CN101108791A - Substituted benzyl ethylene derivant and method of preparing the same and use thereof - Google Patents

Substituted benzyl ethylene derivant and method of preparing the same and use thereof Download PDF

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CN101108791A
CN101108791A CNA2007100703948A CN200710070394A CN101108791A CN 101108791 A CN101108791 A CN 101108791A CN A2007100703948 A CNA2007100703948 A CN A2007100703948A CN 200710070394 A CN200710070394 A CN 200710070394A CN 101108791 A CN101108791 A CN 101108791A
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compound
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benzene derivatives
allyl benzene
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CN101108791B (en
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赵昱
吴昊
张丽娟
邹宏斌
约阿施·史托克希特
巫秀美
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Zhejiang University ZJU
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Abstract

A substituted benzene propylene derivative and the salt are provided, which is that the phenylacrylate substituted by the corresponding group gains the correspondingly substituted phenylallyl compound through the deoxidization of the lithium aluminium hydride and the aluminium trichloride compound. The invention has certain selective cytotoxicity activeness compound from the natural erucic based alcohol compound and has low toxic effect on the normal cells, while the compounds reconstructed by structure and the important midbodies all have better cytotoxicity activeness and can be prepared in the drugs preventing and curing the tumor diseases. The prepared drugs contain the drug excipients or carriers allowed by the preparation. The drug preparation is in a form of liquid, solid, aerial fog spray, drop, gelatin pearl, nano, controlled release and sustained-release preparation. The compound related to by the invention has simple synthetic method and lower cost, therefore having feasible marketalization prospect. The invention has the above general formula.

Description

Allyl benzene derivatives that replaces and its production and use
Technical field
The present invention relates to organic chemistry filed, particularly, the preparation method who relates to the allyl benzene derivatives of replacement, and this series compound is active as the growth of tumour cell inhibition that Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell strain (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), human cervical carcinoma cell (Hela) are carried out to six kinds of tumor cell lines.This compounds is found has certain inhibition tumor cell growth activity, can expect as the antitumor drug purposes.
Background technology
At present, because the problems of bringing in the industrial development such as environmental pollution, the existent environment of people quality constantly descends, and the sickness rate of tumor disease and lethality rate also constantly rise.Yet the specifics of treatment tumor disease can not be satisfactory, and at present the selectivity of antitumor clinical used cytotoxic drug not high cause to Normocellular pernicious killing and wounding, limited the general applicability of such medicine.Therefore, seek and find that the high cytotoxicity antitumor drug of new selectivity is worldwide research focus.We also are devoted to the research of antitumor drug.Zhao Yu in 2002 etc. separate from composite family lotus leaf Farfugium kaemferi and obtain mustard base alcohol compound and find that the KB cell is had certain cytotoxicity (document: J Nat Prod 2002,65,902-908.), therefore the objective of the invention is to this compounds is synthesized and structure of modification, growth produces the allyl benzene derivatives of stronger inhibiting replacement to tumor cell line in the hope of seeking.And according to the susceptibility of often swell knurl spectrum of disease and tumour cell of China especially in the world, the index of having selected Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), human cervical carcinoma cell (Hela) six strain tumour cells to estimate as cell in vitro cytotoxic activity pharmacology, the series compound that synthesizes is carried out screening active ingredients, finished the present invention thus.
Summary of the invention
The purpose of this invention is to provide a kind of compound, particularly, provide a kind of allyl benzene derivatives and pharmacologically acceptable salt thereof of replacement, have following general structure with cytotoxic activity:
Figure A20071007039400041
Be specifically related to five allyl benzene derivatives and pharmacologically acceptable salt thereof, have allyl benzene derivatives and the pharmacologically acceptable salt and the midbody compound of replacement as follows:
Compound I-a:R 1Be hydrogen, R 2Be 4-phenetole methoxy base, R 3Be hydrogen, be called 3-[4-(4-phenetole methoxy base) phenyl]-2-propylene-1-alcohol (2E);
Compound I-b:R 1Be hydrogen, R 2Be hydroxyl, R 3Be benzyloxy, be called 2-benzyloxy-4-(3-hydroxyl-1-propylene)-phenol (1E);
Compound I-c:R 1Be hydrogen, R 2Be hydroxyl, R 3Be amino, be called 2-amino-4-(3-hydroxyl-1-propylene)-phenol (1E);
Compound I-d:R 1Be chlorine, R 2Be hydroxyl, R 3Be methoxyl group, be called 6-chloro-2-methoxyl group-4-(3-hydroxyl-1-propylene)-phenol (1E);
Compound I-e:R 1Be amino, R 2Be hydroxyl, R 3Be methoxyl group, be called 6-amino-2-methoxyl group-4-(3-hydroxyl-1-propylene)-phenol (1E);
Structural formula is:
Figure A20071007039400051
Wherein, Compound I-f and Compound I-g are important intermediate.
(4-phenetole methoxy the base)-phenyl aldehyde of Compound I-f.4-;
(the 4-phenetole methoxy base) phenyl of Compound I-g.3-[4-]-2-ethyl propenoate (2E).
Another object of the present invention provides the allyl benzene derivatives of the described replacement of preparation and the preparation method of pharmacologically acceptable salt thereof; be to reduce through lithium aluminium hydride, aluminum chloride mixture by the cinnamic acid ethyl ester that corresponding group replaces; under protection of inert gas, add tetrahydrofuran (THF); cryosel is bathed and is chilled to 0 ℃; the benzyl ethylene compound that is replaced accordingly, concrete steps are:
(1) preparation of Compound I-f
Syringic aldehyde is dissolved in the acetone, adds Anhydrous potassium carbonate, stir, add the acetone soln to the oxyethyl group cylite, refluxed 4 hours, be cooled to room temperature, suction filtration is removed salt of wormwood, boils off solvent acetone, concentrates, and obtains white solid through column chromatography for separation;
(2) preparation of Compound I-g
With pyridine Compound I-f is dissolved, add monoethyl malonate after splashing into piperidines, reflux, be chilled to room temperature, add in the 2M hydrochloric acid and pyridine, water and ethyl acetate distribute extraction back organic layer to concentrate, and column chromatography purification (petrol ether/ethyl acetate=6: 1, crude product/silica gel=1: 30) gets white solid;
(3) preparation of purpose Compound I-a～I-e
Lithium aluminium hydride and aluminum chloride are placed a there-necked flask, and protection of inert gas adds tetrahydrofuran (THF) down, and cryosel is bathed and is chilled to 0 ℃; Compound I-g that adding is obtained by step (2); stir, add the unnecessary lithium aluminium hydride of water decomposition, it is acid then transferring to pH with 1M hydrochloric acid; ethyl acetate extraction; organic phase saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and filters; filtrate concentrates, column chromatography purification.
Here synthesize example explanation with Compound I-a:
Figure A20071007039400061
Another purpose of the present invention provides these compounds and uses in preparation control tumor disease medicine.
A further object of the present invention provides the application of pharmaceutical composition in preparation anti-tumor disease medicine that contains these compounds.
These compound or pharmaceutically acceptable salt thereofs of the present invention and solvate thereof can combine with auxiliary material or carrier pharmaceutically commonly used, have the active pharmaceutical composition that can be used for anti-curing oncoma of growth of tumour cell inhibition thereby prepare.Above-mentioned various kinds of drug composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment; Can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
Pharmaceutical composition of the present invention can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment; Can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
These compounds among the present invention have important biological, external to six strain vitro culture human body tumour cells, comprise the cytotoxic activity test of Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell strain (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), human cervical carcinoma cell (Hela), show that new compound and intermediate phenyl aldehyde compounds (as I-f) thereof that this type of has the phenylallene structure are inhibited to growth of tumour cell, might develop into new control tumour medicine.
Usefulness of the present invention is: have necessarily an optionally cytotoxic activity compound among the present invention, derive from natural product mustard base alcohol compound, this compounds is lower for Normocellular toxicity, and all have cytotoxic activity preferably through compound and the important intermediate behind the structure of modification, can expect as the antitumor drug purposes.The synthetic method of the compound that the present invention relates to is easy, cost is lower, therefore has more feasible market-oriented prospect.
Embodiment
Further specify the present invention below by embodiment, wherein OMe representation methoxy (OCH 3), OEt represents oxyethyl group (OCH 2CH 3).Embodiment has provided synthetic and the dependency structure appraising datum and the part activity data of representative compounds.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment 1: the preparation of important intermediate I-f (4-(4-phenetole methoxy base)-phenyl aldehyde)
Figure A20071007039400071
This example relates to the general synthetic method of the phenyl aldehyde series compound that the allyl benzene derivatives key intermediate of the replacement with cytotoxic activity replaces.Be specifically related to the synthetic of Compound I-f (4-(4-phenetole methoxy base)-phenyl aldehyde).With syringic aldehyde (298 milligrams, 1.6mmol) be dissolved in 20 milliliters of acetone, add Anhydrous potassium carbonate (567 milligrams, 4.1mmol), stirred ten minutes, (537 milligrams, 10 milliliters of acetone solns 2.5mmol) refluxed 4 hours to the oxyethyl group cylite in the back adding.Show that through thin-layer chromatography (TLC) analysis raw material point primitive reaction is complete, be cooled to room temperature, suction filtration is removed salt of wormwood, boils off solvent acetone.Concentrate the gained crude product and obtain 281 milligrams of white solids through column chromatography for separation, productive rate is 67.0%.
Compound I-f: white solid, fusing point: 85～86 ℃, Rf (n-hexane/ethyl acetate: 3/1) 0.25; 1H NMR (400MHz, CDCl 3): δ 9.89 (1H, s, CHO), 7.84 (2H, d, J=8.8Hz, H-2, H-6), 7.35 (2H, d, J=8.8Hz, H-2 ', H-6 '), 7.08 (2H, d, J=8.8Hz, H-3 ', H-5 '), 6.93 (2H, d, J=8.8Hz, H-3, H-5), 5.07 (2H, s, H-7 '), 4.05 (2H, q, J=7.2Hz, OCH 2CH 3), 1.43 (3H, t, J=7.2Hz, OCH 2CH 3);
Embodiment 2: the preparation of important intermediate I-g (3-[4-(4-phenetole methoxy base) phenyl]-2-ethyl propenoate (2E))
Figure A20071007039400081
This example relates to the general synthetic method of the substituted benzene acrylic ester compound with cytotoxic activity.Be specifically related to the synthetic of Compound I-g (3-[4-(4-phenetole methoxy base) phenyl]-2-ethyl propenoate (2E)).(256 milligrams, 1.0mmol) dissolving adds monoethyl malonate (198 milligrams 1.5mmol), were refluxed 2 hours after splashing into 0.2 milliliter piperidines with Compound I-f with pyridine (5 milliliters) in one 100 milliliters three-necked bottle.Be chilled to room temperature, add in the 2M hydrochloric acid and pyridine, water and ethyl acetate distribute extraction back organic layer to concentrate, column chromatography purification (petrol ether/ethyl acetate=6: 1, crude product/silica gel=1: 30) white solid, yield is 75.1%.
Compound I-g: white solid, fusing point: 103～104 ℃, Rf (n-hexane/ethyl acetate: 3/1) 0.30; 1H NMR (400MHz, CDCl 3): δ 7.65 (1H, d, J=16.0Hz, H-3), 7.48 (2H, d, J=8.8Hz, H-2 ', H-6 '), 7.35 (2H, d, J=8.8Hz, H-2 ", H-6 "), 6.97 (2H, d, J=8.8Hz, H-3 ', H-5 '), 6.92 (2H, d, J=8.8Hz, H-3 ", H-5 "), 6.32 (1H, d, J=16.0Hz, H-2), 5.02 (2H, s, H-7 "), 4.26 (2H, q, J=7.2Hz, OCH 2CH 3-1), 4.05 (2H, q, J=7.2Hz, OCH 2CH 3-4 "), 1.43 (3H, t, J=7.2Hz, OCH 2CH 3-4 "), 1.34 (3H, t, J=7.2Hz, OCH 2CH 3-1);
Embodiment 3: the preparation of Compound I-a (3-[4-(4-phenetole methoxy base) phenyl]-2-propylene-1-alcohol (2E))
Figure A20071007039400082
With (387 milligrams of lithium aluminium hydride; 10.2mmol) and (427 milligrams of aluminum chlorides; 32.0mmol) place a there-necked flask; protection of inert gas adds 10 milliliters of tetrahydrofuran (THF)s down; cryosel is bathed and is chilled to 0 ℃; Compound I-g that adding is obtained by embodiment 2 (3-[4-(4-phenetole methoxy base) phenyl]-2-ethyl propenoate (2E)) 1.043 grams (3.mmol), stirred 1.5 hours.Add the unnecessary lithium aluminium hydride of water decomposition, it is acid then transferring to pH with 1M hydrochloric acid, ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and filters, filtrate concentrate crude product, column chromatography purification (petrol ether/ethyl acetate=4: 1, crude product/silica gel=1: 50) 3-[4-(4-phenetole methoxy base) phenyl]-183.6 milligrams of 2-propylene-1-alcohol (2E), yield is 20.2%.
Compound I-a: white solid, fusing point: 50～52 ℃, Rf (sherwood oil/ethyl ester: 3/1) 0.13; 1H NMR (400MHz, CDCl 3): δ 7.48 (2H, d, J=8.8Hz, H-2 ', H-6 '), 7.35 (2H, d, J=8.0Hz, H-2 ", H-6 "), 6.96 (2H, d, J=8.8Hz, H-3 ', 5 '), 6.91 (2H, d, J=8.0Hz, H-3 ", 5 "), 6.56 (1H, d, J=16.0Hz, H-3), 6.25 (1H, dt, J=16.0,6.0Hz, H-2), 4.99 (2H, s, H-7 "), 4.31 (2H, t; J=6.0Hz, H-1), 4.04 (2H, q, J=7.2Hz, OCH 2CH 3-4 "), 1.44 (3H, t, J=7.2Hz, OCH 2CH 3-4 ").
Embodiment 4: the preparation of Compound I-b (2-benzyloxy-4-(3-hydroxyl-1-propylene)-phenol (1E))
Figure A20071007039400091
According to embodiment 3 described same procedure, with compound 3-[4-hydroxyl-(3-benzyloxy) phenyl]-2-ethyl propenoate (2E) and lithium aluminium hydride and aluminum chloride reaction obtain, and yield is 22.4%.Compound I-b: light yellow oil, fusing point: 71～72 ℃, Rf (petrol ether/ethyl acetate: 3/1) 0.13; 1H NMR (400MHz, CDCl 3): δ 6.66-7.53 (8H, m, Ar-H), 6.48 (1H, d, J=16.0Hz, H-1 "), 6.20 (1H, dt, J=160,5.6Hz, H-2 "), 5.19 (2H, s, H-7 '), 4.18 (2H, d, J=5.6Hz, H-3 ").
Embodiment 5: the preparation of Compound I-c (2-amino-4-(3-hydroxyl-1-propylene)-phenol (1E))
This example relates to the general synthetic method of the substituted benzene allyl alcohol-like compound with cytotoxic activity.Be specifically related to the synthetic of Compound I-c (2-amino-4-(3-hydroxyl-1-propylene)-phenol (1E)).With (402 milligrams of lithium aluminium hydride; 10.6mmol) and (452 milligrams of aluminum chlorides; 33.9mmol) place a there-necked flask; protection of inert gas adds 10 milliliters of tetrahydrofuran (THF)s down; cryosel is bathed and is chilled to 0 ℃; add be dissolved in 15 milliliters of tetrahydrofuran (THF)s compound (3-nitro-4-hydroxyl) cinnamylic acid ethyl ester (2E) (3.4mmol), stirred 1.5 hours.Add the unnecessary lithium aluminium hydride of water decomposition, it is acid then transferring to pH with 1M hydrochloric acid, ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and filters, filtrate concentrate crude product, column chromatography purification (petrol ether/ethyl acetate=2: 1, crude product/silica gel=1: 50) 145 milligrams of 2-amino-4-(3-hydroxyl-1-propylene)-phenol (1E), yield is 19.1%.
Compound I-c: yellow oil, Rf (petrol ether/ethyl acetate: 2/1) 0.22; 1H NMR (400MHz, CDCl 3): δ 7.23 (1H, d, J=80Hz, H-5), 6.63 (1H, d, J=80Hz, H-6), 6.61 (1H, s, H-3), 6.51 (1H, d, J=160Hz, H-1 '), 6.37 (1H, dt, J=16.0,5.2Hz, H-2 '), 4.28 (2H, d, J=5.2Hz, H-3 ');
Embodiment 6: the preparation of Compound I-d (6-chloro-2-methoxyl group-4-(3-hydroxyl-1-propylene)-phenol (1E))
Figure A20071007039400101
This example relates to the general synthetic method of the substituted benzene allyl alcohol-like compound with cytotoxic activity.Be specifically related to the synthetic of Compound I-d (6-chloro-2-methoxyl group-4-(3-hydroxyl-1-propylene)-phenol (1E)).With lithium aluminium hydride (1.176 grams; 31.0mmol) and aluminum chloride (1.377 grams; 10.3mmol) place a there-necked flask; protection of inert gas adds 30 milliliters of tetrahydrofuran (THF)s down; cryosel is bathed and is chilled to 0 ℃; (3.527 grams 13.8mmol), stirred 2 hours to add compound (3-methoxyl group-5-chloro-4-hydroxyl) the cinnamylic acid ethyl ester (2E) that is dissolved in 30 milliliters of tetrahydrofuran (THF)s.Add the unnecessary lithium aluminium hydride of water decomposition, it is acid then transferring to PH with 1M hydrochloric acid, ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and filters, filtrate concentrate crude product, get the 0.68 3-methoxyl group-5-chloro-4-hydroxybenzene vinylcarbinol that restrains through column chromatography purification (petrol ether/ethyl acetate=3: 1, crude product/silica gel=1: 50), yield is 23.1%.
Compound I-d: colorless oil, Rf (petrol ether/ethyl acetate: 2/11) 0.10; 1H NMR (400MHz, CDCl 3): δ 6.97 (1H, d, J=2.0Hz, H-3), 6.92 (1H, d, J=2.0Hz, H-5), 6.47 (1H, d, J=16.0Hz, H-1 '), 6.23 (1H, dt, J=16.0,5.6Hz, H-2 '), 4.30 (2H, d, J=5.6Hz, H-3 '), 3.87 (3H, s, OCH 3);
Embodiment 7: the preparation of Compound I-e (6-chloro-2-methoxyl group-4-(3-hydroxyl-1-propylene)-phenol (1E))
According to embodiment 5 described same procedure, compound (3-methoxyl group-4-hydroxyl-5-nitro) cinnamylic acid ethyl ester (2E) and lithium aluminium hydride and aluminum chloride reaction are obtained, yield is 20.7%.
Figure A20071007039400111
Compound I-e: brown oil, Rf (petrol ether/ethyl acetate: 1/1) 0.33; 1H NMR (400MHz, CDCl 3): δ 6.65 (1H, d, J=1.6Hz, H-5), 6.43 (1H, d, J=1.6Hz, H-3), 6.42 (1H, d, J=16.0Hz, H-1 '), 6.36 (1H, dt, J=16.0,5.2Hz, H-2 '), 4.29 (2H, d, J=5.2Hz, H-3 '), 3.85 (3H, s, OCH 3).
In order to understand essence of the present invention better, respectively with the inhibiting The pharmacological results of the compound among the present invention, its new purposes in the antitumor drug research field is described below to six kinds of tumor cell line growths.Pharmacology embodiment has provided the part activity data of representative compounds.Mandatory declaration, pharmacology embodiment of the present invention is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 8 Compound I-a is to the cytotoxic activity of KB cell
KB (oral epithelium cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/ penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I-a that will newly join joins in each hole with concentration gradient respectively, makes that the compound ultimate density is respectively 100ug/mL in the hole, 33.3ug/mL, 11.1ug/mL and 3.7ug/mL.After 72 hours, the phosphate buffered saline buffer that adds 10 μ LMTT (5mg/mL), continue 37 ℃ of cultivations after 4 hours again, removed unconverted MTT in centrifugal 5 minutes, add 200 μ L methyl-sulphoxides in every hole, with the MTT crystal Jia Za (formazan) of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.Wherein Compound I-a is to KB cell 503nhibiting concentration IC 50Obtain by dose effect curve.
The IC of Compound I-a 50For: 2.40 * 10 -5M; And the positive control cis-platinum is to the IC of KB cell 50Be 1.08 * 10 -5M.
Experiment conclusion: the KB cell is Cytotoxic effective tool and the evaluation index of test compounds to tumour cell.This experiment shows that this type of has the compound of phenylallene structure, and the KB cell is had stronger cytotoxicity, might develop into the new medicine with anti-oral epithelium cancer and related neoplasms effect.
Embodiment 9 Compound I-c is to the cytotoxic activity of PC-3 cell
PC-3 (prostate cancer) cell F-12 culture medium culturing contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.Wherein Compound I-c is to PC-3 cell 503nhibiting concentration (IC 50) obtain by dose effect curve.
The IC of Compound I-c 50For: 3.21 * 10 -4M; And the positive control cis-platinum is to the IC of PC-3 cell 50Be 2.18 * 10 -5M.
Experiment conclusion: this experiment shows that this type of has the compound of phenylallene structure, and the PC-3 cell is had stronger cytotoxicity, might develop into the new medicine with anti-prostate cancer and related neoplasms effect.
Embodiment 10 Compound I-f is to the cytotoxic activity of CNE cell
CNE (nasopharyngeal carcinoma) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.With every hole 5 * 10 3The concentration of cell joins in 96 orifice plates, contains 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.Wherein Compound I-f is to CNE cell 503nhibiting concentration (IG 50) obtain by dose effect curve.
The IC of Compound I-f 50For: 5.46 * 10 -5M; And the positive control cis-platinum is to the IC of CNE cell 50Be 2.12 * 10 -5M.
Experiment conclusion: this experiment shows that this type of has the compound of phenylallene structure, and the CNE cell is had stronger cytotoxicity, might develop into the new medicine with anti-nasopharyngeal carcinoma and related neoplasms effect.
Embodiment 11 Compound I-a is to the cytotoxic activity of A549 cell
A549 (people's lung cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.Wherein Compound I-a is to A549 cell 503nhibiting concentration (IC 50) obtain by dose effect curve.
The IC of Compound I-a 50For: 6.0 * 10 -5M; And the positive control cis-platinum is to the IC of A549 cell 50Be 2.95 * 10 -5M.
Experiment conclusion: this experiment shows that this type of has the compound of phenylallene structure, and the A549 cell is had stronger cytotoxicity, might develop into the new medicine with anti-lung cancer and related neoplasms effect.
Embodiment 12 Compound I-g is to the cytotoxic activity of BEL-7404 cell
BEL-7404 (people's liver cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.Wherein Compound I-g is to BEL-7404 cell 503nhibiting concentration (IC 50) obtain by dose effect curve.
The IC of Compound I-g 50For: 1.29 * 10 -5M; And the positive control cis-platinum is to the IC of BEL-7404 cell 50Be 2.69 * 10 -5M.
Experiment conclusion: this experiment shows that this type of has the compound of phenylallene structure, and the A549 cell is had stronger cytotoxicity, might develop into the new medicine with anti-liver cancer and related neoplasms effect.
Embodiment 13 Compound I-a is to the cytotoxic activity of Hela cell
Hela (human cervical carcinoma) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃ 2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.Wherein Compound I-a is to Hela cell 503nhibiting concentration (IC 50) obtain by dose effect curve.
The IC of Compound I-a 50For: 2.65 * 10 -5M; And the positive control cis-platinum is to the IC of Hela cell 50Be 1.99 * 10 -5M.
Experiment conclusion: this experiment shows that this type of has the compound of phenylallene structure, and the Hela cell is had stronger cytotoxicity, might develop into the new medicine with anti-cervical cancer and related neoplasms effect.
These compound or pharmaceutically acceptable salt thereofs of the present invention and solvate thereof can with antitumor drug that has now gone on the market such as platinum medicine cis-platinum (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), taxol (Paclitaxel) etc. is united use, prepare and have tumor growth and suppress active cytotoxicity composition, can be used for treating tumor disease.

Claims (10)

1. replace allyl benzene derivatives and pharmaceutically useful salt thereof, it is characterized in that having following general structure:
Wherein:
Work as R 1Be hydrogen, R 2Be 4-phenetole methoxy base, R 3During for hydrogen, be Compound I-a;
Work as R 1Be hydrogen, R 2Be hydroxyl, R 3During for benzyloxy, be Compound I-b;
Work as R 1Be hydrogen, R 2Be hydroxyl, R 3During for amino, be Compound I-c;
Work as R 1Be chlorine, R 2Be hydroxyl, R 3During for methoxyl group, be Compound I-d;
Work as R 1Be amino, R 2Be hydroxyl, R 3During for methoxyl group, be Compound I-e.
2. the preparation method of replacement allyl benzene derivatives according to claim 1 and pharmaceutically useful salt thereof; it is characterized in that realizing: reduce through lithium aluminium hydride, aluminum chloride mixture by the cinnamic acid ethyl ester compound that replaces by following steps; under protection of inert gas, add tetrahydrofuran (THF); cryosel is bathed and is chilled to 0 ℃; obtain replacing allyl benzene derivatives, concrete steps are:
(1) preparation of Compound I-f
Syringic aldehyde is dissolved in the acetone, adds Anhydrous potassium carbonate, stir, add the acetone soln to the oxyethyl group cylite, refluxed 4 hours, be cooled to room temperature, suction filtration is removed salt of wormwood, boils off solvent acetone, concentrates, and obtains white solid through column chromatography for separation;
(2) preparation of Compound I-g
With the dissolving of Compound I-f, add monoethyl malonate after splashing into piperidines with pyridine, reflux, be chilled to room temperature, add in the 2M hydrochloric acid and pyridine, water and ethyl acetate distribute extraction back organic layer to concentrate, and column chromatography purification gets white solid;
(3) preparation of purpose Compound I-a～I-e
Lithium aluminium hydride and aluminum chloride are placed a there-necked flask, and protection of inert gas adds tetrahydrofuran (THF) down, and cryosel is bathed and is chilled to 0 ℃; Compound I-g that adding is obtained by step (2); stir, add the unnecessary lithium aluminium hydride of water decomposition, it is acid then transferring to pH with 1M hydrochloric acid; ethyl acetate extraction; organic phase saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and filters; concentrate column chromatography purification.
3. replacement allyl benzene derivatives according to claim 1 and pharmaceutically useful salt thereof are used in preparation control tumor disease medicine.
4. replacement allyl benzene derivatives according to claim 3 and pharmaceutically useful salt thereof are used in preparation control tumor disease medicine, it is characterized in that the application in preparation control oral epithelium cancer drug.
5. replacement allyl benzene derivatives according to claim 3 and pharmaceutically useful salt thereof are used in preparation control tumor disease medicine, it is characterized in that preventing and treating application in the prostate cancer medicine in preparation.
6. replacement allyl benzene derivatives according to claim 3 and pharmaceutically useful salt thereof are used in preparation control tumor disease medicine, it is characterized in that the application in preparation control medicine for nasopharyngeal.
7. replacement allyl benzene derivatives according to claim 3 and pharmaceutically useful salt thereof are used in preparation control tumor disease medicine, it is characterized in that the application in preparation control lung-cancer medicament.
8. replacement allyl benzene derivatives according to claim 3 and pharmaceutically useful salt thereof are used in preparation control tumor disease medicine, it is characterized in that the application in preparation control liver-cancer medicine.
9. replacement allyl benzene derivatives according to claim 3 and pharmaceutically useful salt thereof are used in preparation control tumor disease medicine, it is characterized in that preventing and treating application in the cervical cancer medicine in preparation.
10. replacement allyl benzene derivatives according to claim 3 and pharmaceutically useful salt thereof are used in preparation control tumor disease medicine, it is characterized in that: drug prepared contains preparation allowable pharmaceutical excipients or carrier, and pharmaceutical dosage forms is liquid preparation, solid preparation, aerosol spray, drops, capsule and pill, nanometer formulation, controlled release or sustained release preparation.
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