CN106188069A - 3,6 diaryl 1H pyrazolo [5,1 c] [1,2,4] triazole compounds are as the purposes of tumor cell proliferation inhibitor - Google Patents

3,6 diaryl 1H pyrazolo [5,1 c] [1,2,4] triazole compounds are as the purposes of tumor cell proliferation inhibitor Download PDF

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CN106188069A
CN106188069A CN201610591881.8A CN201610591881A CN106188069A CN 106188069 A CN106188069 A CN 106188069A CN 201610591881 A CN201610591881 A CN 201610591881A CN 106188069 A CN106188069 A CN 106188069A
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compound
diaryl
pyrazolo
acid
amino
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CN106188069B (en
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张为革
徐启乐
吴英良
孙茂林
左代英
王月婷
白兆石
关奇
包凯
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

The invention belongs to pharmaceutical technology field, relate to a kind of 3,6 diaryl 1HPyrazolo [5,1 c] [1,2,4] triazole compound and application thereof, exactly, relates to this compounds as tumor cell proliferation inhibitor application in terms of preparing anti-tumor drug.The structure of described compound is as follows: the definition of each substituent group is as described in claims and description.

Description

3,6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole compound conduct The purposes of tumor cell proliferation inhibitor
Technical field
The invention belongs to pharmaceutical technology field, relate to a kind of 3,6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] three nitrogen Azole compounds and application thereof, exactly, relates to this compounds and is preparing antitumor as tumor cell proliferation inhibitor Medicine in terms of application.
Background technology
Malignant tumor is the serious disease threatening human health with life, is one of main lethal cause of disease in China.Find It is the hot research direction of our times with the new drug finding treatment and prophylaxis of tumours.
Combretastatin A-4 (CA-4) is the natural product of cis-stilbene class of isolated from the willow of South Africa Thing, its chemical name is (Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is tubulin polymerization Inhibitor, presents the strongest suppression proliferative activity o f tumor, due to its poorly water-soluble, has made prodrug CA-4 phosphate ester salt (CA-4P), and to enter phase iii clinical trial conceptual phase.Antitumor activity is carried out for lead compound current with CA-4 There is a large amount of report, but the noval chemical compound of great majority synthesis exists, and activity is prominent not or toxicity is relatively big or synthesis ratio is more tired The shortcomings such as difficulty.Five-ring heterocycles hexa-member heterocycle compounds are as CA-4 analog existing document report, representative change Laminate structures is as follows.(relevant report sees: Lu Y., et al.Journal of Medicinal Chemistry, 2009,52,1701；Chen J.J.,et al.Journal of Medicinal Chemistry,2010,53,7414；Xiao M.,et al.Journal of Medicinal Chemistry,2013,56,3318；Romagnoli R.,et al.Journal of Medicinal Chemistry,2011,54,5144；Lu Y.,et al.Journal of Medicinal Chemistry,2014,57,7355；Hwang D.J.,et al.ACS Medicinal Chemistry Letter,2015,6,993.)
The five-ring heterocycles that the present invention relates to five-ring heterocycles i.e. 3,6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] three Nitrogen azole compounds has not yet to see report as the research of active compound for anti tumor.
Summary of the invention
It is an object of the invention to design, synthesize the Combretastatin with good proliferative activity o f tumor The analog of A-4, the CA-4 of i.e. 3,6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole compound is similar to Thing；Prepared compound anti-tumor activity in vivo and in vitro test manifests good result.
The target product possible constructions formula I of the present invention represents:
Present invention is preferably related to the compounds of formula I being defined as follows:
Wherein, in formula I, R2-R4For C1-C6Alkyl oxy, R1、R5、R6It is each independently hydrogen, halogen, C1-C6Alkyl, C1-C6Alkyl oxy, nitro, amino, C1-C6Alkyl amino, two C1-C6Alkyl amino.
Present invention is preferably related to the compounds of formula I being defined as follows:
Wherein, R in formula I2-R4For C1-C4Alkyl oxy, R1、R5、R6It is each independently hydrogen, halogen, C1-C4Alkyl, C1-C4Alkyl oxy, nitro, amino, C1-C4Alkyl amino, two C1-C4Alkyl amino.
Present invention is preferably related to the compounds of formula I being defined as follows:
Wherein, in formula I, R2-R4For C1-C3Alkyl oxy, R1、R5、R6It is each independently hydrogen, fluorine, chlorine, bromine, iodine, C1- C3Alkyl, C1-C3Alkyl oxy, nitro, amino, C1-C3Alkyl amino, two C1-C3Alkyl amino.
Present invention is preferably related to the compounds of formula I being defined as follows:
Wherein, in formula I, R2-R4For C1-C3Alkyl oxy, R1、R5、R6It is each independently hydrogen, chlorine, C1-C3Alkyl, C1-C3Alkyl oxy, nitro, amino.
Present invention is preferably related to the compounds of formula I being defined as follows:
Wherein, in formula I, R2-R4For methoxyl group, R1、R5、R6Be each independently hydrogen, chlorine, methyl, methoxyl group, nitro, Amino.
It is the most acceptable nontoxic that the compound of the present invention also includes that derivant shown in structure above is formed Salt and hydrate thereof, these pharmaceutically acceptable nontoxic salts include the salt that this derivant is formed with acid.Described acid is permissible For hydrochloric acid, sulphuric acid, hydrobromic acid, the mineral acid of phosphoric acid or selected from acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid Organic acid.The hydration number of described hydrate is any real number in 0～16.
Currently preferred part of compounds structure is as follows:
Compound 1
3-(3,4,5-trimethoxyphenyl)-6-(4-aminomethyl phenyl)-diaryl-1H-pyrazolo [5,1-c] [1,2,4] Triazole
Compound 2
3-(3,4,5-trimethoxyphenyl)-6-(4-chlorphenyl)-diaryl-1H-pyrazolo [5,1-c] [1,2,4] three Nitrogen azoles
Compound 3
3-(3,4,5-trimethoxyphenyl)-6-(4-methoxyphenyl)-diaryl-1H-pyrazolo [5,1-c] [1,2, 4] triazole
Compound 4
3-(3,4,5-trimethoxyphenyl)-6-(3-nitro-4-methoxyphenyl)-diaryl-1H-pyrazolo [5,1- C] [1,2,4] triazole
Compound 5
3-(3,4,5-trimethoxyphenyl)-6-(3-amino-4-methoxyl phenyl)-diaryl-1H-pyrazolo [5,1- C] [1,2,4] triazole
Invention 3,6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole compound can according to following instead Route synthesis is answered to obtain:
Corresponding substituted compound A is joined in eggplant type bottle, makees solvent reaction 2h, TLC with acetic anhydride and detect raw material After disappearance, reactant liquor is poured in frozen water and stir, the solid filtration drying of precipitation, then returns it with concentrated hydrochloric acid-ethanol system Stream；After question response is complete, ethanol is evaporated, adds ethyl acetate, washing, organic layer anhydrous sodium sulfate is evaporated after drying, obtains end Product B, yield 69-84%.
Wherein, containing the 3 of amino, 6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole chemical combination in compound Thing can be prepared through reduction reaction by the compound containing nitro in corresponding compound, and reducing agent is anhydrous ferric trichloride/hydration Hydrazine/activated carbon system.
Detailed description of the invention
Be will assist in by following example and understand the present invention, but present disclosure is not limited to example.
Agents useful for same of the present invention is commercially available, and microwave model used is CEM-discover-sp, and Ultrasound Instrument is KQ- 400KDB type high power numerical control supersonic cleaning device (Kunshan Ultrasonic Instruments Co., Ltd.), nuclear magnetic resoance spectrum is by AVANCE- 400, Bruker ARX-300, Bruker ARX-400, Bruker ARX-600 fourier transform NMR spectrometer measure, Mass spectrum is measured by Brukee Esqure 2000, Shimadzu GCMS-QP5050A type mass spectrograph.
Embodiment 1:3-(3,4,5-trimethoxyphenyl)-6-(4-aminomethyl phenyl)-diaryl-1H-pyrazolo [5,1-c] [1,2,4] preparation of triazole (compound 1):
By 3-(3,4,5-trimethoxyphenyl)-6-(4-aminomethyl phenyl)-[1,2,4] triazole also [3,4-b] [1,3,4] Thiadiazine 0.40g (1mmol) joins in 50ml eggplant type bottle, after making solvent reaction 2h, TLC detection raw material disappearance with acetic anhydride, Reactant liquor is poured in frozen water and stir, the solid filtration drying of precipitation, it is then added in 50ml eggplant type bottle, uses 20ml second Alcohol dissolves, and adds 1ml concentrated hydrochloric acid, back flow reaction 2h；After question response is complete, being evaporated by ethanol, add ethyl acetate, washing, by organic layer It is evaporated after drying with anhydrous sodium sulfate, chromatographic process purification, obtains compound 1；Red brown solid, yield: 81%.M.p.:119- 122℃；1H-NMR(600MHz,CDCl3): δ 9.73 (s, 1H), 7.88 (s, 2H), 7.82 (d, J=8.0Hz, 2H), 7.25 (d, J =8.0Hz, 2H), 6.02 (s, 1H), 4.01 (s, 6H), 3.94 (s, 3H), 2.40 (s, 3H)；13C-NMR(150MHz,CDCl3): δ160.1,153.4(2C),148.4,139.5,139.4,138.4,130.9,129.3(2C),126.0(2C),121.1, 103.8(2C),75.0,60.9,56.2(2C),21.3；ESI-MS:m/z=365.3 [M+H]+,387.3[M+Na]+。
Embodiment 2:3-(3,4,5-trimethoxyphenyl)-6-(4-chlorphenyl)-diaryl-1H-pyrazolo [5,1-c] [1,2,4] preparation of triazole (compound 2):
In addition to using corresponding raw material, prepare compound 2 with the method that embodiment 1 is identical；Red solid, yield: 82%.M.p.:150-151℃；1H-NMR(600MHz,CDCl3): δ 9.65 (s, 1H), 7.86 (s, 2H), 7.85 (d, J= 8.4Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 6.05 (s, 1H), 4.02 (s, 6H), 3.94 (s, 3H)；13C-NMR(150MHz, CDCl3):δ158.7,153.4(2C),148.4,139.7,139.4,134.3,132.3,128.8(2C),127.3(2C), 120.9,103.8(2C),75.3,60.9,56.2(2C)；ESI-MS:m/z=385.0 [M+H]+,407.1[M+Na]+。
Embodiment 3:3-(3,4,5-trimethoxyphenyl)-6-(4-methoxyphenyl)-diaryl-1H-pyrazolo [5,1- C] preparation of [1,2,4] triazole (compound 3):
In addition to using corresponding raw material, prepare compound 3 with the method that embodiment 1 is identical；Red solid, yield: 84%.M.p.:146-147℃；1H-NMR(600MHz,CDCl3): δ 9.89 (s, 1H), 7.87 (s, 2H), 7.86 (d, J= 8.7Hz, 2H), 6.97 (d, J=8.7Hz, 2H), 5.98 (s, 1H), 4.01 (s, 6H), 3.93 (s, 3H), 3.86 (s, 3H)；13C- NMR(150MHz,CDCl3):δ159.9,159.8,153.4(2C),148.4,139.5,139.3,127.3(2C),126.5, 121.2,114.0(2C),103.8(2C),74.6,60.9,56.2(2C),55.3；ESI-MS:m/z=381.3 [M+H]+。
Embodiment 4:3-(3,4,5-trimethoxyphenyl)-6-(3-nitro-4-methoxyphenyl)-diaryl-1H-pyrazoles And the preparation of [5,1-c] [1,2,4] triazole (compound 4):
In addition to using corresponding raw material, prepare compound 4 with the method that embodiment 1 is identical；Yellow solid, yield: 76%.M.p.:149-151℃；1H-NMR(400MHz,DMSO-d6): δ 13.23 (s, 1H), 8.41 (d, J=2.0Hz, 1H), 8.25 (dd, J=8.8Hz, J=2.0Hz, 1H), 7.80 (s, 2H), 7.44 (d, J=8.8Hz, 1H), 6.50 (s, 1H), 3.97 (s,3H),3.93(s,6H),3.76(s,3H)；13C-NMR(100MHz,DMSO-d6):δ156.7,153.7(2C),152.3, 149.2,139.9,139.4,137.8,131.7,126.9,122.3,121.5,115.2,103.6(2C),75.7,60.7, 57.3,56.4(2C)；ESI-MS:m/z=426.1 [M+H]+,448.1[M+Na]+。
Embodiment 5:3-(3,4,5-trimethoxyphenyl)-6-(3-amino-4-methoxyl phenyl)-diaryl-1H-pyrazoles And the preparation of [5,1-c] [1,2,4] triazole (compound 5):
0.26g (0.5mmol) compound 4 is joined in 50mL eggplant type bottle, add activated carbon 20mg and ferric chloride 20mg makees catalyst, makees solvent with dehydrated alcohol, the lower dropping 80% hydrazine hydrate 0.1mL of stirring, back flow reaction 3 hours；TLC detects After completion of the reaction, it is filtered to remove activated carbon, dehydrated alcohol is evaporated, add water, be extracted with ethyl acetate, organic layer is merged dry Dry, decompression distillation obtains crude product, and chromatographic isolation obtains compound 5；Red brown solid, yield: 69%.M.p.:135-137℃；1H- NMR(600MHz,CDCl3): δ 9.86 (s, 1H), 7.85 (s, 2H), 7.31 (s, 2H), 6.84 (d, J=8.8Hz, 1H), 5.95 (s,1H),4.00(s,6H),3.92(s,3H),3.89(s,3H)；ESI-MS:m/z=396.4 [M+H]+。
Embodiment 6: the anti tumor activity in vitro test of the compound of the present invention
External activity method of testing and result are as follows:
Wherein, selecting the CA-4 of document report and the conventional antitumor drug amycin (ADM) of clinic is that positive control is real Test group.
Anti-tumor activity body outer screening test-1
Screening technique: tetrazolium (micoculture tetrozolium, MTT) reducing process
Cell strain: BGC823 cell line SGC-7901cell line
Action time: 72h
Under each compound 10 μ g/mL dosage, the suppression ratio (%) to tumor growth is shown in Table-1.
Anti-tumor activity body outer screening test-2
Screening technique: tetrazolium (micoculture tetrozolium, MTT) reducing process
Cell strain: human oral cavity epithelial JEG-3 KB cell line
Action time: 72h
Under each compound 10 μ g/mL dosage, the suppression ratio (%) to tumor growth is shown in Table-1.
Anti-tumor activity body outer screening test 3
Screening technique: tetrazolium (micoculture tetrozolium, MTT) reducing process
Cell strain: human fibrosarcoma cell strain HT-1080cell line
Action time: 72h
Under each compound 10 μ g/mL dosage, the suppression ratio (%) to tumor growth is shown in Table-1.
Embodiment 7: anti-tumor activity test in the animal body of the compound of the present invention
The preferable compound of external activity 2 and compound 5 is selected to carry out anti-tumor activity test in animal body, mould used Type is mice S-180 sarcoma model, and positive control medicine is clinical conventional antitumor drug fluorouracil (Fluorouracil)。
Experimental technique: select the S-180 tumor kind of 18-22 gram of female KM mice and well-grown 7-11 days, by tumor group Knit and make cell suspension, be seeded to right side of mice armpit subcutaneous, about 1.0-2.0 × 106Cell/only, random after inoculating 24 hours Divide cage, continuous 7 days of intraperitoneal injection.Within after drug withdrawal 24 hours, put to death animal, weigh, tumor weight, calculate each group of average tumor weight, press Equation below is obtained tumor control rate and carries out t inspection.
Tumor control rate=[(blank group average tumor weight-treatment group average tumor weight)/(average tumor of blank group Weight)] × 100%
Experimental result is shown in Table-2.
Embodiment 8: in the animal body of the compound of the present invention, acute toxicity is tentatively tested
In in selection animal body, the preferable compound of anti-tumor activity 2 and compound 5 have carried out animal body, acute toxicity is surveyed Examination.
Select each 10 of 18-22 gram of female KM mice, respectively intraperitoneal injection compound 2, each 500mg/ of compound 5 After kg, occur that autonomic movement suppresses, writhing, and to body weight growth, food ration, the suppression of water uptake, but have no dead mouse.Stop After the medicine a few days, surviving animals recovers normal.The LD of intraperitoneal administration50Value is more than 500mg/kg.
Table-1
Table-2

Claims (10)

1. 3,6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole compound of formula I and salt thereof and hydrate:
Wherein, in formula I, R2-R4For C1-C6Alkyl oxy, R1、R5、R6It is each independently hydrogen, halogen, C1-C6Alkyl, C1-C6 Alkyl oxy, nitro, amino, C1-C6Alkyl amino, two C1-C6Alkyl amino.
2. compound described in claim 1 and salt thereof and hydrate,
Wherein, in formula I, R2-R4For C1-C4Alkyl oxy, R1、R5、R6It is each independently hydrogen, halogen, C1-C4Alkyl, C1-C4 Alkyl oxy, nitro, amino, C1-C4Alkyl amino, two C1-C4Alkyl amino.
3. compound described in claim 1 or 2 and salt thereof and hydrate,
Wherein, in formula I, R2-R4For C1-C3Alkyl oxy, R1、R5、R6It is each independently hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkane Base, C1-C3Alkyl oxy, nitro, amino, C1-C3Alkyl amino, two C1-C3Alkyl amino.
4. compound described in claim 1-3 any one and salt thereof and hydrate,
Wherein, in formula I, R2-R4For methoxyl group, R1、R5、R6It is each independently hydrogen, chlorine, methyl, methoxyl group, nitro, amino.
5., according to the compound described in claim 1-4 any one and salt thereof and hydrate, it is selected from:
Compound 1
3-(3,4,5-trimethoxyphenyl)-6-(4-aminomethyl phenyl)-diaryl-1H-pyrazolo [5,1-c] [1,2,4] three nitrogen Azoles
Compound 2
3-(3,4,5-trimethoxyphenyl)-6-(4-chlorphenyl)-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole Compound 3
3-(3,4,5-trimethoxyphenyl)-6-(4-methoxyphenyl)-diaryl-1H-pyrazolo [5,1-c] [1,2,4] three Nitrogen azoles
Compound 4
3-(3,4,5-trimethoxyphenyl)-6-(3-nitro-4-methoxyphenyl)-diaryl-1H-pyrazolo
[5,1-c] [1,2,4] triazole
Compound 5
3-(3,4,5-trimethoxyphenyl)-6-(3-amino-4-methoxyl phenyl)-diaryl-1H-pyrazolo
[5,1-c] [1,2,4] triazole.
6. according to the compound described in claim 1-5 any one and salt thereof and hydrate, it is characterised in that: described salt is The salt that this compound is formed with acid, described acid is hydrochloric acid, sulphuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, winestone Acid, benzoic acid, malic acid；The hydration number of described hydrate is any real number in 0-16.
7. 3,6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole compound as claimed in claim 1 Preparation method, it is characterised in that:
Corresponding substituted compound A is joined in eggplant type bottle, makees solvent reaction with acetic anhydride, after TLC detection raw material disappears, Reactant liquor is poured in frozen water and stir, the solid filtration drying of precipitation, then used concentrated hydrochloric acid-ethanol system backflow；Treat anti- After having answered, ethanol is evaporated, adds ethyl acetate, washing, organic layer anhydrous sodium sulfate is evaporated after drying, obtains end-product B；
Wherein, containing the 3 of amino in compound, 6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole compound can Being prepared through reduction reaction by the compound containing nitro in corresponding compound, reducing agent is anhydrous ferric trichloride/hydrazine hydrate/work Property charcoal system.
8. a pharmaceutical composition, comprises the compound described in claim 1-6 any one and salt thereof and hydrate and pharmacy Upper acceptable carrier.
9. 3,6-diaryl-1H-pyrazolo [5,1-c] [1,2,4] triazole in any of the one of claim 1-7 Compound and salt thereof and hydrate or the application in preparing antitumor drug of the pharmaceutical composition described in claim 8.
Apply the most as claimed in claim 9, it is characterised in that described tumor is gastric cancer, oral epithelium cancer or fiber meat Tumor.
CN201610591881.8A 2016-07-26 2016-07-26 Purposes of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound as tumor cell proliferation inhibitor Expired - Fee Related CN106188069B (en)

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Publication number Priority date Publication date Assignee Title
CN113929635A (en) * 2021-11-09 2022-01-14 沈阳药科大学 1, 6-diphenyl-1H-benzo [ d ] [1,2,3] triazole compound and preparation method and application thereof
CN113929635B (en) * 2021-11-09 2023-08-22 沈阳药科大学 1, 6-diphenyl-1H-benzo [ d ] [1,2,3] triazole compound and preparation method and application thereof

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