Hyperplasia, anti-hypertension, anticancer etc..Such as compound E4896 is currently under phase III clinical trial, can be used for breast cancer,
Lung cancer, advanced ovarian cancer, the treatment of kidney, show micromolecular lung cancer activity experiment result in addition：It can reduce 51%
Angiogenesis.
The content of the invention
The present invention has multiple avtive spots according to naphthalimide, and structure is also easy to modification, will be with bioactivity
Cyclic amine be connected to 4 of naphthalimide, and maintain the triazole that the imines position nitrogen-atoms of naphthalimide is connected with side chain
Atom is separated by two structures of carbon.Additionally, sulfur heterocyclic ring benzothiazole is also introduced molecule by the link by triazole, continue to open up
The diversity of naphthalimide derivative is opened up, expects to improve the bioactivity of naphthalimide, improve the identification to DNA and embedding energy
Power.Of the invention is to introduce five yuan of triazole rings and to connect sulfydryl with flexible side-chains on the bromo- 1,8 naphthalene anhydride parents of 4- containing compound
Benzothiazole group, the purpose is to：By amino condensation, amino substitution, phosphorus tribromide substituted hydroxy, Azide, " Click
Chemistry " etc. is reacted, and synthesis is given birth to containing benzothiazole and the double heterocycle naphthoyl imide compounds of triazole to tumor cell in vitro
It is long that there is rejection ability.
The present invention solves the technical scheme that is used of above-mentioned technical problem：Condensed ring containing benzothiazole and the double heterocycles of triazole
Compound, the compound has the structure of formula Y：
In formula Y：R is selected from X1、X2、X3、X4、X5Or X6
Further, the compound is selected from：
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- hexahydropyridines -1,8-
Naphthalimide；
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- morpholine -1,8- naphthoyls
Imines；
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- thiomorpholines -1,8-
Naphthalimide；
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- methyl piperazines -1,8-
Naphthalimide；
Or N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- pyrroles's -1,8- naphthalenes
Acid imide.
The preparation method of compound of the present invention, comprises the following steps：
1. intermediate 1 is prepared：In the presence of triethylamine, with acetone as solvent, propargyl bromide reacts with 2-mercaptobenzothiazole
Generation 2- (2- alkynes -1- propyl dithiocarbamates) benzo [d] thiazole, as intermediate 1；
2. intermediate 3 is prepared：Bromo- 1, the 8- naphthalene anhydrides of 4- and monoethanolamine are dissolved in ethanol, are warming up to back flow reaction, generation N- (2 '-
Hydroxyethyl) bromo- 1, the 8- naphthalimides of -4-, as intermediate 3；
3. intermediate 4 is prepared：Intermediate 3 is dissolved in glycol monoethyl ether, corresponding cyclic amine is added, reaction is had
The intermediate 4 of logical structure shown in formula I；
4. intermediate 5 is prepared：Intermediate 4 is dissolved in ethyl acetate, adds phosphorus tribromide reaction generation that there is the knot of formula II
The intermediate 5 of structure；
5. intermediate 6 is prepared：Intermediate 5 is dissolved in DMF, NaN is added3, centre of the reaction generation with general formula III structure
Body 6；
6. the compound is prepared：Intermediate 6 and intermediate 1 are dissolved in the mixed liquor of the tert-butyl alcohol and water, catalysis is added
Agent sodium ascorbate and cupric sulfate pentahydrate, under nitrogen protection, the reaction generation compound.
Synthetic route is as follows：
Further, step 1. in, propargyl bromide：2-mercaptobenzothiazole：The optimum mole ratio of triethylamine is 1:1:1；First
By 2-mercaptobenzothiazole with acetone solution, triethylamine is added, now reaction solution is in orange transparency liquid, adds propargyl bromide,
Sonic oscillation reacts about 10min, and filtering obtains brown filtrate, filtrate decompression is distilled off into solvent, obtains brown oil solid.
Further, step 2. middle 4- bromo- 1,8 naphthalene anhydrides are 1 according to optimum mole ratio with monoethanolamine:1.2 feed intake, and are warming up to
Backflow, there is amino condensation reaction in the two, TLC tracks to reaction completely, and frozen water is poured into cooling, separates out pale precipitation, is taken out
Filter, dries.
Further, 3. middle intermediate 3 is 1 with the mol ratio of corresponding cyclic amine to step:2.9~3.5 generation amino take
Generation reaction, reaction temperature is most preferably the reflux temperature of 125 DEG C, i.e. glycol monoethyl ether, and after the completion of reaction, cooling is poured into cold
Yellow mercury oxide is separated out in water, is filtered, washing, dry yellow solid.
Further, 4. middle intermediate 4 is dissolved in ethyl acetate to step under condition of ice bath, and ice is continued after adding phosphorus tribromide
The optimum mole ratio 1 of bath 0.5h, intermediate 4 and phosphorus tribromide:2.9~3.1；Remove ice bath, be heated to reflux temperature, TLC with
Track extremely reacts complete, cools down, and pours into and Huang is separated out in saturated aqueous common salt to no longer smoldering with excessive phosphorus tribromide in addition methyl alcohol
Color is precipitated, filtering, washing, dry yellow solid.
Further, 5. middle intermediate 5 and the optimum mole ratio of Sodium azide are 1 to step:3, this azido reaction temperature one
As be less than 60 DEG C, most preferably 55 DEG C of reaction temperature after reaction terminates, pours into saline solution, suction filtration, and washing is dried, and obtains yellow and consolidates
Body.
Further, step 6. in, the optimum mole ratio of intermediate 6 and intermediate 1 is 1:2, the tert-butyl alcohol and water are with 1:1 mixes
Close, " the Click chemistry " being catalyzed through Cu (I) reacts, 70 DEG C of lucifuges react complete to reaction, and saturation food is poured into cooling
In salt solution, stand, filtering is dried, the isolated solid of silica gel column chromatography, as described compound.
Compound of the present invention has the effect for suppressing growth of tumour cell, and the tumour cell includes MCF-7 mammary gland
Cancer cell, Hela cervical cancer cells and SMMC-7721 HCCs.
Compound of the present invention is thin to MCF-7 breast cancer cells, Hela cervix cancers with tetrazolium reducing process
Born of the same parents and SMMC-7721 HCCs carry out the measure of extracorporeal suppression tumor cell growth activity, as a result show, such compound pair
The tumour cell of various different tissue sources such as cervical carcinoma, liver cancer, breast cancer has the activity of Developing restraint.
The tetrazolium reducing process experimental procedure is as follows：
1st, inoculating cell
MCF-7 Breast Cancer Cell, human cervical carcinoma Hela cell and SMMC-7721 liver cancer cells are collected into culture medium respectively
In, 200 μ L cell suspensions are inoculated with after cell is diluted per hole, it is ensured that per 2000~5000 cells of Kong Zhongyue, outermost is added
200 μ LPBS, there is provided sufficient moisture ensures the growing environment of cell, and culture plate is put to 37 DEG C, 5%CO2Environment in incubate
Incubate 24h~48h.
2nd, medicine is added
Compound of the present invention is diluted to 10 respectively with culture medium-8、10-7、10-6、10-5Tetra- gradient concentrations of M, inhale
The culture medium of 2-11 row in 96 orifice plates is removed, is careful that cell should not be siphoned away herein；Medicine is subsequently adding, 6 multiple holes are set, reduced
Error；After the completion for the treatment of, 96 orifice plates are put back into CO2In incubator, 48h is cultivated.
3rd, the detection of survivaling cell number
20 μ L MTT are added in all Kong Zhongjun, CO is put into24h is incubated in incubator；The culture medium and MTT in hole are discarded,
200 μ L DMSO are added, the MTT- formazans crystallization of residual is dissolved.Each hole absorbance record result is determined on ELIASA, by following
Formula calculates inhibiting rate of the measured object to growth of cancer cells：
Tumor control rate=(control group OD values-treatment group OD values)/control group OD value × 100%.
Beneficial effects of the present invention：
First, the present invention is connected to 4 of naphthalimide in the cyclic amine with bioactivity, and maintains naphthalimide
The imines position triazole nitrogen-atoms that is connected with side chain of nitrogen-atoms be separated by two structures of carbon, thia will also be contained by the link of triazole
Ring benzothiazole introduces molecule, expands the diversity of naphthalimide derivative, improves the bioactivity of naphthalimide, improves
Identification and embedded ability to DNA；
Second, the fused ring compound containing benzothiazole and the double heterocycles of triazole of the invention has to tumor cell in vitro growth
Rejection ability, such as MCF-7 breast cancer cells, Hela cervical cancer cells and SMMC-7721 HCCs.
Specific embodiment
Below by embodiment, the present invention is further illustrated, but do not limit the invention in any way.
Embodiment 1
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- hexahydropyridines -1,8-
The synthesis of naphthalimide (compound F4)：
(1) synthesis of 2- (2- alkynes -1- propyl dithiocarbamates) benzo [d] thiazole (intermediate 1)
2-mercaptobenzothiazole 3.02g (18mmol) mercaptobenzothiazoler is weighed, 35mL acetone solutions are used, 2.51mL is added
(18mmol) triethylamine, now reaction solution is in orange transparency liquid, adds 1.41mL (18mmol) propargyl bromide, 10 points of ultrasonic vibration
Clock, stops reaction, and filtering obtains brown filtrate, filtrate decompression is distilled off into solvent.Obtain brown oil solid 3.61g, yield：
98.0%.
(2) synthesis of the bromo- 1,8- naphthalimides (intermediate 3) of N- (2 '-hydroxyethyl) -4-
In 50mL bottle with two necks, add bromo- 1, the 8- naphthalene anhydrides of 2.76g (10mmol) 4-, add 0.7mL monoethanolamines, 28mL without
Backflow is warming up under water-ethanol, magnetic agitation, 3h is reacted at a reflux temperature, it is complete that TLC tracks to reaction.Stop heating, it is cold
But to after room temperature, reaction system is poured into frozen water, separates out pale precipitation, suction filtration, dry product 2.79g.Yield：
87.4%.
(3) synthesis of N- (2 '-hydroxyethyl) -4- hexahydropyridines base -1,8- naphthalimides (intermediate 4)
2.0g (6.3mmol) intermediate 3 is taken, 25mL glycol monoethyl ether stirring and dissolvings is added, then add in system
1.86mL (1.9mmol) hexahydropyridine, is heated to 125 DEG C, keeps this temperature to continue to react 3h, and TLC tracks to reaction completely, stops
Only heat, the system for the treatment of is cooled to room temperature, be poured into water precipitation yellow mercury oxide, filter, washing, dry yellow solid 1.99g.Produce
Rate：98.2%.
(4) synthesis of N- (2 '-bromoethyl) -4- hexahydropyridines base -1,8- naphthalimides (intermediate 5)
1.99g (6.1mmol) intermediate 4 is taken, 25mL ethyl acetate stirring and dissolving under ice-water bath is added, treats that system is near
After 0 DEG C, 1.75mL (18.5mmol) phosphorus tribromide is slowly added dropwise to system, continues ice bath 0.5h, remove ice-water bath, reaction is added
2h is reacted under heat to reflux temperature, TLC tracks to reaction completely, stops heating, and standing is cooled to room temperature, is fitted to being added in system
With excessive phosphorus tribromide in the methyl alcohol of amount, untill treating no longer to smolder.Pour into and yellow mercury oxide separated out in saturated aqueous common salt, filter,
Washing, dry yellow solid 2.24g.Yield：94.3%.
(5) synthesis of N- (2 '-azidoethyl) -4- hexahydropyridines base -1,8- naphthalimides (intermediate 6)
2.24g (5.8mmol) compound 5 is added in 50mL reaction bottle with two necks, 28mL DMF solvents are added, then to system
It is slowly added to 1.13g NaN3(17.4mmol), is heated to 55 DEG C, after reaction 1.5h, system is cooled into room temperature, pours into saturation
Saline solution, suction filtration, washing is dried, and obtains yellow solid 1.89g.Yield：93.3%.
(6) N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- hexahydropyridine -1,
The synthesis of 8- naphthalimides (compound F4)
1.89g (5.42mmol) compound 6,2.22g (10.84mmol) intermediate 1 is added to use in 50mL bottle with two necks
The 1 of the 32mL tert-butyl alcohols and water:1 mixed solution stirring and dissolving, add catalyst 3.22g sodium ascorbates (VC sodium) and
1.36g cupric sulfate pentahydrates, N2Under protection, in 70 DEG C of lucifuge reaction 24h, it is complete that TLC tracks to reaction.After reaction terminates, by body
System is poured into saturated aqueous common salt after being cooled to room temperature, is stood, and filtering is dried.Silica gel column chromatography separates that (column chromatography eluent is
CH2Cl2:CH3OH=20:1) target product 1.26g (compound F4), yellow solid, yield 42.0%, are obtained.Fusing point：
176.1-178.4℃。
1H NMR(400MHz,CDCl3) δ 8.45 (dd, J=7.3,1.1Hz, 1H), 8.41-8.32 (m, 2H), 7.82 (d, J
=7.8Hz, 1H), 7.74 (s, 2H), 7.61 (d, J=1.0Hz, 1H), 7.42-7.36 (m, 1H), 7.29 (dd, J=11.5,
4.5Hz, 1H), 7.12 (d, J=8.2Hz, 1H), 4.71 (t, J=6.1Hz, 2H), 4.67-4.59 (m, 4H), 3.28-3.12
(m,4H),1.93–1.84(m,4H),1.77–1.69(m,2H).
+ESI MS(M+H):C29H26N6O2S2, calculated value：555.1559, measured value：555.1628.
Embodiment 2
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- morpholine -1,8- naphthoyls
The synthesis of imines (compound F1)：
In addition to hexahydropyridine is replaced with morpholino in (3), other synthesis and experiment process method are with embodiment 1.Through silica gel
(column chromatography eluent is CH to column chromatography for separation2Cl2:CH3OH=14:1) target product F1, greenish yellow solid, yield, are obtained
79.8%.Fusing point：212.2-215.6℃.
1H NMR(400MHz,CDCl3) δ 8.48 (d, J=7.3Hz, 1H), 8.41 (dd, J=13.7,8.2Hz, 2H),
7.86 (d, J=8.0Hz, 1H), 7.74 (d, J=8.4Hz, 2H), 7.69-7.62 (m, 1H), 7.41 (t, J=7.2Hz, 1H),
7.31 (d, J=8.0Hz, 1H), 7.18 (d, J=8.1Hz, 1H), 4.72 (t, J=6.0Hz, 2H), 4.70-4.48 (m, 4H),
4.16–3.91(m,4H),3.37–3.11(m,4H).13C NMR(101MHz,CDCl3)δ165.99,164.10,163.56,
155.97,153.00,135.40,132.85,131.43,130.47,129.92,126.05,126.02,125.79,124.28,
123.52,122.58,121.48,121.02,116.28,114.93,66.93,53.40,47.95,39.43,27.87.
+ESI MS(M+H):C28H24N6O3S2, calculated value：557.1351, measured value：557.1427.
Embodiment 3
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- thiomorpholines -1,8-
The synthesis of naphthalimide (compound F2)：
In addition to hexahydropyridine is replaced with thiomorpholine in (3), other synthesis and experiment process method are with embodiment 1.Through
(column chromatography eluent is CH for silica gel column chromatography separation2Cl2:CH3OH=6:1) target product F2, yellow solid, yield, are obtained
75.7%.Fusing point：206.5-208.1℃.
1H NMR(400MHz,CDCl3) δ 8.48 (dd, J=7.3,1.0Hz, 1H), 8.42 (d, J=8.1Hz, 1H), 8.34
(dd, J=8.4,1.0Hz, 1H), 7.85 (d, J=7.7Hz, 1H), 7.75 (d, J=7.9Hz, 2H), 7.66 (dd, J=8.4,
7.4Hz, 1H), 7.41 (t, J=7.2Hz, 1H), 7.30 (t, J=7.6Hz, 1H), 7.19 (d, J=8.1Hz, 1H), 4.73 (t,
J=6.0Hz, 2H), 4.70-4.56 (m, 4H), 3.51 (s, 4H), 2.99 (s, 4H)
+ESI MS(M+H):C28H24N6O2S3, calculated value：573.1123, measured value：573.1181.
Embodiment 4
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- methyl piperazines -1,8-
The synthesis of naphthalimide (compound F3)：
In addition to hexahydropyridine is replaced with methyl piperazine in (3), other synthesis and experiment process method are with embodiment 1.Through
(column chromatography eluent is CH for silica gel column chromatography separation2Cl2:CH3OH:Triethylamine=14:1:1) target product F3, is obtained, it is yellowish green
Color solid, yield 50.3%.Fusing point：186.4-188.0℃.
1H NMR(400MHz,CDCl3) δ 8.48 (d, J=7.2Hz, 1H), 8.41 (d, J=8.1Hz, 1H), 8.38 (d, J
=8.4Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.73 (d, J=7.2Hz, 2H), 7.68-7.59 (m, 1H), 7.43-7.37
(m, 1H), 7.33-7.28 (m, 1H), 7.17 (d, J=8.1Hz, 1H), 4.72 (t, J=6.1Hz, 2H), 4.69-4.57 (m,
4H),3.31(s,4H),2.76(s,4H),2.45(s,3H).
+ESI MS(M+H):C29H27N7O2S2, calculated value：570.1668, measured value：570.1729.
Embodiment 5
N- [2 '-(4- ((benzothiazole -2- sulfydryls) methyl)-[1,2,3]-triazole)-ethyl] -4- pyrroles's -1,8- naphthoyls
The synthesis of imines (compound F5)：
In addition to hexahydropyridine is replaced with pyrroles in (3), other synthesis and experiment process method are with embodiment 1.Through silica gel
(column chromatography eluent is CH to column chromatography for separation2Cl2:CH3OH=17:1) target product F5, Chinese red solid, yield, are obtained
58.1%.Fusing point：117.7-119.2℃.
1H NMR(400MHz,CDCl3) δ 8.55 (d, J=8.6Hz, 1H), 8.47 (d, J=6.7Hz, 1H), 8.32 (d, J
=8.7Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.79-7.67 (m, 2H), 7.53-7.44 (m, 1H), 7.39 (t, J=
7.7Hz, 1H), 7.29 (d, J=7.1Hz, 1H), 6.76 (d, J=8.7Hz, 1H), 4.72 (t, J=6.0Hz, 2H), 4.69-
(m, the 4H) of 4.45 (m, 4H), 3.78 (t, J=6.4Hz, 4H), 2.29-2.00
+ESI MS(M+H):C28H24N6O2S2, calculated value：541.1402, measured value：541.1449.
Application examples
Extracorporeal suppression tumor cell growth activity is determined：
With tetrazolium (microculture tetrozolium, MTT) reducing process to MCF-7 breast cancer cells, Hela
Cervical cancer cell and SMMC-7721 HCCs carry out extracorporeal suppression tumor cell growth activity measure.
By taking compound F1 as an example, the concrete operations of tetrazolium (MTT) reducing process are：
1st, inoculating cell
The tumour cell that certain amount is in exponential phase is collected into culture medium, is inoculated with per hole after cell is diluted
200 μ L cell suspensions, it is ensured that per 2000~5000 cells of Kong Zhongyue, outermost adds 200 μ L PBS, there is provided sufficient moisture
Ensure the growing environment of cell, culture plate is put to 37 DEG C, 5%CO224h is incubated in the incubator of environment.
2nd, medicine is added
The compound F1 for being prepared embodiment 1 with culture medium is diluted to 10 respectively-8、10-7、10-6、10-5Tetra- gradients of M are dense
Degree；The culture medium of 2-11 row in 96 orifice plates is sucked, is careful that cell should not be siphoned away herein, be subsequently adding medicine, each concentration sets
6 multiple holes are put, reduces error；After the completion for the treatment of, 96 orifice plates are put back into CO2In incubator, 48h is cultivated.
3rd, the detection of survivaling cell number
20 μ L MTT are added in all Kong Zhongjun, CO is put into24h is incubated in incubator；The culture medium and MTT in hole are discarded,
Add 200 μ L DMSO, lysigenous crystallization.Each hole absorbance record result is determined on ELIASA, is calculated by following equation
Inhibiting rate of the measured object to growth of cancer cells：
Tumor control rate=(control group OD values-treatment group OD values)/control group OD value × 100%.
The detection method of compound F2~F5 is ibid.
According to the tumor control rate of compound F1~F5, its IC is calculated50Value, as a result such as following table：
The compound F1 of table 1.~F5 is to Hela, MCF-7 and the IC of 7721 cancer cells50Value
Table 1 lists compound F1~F5 to MCF-7, Hela and the IC of 7,721 3 kinds of cancer cells50Value, the serial chemical combination
Thing general performance goes out preferable antitumous effect, wherein better than 7721 cells to the selectivity of MCF-7 and Hela cells.F1
Stronger inhibition, IC are shown to three kinds of cells50Value is respectively 0.65 μM, 2.26 μM and 3.15 μM, especially to MCF-7
IC50Value is 2.58 times of amonafide.The F2 for connecting thiomorpholine does not show more preferable inhibitory activity, explanation than F1
Sulphur atom is the cytotoxicity that can strengthen compound in some cases.ICs of the F3 to MCF-7501.07 μM are reached, is
1.57 times of amonafide, to the IC of Hela cells500.84 μM is reached, is 2.06 times of amonafide.
Claims (3)
1. the fused ring compound of benzothiazole and the double heterocycles of triazole is contained, it is characterised in that the compound has the structure of formula Y：
In formula Y：R is selected from X1、X2、X3、X4、X5；
2. the preparation method of compound described in claim 1, it is characterised in that comprise the following steps：
1. intermediate 1 is prepared：In the presence of triethylamine, with acetone as solvent, propargyl bromide reacts generation with 2-mercaptobenzothiazole
2- (2- alkynes -1- propyl dithiocarbamates) benzo [d] thiazole, as intermediate 1；
2. intermediate 3 is prepared：Bromo- 1, the 8- naphthalene anhydrides of 4- are dissolved in ethanol with monoethanolamine, are warming up to back flow reaction, generate N- (2 '-hydroxyls
Ethyl) bromo- 1, the 8- naphthalimides of -4-, as intermediate 3；
3. intermediate 4 is prepared：Intermediate 3 is dissolved in glycol monoethyl ether, corresponding cyclic amine is added, reaction is obtained with formula
The intermediate 4 of I structure；
4. intermediate 5 is prepared：Intermediate 4 is dissolved in ethyl acetate, adds phosphorus tribromide reaction generation that there is the structure of formula II
Intermediate 5；
5. intermediate 6 is prepared：Intermediate 5 is dissolved in DMF, NaN is added3, reaction intermediate 6 of the generation with general formula III structure；
6. the compound is prepared：Intermediate 6 and intermediate 1 are dissolved in the mixed liquor of the tert-butyl alcohol and water, add catalyst to resist
Bad hematic acid sodium and cupric sulfate pentahydrate, under nitrogen protection, compound described in reaction generation formula Y；
Wherein, R is selected from formula I, II, III
Corresponding cyclic amine is selected from
3. the compound described in claim 1 is preparing the application in suppressing growth of tumour cell medicine, described tumour cell
Selected from MCF-7 breast cancer cells, Hela cervical cancer cells and SMMC-7721 HCCs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410249790.7A CN104059062B (en) | 2014-06-05 | 2014-06-05 | Fused ring compound and its application containing benzothiazole and the double heterocycles of triazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410249790.7A CN104059062B (en) | 2014-06-05 | 2014-06-05 | Fused ring compound and its application containing benzothiazole and the double heterocycles of triazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104059062A CN104059062A (en) | 2014-09-24 |
| CN104059062B true CN104059062B (en) | 2017-06-27 |
Family
ID=51547027
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410249790.7A Expired - Fee Related CN104059062B (en) | 2014-06-05 | 2014-06-05 | Fused ring compound and its application containing benzothiazole and the double heterocycles of triazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104059062B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540608B (en) * | 2017-07-17 | 2021-10-19 | 大连理工大学 | 4-substituted naphthalimide compound and application thereof |
| CN112979671B (en) * | 2021-03-05 | 2022-02-22 | 郑州大学 | Oridonin-naphthalimide fluorescent probe as well as preparation method and application thereof |
| CN115109033B (en) * | 2021-05-07 | 2023-11-14 | 河南师范大学 | Synthesis and bioactivity research of 1, 8-naphthalimide derivative |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1560052A (en) * | 2004-02-26 | 2005-01-05 | 华东理工大学 | Derivant of electrophosphorescence 1,8-naphthimide and luminous ligand thereof |
| WO2007030939A2 (en) * | 2005-09-15 | 2007-03-22 | Painceptor Pharma Corporation | Methods of modulating neurotrophin-mediated activity |
-
2014
- 2014-06-05 CN CN201410249790.7A patent/CN104059062B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1560052A (en) * | 2004-02-26 | 2005-01-05 | 华东理工大学 | Derivant of electrophosphorescence 1,8-naphthimide and luminous ligand thereof |
| WO2007030939A2 (en) * | 2005-09-15 | 2007-03-22 | Painceptor Pharma Corporation | Methods of modulating neurotrophin-mediated activity |
Non-Patent Citations (1)
| Title |
|---|
| 含三氮唑杂环化合物的合成及生物活性研究;赵雯雯;《大连理工大学硕士学位论文》;20091015;19-39 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104059062A (en) | 2014-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102887895B (en) | Pyridopyrimidine class mTOR inhibitors | |
| CN105153142B (en) | The Furazan Derivatives and antitumor activity of cumarin parent nucleus | |
| CN104326979B (en) | 2-methyl-9-acridine (to methoxy benzamide base) thiocarbamide and its production and use | |
| CN104072493B (en) | One class contains 2-mercaptobenzothiazole and the naphthalimide compound of triazole heterocycle, its preparation method and application thereof | |
| CN106565589A (en) | Preparation method and application of hydrazide indoles drugs | |
| CN104059062B (en) | Fused ring compound and its application containing benzothiazole and the double heterocycles of triazole | |
| CN106478606A (en) | N substituted indole analog derivative and its application | |
| CN105814039B (en) | Fluorophenyl pyrazole compound | |
| CN112300082B (en) | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application | |
| CN103450176A (en) | Naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and application thereof | |
| CN101914094B (en) | 1,3,4-oxadiazole derivative, preparation method and application thereof in preparing antitumor drug | |
| CN105130897B (en) | The naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application | |
| CN109970679A (en) | Paeonol thiazole and its preparation method and application | |
| CN106117182A (en) | Quinazoline N phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application | |
| CN102584679B (en) | Benzocarbazole acylamide compound and preparation method and application thereof | |
| CN106045971B (en) | Pirfenidone derivative and preparation method thereof | |
| CN107973788A (en) | BBI608 derivatives and its preparation and purposes | |
| CN101704813B (en) | 1'-thio-indigo red compound as well as application and preparation method thereof | |
| CN106543155B (en) | Chalcone and flavonoid derivative as aurora kinase inhibitor | |
| CN106565599A (en) | 2-aminomethylpyridylnicotinamides and preparation method and application thereof | |
| CN106083817B (en) | Pirfenidone derivative and preparation method thereof | |
| CN104327064B (en) | Acridine-1,3,4-oxadiazole compound having anti-tumor activity, preparation method and uses thereof | |
| CN105130896B (en) | The naphthalimide derivative of a kind of substituent containing thiocarbamide, its preparation method and application | |
| CN103435574B (en) | Mercapto benzothiazole substituent acenaphtho-heterocycle compound and application thereof | |
| CN103992289B (en) | Substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170627 Termination date: 20200605 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |