CN102911177A

CN102911177A - 7-(4-chlorphenyl)-5,6-dihydro-7aH-benzo[h]1,2,4-triazolo[3,4-b]quinazoline-5,6-diketone and synthetic method thereof

Info

Publication number: CN102911177A
Application number: CN2012104387279A
Authority: CN
Inventors: 武利强; 黄艳芹; 杨晓娟; 律海霞; 李慧智
Original assignee: Xinxiang Medical University
Current assignee: Xinxiang Medical University
Priority date: 2012-11-07
Filing date: 2012-11-07
Publication date: 2013-02-06
Anticipated expiration: 2032-11-07
Also published as: CN102911177B

Abstract

The invention provides 7-(4-chlorphenyl)-5,6-dihydro-7aH-benzo[h]1,2,4-triazolo[3,4-b]quinazoline-5,6-diketone and a synthetic method thereof. The method comprises the following steps of: uniformly mixing 3-amino-1,2,4-triazole, p-chlorobenzaldehyde, 2-hydroxyl-1,4-naphthaquinone and p-methylbenzene sulfonic acid with a usage amount of catalyst, heating and stirring, controlling the temperature at 110-125 DEG C and reacting for 2.5-3 hours. The 7-(4-chlorphenyl)5,6-dihydro-7aH-benzo[h]1,2,4-triazolo[3,4-b]quinazoline-5,6-diketone prepared according to the invention introduces chlorine atoms, thus having stronger activity and being more beneficial to absorption. The method provided by the invention is green and environment-friendly, and has the characteristics that the raw materials are available, the operation is simple and the yield is high.

Description

7-(4-chloro-phenyl-)-5,6-dihydro-7aH-benzo [h] 1,2, the 4-triazole is [3,4-b] quinazoline-5 also, 6-diketone and synthetic method thereof

Technical field

The present invention relates to a kind ofly 1, the 2-naphthoquinone derivatives specifically, relates to a kind of 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5, the 6-diketone.

Background technology

Cancer is a class disease of serious threat human health, and seeking effective cancer therapy drug is the important research topic of present world medical circle, and according to the literature, 1,2-naphthoquinone derivatives has antitumor, anti-inflammatory, the multiple biological activity such as antibiotic.In recent years 1, the anti-tumor activity of 2-naphthoquinone derivatives gets more and more people's extensive concerning day by day, and some are natural 1, the 2-naphthoquinone compound as: β1 of-lapachol, Rhinacanthone, Biflorin, mansonone E and synthetic, the 2-naphthoquinone compound all demonstrates unique antitumor action such as: Squamocin A.Compare with the 1,4-naphthoquinone compounds, the antitumor action of 1,2-naphthoquinone compound has following three advantages; 1) antitumour activity is strong, and the 1,4-naphthoquinone of similar and 1,2-naphthoquinone compound, the latter's antitumour activity are than the former large 2-5 doubly; 2) selectivity is good, 1,2-naphthoquinone compound to Normocellular killing action a little less than, have stronger selectivity; 3) topoisomerase is had stronger restraining effect, topoisomerase enzyme inhibitor has indicated a direction for we develop optionally.

Nitrogen heterocyclic is a kind of important intermediate in the Synthetic Organic Chemistry, has a wide range of applications in fine chemistry industry, agricultural chemicals and other relevant industries, and nitrogen heterocyclic also is the key structure segment of some biologically active substance and medicine simultaneously.With nitrogen heterocyclic and the amalgamation of 1,2-naphthoquinones, can obviously increase the activity of compound.

Chlorine-containing organic compounds is owing to its unique physics, and chemical property and biological activity have all adopted chloride compound in many medicines, such as microbiotic paraxin, and antipsychotic drug Torazina, anti-inflammation and analgesic drugs diclofenac etc.

Innovation of the present invention has been to synthesize a kind of nitrogen heterocyclic and 1 that chlorine replaces that contains, and 2-naphthoquinone compound, this compound not yet have report at present.Through preliminary determination of pharmacological activity, this compound has stronger antitumour activity.

Summary of the invention

The purpose of this invention is to provide a kind of new compound 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5, the 6-diketone.

Another object of the present invention provides the synthetic method of this compound.

In order to realize the object of the invention, 7-of the present invention (4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5, the 6-diketone, it is the compound with structure shown in the formula I:

。

Specifically, of the present invention 1, the 2-naphthoquinone compound is 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5,6-diketone, molecular formula: C ₁₉H ₉ClN ₄O ₂, molecular weight: 360.04, outward appearance: yellow solid, fusing point: 245-246 ℃.

7-of the present invention (4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5, the synthetic method of 6-diketone adopts first with 3-amino-1, the tosic acid of 2,4-triazole, 4-chlorobenzaldehyde, 2 hydroxy 1,4 naphthoquinone (lawsone) and catalyst levels mixes, heated and stirred, temperature are controlled at 110-125 ℃, react 2.5-3 hour.

Wherein, described 3-amino-1,2, the mol ratio of 4-triazole, 4-chlorobenzaldehyde, 2 hydroxy 1,4 naphthoquinone (lawsone) is 1:1 ~ 1.1:1.After the reaction, reaction mixture dissolves with methylene dichloride, water washing twice, and steaming desolventizes, and uses 95% ethyl alcohol recrystallization, obtains 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5, the 6-diketone.

Its reaction formula is:

。

Embodiment

Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.

With 0.84g 3-amino-1,2, the 4-triazole, 1.40g 4-chlorobenzaldehyde, 1.74g 2 hydroxy 1,4 naphthoquinone (lawsone) and 0.2g tosic acid place 50 milliliters of reaction flasks to mix together, and heated and stirred, temperature are controlled at 110 ℃, react after 2.5 hours.Reaction mixture dissolves with 20 milliliters of methylene dichloride, 20 ml water washed twice, and anhydrous sodium sulfate drying, steaming desolventizes, and uses 95% ethyl alcohol recrystallization, gets yellow corresponding product 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5,6-diketone 3.17g, productive rate are 88 %.

After testing, molecular formula: C ₁₉H ₉ClN ₄O ₂, molecular weight: 360.04, outward appearance: yellow solid, fusing point: 245-246 ℃;

IR (KBr) ν: 3074, 2923, 1684, 1598, 1586, 1512, 1501, 1478, 1449, 1296, 1281, 1273, 1228, 1093, 766 cm ^-1；

¹H NMR (CDCl ₃, 400 MHz) δ: 8.99 (d, J = 7.6 Hz, 1H, ArH), 8.59 (s, 1H, CH), 8.26 (d, J = 7.6 Hz, 1H, ArH), 7.97-7.50 (m, 6H, ArH);

¹³C NMR (CDCl ₃, 100 MHz) δ: 178.6, 178.2, 159.3, 157.3, 155.6, 152.9, 138.2, 136.7, 135.5, 134.9, 133.5, 132.1, 130.4, 130.1, 129.6, 129.3, 128.1, 126.4, 113.9；

C ₁₉H ₉ClN ₄O ₂Constituent content: C 63.26%, H 2.51%, and N 15.53%; Determine: C 63.32%, and H 2.42%, and N 15.60%.

With 8.4g 3-amino-1,2, the 4-triazole, 14.7g 4-chlorobenzaldehyde, 17.4g 2 hydroxy 1,4 naphthoquinone (lawsone) and 2g tosic acid place 250 milliliters of reaction flasks to mix together, and heated and stirred, temperature are controlled at 120 ℃, react after 3 hours.Reaction mixture dissolves with 200 milliliters of methylene dichloride, 200 ml water washed twice, and anhydrous sodium sulfate drying, steaming desolventizes, and uses 95% ethyl alcohol recrystallization, gets yellow corresponding product 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5,6-diketone 31.0g, productive rate are 85 %.

With 42g 3-amino-1,2, the 4-triazole, 77.6g 4-chlorobenzaldehyde, 87g 2 hydroxy 1,4 naphthoquinone (lawsone) and 10g tosic acid place 1000 milliliters of reaction flasks to mix together, and heated and stirred, temperature are controlled at 125 ℃, react after 2.5 hours.Reaction mixture dissolves with 1000 milliliters of methylene dichloride, 1000 ml water washed twice, and anhydrous sodium sulfate drying, steaming desolventizes, and uses 95% ethyl alcohol recrystallization, gets yellow corresponding product 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5,6-diketone 162g, productive rate are 90 %.

Adopt the anti-tumor activity of mtt assay test target compound.Take breast cancer cell MCF-7 as the test cell strain, select the adherent tumour cell of logarithmic phase, after trysinization, be made into the cell suspension of 5000/mL with the RPMI l640 substratum that contains 10% calf serum, be seeded in 96 well culture plates, 200 μ L are inoculated in every hole, 37 ℃, 5%CO ₂Cultivate 24 h.Set up negative control group, positive controls and administration group.The substratum that contains the different concns sample that experimental group renews, control group then changes the substratum that contains the equal-volume solvent, and positive controls gives the positive control drug Zorubicin, and (being diluted to concentration with perfect medium is 10 μ molL ^-1), establish 3～5 parallel holes for every group, 37 ℃, 5%CO ₂Cultivate 4～5d.Abandoning supernatant, every hole add the serum free medium of the freshly prepared 0.2mg/mL of the containing MTT of 200 μ L.37 ℃ are continued to cultivate 4h.Carefully abandon supernatant, and add 200 μ LDMSO, behind miniature ultrasonic vibrator mixing, take tested wavelength as 570nm, reference wavelength is that 450nm measures optical density value on microplate reader.Be calculated as follows medicine to the inhibiting rate of growth of tumour cell: growth of tumour cell inhibiting rate %=(1-OD experiment/OD contrast) * 100%.With 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] [1,2,4]-triazole [3,4-also b] quinazoline-5, mapping can obtain dose response curve to the different concns of 6-diketone to the growth of tumour cell inhibiting rate, therefrom obtains the half casualty-producing concentrations IC of sample ₅₀Its IC ₅₀Value is 5.84 μ g/mL.

Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.

Claims

(1.7-4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] 1,2, the 4-triazole is [3,4-also b] quinazoline-5, the 6-diketone, its structural formula is as follows:

。
2. prepare 7-claimed in claim 1 (4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] 1,2, the 4-triazole is [3,4-also b] quinazoline-5, the synthetic method of 6-diketone is characterized in that, it adopts first with 3-amino-1, the tosic acid of 2,4-triazole, 4-chlorobenzaldehyde, 2 hydroxy 1,4 naphthoquinone (lawsone) and catalyst levels mixes, heated and stirred under 110-125 ℃, was reacted 2.5-3 hour.
3. method according to claim 2 is characterized in that, 3-amino-1,2, and the mol ratio of 4-triazole, 4-chlorobenzaldehyde, 2 hydroxy 1,4 naphthoquinone (lawsone) is 1:1 ~ 1.1:1.
4. according to claim 2 or 3 described methods, it is characterized in that after the reaction, reaction mixture dissolves with methylene dichloride, water washing twice, steaming desolventizes, and uses 95% ethyl alcohol recrystallization, obtains 7-(4-chloro-phenyl-)-5,6-dihydro-7a H-benzo [ h] 1,2, the 4-triazole is [3,4-also b] quinazoline-5, the 6-diketone.