CN103980252A - 1, 2, 4-triazole-contained triazole Schiff base drug for treating tumor - Google Patents

1, 2, 4-triazole-contained triazole Schiff base drug for treating tumor Download PDF

Info

Publication number
CN103980252A
CN103980252A CN201410235208.1A CN201410235208A CN103980252A CN 103980252 A CN103980252 A CN 103980252A CN 201410235208 A CN201410235208 A CN 201410235208A CN 103980252 A CN103980252 A CN 103980252A
Authority
CN
China
Prior art keywords
triazole
pyrazoles
phenyl
methoxy
phenmethyl
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.)
Pending
Application number
CN201410235208.1A
Other languages
Chinese (zh)
Inventor
张磊
王京
姚其正
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zunyi Medical University
Original Assignee
Zunyi Medical University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zunyi Medical University filed Critical Zunyi Medical University
Priority to CN201410235208.1A priority Critical patent/CN103980252A/en
Publication of CN103980252A publication Critical patent/CN103980252A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

The invention discloses a 1, 2, 4-triazole-contained triazole Schiff base drug for treating tumor and a pharmaceutically acceptable salt of the 1, 2, 4-triazole-contained triazole Schiff base drug as shown in the specification, wherein R1 and R3 respectively represent for fatty cyclic radical, aryl or 5-7-membered heterocyclic radical; R2 represents for alkyl, alkoxy, C1-C6 saturated or unsaturated straight-chain or branched-chain hydrocarbyl, C3-C7 cycloalkane, aryl or 5-7-membered heterocyclic radical; aryl is phenyl, substituted phenyl, naphthyl or biphenyl; the substituted phenyl contains 1-4 substituent groups selected from halogens, C1-C6 branched chains or branched-chain alkanes, nitro, trifluoromethoxy, a nitrile group, hydroxymethyl, trifluoromethyl or C1-C4 alkoxy; the 5-7-membered heterocyclic radical contains 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, is merged by phenyl and contains one or more substituent groups selected from halogen, C1-C6 branch chain or branch-chain alkyl, nitro, amino, trifluoromethoxy, nitrile group, trifluoromethyl, C1-C4 alkoxy and aryl; halogen is selected from fluorine, chloride, bromine or iodine.

Description

Preparation is containing the medicine of the pyrazoles Schiff's base treatment tumour of 1,2,4-triazole
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of medicine, its preparation method and medicinal use thereof that contains the pyrazoles Schiff's base of 1,2,4-triazole, particularly at the medicine for the preparation for the treatment of or prophylaxis of tumours.
Background technology
The world today, heterogeneous ring compound occupies very consequence in the research and development of medicine, agricultural chemicals.No matter be natural or the heterogeneous ring compound of synthetic, in medicine, agricultural chemicals, all play a part very important.Wherein, nitrogen heterocyclic is one of important directions of current medicament research and development.Research in recent years shows, pyrazoles nitrogen heterocyclic has anti-inflammatory, anti-arrhythmia, antitumor quiet, oxidase inhibitor, anti-diabetic and multiple pharmacologically active (ARKIVOC, 2014, the 2:233-293 such as antibacterial; Eur. J. Med. Chem., 2013,69:735-753).The people such as Zhao have reported the derivative that a series of 3-of take phenyl-1-fragrance methylpyrazole is skeleton, pharmacologically active test result shows, these a series of pyrazole derivatives are by promoting the mechanism of A549 tumour cell autophagy or apoptosis to carry out propagation (the Bioorg. Med. Chem. of inhibition tumor cell, 2009,17 (5): 1957-1962; Bioorg. Med. Chem. Lett. 2010,2,4766-4770).Medicinal design principle based on 3D-QSAR, the people such as Vujasinovic have designed and synthesized the pyrazole derivatives of series of novel, research finds that the compound of synthesized has stronger inhibition active to A549 and two kinds of tumour cells of NCIH23, the active IC that strengthens compound most 50value is 1.54 μ M(Bioorg. Med. Chem. 2012,20,2101-2110).The people such as Zheng have synthesized pyrazoles [1,5-α] pyrazine-4 (5H)-one analog derivative, and it all has inhibition to a certain degree active to A549 and H322, and is dosage-time-dependent manner, IC 50respectively between 24.2-62.6 μ M and 29.4-91.0 μ M, inhibition activity to A549 tumour cell is generally better than H322, on morphology, these pyrazole derivatives can the shrinkage so that A549 and H322 tumour cell become, quantity reduces and be fragmented into spherical (Bioorg. Med. Chem. Lett. 2011,21,3909-3913).In addition, 1,2,4-triazole compound is also that a class has multiple bioactive nitrogen heterocyclic, as antibacterium, antiviral, antimycotic and antitumor etc.Meanwhile, by the derivative Schiff's base obtaining of 1,2,4-triazole, there is multiple important pharmacologically active, be also subject to extensive concern (Chin. J. Chem., 2008,26 (6): 1145-1149; Eur. J. Med. Chem., 2011,46 (6): 2066-2074).
Summary of the invention
?the object of the invention is to disclose a kind of medicine of preparing containing the pyrazoles Schiff's base treatment tumour of 1,2,4-triazole ,and preparation method.
The present invention is by pyrazoles, 1,2, and these three kinds pharmacophore skeletons with anti-tumor activity of 4-triazole and Schiff's base carry out amalgamation, has designed and synthesized the pyrazoles Schiff's base (I) containing 1,2,4-triazole of a class brand new.In Vitro Anti propagation test shows, the compounds of this invention has certain restraining effect to human liver cancer cell HepG2, for the control of tumor disease provides new selection.
The general structure of the pyrazoles Schiff's base that contains 1,2,4-triazole of the present invention is as shown in following general formula (I):
Wherein:
R 1and R 3represent independently of one another fatty cyclic group, aromatic base or 5-7 unit heterocyclic radical;
R 2represent alkyl, alkoxyl group, C1 ~ C6 is direct-connected or the saturated or unsaturated alkyl of side chain, C3 ~ C7 naphthenic hydrocarbon, aromatic base or 5-7 unit heterocyclic radical;
Described aromatic base is phenyl, substituted-phenyl, naphthyl or xenyl; Wherein said substituted-phenyl is containing 1-4 substituting group, and this substituting group is taken from halogen, C1 ~ C6 side chain or branched paraffin, nitro, trifluoromethoxy, itrile group, methylol, trifluoromethyl or C1 ~ C4 alkoxyl group;
Described 5-7 unit heterocyclic radical contains 1-3 heteroatoms that is selected from oxygen, sulphur or nitrogen, can be merged by phenyl, and can contain one or more substituting groups that are selected from halogen, C1 ~ C6 side chain or branched hydrocarbyl, nitro, amino, trifluoromethoxy, itrile group, trifluoromethyl, C1 ~ C4 alkoxyl group and aromatic base;
Described halogen is fluorine, chlorine, bromine or iodine.
According to the present invention, pharmacy acceptable salt comprises the acid salt that general formula (I) compound and following acid form: tartrate, propanedioic acid, succsinic acid, hydrochloric acid, nitric acid, sulfuric acid, fumaric acid, phosphoric acid, Phenylsulfonic acid, Hydrogen bromide or tosic acid.
The pharmaceutically acceptable solvate of the compound that general formula of the present invention (I) represents comprises the compound of general formula (I) expression and the solvate of water, ethanol, ether, Virahol or acetone without limitation.
Pharmaceutical composition of the present invention, wherein, containing significant quantity the compounds of this invention, its pharmaceutically receptible salt or pharmaceutically receptible solvate, formulation can be tablet, powder, pill, capsule, suppository, granule, suspensoid, oral liquid, injection formulation pharmaceutically; Wherein tablet for oral use and capsule contain traditional vehicle as weighting material, lubricant, dispersion agent, thinner and tackiness agent etc.
Part of compounds of the present invention is:
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-α-tolylene imido grpup-5-sulfydryl-1,2,4-triazole (I-1)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2,4 dichloro benzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-2)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-hydroxyl-3,5-dimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-3) 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3,4,5-trimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-4)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-N, N-dimethyl benzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-5)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-oil of mirbane methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-6)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-anisole methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-7)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-chlorobenzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-8)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-9)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3-hydroxyl-4-anisole methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-10)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-methylbenzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-11)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2-furyl) imido grpup-5-sulfydryl-1,2,4-triazole (I-12)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-13)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3,4-dimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-14)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-15)
The preparation method of general formula target compound of the present invention (I) is as follows:
R wherein 1, R 2and R 3definition the same.
While preparing midbody compound (III) by intermediate (II) and dithiocarbonic anhydride, 80% hydrazine hydrate, wherein a represents reaction conditions: available solvent has methyl alcohol, ethanol, acetonitrile, methylene dichloride, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) or trichloromethane wherein a kind of; Preferred alcohol.Alkali has salt of wormwood, sodium carbonate, Quilonum Retard, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, diethylamine or piperidines; Preferred potassium hydroxide.
By midbody compound (III) and R 3when CHO prepares target compound (I), wherein b represents reaction conditions: available solvent has dioxane, DMF, tetrahydrofuran (THF), acetic acid, methylene dichloride, methyl alcohol, Virahol, the trimethyl carbinol, ethanol, acetonitrile or acetone; Preferred acetic acid.
Wherein, the preparation of intermediate (II) can reference literature (Bioorg. Med. Chem., 2007,15 (22): 6893-6899; J. Chem. Soc., Dalton Trans., 1999,9:1461-1466; Chin. J. Org. Chem., 2007,27 (12): the 1542-1546) method of report, the ethyl ketone compounds (III) of take is raw material, synthetic method is as follows:
Pharmacological activity test proves, general formula of the present invention (I) compound can effectively suppress the propagation of human liver cancer cell HepG2.
Below pharmacologically active testing method and the result of part of compounds of the present invention:
Mtt assay test anti tumor activity in vitro
Positive drug: 5 FU 5 fluorouracil (5-FU).
Experimental technique:
It is 3～4 * 10 that tumour cell digests, counts, is mixed with concentration 4the cell suspension of individual/mL, in 96 porocyte culture plates, every hole adds 100 μ L cell suspension (every holes 3～4 * 10 3individual cell); 96 porocyte culture plates are placed in 37 ℃, 5% CO 2in incubator, cultivate 24 hours; With perfect medium dilution medicine, to desired concn, every hole adds the corresponding pastille substratum of 100 μ L, sets up negative control group, positive controls simultaneously; 96 porocyte culture plates are placed in 37 ℃, 5% CO 2in incubator, cultivate 72 hours; 96 orifice plates are carried out to MTT dyeing, and λ=490 nm, measures OD value; Every hole adds 20 μ L MTT(5 mg/mL), at incubator, continue to cultivate 4 hours; Discard substratum, every hole adds 150 μ L DMSO to dissolve, and shaking table mixes for 10 minutes lightly; λ=490 nm, microplate reader is read the OD value in every hole.Calculate each group inhibiting rate, inhibiting rate (%)=[(negative control group OD value-experimental group OD value)/negative control group OD value] * 100%.Utilize SPSS17.0 computed in software to go out half-inhibition concentration (IC 50).With inverted phase contrast microscope, observe the growing state of HepG2 cell.
Anti tumor activity in vitro test result is as follows:
The anti tumor activity in vitro of table 1 part of compounds of the present invention to HepG2 cell
Above experimental result demonstration, the present invention partly has certain antiproliferative effect containing the pyrazoles Schiff's base of 1,2,4-triazole to HepG2 human liver cancer cell.Wherein, the activity of Compound I-5 is the strongest, its IC 50value is 31.28 μ M, is better than positive drug 5 FU 5 fluorouracil (IC 50value is 37.57 μ M), illustrate that the pyrazoles Schiff's base containing 1,2,4-triazole that we design has certain anti-tumor activity really, has the value of further investigation.
The impact of Compound I-5 on HepG2 cellular form and quantity
Under inverted microscope, visible control group (A) HepG2 cell quantity is more, and cell outline is clear, flushes; And act on after HepG2 cell with Compound I-5 of 100 μ M concentration, experimental group (B) cell quantity significantly reduces, and form atrophy becomes circle, and occurs apoptotic body.This explanation thing I-5 of the present invention can reduce the quantity of tumour cell significantly, and changes the form of cell, and further proved contrivance I-5 has stronger anti-tumor activity.
Embodiment
The specific embodiment of the present invention:
Instrument and reagent
The prepared fusing point that contains the pyrazoles Schiff's base (I) of 1,2,4-triazole of the present invention is measured with Mel-TEMP melting point apparatus, and thermometer is not calibrated; 1bruck AV-300 type nmr determination for H NMR, solvent for use is CDCl 3or DMSO- d6, interior mark TMS; ESI-MS measures with HP1100LC/MSD mass spectrograph; Infrared spectrometer is Nicolet Impact 410 types, KBr compressing tablet.
The following examples are used for illustrating the preparation of thing of the present invention (I), but the present invention is not limited to the following example.
Embodiment 1
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-α-tolylene imido grpup-5-sulfydryl-1,2,4-triazole (I-1)
0.84 g (15 mmol) potassium hydroxide is joined in 25 mL ethanol, after stirring and dissolving, add 3.22 g (10 mmol) 1-arylmethyl-3-(4-p-methoxy-phenyl) pyrazoles-5-formyl hydrazines (II-1), stirring and dissolving.Under stirring, slowly drip the mixing solutions of 0.9 mL (15 mmol) dithiocarbonic anhydride and 5 mL ethanol, continue to stir 4 h, suction filtration, filter cake ice washing with alcohol three times, ether washs once, the yellow solid obtaining, vacuum-drying.The yellow solid obtaining and 3.12 mL (50 mmol), 80% hydrazine hydrate are joined in reaction flask to N 2under protection, be heated to reflux, stirring reaction 5 h, cooling; in impouring mixture of ice and water, under stirring, add 1M HCl to regulate pH=3, occur a large amount of white precipitates; quiet to filtering, filter cake washes with water three times, vacuum-drying; gained solid dehydrated alcohol recrystallization; obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-amino-5-sulfydryl-1,2,4-triazole (III-1), 2.95 g; yield 78%
m.?p.?237-239?°C;?IR?(KBr,? v):?3297,?3085,?3008,?2934,?2820,?2737,?2029,?1899,?1610,?1514,?1467,?1430,?1313,?1288,?1242,?1174,?1113,?1024,?1005,?937?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.78?(s,?3H,?OCH 3),?5.69?~?5.75?(m,?2H,?CH 2Ph),?5.84?(s,?2H,?NH 2),?6.98?(d,? J?=?8.7?Hz,?2H,?ArH),?7.13?~?7.73?(m,?5H,?ArH),?7.49?(s,?1H,?ArH),?7.72?(d,? J?=?8.7?Hz,?2H,?ArH),?14.10?(s,?1H,?SH);?ESI-MS?m/z:?379.1?[M+H] +,?401.1?[M+Na] +;? 13C?NMR?(300?MHz,?DMSO- d6)?δ:?54.54,?55.62,?106.52,?114.71,?125.37,?126.99,?127.48,?127.86,?128.91,?129.51,?137.82,?142.62,?150.34,?159.70,?166.97。
0.2 g (0.53 mmol) intermediate (III-1) and 0.056 mL (0.55 mmol) phenyl aldehyde are joined in 3 mL acetic acid to N 2under protection; back flow reaction 3 ~ 4 h; there are a large amount of solids to separate out, are cooled to room temperature, suction filtration; filter cake ice washing with alcohol three times; vacuum-drying, obtains white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-α-tolylene imido grpup-5-sulfydryl-1,2; 4-triazole (I-1) 0.222 g, yield 90%.
m.?p.?248-250?°C;?IR?(KBr,? v):?3439,?3073,?2993,?2035,?2771,?1612,?1598,?1572,?1505,?1478,?1463,?1432,?1407,?1285,?1251,?1173,?1030,?968?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.76?(s,?3H,?OCH 3),?5.68?(s,?2H,?CH 2Ph),?6.96?(d,? J?=?8.0?Hz,?2H,?ArH),?7.17?~?7.31?(m,?5H,?ArH),?7.58?~?7.72?(m,?4H,?ArH),?7.91?(d,? J?=?7.0?Hz,?2H,?ArH),?9.70?(s,?1H,?CH=),?14.4?(s,?1H,?SH);?ESI-MS?m/z:?467.1?[M+H] +。
Embodiment 2
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2,4 dichloro benzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-2)
With 2,4-dichlorobenzaldehyde substitutes phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white-yellowish solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2,4 dichloro benzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole, yield 92%.
m.?p.?224-225?°C;?IR?(KBr,? v):?3404,?3087,?2999,?2945,?2836,?2768,?1613,?1599,?1585,?1505,?1462,?1434,?1393,?1290,?1276,?1249,?1174,?1035,?968?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?5.65?(s,?2H,?CH 2Ph),?6.97?(d,? J?=?8.7?Hz,?2H,?ArH),?7.17?~?7.29?(m,?6H,?ArH),?7.73?(d,? J?=?8.7?Hz,?2H,?ArH),?7.88?(s,?1H,?ArH),?8.06?(d,? J?=?8.5?Hz,?2H,?ArH),?10.4?(s,?1H,?CH=),?14.5?(s,?1H,?SH);?ESI-MS?m/z:?535.0?[M+H] +。
Embodiment 3
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-hydroxyl-3,5-dimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-3)
With 4-hydroxyl-3,5-dimethoxy benzaldehyde substitutes phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-hydroxyl-3,5-dimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole, yield 90%.
m.?p.?230-231?°C;?IR?(KBr,? v):?3527,?3260,?3032,?2938,?2825,?1614,?1582,?1515,?1496,?1454,?1430,?1396,?1364,?1324,?1316,?1242,?1204,?1176,?1108,?960,?947?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?3.83?(s,?6H,?OCH 3),?5.71?(s,?2H,?CH 2Ph),?6.96?(d,? J?=?8.5?Hz,?2H,?ArH),?7.18?~?7.35?(m,?8H,?ArH),?7.69?(d,? J?=?8.7?Hz,?2H,?ArH),?9.47?(s,?2H,?CH=?and?OH),?14.3?(s,?1H,?SH);? 13C?NMR?(300?MHz,?DMSO- d6)?δ:?54.59,?55.63,?56.59,?106.86,?106.94,?114.70,?122.34,?125.21,?126.87,?127.59,?127.91,?128.93,?129.32,?137.75,?141.22,?141.36,?148.76,?150.42,?159.75,?162.47,?166.95;?ESI-MS?m/z:?543.1?[M+H] +,?565.1?[M+Na] +。
Embodiment 4
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3,4,5-trimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-4)
With 3,4,5-TMB substitutes phenyl aldehyde, and by the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3,4,5-trimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole, yield 94%.
m.?p.?235-236?°C;?IR?(KBr,?v):?3433,?3088,?3001,?2941,?2905,?2837,?2766,?2696,?1613,?1574,?1506,?1460,?1433,?1416,?1329,?1309,?1250,?1179,?1129,?1029,?1004,?960?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?6H,?2×OCH 3),?3.84?(s,?6H,?2×OCH 3),?5.70?(s,?2H,?CH 2Ph),?6.96?(d,? J?=?8.7?Hz,?2H,?ArH),?7.18?(d,? J?=?6.6?Hz,?2H,?ArH),?7.25?~?7.35?(m,?6H,?ArH),?7.70?(d,? J?=?8.7?Hz,?2H,?ArH),?9.69?(s,?1H,?CH=),?14.4?(s,?1H,?SH);?ESI-MS?m/z:?557.1?[M+H] +。
Embodiment 5
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-N, N-dimethyl benzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-5)
With 4-N, N-dimethylbenzaldehyde substitutes phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white-yellowish solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-N, N-dimethyl benzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole, yield 89%.
m.?p.?223-224?°C;?IR?(KBr,? v):?3084,?2999,?2931,?2768,?1589,?1531,?1509,?1462,?1434,?1367,?1316,?1286,?1246,?1174,?1110,?1033?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.03?(s,?6H,?N(CH 3) 2),?3.76?(s,?3H,?OCH 3),?5.69?(s,?2H,?CH 2Ph),?6.79?(d,? J?=?8.9?Hz,?2H,?ArH),?6.95?(d,? J?=?8.7?Hz,?2H,?ArH),?7.25?~?7.34?(m,?6H,?ArH),?7.66?~?7.74?(dd, ?J?=?12.8?Hz,?4H,?ArH),?9.17?(s,?1H,?CH=),?14.3?(s,?1H,?SH);?ESI-MS?m/z:?510.1?[M+H] +。
Embodiment 6
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-oil of mirbane methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-6)
With 4-nitrobenzaldehyde, substitute phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain orange solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-oil of mirbane methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole, yield 91%.
m.?p.?236-237?°C;?IR?(KBr,? v):?3264,?3138,?2991,?2932,?2831,?1702,?1613,?1583,?1524,?1494,?1463,?1434,?1345,?1304,?1247,?1177,?1032,?960?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?5.68?(s,?2H,?CH 2Ph),?6.96?(d,? J?=?8.7?Hz,?2H,?ArH),?7.17~7.31?(m,?6H,?ArH),?7.72?(d,? J?=?8.7?Hz,?2H,?ArH),?8.16?(d,? J?=?8.7?Hz,?2H,?ArH),?8.37?(d,? J?=?8.7?Hz,?2H,?ArH),?10.0?(s,?1H,?CH=),?14.5?(s,?1H,?SH);?ESI-MS?m/z:?512.0?[M+H] +。
Embodiment 7
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-anisole methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-7)
By 4-methoxybenzaldehyde, substitute phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-anisole methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole, yield 92%.
m.?p.?235-236?°C;?IR?(KBr,? v):?3088,?2992,?2959,?2825,?2766,?1605,?1570,?1508,?1479,?1463,?1434,?1334,?1310,?1287,?12155,?1170,?1107,?1080,?1025,?965?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.78?(s,?3H,?OCH 3),?3.86?(s,?3H,?OCH 3),?5.69?(s,?2H,?CH 2Ph),?6.96?(d,? J?=?8.7?Hz,?2H,?ArH),?7.14~7.34?(m,?8H,?ArH),?7.68?(d,? J?=?8.7?Hz,?2H,?ArH),?7.87?(d,? J?=?8.7?Hz,?2H,?ArH),?9.48?(s,?1H,?CH=),?14.3?(s,?1H,?SH);?ESI-MS?m/z:?497.1?[M+H] +。
Embodiment 8
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-chlorobenzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-8)
With 4-chlorobenzaldehyde, substitute phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white-yellowish solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-chlorobenzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole, yield 93%.
m.?p.?230-231?°C;?IR?(KBr,?v):?3297,?3084,?2994,?2937,?2837,?2761,?1613,?1595,?1499,?1463,?1432,?1310,?1336,?1286,?1251,?1173,?1091,?1030,?1012?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?5.68?(s,?2H,?CH 2Ph),?6.99?(t,? J?=?8.7?Hz,?2H,?ArH),?7.13~7.33?(m,?6H,?ArH),?7.63?~?7.76?(m,?4H,?ArH),?7.93?(d,? J?=?8.5?Hz,?2H,?ArH),?9.77?(s,?1H,?CH=),?14.4?(s,?1H,?SH);?ESI-MS?m/z:?501.1?[M+H] +。
Embodiment 9
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-9)
With Benzaldehyde,2-hydroxy, substitute phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole, yield 91%.
m.?p.?245-246?°C;?IR?(KBr,? v):?3063,?2996,?2923,?2359,?2336,?2053,?1964,?1879,?1618,?1602,?1560,?1507,?1462,?1434,?1404,?1298,?1265,?1251,?1173,?1150,?1029,?906?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?5.68?(s,?2H,?CH 2Ph),?6.93~7.02?(m,?4H,?ArH),?7.17?~?7.34?(m,?6H,?ArH),?7.42?~?7.48?(m,?1H,?ArH),?7.69?(d,? J?=?8.7?Hz,?2H,?ArH),?7.87?~?7.90?(m,?1H,?ArH),?9.92?(s,?1H,?CH=),?10.50?(s,?1H,?OH),?14.3?(s,?1H,?SH);?ESI-MS?m/z:?483.1?[M+H] +,?505.1?[M+Na] +。
Embodiment 10
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3-hydroxyl-4-anisole methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-10)
With 3-hydroxyl-4-methoxybenzaldehyde, substitute phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3-hydroxyl-4-anisole methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole, yield 93%.
m.?p.?218-219?°C;?IR?(KBr,? v):?3519,?3380,?3085,?2997,?2936,?2837,?2772,?2029,?1603,?1577,?1513,?1463,?1434,?1332,?1277,?1249,?1173,?1121,?1028,?969,?955?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?3.86?(s,?3H,?OCH 3),?5.69?(s,?2H,?CH 2Ph),?6.96?(d,? J?=?8.4?Hz,?2H,?ArH),?7.07?(d,? J?=?8.3?Hz,?1H,?ArH),7.17~7.31?(m,?7H,?ArH),?7.42?(s,?1H,?ArH),?7.68?(d,? J?=?8.4?Hz,?2H,?ArH),?9.38?(s,?1H,?ArH),?9.60?(s,?1H,?CH=),?14.3?(s,?1H,?SH);?ESI-MS?m/z:?513.2?[M+H] +,?535.1?[M+Na] +。
Embodiment 11
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-methylbenzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-11)
With 4-tolyl aldehyde, substitute phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-methylbenzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole, yield 91%.
m.?p.?249-250?°C;?IR?(KBr,? v):?3085,?2939,?2776,?1603,?1502,?1479,?1463,?1432,?1406,?1337,?1311,?1287,?1251,?1173,?1080,?1031,?956,?877?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?2.40?(s,?3H,?CH 3),?3.76?(s,?3H,?OCH 3),?5.69?(s,?2H,?CH 2Ph),?6.96?(d,? J?=?8.6?Hz,?2H,?ArH),?7.17~7.33?(m,?6H,?ArH),?7.37?(d,? J?=?7.9?Hz,?2H,?ArH),?7.69?(d,? J?=?8.6?Hz,?2H,?ArH),?7.81?(d,? J?=?7.9?Hz,?2H,?ArH),?9.61?(s,?1H,?CH=),?14.4?(s,?1H,?SH);?ESI-MS?m/z:?481.2?[M+H] +,?503.2?[M+Na] +。
Embodiment 12
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2-furyl) imido grpup-5-sulfydryl-1,2,4-triazole (I-12)
With 2 furan carboxyaldehyde, substitute phenyl aldehyde, by the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2-furyl) imido grpup-5-sulfydryl-1,2,4-triazole, yield 94%.
m.?p.?255-256?°C;?IR?(KBr,?v):?3081,?2937,?2772,?2542,?2052,?1879,?1746,?1613,?1594,?1509,?1479,?1459,?1433,?1390,?1284,?1250,?1174,?1154,?1086,?1030,?1015,?968,?953?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?5.67?(s,?2H,?CH 2Ph),?6.79?~?6.81?(m,?1H,?ArH),?6.97?(d,? J?=?8.7?Hz,?2H,?ArH),?7.17?~?7.33?(m,?6H,?ArH),?7.41?(d,? J?=?3.4?Hz,?1H,?ArH),?7.70?(d,? J?=?8.7?Hz,?2H,?ArH),?8.10?(s,?1H,?ArH),?9.65?(s,?1H,?CH=),?14.4?(s,?1H,?SH);?ESI-MS?m/z:?557.1?[M+H] +,?579.1?[M+Na] +。
Embodiment 13
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-13)
With 3-hydroxy benzaldehyde, substitute phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole, yield 92%.
m.?p.?209-210?°C;?IR?(KBr,? v):?3598,?3094,?3005,?2959,?2904,?2778,?2601,?1608,?1579,?1514,?1478,?1454,?1434,?1402,?1305,?1281,?1249,?1175,?1116,?1080,?1029,?958?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?5.69?(s,?2H,?CH 2Ph),?6.96~7.05?(m,?3H,?ArH),?7.05~7.41?(m,?9H,?ArH),?7.69?(d,? J?=?8.7?Hz,?2H,?ArH),?9.60?(s,?1H,?CH=),?9.90?(s,?1H,?OH),?14.4?(s,?1H,?SH);?ESI-MS?m/z:?483.2?[M+H] +。
Embodiment 14
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3,4-dimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-14)
With 3,4-dimethoxy benzaldehyde substitutes phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3,4-dimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole, yield 90%.
m.?p.?225-226?°C;?IR?(KBr,? v):?3086,?2936,?2837,?2761,?1612,?1597,?1571,?1513,?1456,?1421,?1274,?1250,?1177,?1137,?1027,?1017,?949?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.77?(s,?3H,?OCH 3),?3.78?(s,?3H,?OCH 3),?3.81?(s,?3H,?OCH 3),?5.70?(s,?2H,?CH 2Ph),?6.95?(d,? J?=?8.8?Hz,?2H,?ArH),?7.12~7.34?(m,?7H,?ArH),?7.44?~?7.47?(m,?1H,?ArH),?7.53?(s,?1H,?ArH),?7.69?(d,? J?=?8.7?Hz,?2H,?ArH),?9.54?(s,?1H,?CH=),?14.39?(s,?1H,?SH);?ESI-MS?m/z:?527.2?[M+H] +。
Embodiment 15
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-15)
With 4-hydroxy benzaldehyde, substitute phenyl aldehyde, press the method described in embodiment 1, all the other desired raw materials, reagent are with embodiment 1, obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole, yield 89%.
m.?p.?250-251?°C;?IR?(KBr,? v):?3528,?3079,?2938,?2766,?2336,?2047,?1879,?1600,?1577,?1515,?1495,?1463,?1433,?1405,?1273,?1250,?1172,?1101,?1030,?968?cm -1;? 1H?NMR?(300?MHz,?DMSO- d6)?δ:?3.76?(s,?3H,?OCH 3),?5.69?(s,?2H,?CH 2Ph),?6.96?(t,? J?=?9.2?Hz,?4H,?ArH),?7.16?(d,? J?=?6.6?Hz,?3H,?ArH),?7.23?~?7.33?(m,?3H,?ArH),?7.68?(d,? J?=?8.7?Hz,?2H,?ArH),?7.77?(d,? J?=?8.6?Hz,?2H,?ArH),?9.35?(s,?1H,?CH=),?10.45?(s,?1H,?OH),?14.36?(s,?1H,?SH);? 13C?NMR?(300?MHz,?DMSO- d6)?δ:?54.57,?55.59,?106.68,?114.70,?116.66,?123.11,?125.22,?126.98,?127.56,?127.90,?128.92,?129.40,?131.61,?137.72,?141.29,?150.47,?159.72,?162.59,?167.73;?ESI-MS?m/z:?482.2?[M+H] +。

Claims (5)

1. preparation, containing the medicine of the pyrazoles Schiff's base treatment tumour of 1,2,4-triazole, is characterized in that :
The pyrazoles Schiff's base containing 1,2,4-triazole that one class is represented by following general formula (I) or its be receptible salt pharmaceutically:
Wherein:
R 1and R 3represent independently of one another fatty cyclic group, aromatic base or 5-7 unit heterocyclic radical;
R 2represent alkyl, alkoxyl group, C1 ~ C6 is direct-connected or the saturated or unsaturated alkyl of side chain, C3 ~ C7 naphthenic hydrocarbon, aromatic base or 5-7 unit heterocyclic radical;
Described aromatic base is phenyl, substituted-phenyl, naphthyl or xenyl; Wherein said substituted-phenyl is containing 1-4 substituting group, and this substituting group is taken from halogen, C1 ~ C6 side chain or branched paraffin, nitro, trifluoromethoxy, itrile group, methylol, trifluoromethyl or C1 ~ C4 alkoxyl group;
Described 5-7 unit heterocyclic radical contains 1-3 heteroatoms that is selected from oxygen, sulphur or nitrogen, can be merged by phenyl, and can contain one or more substituting groups that are selected from halogen, C1 ~ C6 side chain or branched hydrocarbyl, nitro, amino, trifluoromethoxy, itrile group, trifluoromethyl, C1 ~ C4 alkoxyl group and aromatic base;
Described halogen is fluorine, chlorine, bromine or iodine;
Part of compounds of the present invention is:
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-α-tolylene imido grpup-5-sulfydryl-1,2,4-triazole (I-1)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2,4 dichloro benzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-2)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-hydroxyl-3,5-dimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-3) 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3,4,5-trimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-4)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-N, N-dimethyl benzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-5)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-oil of mirbane methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-6)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-anisole methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-7)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-chlorobenzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-8)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-9)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3-hydroxyl-4-anisole methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-10)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-methylbenzene methylene radical) imido grpup-5-sulfydryl-1,2,4-triazole (I-11)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(2-furyl) imido grpup-5-sulfydryl-1,2,4-triazole (I-12)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-13)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(3,4-dimethoxy α-tolylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-14)
3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-(4-phenol methylene) imido grpup-5-sulfydryl-1,2,4-triazole (I-15)
The preparation method of general formula target compound (I) is as follows:
R wherein 1, R 2and R 3definition the same,
While preparing midbody compound (III) by intermediate (II) and dithiocarbonic anhydride, 80% hydrazine hydrate, wherein a represents reaction conditions: available solvent has methyl alcohol, ethanol, acetonitrile, methylene dichloride, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) or trichloromethane wherein a kind of; Preferred alcohol.Alkali has salt of wormwood, sodium carbonate, Quilonum Retard, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, diethylamine or piperidines; Preferred potassium hydroxide;
By midbody compound (III) and R 3when CHO prepares target compound (I), wherein b represents reaction conditions: available solvent has dioxane, DMF, tetrahydrofuran (THF), acetic acid, methylene dichloride, methyl alcohol, Virahol, the trimethyl carbinol, ethanol, acetonitrile or acetone; Preferred acetic acid;
Wherein, the method for the preparation of intermediate (II), the ethyl ketone compounds (III) of take is raw material, synthetic method is as follows:
As: 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-α-tolylene imido grpup-5-sulfydryl-1,2,4-triazole
0.84 g (15 mmol) potassium hydroxide is joined in 25 mL ethanol, after stirring and dissolving, add 3.22 g (10 mmol) 1-arylmethyl-3-(4-p-methoxy-phenyl) pyrazoles-5-formyl hydrazines (II-1), stirring and dissolving; Under stirring, slowly drip the mixing solutions of 0.9 mL (15 mmol) dithiocarbonic anhydride and 5 mL ethanol, continue to stir 4 h, suction filtration, filter cake ice washing with alcohol three times, ether washs once, the yellow solid obtaining, vacuum-drying; The yellow solid obtaining and 3.12 mL (50 mmol), 80% hydrazine hydrate are joined in reaction flask to N 2under protection, be heated to reflux, stirring reaction 5 h, cooling; in impouring mixture of ice and water, under stirring, add 1M HCl to regulate pH=3, occur a large amount of white precipitates; quiet to filtering; filter cake washes with water three times, vacuum-drying, gained solid dehydrated alcohol recrystallization; obtain white solid 3-[3-(4-p-methoxy-phenyl)-1-phenmethyl-pyrazoles-5-yl]-4-amino-5-sulfydryl-1; 2,4-triazole (III-1), 2.95 g, yield 78%.
2. by preparation claimed in claim 1, contain 1,2, the medicine of the pyrazoles Schiff's base treatment tumour of 4-triazole, it is characterized in that: described compound or its be receptible salt pharmaceutically, wherein pharmaceutically receptible salt is the acid salt that general formula (I) compound and following acid form: tartrate, propanedioic acid, succsinic acid, hydrochloric acid, nitric acid, sulfuric acid, fumaric acid, phosphoric acid, Phenylsulfonic acid, Hydrogen bromide or tosic acid.
3. by preparation claimed in claim 1, contain 1,2, the medicine of the pyrazoles Schiff's base treatment tumour of 4-triazole, it is characterized in that: the pharmaceutically receptible solvate of the compound that described general formula (I) represents, comprises the compound of general formula (I) expression and the solvate of water, ethanol, ether, Virahol or acetone.
4. by preparation claimed in claim 1, contain 1,2, the medicine of the pyrazoles Schiff's base treatment tumour of 4-triazole, it is characterized in that: described pharmaceutical composition, wherein contain this compound of significant quantity, its pharmaceutically receptible salt or pharmaceutically receptible solvate, formulation is tablet, powder, pill, capsule, suppository, granule, suspensoid, oral liquid, injection formulation pharmaceutically; Wherein tablet for oral use and capsule contain traditional vehicle as weighting material, lubricant, dispersion agent, thinner and tackiness agent.
5. by the preparation described in claim 1 or 2 or 3, contain 1,2, the medicine of the pyrazoles Schiff's base treatment tumour of 4-triazole, it is characterized in that: described contains 1, the pyrazoles Schiff's base of 2,4-triazole, its pharmaceutically receptible salt and the pharmaceutically medicine of receptible solvate aspect preparation treatment or prophylaxis of tumours disease.
CN201410235208.1A 2014-05-30 2014-05-30 1, 2, 4-triazole-contained triazole Schiff base drug for treating tumor Pending CN103980252A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410235208.1A CN103980252A (en) 2014-05-30 2014-05-30 1, 2, 4-triazole-contained triazole Schiff base drug for treating tumor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410235208.1A CN103980252A (en) 2014-05-30 2014-05-30 1, 2, 4-triazole-contained triazole Schiff base drug for treating tumor

Publications (1)

Publication Number Publication Date
CN103980252A true CN103980252A (en) 2014-08-13

Family

ID=51272446

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410235208.1A Pending CN103980252A (en) 2014-05-30 2014-05-30 1, 2, 4-triazole-contained triazole Schiff base drug for treating tumor

Country Status (1)

Country Link
CN (1) CN103980252A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104151247A (en) * 2014-08-23 2014-11-19 桂林理工大学 4-aminoantipyrine-isovanillin Schiff base and application thereof
CN104151246A (en) * 2014-08-23 2014-11-19 桂林理工大学 4-aminoantipyrine-2-naphthaldehyde Schiff base and application thereof
CN104193684A (en) * 2014-08-23 2014-12-10 桂林理工大学 4-aminophenazone 2,5-dihydroxy benzaldehyde Schiff base and application thereof
CN106496188A (en) * 2016-09-13 2017-03-15 桂林理工大学 2 pyridine carboxaldehydes contracting 4 amino, 1,2,4 triazole schiff base ligand and synthetic method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IRENE KOUSKOUMVEKAKI ET AL.: "Discovery of a Novel Selective PPARγ Ligand with Partial Agonist Binding Properties by Integrated in Silico/in Vitro Work Flow", 《JOURNAL OF CHEMICAL INFORMATION AND MODELING》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104151247A (en) * 2014-08-23 2014-11-19 桂林理工大学 4-aminoantipyrine-isovanillin Schiff base and application thereof
CN104151246A (en) * 2014-08-23 2014-11-19 桂林理工大学 4-aminoantipyrine-2-naphthaldehyde Schiff base and application thereof
CN104193684A (en) * 2014-08-23 2014-12-10 桂林理工大学 4-aminophenazone 2,5-dihydroxy benzaldehyde Schiff base and application thereof
CN104193684B (en) * 2014-08-23 2016-06-29 桂林理工大学 4-AA contracting 2,5-4-dihydroxy benzaldehyde Schiff's base and application
CN106496188A (en) * 2016-09-13 2017-03-15 桂林理工大学 2 pyridine carboxaldehydes contracting 4 amino, 1,2,4 triazole schiff base ligand and synthetic method

Similar Documents

Publication Publication Date Title
JP5193876B2 (en) Pyrrolotriazine derivatives useful for treating cancer by inhibition of Aurora kinase
EP3936502A1 (en) Pyrazine derivative and application thereof in inhibiting shp2
CN1807413B (en) Carbazole sulfonamide derivative and its preparation method
EP2297133A1 (en) 1, 2 disubstituted heterocyclic compounds
EA027533B1 (en) Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors
CN107176932B (en) Benzoxazinone derivative and preparation method and application thereof
ES2949357T3 (en) 3-Phosphoglycerate dehydrogenase inhibitors and uses thereof
JP2008506673A (en) Pyrido-pyrimidine derivatives, their preparation, their therapeutic use for cancer treatment
CN103980252A (en) 1, 2, 4-triazole-contained triazole Schiff base drug for treating tumor
JP2022000455A (en) Flavagline derivative
CN102134234B (en) Indazolyl urea compounds and preparation method and medicinal use thereof
CN103304466A (en) Synthetic method of 3-alkyl-substituted indole compound
CN102432622B (en) 4-amino oxadiazole epipodophyllotoxin derivative and preparation method and application thereof
CN103965182A (en) Medicament of 1,3,4-oxadiazole containing pyrazole compound prepared for treating tumor
CN107708419B (en) Pyrazolo [4,3-c ] quinoline derivatives having inhibitory activity on bacterial glucuronidase
EP2649078B1 (en) 4-aza-2, 3-didehydropodophyllotoxin compounds and process for the preparation thereof
ES2605621T3 (en) Procedure for the preparation of imidazo derivatives [2,1-b] [1,3] benzothiazole
CN108456214B (en) Quinazoline compound containing oxazole or imidazole structure and application thereof
CN107879975A (en) Histon deacetylase (HDAC) inhibitor and its application
CN103833671B (en) One class thiazoline ketone compounds and pharmaceutical composition thereof and purposes
EP2597093B1 (en) Benzofuranone compound and pharmaceutical composition containing same
JP2018087173A (en) Anti-malignant brain tumor therapeutic agent
CN104000817B (en) One class is containing the purposes of pyrazole derivatives in preparation treatment, preventing tumor disease medicament of 1,3,4-oxadiazole quinoline
JP7333420B2 (en) Triazolopyrimidine compounds and salts thereof, compositions and uses
CN106986874A (en) (1H- pyrazoles [3,4-d] pyrimidine) -4- aminoderivatives and its purposes as IDO inhibitor in medicine preparation

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20140813