CN103804322A - Phenylpiperazine derivatives as well as preparation method and applications thereof - Google Patents

Phenylpiperazine derivatives as well as preparation method and applications thereof Download PDF

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CN103804322A
CN103804322A CN201410091290.5A CN201410091290A CN103804322A CN 103804322 A CN103804322 A CN 103804322A CN 201410091290 A CN201410091290 A CN 201410091290A CN 103804322 A CN103804322 A CN 103804322A
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preparation
phenylpiperazine derivatives
phenylpiperazine
drying
piperazine
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CN103804322B (en
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朱海亮
孙娟
郭凤娇
王忻怡
秦洁
钱绍松
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Shandong University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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Abstract

The invention belongs to the field of organic synthesis, and particularly relates to phenylpiperazine derivatives as well as a preparation method and applications thereof. The preparation method comprises the steps of putting 2,4'-dibromoacetophenone, substituted piperazine, potassium carbonate and acetonitrile into a round-bottom flask with a reflux device, heating oil bath, performing reflux reaction, then filtering precipitate, drying the filtrate by distillation, extracting with water and ethyl acetate, keeping an organic layer, drying to obtain a product after drying with anhydrous sodium sulfate; by taking ethanol as a reaction solvent, reacting the product with NaBH4 at normal temperature, drying the solvent by distillation after the reaction is thoroughly completed, extracting with water and ethyl acetate, keeping an organic solvent layer, and drying by distillation to obtain the phenylpiperazine derivatives after drying with anhydrous sodium sulfate. The 2,4'-dibromoacetophenone with excellent anticancer activity is introduced in a phenylpiperazine ring to prepare phenylpiperazine derivatives containing bromoacetophenone. The phenylpiperazine derivatives play an obvious role in inhibiting the growth of cancer cells, and can be applied to preparation of anticancer drugs.

Description

Phenylpiperazine derivatives and preparation method thereof and purposes
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of Phenylpiperazine derivatives and preparation method thereof and purposes.
Background technology
In recent years, the application of piperazine compounds in organic synthesis and medicine caused the extensive concern of organise educational circles and pharmacy circle, and piperazine heterocycle, compared with traditional organic drug, has the symmetrical structure of better nitrogen equilibrium.Piperazine ring is the hexa-member heterocycle containing two nitrogen-atoms in molecule, is the ideal structure unit of azotic heterocyclic compound, has the features such as Enthalpies of Formation is high, Heat stability is good.In organic synthesis, as reactive intermediate, can further synthesize many type organic compound containing the compound of piperazine ring, these compounds have efficient pharmacologically active mostly, and some has been developed becomes clinical medicine.
Phenylpiperazine derivatives has obvious restraining effect to growth of cancer cells, and therefore, Phenylpiperazine derivatives extremely merits attention as the prospect of very potential cancer therapy drug.Along with deepening continuously of phenylpiperazine class drug research, on the basis that its mechanism of anticancer action is constantly understood, carry out effective structure of modification and modification and molecular designing, the phenylpiperazine kind anti-cancer drugs thing of, low toxicity increasing efficient by having, for clinical, promotes the well-being of mankind.
Summary of the invention
The object of this invention is to provide a kind of Phenylpiperazine derivatives, cancer cells is had to obvious restraining effect; The present invention provides the preparation method of Phenylpiperazine derivatives simultaneously, scientific and reasonable, simple; The purposes of Phenylpiperazine derivatives is to prepare cancer therapy drug.
Phenylpiperazine derivatives of the present invention, general formula is as follows:
In formula, R is:
Figure BDA0000476382740000012
The preparation method of Phenylpiperazine derivatives of the present invention, step is as follows:
(1) by 2,4 '-dibromobenzene ethyl ketone, substituted-piperazinyl, salt of wormwood and acetonitrile are placed in the round-bottomed flask with reflux, oil bath heating, back flow reaction, then elimination precipitation, evaporate to dryness filtrate, water and ethyl acetate extraction, retain organic layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains product;
(2) by step (1) product and NaBH 4react, reaction solvent is ethanol, normal-temperature reaction, and solvent evaporated after reacting completely, water and ethyl acetate extraction, retain organic solvent layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains Phenylpiperazine derivatives.
Described in step (1) 2, the mol ratio of 4 '-dibromobenzene ethyl ketone, substituted-piperazinyl and salt of wormwood is 1:1-1.5:1-3.
Described in step (1) 2, the proportioning of 4 '-dibromobenzene ethyl ketone and acetonitrile is 1mmol:20-50ml.
Back flow reaction temperature described in step (1) is 60-85 ℃, and reflux time is 1-6h.
Step (1) product and NaBH described in step (2) 4mol ratio be 1:1-6.
The normal-temperature reaction time described in step (2) is 2-8h.
The purposes of Phenylpiperazine derivatives of the present invention is can be applied to prepare cancer therapy drug.
Described substituted-piperazinyl refers to the piperazine that various substituting groups replace, for example m-methoxyphenyl piperazine, m-chloro phenylpiperazine, adjacent fluorophenyl piperazine, phenylpiperazine, o-methoxyphenyl piperazine, Chloro-O-Phenyl piperazine, p-nitrophenyl piperazine, p-methoxyphenyl piperazine, to fluorophenyl piperazine, 2,4-dimethylphenylpiperazinium, 2,3-dichlorophenyl piperazine, 3,4-dichlorophenyl piperazine, pyridyl piperazine, benzyl diethylenediamine, p-trifluoromethyl phenyl piperazine, diphenylmethyl piperazine, 4-chlorodiphenyl ylmethyl piperazine, biconjugate fluorine diphenylmethyl piperazine etc.
The present invention compared with prior art, has following beneficial effect:
The present invention will have 2 of high anti-cancer activity, and 4 '-dibromobenzene ethyl ketone is introduced phenylpiperazine ring, the phenylpiperazine analog derivative that preparation contains bromoacetophenone.Phenylpiperazine derivatives has obvious restraining effect to growth of cancer cells, can be applied to and prepare cancer therapy drug.
Embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
The preparation of 2-(4-benzhydryl piperazidine-1-yl)-1-(4-bromophenyl) ethanol (compound 1).
(1) by 1mmol2,4 '-dibromobenzene ethyl ketone, 1mmol1-benzhydryl piperazidine, 1.5mmol salt of wormwood, 25mL acetonitrile is placed in the round-bottomed flask with reflux, oil bath heating, back flow reaction 2h at 85 ℃.Then elimination precipitation, evaporate to dryness filtrate, water and ethyl acetate extraction, retain organic layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains product;
(2) by the NaBH of 1mmol step (1) product and 1.5mmol 4react, reaction solvent is ethanol, normal-temperature reaction 4h, and solvent evaporated after reacting completely, water and ethyl acetate extraction, retain organic solvent layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains Phenylpiperazine derivatives.
White powder, productive rate is 85%, m.p.148.1-148.5 ℃; 1h NMR (400MHz, DMSO) δ (ppm): 2.49-2.62 (m, 8H), 2.86 (s, 2H), 4.3 (s, 1H), 4.76-4.79 (m, 1H), 7.21-7.25 (m, 2H), 7.28 (s, 1H), 7.30-7.35 (m, 6H), 7.45-7.47 (m, 3H), 7.49-7.51 (m, 2H).
Embodiment 2
The preparation of 2-(4-(two (4-fluorophenyl) methyl) piperazine-1-yl)-1-(4-bromophenyl) ethanol (compound 2).
Figure BDA0000476382740000031
(1) by 1mmol2,4 '-dibromobenzene ethyl ketone, 1.5mmol1-biconjugate fluorophenyl methyl piperazine, 1mmol salt of wormwood, 20mL acetonitrile is placed in the round-bottomed flask with reflux, oil bath heating, back flow reaction 1h at 75 ℃.Then elimination precipitation, evaporate to dryness filtrate, water and ethyl acetate extraction, retain organic layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains product;
(2) by the NaBH of 1mmol step (1) product and 1mmol 4react, reaction solvent is ethanol, normal-temperature reaction 2h, and solvent evaporated after reacting completely, water and ethyl acetate extraction, retain organic solvent layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains Phenylpiperazine derivatives.
White powder, productive rate is 80%, m.p.134.3-134.5 ℃.
Embodiment 3
The preparation of 2-(4-benzyl piepridine-1-yl)-1-(4-bromophenyl) ethanol (compound 3).
Figure BDA0000476382740000032
(1) by 1mmol2,4 '-dibromobenzene ethyl ketone, 1.2mmol1-benzyl methylpiperazine, 3mmol salt of wormwood, 50mL acetonitrile is placed in the round-bottomed flask with reflux, oil bath heating, back flow reaction 6h at 60 ℃.Then elimination precipitation, evaporate to dryness filtrate, water and ethyl acetate extraction, retain organic layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains product;
(2) by the NaBH of 1mmol step (1) product and 6mmol 4react, reaction solvent is ethanol, normal-temperature reaction 8h, and solvent evaporated after reacting completely, water and ethyl acetate extraction, retain organic solvent layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains Phenylpiperazine derivatives.
White powder, productive rate is 85%, m.p.151.6-151.9 ℃; 1h NMR (400MHz, DMSO) δ (ppm): 2.46-2.61 (m, 8H), 2.86 (s, 2H), 3.57-3.64 (m, 2H), 4.74-4.78 (m, 1H), 7.28-7.34 (m, 3H), 7.35-7.38 (m, 4H), 7.50-7.52 (m, 2H).
Embodiment 4
The preparation of 1-(4-bromophenyl)-2-(4-(pyridine-2-yl) piperazine-1-yl) ethanol (compound 4).
Figure BDA0000476382740000041
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 2-pyridyl piperazine, obtain target compound.
White powder, productive rate is 80%, m.p.128.0 ℃; 1h NMR (400MHz, DMSO) δ (ppm): 2.62-2.65 (m, 4H), 2.88-2.94 (m, 2H), 3.58-3.70 (m, 4H), 4.79-4.83 (m, 1H), 6.68-6.72 (m, 2H), 7.31-7.33 (m, 2H), 7.52-7.56 (m, 3H), 8.24-8.25 (m, 1H).
Embodiment 5
The preparation of 1-(4-bromophenyl)-2-(4-phenylpiperazine-1-yl) ethanol (compound 5).
Figure BDA0000476382740000042
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-php, obtain target compound.
White powder, productive rate is 85%, m.p.151.5-152.9 ℃.
Embodiment 6
The preparation of 1-(4-bromophenyl)-2-(4-(4-fluorophenyl) piperazine-1-yl) ethanol (compound 6).
Figure BDA0000476382740000043
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-4-fluorophenyl piperazine, obtain target compound.
White powder, productive rate is 80%, m.p.158.9-159.0 ℃.
Embodiment 7
The preparation of 1-(4-bromophenyl)-2-(4-(2-fluorophenyl) piperazine-1-yl) ethanol (compound 7).
Figure BDA0000476382740000051
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-2-fluorophenyl piperazine, obtain target compound.
White powder, productive rate is 85%, m.p.133.8-134.1 ℃; 1h NMR (400MHz, DMSO) δ (ppm): 2.66-2.70 (m, 4H), 2.93-2.98 (m, 2H), 3.25-3.35 (m, 4H), 4.80-4.83 (m, 1H), 6.83-6.94 (m, 3H), 7.20-7.24 (m, 1H), 7.31-7.33 (m, 2H), 7.52-7.54 (m, 2H).
Embodiment 8
The preparation of 1-(4-bromophenyl)-2-(4-(3-(trifluoromethyl) phenyl) piperazine-1-yl) ethanol (compound 8).
Figure BDA0000476382740000052
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-3-(trifluoromethyl) phenylpiperazine, obtain target compound.
White powder, productive rate is 80%, m.p.114.8-115.0 ℃; 1h NMR (400MHz, DMSO) δ (ppm): 2.69-2.74 (m, 4H), 2.96-3.01 (m, 2H), 3.31-3.40 (m, 4H), 4.82-4.85 (m, 1H), 7.11-7.17 (m, 3H), 7.31-7.33 (m, 2H), 7.39-7.43 (m, 1H), 7.52-7.54 (m, 2H).
Embodiment 9
The preparation of 1-(4-bromophenyl)-2-(4-(2-chloro-phenyl-) piperazine-1-yl) ethanol (compound 9).
Figure BDA0000476382740000053
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-2-chloro-phenyl-piperazine, obtain target compound.
White powder, productive rate is 85%, m.p.125.0-125.3 ℃.
Embodiment 10
The preparation of 1-(4-bromophenyl)-2-(4-(3-chloro-phenyl-) piperazine-1-yl) ethanol (compound 10).
Figure BDA0000476382740000061
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-3-chloro-phenyl-piperazine, obtain target compound.
Yellowish powder, productive rate is 80%, m.p.155.4-155.7 ℃.
Embodiment 11
The preparation of 1-(4-bromophenyl)-2-(4-(4-nitrophenyl) piperazine-1-yl) ethanol (compound 11).
Figure BDA0000476382740000062
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-4-nitrophenyl piperazine, obtain target compound.
Yellow powder, productive rate is 85%, m.p.168.7-169.0 ℃.
Embodiment 12
The preparation of 1-(4-bromophenyl)-2-(4-(2,3-dichlorophenyl) piperazine-1-yl) ethanol (compound 12).
Figure BDA0000476382740000063
Preparation method is with embodiment 1.With 1-2,3-dichlorophenyl piperazine replaces 1-benzhydryl piperazidine, obtains target compound.
White powder, productive rate is 85%, m.p.145.5-145.6 ℃.
Embodiment 13
The preparation of 1-(4-bromophenyl)-2-(4-(3,4-dichlorophenyl) piperazine-1-yl) ethanol (compound 13).
Figure BDA0000476382740000064
Preparation method is with embodiment 1.With 1-3,4-dichlorophenyl piperazine replaces 1-benzhydryl piperazidine, obtains target compound.
White powder, productive rate is 85%, m.p.147.3-147.5 ℃; 1h NMR (400MHz, DMSO) δ (ppm): 2.51-2.68 (m, 4H), 2.90-2.96 (m, 2H), 3.21-3.31 (m, 4H), 4.78-4.81 (m, 1H), 6.78-6.81 (m, 1H), 7.01-7.02 (m, 1H), 7.30-7.34 (m, 4H), 7.52-7.54 (m, 2H).
Embodiment 14
The preparation of 1-(4-bromophenyl)-2-(4-(2,4-3,5-dimethylphenyl) piperazine-1-yl) ethanol (compound 14).
Figure BDA0000476382740000071
Preparation method is with embodiment 1.With 1-2,4-dimethylphenylpiperazinium replaces 1-benzhydryl piperazidine, obtains target compound.
White powder, productive rate is 80%, m.p.168.1-168.6 ℃; 1h NMR (400MHz, DMSO) δ (ppm): 2.32-2.33 (m, 6H), 2.55-2.68 (m, 4H), 2.97-3.03 (m, 6H), 4.80-4.83 (m, 1H), 6.99-7.06 (m, 3H), 7.31-7.34 (m, 2H), 7.52-7.54 (m, 2H).
Embodiment 15
The preparation of 1-(4-bromophenyl)-2-(4-(2-p-methoxy-phenyl) piperazine-1-yl) ethanol (compound 15).
Figure BDA0000476382740000072
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-2-methoxyphenylpiperazderivatives, obtain target compound.
Buff powder, productive rate is 85%, m.p.121.7-122.1 ℃.
Embodiment 16
The preparation of 1-(4-bromophenyl)-2-(4-(3-p-methoxy-phenyl) piperazine-1-yl) ethanol (compound 16).
Figure BDA0000476382740000073
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-3-methoxyphenylpiperazderivatives, obtain target compound.
Buff powder, productive rate is 75%, m.p.120.5-120.8 ℃; 1h NMR (400MHz, DMSO) δ (ppm): 2.62-2.70 (m, 4H), 2.94-2.97 (m, 2H), 3.28-3.32 (m, 4H), 3.85 (s, 3H), 4.81 (m, 1H), 6.48-6.53 (m, 2H), 6.59-6.61 (m, 1H), 7.21-7.25 (m, 1H), 7.31-7.33 (m, 2H), 7.52-7.54 (m, 2H).
Embodiment 17
The preparation of 1-(4-bromophenyl)-2-(4-(4-p-methoxy-phenyl) piperazine-1-yl) ethanol (compound 17).
Figure BDA0000476382740000081
Preparation method is with embodiment 1.Replace 1-benzhydryl piperazidine with 1-4-methoxyphenylpiperazderivatives, obtain target compound.
White powder, productive rate is 85%, m.p.157.4-158.0 ℃.
The product that embodiment 1-17 is obtained carries out following Anticancer Activities:
1, experiment material
1.1 cell strain
Human stomach cancer cell line (Human gastric carcinoma cells), SGC-7901;
1.2 reagent
RPMI1640 substratum (GIBCO), new-born calf serum (Hangzhou folium ilicis chinensis biological engineering material), trypsin Sigma), MTT(Sigma), (the auspicious positive pharmacy in Shandong of injection Streptomycin sulphate, 1g100 ten thousand units /), benzylpenicillin sodium for injection (the anti-medicine in Shandong, Shandong, 800,000 units /).Other conventional chemical reagent is domestic analytical pure.
2, experimental technique
The preparation of 2.1 substratum
One bag of RPMI1640 substratum (Gibcio USA) adds water one liter, adds 2g sodium bicarbonate, and 100,000 unit penicillin and 100mg Streptomycin sulphate regulate pH value to 7.4, the degerming of use 0.22mm degerming membrane filtration.90mL substratum adds deactivation new-born calf serum 10mL and is complete culture solution.Trypsinase is made into 0.25% solution with D-hanks damping fluid, and after filtration sterilization, 4 ℃ save backup.
The preparation of 2.2 liquids
Accurately take sample 1.0mg, be added in the 1.5mL centrifuge tube of sterilizing, add DMSO1mL, be made into 1mg/mL stoste ,-40 ℃ of freezing preservations.After melting before use, be diluted to respective concentration application with appropriate D-hanks.
2.3 cell cultures and going down to posterity
The equal adherent culture of cell is in containing 10mL complete culture solution Tissue Culture Flask, in 37 ℃, 5%CO 2, cultivate under saturated humidity.After at the bottom of cell covers with bottle, wash twice with sterilizing D-hanks liquid, add 0.25% trypsin digestion and cell 2min, outwell trypsinase, after jog cell can come off completely, add after complete culture solution 30mL, dispel cell with transfer pipet, be sub-packed in 3 new Tissue Culture Flasks, continue to cultivate.
2.4 antitumour activity tests
Get one bottle, the cell that just grows up to complete individual layer, collecting cell after tryptic digestion, even with transfer pipet piping and druming, get two cell suspension Trypan Blues (Trypan Blue) dyeing, living cell counting number under microscope (dead cell number must not exceed 5%), with complete culture solution adjustment cell number to 1 × 10 4individual cell/mL.In 96 porocyte culture plates, every hole adds 100 μ L cell suspensions, and culture plate is placed in to CO 2in incubator, cultivate 24h, after taking out culture plate, in every hole, add the solution of 11 μ L containing different concns sample, make medicine final concentration be respectively 60,20,6.67,2.22,0.74,0.25 and 0.082 μ g/mL, each concentration is established 3 parallel holes, separately establishes 6 porocytes and makes normal control hole and positive cis-platinum control wells.After adding medicine, culture plate vibrates and mixes on microwell plate vibrator, is placed in CO 2in incubator, continue to cultivate 24h.Take out culture plate, every hole adds the MTT liquid of 25 μ L5mg/mL, and vibration mixes, and continues to cultivate 4h.After adding every hole 100 μ L DMSO, cultivate 10min.Microplate reader is measured each hole photoabsorption (OD value), measures wavelength 490nm.Pass through the inhibiting rate of CalcuSyn computed in software medicine to two kinds of cell proliferations, i.e. IC according to each hole OD value 50value, experimental result is in table 1,
The inhibiting rate of table 1 medicine to human stomach cancer cell line SGC-7901
Figure BDA0000476382740000091

Claims (8)

1. a Phenylpiperazine derivatives, is characterized in that general formula is as follows:
Figure FDA0000476382730000011
In formula, R is:
Figure FDA0000476382730000012
2. a preparation method for Phenylpiperazine derivatives claimed in claim 1, is characterized in that step is as follows:
(1) by 2,4 '-dibromobenzene ethyl ketone, substituted-piperazinyl, salt of wormwood and acetonitrile are placed in the round-bottomed flask with reflux, oil bath heating, back flow reaction, then elimination precipitation, evaporate to dryness filtrate, water and ethyl acetate extraction, retain organic layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains product;
(2) by step (1) product and NaBH 4react, reaction solvent is ethanol, normal-temperature reaction, and solvent evaporated after reacting completely, water and ethyl acetate extraction, retain organic solvent layer, and after anhydrous sodium sulfate drying, evaporate to dryness obtains Phenylpiperazine derivatives.
3. the preparation method of Phenylpiperazine derivatives according to claim 2, is characterized in that 2 described in step (1), and the mol ratio of 4 '-dibromobenzene ethyl ketone, substituted-piperazinyl and salt of wormwood is 1:1-1.5:1-3.
4. the preparation method of Phenylpiperazine derivatives according to claim 2, is characterized in that 2 described in step (1), and the proportioning of 4 '-dibromobenzene ethyl ketone and acetonitrile is 1mmol:20-50ml.
5. the preparation method of Phenylpiperazine derivatives according to claim 2, is characterized in that the back flow reaction temperature described in step (1) is 60-85 ℃, and reflux time is 1-6h.
6. the preparation method of Phenylpiperazine derivatives according to claim 2, is characterized in that step (1) product and the NaBH described in step (2) 4mol ratio be 1:1-6.
7. the preparation method of Phenylpiperazine derivatives according to claim 2, is characterized in that the normal-temperature reaction time described in step (2) is 2-8h.
8. a purposes for Phenylpiperazine derivatives claimed in claim 1, is characterized in that being applied to and prepares cancer therapy drug.
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