CN103601681B - Containing 3, the 5-pyrazodione derivatives and its production and use of exocyclic double bond structural unit - Google Patents

Containing 3, the 5-pyrazodione derivatives and its production and use of exocyclic double bond structural unit Download PDF

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CN103601681B
CN103601681B CN201310621163.7A CN201310621163A CN103601681B CN 103601681 B CN103601681 B CN 103601681B CN 201310621163 A CN201310621163 A CN 201310621163A CN 103601681 B CN103601681 B CN 103601681B
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bis
pyrazolidinedione
couples
rubigan
bromophenyl
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CN103601681A (en
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刘宏民
张秋荣
陈婷
顾一飞
李岩琦
章旭耀
吴朝阳
薛登启
贺鹏
邵坤鹏
陈鹏举
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Zhengzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms
    • C07D231/36—Oxygen atoms with hydrocarbon radicals, substituted by hetero atoms, attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms
    • C07D231/34—Oxygen atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached in position 4
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The invention belongs to pharmaceutical chemistry synthesis technical field, disclose 3,5-pyrazodione double bond compounds, its preparation method and use of N-replacement to halobenzene ring with anti-tumor activity.The compounds of this invention has general formula <b> I </b> structure, in general formula <b> I </b>: X is respectively F, Cl, Br; R 1for to fluorophenyl, rubigan, to bromophenyl, 3-methoxyl group-4-hydroxy phenyl, 2,3-di-p-methoxy phenyl, 3,4-difluorophenyls, cinnamyl group, 2-furan allyl.Prove through anti tumor activity in vitro experiment, this compounds has significantly suppression and lethal effect to kinds of tumor cells, may be used for preparation treatment tumor disease medicine.

Description

Containing 3, the 5-pyrazodione derivatives and its production and use of exocyclic double bond structural unit
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, relate to 3,5-pyrazodione analog derivative, be specifically related to N-replacement 3,5-pyrazodione double bond compounds, its preparation method and use to halobenzene ring of anti-tumor activity.
Background technology
3,5-pyrazodione class belongs to the one of NSAID (non-steroidal anti-inflammatory drug), and its main representative medicine is Phenylbutazone and Tacote.It has good anti-inflammatory analgesic action, is used for the treatment of rheumatoid-arthritis, similar rheumatism class sacroiliitis.The NSAID (non-steroidal anti-inflammatory drug) of 3,5-pyrazodione class belongs to nonselective cox 2 inhibitor.In recent years, the further investigation along with molecular pharmacology finds that the generation of the various tumour cells of COX-2 and the mankind, development and transfer have close relationship, and cox 2 inhibitor can as antitumor drug; Or with antitumor drug drug combination, for improving antineoplastic curative effect, reduce side effect.But have no this type of at present containing the antineoplastic bibliographical information of 3,5-pyrazodione double bond compound.
Summary of the invention
For developing existing clinical medicine resource, the object of the invention is to provide 3, the 5-pyrazodione double bond compounds of a class N-replacement to halobenzene ring, thus opens up a new way for finding new active compound for anti tumor; Another object of the present invention is to provide its preparation method; Another object is to provide it preparing the application in antitumor drug.
N-of the present invention replaces as follows to 3,5-pyrazodione double bond compound general structures of halobenzene ring:
General formula iin: X is respectively F, Cl, Br; R 1for to fluorophenyl, rubigan, to bromophenyl, 3-methoxyl group-4-hydroxy phenyl, 2,3-di-p-methoxy phenyl, 3,4-difluorophenyls, cinnamyl group, 2-furan allyl.
N-of the present invention replaces to halobenzene ring 3, the method of 5-pyrazodione double bond compound, it is characterized in that: comprise following synthesis step: contraposition halogen (fluorine, chlorine, bromine) substituted aniline under the effect of manganese dioxide-catalyst, diazotization reaction is occurred by a., obtains contraposition halogen substiuted nitrogen benzide; B. contraposition halogen substiuted nitrogen benzide is generated hydrogenation to chlorine nitrogen benzide with zinc powder generation reduction reaction under the effect of ammonium chloride catalyzer; C. under the effect of sodium ethylate, be there is ring-closure reaction to chlorine nitrogen benzide and diethyl malonate in hydrogenation to generate N-and replace 2-(4-contraposition halogen substituted phenyl)-3,5-pyrazodione compounds; D. aldehyde reaction N-being replaced 2-(4-contraposition halogen substituted phenyl)-3,5-pyrazodione compounds and replacement obtains target compound.The aldehyde cpd replaced has: p-Fluorobenzenecarboxaldehyde, 4-chloro-benzaldehyde, p-bromobenzaldehyde, Vanillin, 2,3 dimethoxy benzaldehydes, 3,4-difluorobenzaldehydes, phenylacrolein, 3-(2-furyl)-propenal.
Synthetic route is as follows:
Be preferably as follows compound:
N-of the present invention replaces has good restraining effect to halobenzene ring 3,5-pyrazodione double bond compound to stomach cancer cell (MGC-803 and HGC-27), esophageal squamous cell carcinoma cell (EC9706 and ECa109), prostate cancer (PC-3), cervical cancer (Hela).Wherein some compound is to the IC of stomach cancer cell (MGC-803 and HGC-27) 50value is less than 10 μMs, contrasts, be better than 5 FU 5 fluorouracil activity with the antitumor drug 5 FU 5 fluorouracil (5-Fu) used clinically.Therefore, provided by the invention this type of 3,5-pyrazodione double bond compound is that the drug combination of development of new antitumor drug and medicine opens another effective way, the compounding design of this compounds is reasonable, reaction conditions is gentle, simple to operate, reaction yield is high, will have good market application foreground.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be appreciated that these embodiments are only not used in restriction the scope of protection of present invention for illustration of the present invention.
Synthetic compound characterizes the instrument used: fusing point uses X5 type microscopic digital melting point detector, and temperature is not calibrated; NMR spectrum uses Sweden BrukerDPX-400 type NMR spectrometer with superconducting magnet to measure, and TMS is interior mark; High resolution mass spectrum uses Waters-Micromass company Q-Tof mass spectrograph to measure.
Rubigan-4-is to the preparation of fluorobenzylidene-3,5-pyrazolidinedione for embodiment 11,2-bis-
2.008g(15.74mmol is added in the there-necked flask of 100ml) p-Chlorobenzoic acid amide and 50ml toluene, stirring and dissolving, installs return line and drying tube, adds 6.892g(79.31mmol) MnO 2, be heated to 90 DEG C, after constant temperature 15min, be warming up to 118 DEG C, start backflow.Every 30min point thin layer plate to monitor reaction process (developping agent sherwood oil: chloroform=2:1).Reflect that complete stopping is heated, the reacting liquor while hot sand core funnel suction filtration being covered with silica gel, filter cake toluene washes twice.Filtrate revolving is steamed to obtain orange/yellow solid.Continue washing leaching cake with revolving the toluene steamed, the filtrate after repetitive operation to washing is colourless.Obtain compound to chlorine nitrogen benzide.
By 0.645g(2.57mmol) chlorine nitrogen benzide is joined in 50ml there-necked flask, then add 30ml acetone, add the saturated NH of 4ml under stirring 4cl solution.1.982g(30.9mmol is added in there-necked flask) zinc powder, stir, visible solution gradually becomes canescence.Every 30min point thin layer plate monitoring reaction process (developping agent sherwood oil: chloroform=2:1).Reflect the complete sand core funnel suction filtration with being covered with silica gel, filter cake acetone is washed till clarification.Filtrate revolves the half of steaming to original volume, adds frozen water, stirs one hour under nitrogen protection, separates out and precipitates in a large number.Stop stirring, revolve after steaming acetone and water, add water and wash out precipitation, and suction filtration obtains hydrogenation to chlorine nitrogen benzide.Hydrogenation is put into P to chlorine nitrogen benzide 2o 5dry in drying bottle.
Take 57.4mg(2.39mmol) sodium, be cut into small pieces after removing surface oxide layer, join in the there-necked flask of 100ml, add 5ml dehydrated alcohol, dissolve.Add above-mentioned hydrogenation under nitrogen protection to chlorine nitrogen benzide, be heated to 50 DEG C.Dissolve completely, drip 0.5ml(3.3mmol) diethyl malonate, stirs 15min, after backflow 8h, removes reflux, be warming up to 140 DEG C, after shooting volatile matter, be dissolved in water, filter out water-fast part.Filtrate adjusts pH=5 with hydrochloric acid, suction filtration, and filter cake methylene dichloride dissolves, with brine three times.Add MgSO4 after dry six hours, steam methylene dichloride.Obtaining white solid with ethyl alcohol recrystallization is 1,2-dichlorophenyl tetrahydro-pyrazole-3,5-diketone, directly carries out next step reaction.
Take 1,2-dichlorophenyl tetrahydro-pyrazole-3,5-diketone white solid 0.320g(1mmol) in the single port flask of 25ml after add the methyl alcohol of 10ml after; after stirring and refluxing device is installed, when being heated to 65 DEG C, add 1.5mmol p-Fluorobenzenecarboxaldehyde; backflow 2h; cooling, after product is separated out, after recrystallizing methanol; obtaining yellow solid compound is that 2-bis-rubigan-4-is to fluorobenzylidene-3; 5-pyrazolidinedione, yield is 92.1%, m.p.169-171 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.66 – 8.59 (m, 2H), 8.13 (s, 1H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.33 (d, j=8.9Hz, 2H), 7.33 (d, j=8.9Hz, 2H), 7.22 (t, j=8.6Hz, 2H). 13cNMR (101MHz, CDCl 3) δ 167.72,165.13,163.74,162.05,153.29,138.09,138.00,134.96,134.85,132.41,132.14,129.25,129.23,128.90,128.87,123.73,123.25,116.62,116.40,115.94.HRMS (ESI): m/zcacld.forC 22h 13cl 2n 2o 2f (M+H) +, 427.0416, found, 427.0415.
Rubigan-4-is to the preparation of chlorobenzene methylene radical-3,5-pyrazolidinedione for embodiment 21,2-bis-
4-chloro-benzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 1, obtains yellow solid compound, and yield is 93.9%, m.p.204-206 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.51 (d, j=8.5Hz, 2H), 8.11 (s, 1H), 7.51 (d, j=8.5Hz, 2H), 7.40 (dd, j=9.1,2.2Hz, 2H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.31 (d, j=8.9Hz, 2H), 7.31 (d, j=8.9Hz, 2H). 13cNMR (101MHz, CDCl 3) δ 163.51,161.84,153.06,141.23,136.22,134.87,134.77,132.47,132.20,130.73,129.46,129.26,129.24,123.74,123.26,116.89.HRMS (ESI): m/zcacld.forC 22h 13cl 3n 2o 2(M+H) +, 443.0121, found, 443.0126.
Rubigan-4-is to the preparation of bromobenzene methylene radical-3,5-pyrazolidinedione for embodiment 31,2-bis-
P-bromobenzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 1, obtains yellow solid compound yield 94.2%, m.p.191-192 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.39 (d, j=8.6Hz, 2H), 8.07 (s, 1H), 7.66 (d, j=8.6Hz, 2H), 7.35 (dd, j=9.1,2.2Hz, 2H), 7.35 (dd, j=9.1,2.2Hz, 2H), 7.30 (d, j=8.9Hz, 2H), 7.30 (d, j=8.9Hz, 2H). 13cNMR (101MHz, CDCl 3) δ 161.41,160.65,152.11,140.32,135.13,133.76,133.24,131.34,131.11,129.66,128.44,128.23,128.16,122.65,122.14,115.23.HRMS (ESI): m/zcacld.forC 22h 13cl 2n 2o 2br (M+H) +, 486.9616, found, 486.9612.
Embodiment 41,2-bis-rubigan-4-(4-hydroxy-3-methoxy) α-tolylene-3,5-pyrazolidinedione
Vanillin is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 1, obtains yellow solid compound, yield 92.1%, m.p.120-122 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.91 (d, j=1.8Hz, 1H), 8.04 (s, 1H), 7.71 (dd, j=8.4,1.9Hz, 1H), 7.38 (dd, j=9.1,2.2Hz, 2H), 7.38 (dd, j=9.1,2.2Hz, 2H), 7.27 (d, j=8.9Hz, 2H), 7.27 (d, j=8.9Hz, 2H), 7.01 (d, j=8.3Hz, 1H), 6.71 (s, 1H), 4.02 (s, 3H). 13cNMR (101MHz, CDCl 3) δ 164.75,163.08,155.07,152.76,146.63,135.48,135.23,133.62,132.19,131.82,129.20,129.15,125.99,123.98,123.26,116.02,114.89,112.36,56.36.HRMS (ESI): m/zcacld.forC 23h 16cl 2n 2o 4(M+H) +, 455.0565, found, 455.0569.
Embodiment 51,2-bis-rubigan-4-(2,3-dimethoxy) α-tolylene-3,5-pyrazolidinedione
2,3-dimethoxy benzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 1, obtains yellow solid compound, yield 80.5%, m.p.104-106 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.72 (s, 1H), 8.67 (dd, j=6.7,2.8Hz, 1H), 7.41 (dd, j=9.1,2.2Hz, 2H), 7.41 (dd, j=9.1,2.2Hz, 2H), 7.32 (d, j=8.9Hz, 2H), 7.32 (d, j=8.9Hz, 2H), 7.21 – 7.14 (m, 2H), 3.99 (s, 3H), 3.93 (s, 3H). 13cNMR (101MHz, CDCl 3) δ 163.95,162.00,152.47,151.78,149.62,135.20,135.07,132.18,131.92,129.16,129.13,126.29,125.55,123.78,123.63,123.09,119.08,116.63,62.31,56.06.HRMS (ESI): m/zcacld.forC 24h 18cl 2n 2o 4(M+Na) +, 491.0541, found, 491.0539.
Embodiment 61,2-bis-rubigan-4-(3,4-difluoro) α-tolylene-3,5-pyrazolidinedione
3,4-difluorobenzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 1, obtains yellow solid compound yield 93.5%, m.p.200-202 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.83 (ddd, j=11.3,7.8,2.0Hz, 1H), 8.16 – 8.08 (m, 1H), 8.05 (s, 1H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.33 (d, j=8.9Hz, 2H), 7.33 (d, j=8.9Hz, 2H), 7.32 (d, j=9.3Hz, 1H). 13cNMR (101MHz, CDCl 3) δ 167.62,165.17,163.75,157.15,154.30,138.12,138.07,134.89,134.72,132.35,132.15,129.23,129.13,128.89,128.56,123.79,123.54,116.96,116.36,115.77.HRMS (ESI): m/zcacld.forC 22h 12cl 2f 2n 2o 2(M+H) +, 445.0322, found, 445.0320.
Embodiment 71,2-bis-rubigan-4-(3-phenyl) allylidene base-3,5-pyrazolidinedione
Phenylacrolein is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 1, obtains red solid compound, yield 97%, m.p.220-222 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.41 (dd, j=15.5,12.0Hz, 1H), 7.89 (d, j=12.0Hz, 1H), 7.70 – 7.63 (m, 2H), 7.44 (dd, j=11.0,4.4Hz, 4H), 7.36 – 7.28 (m, 8H). 13cNMR (101MHz, CDCl 3) δ 163.48,162.98,153.80,152.45,135.18,135.13,135.02,131.99,131.89,131.85,129.21,129.15,129.13,123.20,123.16,123.09,115.03,77.33,77.02,76.70.HRMS (ESI): m/zcacld.forC 24h 16cl 2n 2o 2(M+H) +, 435.0667, found, 435.0666.
Embodiment 81,2-bis-rubigan-4-[3-(2-furans)] allylidene base-3,5-pyrazolidinedione
By 3-(2-furyl)-propenal substitutes p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 1, obtains red solid compound, yield 96%, m.p.160-162 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.22 (dd, j=15.1,12.4Hz, 1H), 7.82 (d, j=12.4Hz, 1H), 7.64 (d, j=1.6Hz, 1H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.30 (d, j=8.9Hz, 2H), 7.30 (d, j=8.9Hz, 2H), 7.20 (d, j=15.2Hz, 1H), 6.89 (d, j=3.5Hz, 1H), 6.59 (dd, j=3.5,1.7Hz, 1H). 13cNMR (101MHz, CDCl 3) δ 163.70,163.11,152.01,151.67,147.22,138.22,135.26,135.22,131.78,131.74,129.13,129.08,123.10,123.02,121.45,118.46,114.16,113.62.HRMS (ESI): m/zcacld.forC 22h 14cl 2n 2o 3(M+H) +, 425.0460, found, 425.0458.
Embodiment 91,2-bis-couples of bromophenyl-4-are to fluorobenzylidene-3,5-pyrazolidinedione
Para-bromoaniline is substituted p-Chlorobenzoic acid amide, and preparation method, with embodiment 1, obtains yellow solid compound, yield 91.1%, m.p.179-181 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.69 – 8.56 (m, 2H), 8.13 (s, 1H), 7.56 – 7.44 (m, 4H), 7.33 – 7.30 (m, 2H), 7.29 (t, j=2.3Hz, 2H), 7.22 (dd, j=12.0,5.3Hz, 2H). 13cNMR (101MHz, CDCl 3) δ 165.34,164.69,160.56,157.22,137.21,135.87,135.47,133.47,133.20,130.73,129.46,125.76,125.14,119.89,119.14,113.76.HRMS (ESI): m/zcacld.forC 22h 13br 2fN 2o 2(M+H) +, 516.9386, found, 516.9388.
Embodiment 101,2-bis-couples of bromophenyl-4-are to chlorobenzene methylene radical-3,5-pyrazolidinedione
4-chloro-benzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 9, obtains yellow solid compound, yield 95.7%, m.p.163-165 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.50 (d, j=8.6Hz, 2H), 8.11 (s, 1H), 7.50 (ddd, j=6.6,6.0,3.0Hz, 6H), 7.30 (dt, j=3.2,2.0Hz, 4H). 13cNMR (101MHz, CDCl 3) δ 164.51,163.84,154.06,142.23,137.22,132.87,132.77,131.47,131.20,130.73,129.46,129.26,129.24,119.74,119.26,114.89.HRMS (ESI): m/zcacld.forC 22h 13br 2clN 2o 2(M+H) +, 532.9090, found, 532.9051.
Embodiment 111,2-bis-couples of bromophenyl-4-are to bromobenzene methylene radical-3,5-pyrazolidinedione
P-bromobenzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 9, obtains yellow solid compound, yield 96.7%, m.p.196-198 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.59 – 8.32 (m, 2H), 8.08 (s, 1H), 7.77 – 7.58 (m, 2H), 7.54 – 7.40 (m, 4H), 7.29 (dd, j=6.7,2.2Hz, 4H). 13cNMR (101MHz, CDCl 3) δ 164.78,163.98,157.26,142.23,135.22,134.87,134.77,132.47,132.20,130.73,129.46,129.26,129.24,119.74,119.26,114.89.HRMS (ESI): m/zcacld.forC 22h 13br 3n 2o 2(M+H) +, 576.8581, found, 576.8561.
Embodiment 121,2-bis-pairs of bromophenyl-4-(4-hydroxy-3-methoxy) α-tolylene-3,5-pyrazolidinediones
Vanillin is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 9, obtains yellow solid compound, yield 94.5%, m.p.130-132 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.92 (s, 1H), 8.05 (s, 1H), 7.72 (d, j=8.2Hz, 1H), 7.48 (t, j=7.9Hz, 4H), 7.30 (dd, j=8.8,3.3Hz, 4H), 7.02 (d, j=8.3Hz, 1H), 4.03 (s, 3H). 13cNMR (101MHz, CDCl 3) δ 164.71,163.02,155.10,152.86,146.67,136.04,135.77,133.63,132.13,132.08,125.97,124.21,123.50,120.04,119.65,116.08,114.94,112.27,56.35.HRMS (ESI): m/zcacld.forC 23h 16br 2n 2o 4(M+H) +, 544.9535, found, 544.9536.
Embodiment 131,2-bis-pairs of bromophenyl-4-(2,3-dimethoxy) α-tolylene-3,5-pyrazolidinediones
2,3-dimethoxy benzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 9, obtains yellow solid compound, yield 75.3%, m.p.237-239 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.72 (s, 1H), 8.67 (dd, j=6.7,2.8Hz, 1H), 7.49 (d, j=8.3Hz, 4H), 7.31 (ddd, j=6.6,4.6,2.4Hz, 4H), 7.21 – 7.14 (m, 2H), 3.99 (s, 3H), 3.93 (d, j=4.4Hz, 3H). 13cNMR (101MHz, CDCl 3) δ 163.91,161.94,152.47,151.80,149.68,135.74,135.61,132.11,132.08,126.29,125.55,123.85,123.78,123.31,120.02,119.74,119.12,116.58,62.30,56.07.HRMS (ESI): m/zcacld.forC 24h 18br 2n 2o 4(M+H) +, 558.9691, found, 558.9709.
Embodiment 141,2-bis-pairs of bromophenyl-4-(3,4-difluoro) α-tolylene-3,5-pyrazolidinediones
3,4-difluorobenzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 9, obtains yellow solid compound ,yield 95%, m.p.198-199 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.82 (ddd, j=11.3,7.8,2.0Hz, 1H), 8.16 – 8.08 (m, 1H), 8.05 (s, 1H), 7.55 – 7.46 (m, 4H), 7.37 – 7.25 (m, 5H). 13cNMR (101MHz, CDCl 3) δ 163.16,161.60,152.01,135.25,135.17,133.12,133.08,133.05,132.24,124.01,123.51,123.39,123.20,120.46,120.15,118.05,117.88,117.25,117.22.HRMS (ESI): m/zcacld.forC 22h 12br 2f 2n 2o 2(M+H) +, 534.9291, found, 534.9271.
Embodiment 151,2-bis-pairs of bromophenyl-4-(3-phenyl) allylidene base-3,5-pyrazolidinedione
Phenylacrolein is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 9, obtains yellow solid compound ,yield 83.9%, m.p.250-252 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.42 (dd, j=15.5,12.1Hz, 1H), 7.91 (d, j=12.0Hz, 1H), 7.73 – 7.65 (m, 2H), 7.54 – 7.41 (m, 8H), 7.30 (dd, j=13.7,7.3Hz, 4H). 13cNMR (101MHz, CDCl 3) δ 163.42,162.91,153.95,152.56,135.65,135.60,134.98,132.11,132.09,131.91,129.24,123.41,123.31,123.12,119.79,119.70,114.92.HRMS (ESI): m/zcacld.forC 24h 16br 2n 2o 2(M+H) +, 524.9636, found, 524.9645.
Embodiment 161,2-bis-couples of bromophenyl-4-[3-(2-furans)] allylidene base-3,5-pyrazolidinedione
By 3-(2-furyl)-propenal substitutes p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 9, obtains red solid compound, yield 91%, m.p.167-169 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.22 (dd, j=15.1,12.4Hz, 1H), 7.82 (d, j=12.4Hz, 1H), 7.64 (d, j=1.6Hz, 1H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.37 (dd, j=9.1,2.2Hz, 2H), 7.30 (d, j=8.9Hz, 2H), 7.30 (d, j=8.9Hz, 2H), 7.20 (d, j=15.2Hz, 1H), 6.89 (d, j=3.5Hz, 1H), 6.59 (dd, j=3.5,1.7Hz, 1H). 13cNMR (101MHz, CDCl 3) δ 163.70,163.11,152.01,151.67,147.22,138.22,135.26,135.22,131.78,131.74,129.13,129.08,123.10,123.02,121.45,118.46,114.16,113.62.HRMS (ESI): m/zcacld.forC 22h 14br 2n 2o 3(M+H) +, 512.9449, found, 512.9452.
Embodiment 171,2-bis-couples of fluorophenyl-4-are to fluorobenzylidene-3,5-pyrazolidinedione
Para-fluoroaniline is substituted p-Chlorobenzoic acid amide, and preparation method, with embodiment 1, obtains yellow solid compound, yield 95.2%, m.p.171-173 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.71 – 8.57 (m, 2H), 8.12 (s, 1H), 7.48 – 7.35 (m, 4H), 7.26 – 7.17 (m, 2H), 7.15 – 7.02 (m, 4H). 13cNMR (101MHz, CDCl 3) δ 167.63,165.04,163.87,162.25,162.20,162.11,159.79,159.65,152.93,137.99,137.89,132.34,132.31,132.28,132.25,128.95,128.92,124.85,124.77,124.39,124.30,116.55,116.34,116.17,116.16,115.94,115.93.HRMS (ESI): m/zcacld.forC 22h 13f 3n 2o 2(M+H) +, 395.1007, found, 395.1005.
Embodiment 181,2-bis-couples of fluorophenyl-4-are to chlorobenzene methylene radical-3,5-pyrazolidinedione
4-chloro-benzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 17, obtains yellow solid compound ,yield 94.4%, m.p.181-183 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.51 (d, j=8.6Hz, 2H), 8.10 (s, 1H), 7.50 (d, j=8.6Hz, 2H), 7.45 – 7.34 (m, 4H), 7.07 (td, j=8.6,3.6Hz, 4H). 13cNMR (101MHz, CDCl 3) δ 163.65,162.28,162.13,161.98,159.82,152.71,141.03,136.15,132.20,130.78,129.40,124.89,124.80,124.43,124.35,117.16,116.18,115.95.HRMS (ESI): m/zcacld.forC 22h 13f 2clN 2o 2(M+H) +, 411.0712, found, 411.0714.
Embodiment 191,2-bis-couples of fluorophenyl-4-are to bromobenzene methylene radical-3,5-pyrazolidinedione
P-bromobenzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 17, obtains yellow solid compound ,yield 90.5%, m.p.156-158 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.43 (d, j=8.6Hz, 2H), 8.09 (s, 1H), 7.71 – 7.65 (m, 2H), 7.46 – 7.35 (m, 4H), 7.13 – 7.00 (m, 4H). 13cNMR (101MHz, CDCl 3) δ 163.61,162.28,161.96,159.68,152.81,136.11,132.43,132.14,131.15,130.02,124.87,124.79,124.41,124.33,117.39,116.19,115.96.HRMS (ESI): m/zcacld.forC 22h 13f 2brN 2o 2(M+H) +, 455.0207, found, 455.0205.
Embodiment 201,2-bis-pairs of fluorophenyl-4-(4-hydroxy-3-methoxy) α-tolylene-3,5-pyrazolidinediones
Phenylacrolein is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 17, obtains yellow solid compound ,yield 94.2%, m.p.191-192 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.39 (d, j=8.6Hz, 2H), 8.07 (s, 1H), 7.66 (d, j=8.6Hz, 2H), 7.35 (dd, j=9.1,2.2Hz, 2H), 7.35 (dd, j=9.1,2.2Hz, 2H), 7.30 (d, j=8.9Hz, 2H), 7.30 (d, j=8.9Hz, 2H). 13cNMR (101MHz, CDCl 3) δ 161.41,160.65,152.11,140.32,135.13,133.76,133.24,131.34,131.11,129.66,128.44,128.23,128.16,122.65,122.14,115.23.HRMS (ESI): m/zcacld.forC 22h 13cl 2n 2o 2br (M+H) +, 486.9616, found, 486.9612.
Embodiment 211,2-bis-pairs of fluorophenyl-4-(2,3-dimethoxy) α-tolylene-3,5-pyrazolidinediones
2,3-dimethoxy benzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 17, obtains yellow solid compound, yield 75.3%, m.p.110-112 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.76 – 8.61 (m, 2H), 7.47 – 7.34 (m, 5H), 7.11 – 7.01 (m, 5H), 3.99 (s, 3H), 3.92 (s, 3H). 13cNMR (101MHz, CDCl 3) δ 164.09,162.15,152.46,151.68,149.27,132.42,126.33,125.54,124.73,124.65,124.21,124.12,123.79,118.92,116.92,116.06,115.83,115.59,62.30,58.45,56.05.HRMS (ESI): m/zcacld.forC 24h 18f 2n 2o 2(M+H) +, 437.1313, found, 437.1310.
Embodiment 221,2-bis-pairs of fluorophenyl-4-(3,4-difluoro) α-tolylene-3,5-pyrazolidinediones
3,4-difluorobenzaldehyde is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 17, obtains yellow solid compound, yield 92%, m.p.138-140 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.85 (ddd, j=11.4,7.8,2.1Hz, 1H), 8.15 – 8.08 (m, 1H), 8.05 (s, 1H), 7.43 – 7.36 (m, 4H), 7.35 – 7.29 (m, 1H), 7.13 – 7.02 (m, 4H). 13cNMR (101MHz, CDCl 3) δ 163.34,162.35,162.19,161.80,159.89,159.73,151.65,132.96,132.03,129.40,124.96,124.88,124.49,124.40,123.34,123.15,118.00,117.82,117.55,116.24,116.01.HRMS (ESI): m/zcacld.forC 22h 12f 4n 2o 2(M+H) +, 413.0913, found, 413.0915.
Embodiment 231,2-bis-pairs of fluorophenyl-4-(3-phenyl) allylidene base-3,5-pyrazolidinedione
Phenylacrolein is substituted p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 17, obtains yellow solid compound, yield 85.5%, m.p.263-265 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.44 (dd, j=15.3,12.1Hz, 1H), 7.91 (d, j=12.0Hz, 1H), 7.69 (d, j=7.4Hz, 2H), 7.55 – 7.33 (m, 8H), 7.06 (td, j=8.4,3.9Hz, 4H). 13cNMR (101MHz, CDCl 3) δ 163.63,163.15,162.05,162.00,159.60,159.54,153.44,152.15,135.06,132.55,132.48,132.45,131.75,129.20,129.15,124.29,124.20,124.19,124.10,123.17,116.07,116.05,115.84,115.82,115.32.HRMS (ESI): m/zcacld.forC 24h 16f 2n 2o 2(M+H) +, 403.1258, found, 403.1255.
Embodiment 241,2-bis-couples of fluorophenyl-4-[3-(2-furans)] allylidene base-3,5-pyrazolidinedione
By 3-(2-furyl)-propenal substitutes p-Fluorobenzenecarboxaldehyde, and preparation method, with embodiment 17, obtains orange solids compound, yield 94.6%, m.p.187-189 DEG C; 1hNMR (400MHz, CDCl 3) δ 8.23 (dd, j=15.2,12.4Hz, 1H), 7.81 (d, j=12.4Hz, 1H), 7.63 (d, j=1.3Hz, 1H), 7.38 (dd, j=8.9,4.7Hz, 4H), 7.19 (d, j=15.2Hz, 1H), 7.12 – 6.99 (m, 4H), 6.88 (d, j=3.5Hz, 1H), 6.58 (dd, j=3.5,1.7Hz, 1H). 13cNMR (101MHz, CDCl 3) δ 163.84,163.29,161.97,161.93,159.51,159.48,152.06,151.31,147.03,137.87,132.70,132.67,132.64,132.61,124.17,124.10,124.02,121.51,118.08,116.02,115.96,115.79,115.73,114.56,113.51.HRMS (ESI): m/zcacld.forC 22h 14f 2n 2o 3(M+H) +, 393.1051, found, 393.1054.
application example
Anti tumor activity in vitro is tested: adopt seven kinds of clones with mtt assay, be respectively stomach cancer cell (MGC-803 and HGC-27), esophageal squamous cell carcinoma cell (EC-9706 and ECa109), prostate cancer cell (PC-3), liver cancer cell (SMMC-7721) and cervical cancer cell (Hela).Collect logarithmic phase cell, adjustment concentration of cell suspension, every hole adds 200 μ l, and bed board makes cell to be measured adjust density to 6000/hole, (marginal pore PBS fills).5%CO 2hatch 24 hours for lower 37 DEG C, be paved with (96 level land, hole plate) at the bottom of hole to cell monolayer, add the compound of concentration gradient the present invention synthesis, generally establish 9 concentration, every hole 200 μ l, if 6 multiple holes.5%CO 2hatch 72h, observe under inverted microscope for lower 37 DEG C, every hole adds 20 μ lMTT solution (5mg/ml, i.e. 0.5%MTT), continues to cultivate 4h.Stop cultivating, carefully suck nutrient solution in hole, every hole adds 150 μ l dimethyl sulfoxide (DMSO), puts low-speed oscillation 10min on shaking table, compound is fully dissolved.The light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument OD490nm place.With SPSS software experimental result added up and calculate IC 50value, result is as following table.
The experimental data of table 1 anti tumor activity in vitro

Claims (3)

1.N-replaces 3, the 5-pyrazodione double bond compounds to halobenzene ring, and it is characterized in that, this compound is one of following compound:
(1) 1,2-bis-rubigan-4-is to fluorobenzylidene-3,5-pyrazolidinedione
(2) 1,2-bis-rubigan-4-are to chlorobenzene methylene radical-3,5-pyrazolidinedione
(3) 1,2-bis-rubigan-4-are to bromobenzene methylene radical-3,5-pyrazolidinedione
(4) 1,2-bis-rubigan-4-(4-hydroxy-3-methoxy) α-tolylene-3,5-pyrazolidinediones
(5) 1,2-bis-rubigan-4-(2,3-dimethoxy) α-tolylene-3,5-pyrazolidinediones
(6) 1,2-bis-rubigan-4-(3,4-difluoro) α-tolylene-3,5-pyrazolidinediones
(7) 1,2-bis-rubigan-4-(3-phenyl) allylidene base-3,5-pyrazolidinedione
(8) 1,2-bis-rubigan-4-[3-(2-furans)] allylidene base-3,5-pyrazolidinedione
(9) 1,2-bis-couples bromophenyl-4-are to fluorobenzylidene-3,5-pyrazolidinedione
(10) 1,2-bis-couples bromophenyl-4-are to chlorobenzene methylene radical-3,5-pyrazolidinedione
(11) 1,2-bis-couples bromophenyl-4-are to bromobenzene methylene radical-3,5-pyrazolidinedione
(12) 1,2-bis-couples bromophenyl-4-(4-hydroxy-3-methoxy) α-tolylene-3,5-pyrazolidinediones
(13) 1,2-bis-couples bromophenyl-4-(2,3-dimethoxy) α-tolylene-3,5-pyrazolidinediones
(14) 1,2-bis-couples bromophenyl-4-(3,4-difluoro) α-tolylene-3,5-pyrazolidinediones
(15) 1,2-bis-couples bromophenyl-4-(3-phenyl) allylidene base-3,5-pyrazolidinedione
(16) 1,2-bis-couples bromophenyl-4-[3-(2-furans)] allylidene base-3,5-pyrazolidinedione
(17) 1,2-bis-couples fluorophenyl-4-are to fluorobenzylidene-3,5-pyrazolidinedione
(18) 1,2-bis-couples fluorophenyl-4-are to chlorobenzene methylene radical-3,5-pyrazolidinedione
(19) 1,2-bis-couples fluorophenyl-4-are to bromobenzene methylene radical-3,5-pyrazolidinedione
(20) 1,2-bis-couples fluorophenyl-4-(4-hydroxy-3-methoxy) α-tolylene-3,5-pyrazolidinediones
(21) 1,2-bis-couples fluorophenyl-4-(2,3-dimethoxy) α-tolylene-3,5-pyrazolidinediones
(22) 1,2-bis-couples fluorophenyl-4-(3,4-difluoro) α-tolylene-3,5-pyrazolidinediones
(23) 1,2-bis-couples fluorophenyl-4-(3-phenyl) allylidene base-3,5-pyrazolidinedione
(24) 1,2-bis-couples fluorophenyl-4-[3-(2-furans)] allylidene base-3,5-pyrazolidinedione.
2. N-as claimed in claim 1 replaces the application of 3,5-pyrazodione double bond compounds in medicine preparation to halobenzene ring, it is characterized in that: as activeconstituents for the preparation of antitumor drug.
3. N-as claimed in claim 1 replaces the application of 3,5-pyrazodione double bond compounds in medicine preparation to halobenzene ring, it is characterized in that: as activeconstituents for the preparation of anti-cancer of the stomach, the esophageal carcinoma, liver cancer, cervical cancer or prostate cancer medicine.
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