CN100596294C - 4'-substituted benzyloxy-phenyl butadiene derivatives and preparation and uses thereof - Google Patents

4'-substituted benzyloxy-phenyl butadiene derivatives and preparation and uses thereof Download PDF

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CN100596294C
CN100596294C CN200710156910A CN200710156910A CN100596294C CN 100596294 C CN100596294 C CN 100596294C CN 200710156910 A CN200710156910 A CN 200710156910A CN 200710156910 A CN200710156910 A CN 200710156910A CN 100596294 C CN100596294 C CN 100596294C
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dimethoxyphenyl
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benzyloxy
butadiene derivatives
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CN101161629A (en
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邹宏斌
吴昊
约阿施·史托克希特
赵昱
张勇民
俞永平
曾苏
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Zhejiang University ZJU
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Abstract

The present invention provides a 4'-substituted benzyloxy -3',5'-dimethoxyphenyl-butadiene type derivatives and the medical salt or solvent thereof with the above general formula , wherein 4'-subsituted benzyloxy -3',5'-dimethoxyphenyl-benaldehyde and bromoethylcrotonate-triphenylphosphonium are mixed, and the mixture is reduced by a complex of lithium aluminium hydride and aluminium chloride to obtain the corresponding chemical compound. The chemical compound provided by the present invention has important biological activity, cytotoxicity experiments in vitro on human lung cancer cells (A549), human chronic myeloid leukemia cell Line (K562), human karyotype leukemia cell(HL-60), and mice lymph-type tumor (P388D1) tumor cells indicate that the derivatives of 4'-substrate benzyloxy -3',5'-dimethoxyphenyl-butadiene has the suppressive function on both the growth of tumor cells and multiple tumors in vitro, and can be applied to preparation of drugs for tumor prevention and treatment.

Description

4 ＇-substituted benzyloxy-phenyl butadiene derivatives and preparation and purposes
Invention field
The invention belongs to organic chemistry, pharmaceutical chemistry and area of pharmacology, relate to 4 '-substituted benzyloxy-3,5-Dimethoxyphenyl-butadiene derivatives and preparation method, and the purposes of this compounds in the preparation antitumor drug.
Background of invention
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.
Caffeic acid phenethyl ester compound with anti-tumor activity is considered to have a class natural product (Xuan, the H Z that great exploitation is worth at present, Hu, F L, Gu, M E, Advances in the Researchof Caffeic Acid Phenyl Ester in Propolis.Food Research and Development2006,27,14-15), Zhao Yu in 2002 etc. separate from composite family lotus leaf Farfugium kaemferi and obtain trisubstituted benzyl ethylene compound, and it has been made cell toxicity test, find that some compound has certain cytotoxicity (Zhao to the KB cell, Y, Hao, X J, Lu, W, Cai, J C, Yu, H, Sev é net, T and Gu é ritte, F, (2002) J Nat Prod 65,902-908), so we explore this analog derivative of development of new emphatically among the present invention, and growth produces stronger inhibiting compound to tumor cell line in order to seek, we have synthesized its phenyl conjugated diolefine analog derivative, in the hope of finding the more antitumor exclusive medicine of high-efficiency low-toxicity.According to the whole world especially susceptibility of often swell the knurl spectrum of disease and the tumour cell of China, we have selected human lung carcinoma cell (A549), the chronic myelogone leukemia cell of people (K562), people's promyelocytic leukemia cell (HL-60), the index that cell strains such as mouse lymph sample knurl (P388D1) tumour cell are estimated as cell in vitro cytotoxic activity pharmacology is finished the present invention in view of the above.
Summary of the invention
The purpose of this invention is to provide a kind of 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives and their pharmacologically acceptable salt or solvate, have following general structure:
Figure C20071015691000051
Wherein: R 1, R 2, R 3, R 4And R 5Can be identical or different, can be hydrogen, nitro, hydroxyl, halogen contains the saturated or unsaturated alkyl or the alkoxyl group of 1～8 carbon, contains the alkylamino radical of 1～8 carbon.
R can be-COOH ,-CH 2OH ,-CHO ,-COOR 6,-CONHNH 2,-CONH 2,-CONHR 6,-CON (R 6) 2, R wherein 6It is the alkyl group that contains 1～8 carbon.
R 1, R 2, R 3, R 4And R 5Can not be hydrogen simultaneously.
Substituent R is COOCH in formula (1) 2CH 3The time, be following formula (I) compound:
Radicals R wherein 1, R 2, R 3, R 4And R 5Definition and formula (1) in identical.Preferred formula (I) compound is:
I-a. (2E, 4E)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diolefinic acid ethyl ester;
I-b. (2E, 4Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diolefinic acid ethyl ester;
I-c. (2Z, 4Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diolefinic acid ethyl ester.
Substituent R is CH in formula (1) 2During OH, be following formula (II) compound:
Figure C20071015691000061
Radicals R wherein 1, R 2, R 3, R 4And R 5Definition and formula (1) in identical.Preferred formula (II) compound is:
II-a. (2E, 4E)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diene-1-alcohol;
II-b. (2E, 4Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diene-1-alcohol;
II-c. (2Z, 4Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diene-1-alcohol;
II-d. (2Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2-alkene-1-alcohol.
Figure C20071015691000062
Another object of the present invention provides a kind of method by substituted benzoyl aldehyde compound preparation formula (I) and formula (II) compound: with 4 '-substituted benzyloxy-3 ', 5 '-dimethoxy benzaldehyde and bromo ethyl crotonate triphenylphosphine salt prepare formula (I) compound, formula (I) compound obtains corresponding formula (II) compound through the reduction of lithium aluminum hydride-aluminum chloride mixture, and reaction formula is:
Figure C20071015691000071
Radicals R wherein 1, R 2, R 3, R 4And R 5Definition and formula (1) in identical.
Another purpose of the present invention provides 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives and their pharmacologically acceptable salt or the application of solvate in preparation control tumor disease medicine.
A further object of the present invention provides 4 '-substituted benzyloxy-3 ', 5 '-application of pharmaceutical composition in preparation anti-tumor disease medicine of Dimethoxyphenyl-butadiene derivatives and their pharmacologically acceptable salt or solvate.
Formula of the present invention (1) compound has important biological, external to human lung carcinoma cell (A549), the chronic myelogone leukemia cell of people (K562), people's promyelocytic leukemia cell (HL-60), the test of the cytotoxic activity of mouse lymph sample knurl (P388D1) tumour cell show this type of 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives is inhibited to growth of tumour cell, might develop into new control tumour medicine.
Formula of the present invention (1) or its pharmacologically acceptable salt and solvate thereof can combine with spoke 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.
Formula of the present invention (1) or its pharmacologically acceptable salt 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.Such pharmaceutical composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Usefulness of the present invention is: emphatically exploitation CAPE analog derivative is explored, provided tumor cell line growth to produce stronger restraining effect, the antitumor exclusive medicine of high-efficiency low-toxicity more.Provide 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives has important biological, external have restraining effect to kinds of tumor cells, is expected to become new control tumour medicine.
Embodiment
Further specify the present invention below by specific embodiment, wherein OMe representation methoxy (OCH 3), OMOM represents methoxy methoxy base (OCH 2OCH 3), OEt represents oxyethyl group (OCH 2CH 3).Following embodiment has provided the synthetic and dependency structure appraising datum 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.
Embodiment 1: isomer 5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2, (the preparation of I-a～I-c) of 4-diolefinic acid ethyl ester
Figure C20071015691000081
This example relate to a class suc as formula the 5-shown in (I) with cytotoxic activity (4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl) penta-2, the general synthetic method of 4-diolefinic acid ethyl ester derivative.Be specifically related to 5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diolefinic acid ethyl ester synthetic.With (85 milligrams in sodium; 3.67 mmole) with dehydrated alcohol (2 milliliters) stirring reaction under argon shield; when treating to the homogeneous mixing solutions; reduce to room temperature; add 10 milliliters of tetrahydrofuran (THF)s, add again bromo ethyl crotonate triphenylphosphine salt (1.84 grams, 4.04 mmoles); be yellow muddy liquid; under agitation add 3 again, the 5-dimethoxy-4 '-to ethoxy benzyl phenyl aldehyde (1.16 grams, 3.67 mmoles); stirring at room 2 hours; add less water cancellation reaction, it is about 7 that 1M hydrochloric acid is transferred pH, concentrates and removes reaction solvent; the gained crude product obtains 3 isomeric compound I-a～I-c through column chromatography for separation.
Explain the physics and the chemical data of the synthetic compound that obtains below with unified mode.Comprise fusing point (mp), Rf value (Rf) and launch solvent, proton nmr spectra ( 1H NMR, data obtain in the 400MHz nuclear magnetic resonance analyser), carbon-13 nmr spectra ( 13C NMR, data obtain in the 100MHz nuclear magnetic resonance analyser), electrospray ionization mass spectrum (ESI-MS); 1H NMR and 13The employed reagent of C NMR is generally deuterochloroform (CDCl 3) or deuterated acetone (CD 3) 2CO; NMR spectrogram peak shape is expressed as: unimodal (s), bimodal (d), wide unimodal (brs), double doublet (dd), triplet (t), quartet (q); The unit of coupling constant (J) represents with hertz (Hz); Chemical displacement value (δ) unit represents with ppm.
Compound I-a: yield: 68.8%; White solid; Mp 112-114 ℃; Rf (n-hexane/ethyl acetate 5: 2) 0.25; 1H NMR (400MHz, CDCl 3): δ 7.49 (1H, dd, J=15.6,9.2Hz, H-3), 7.39 (2H, d, J=8.4Hz, H-3 ", 7 "), 6.85 (2H, d, J=8.4Hz, H-4 ", 6 "), 6.76 (2H, m, H-4,5), 6.66 (2H, s, H-2 ', 6 '), 5.98 (1H, d, J=15.6Hz, H-2), 4.97 (2H, s, H-1 "), 4.22 (2H, q, J=7.2Hz, OCH 2CH 3-1), 4.03 (2H, q, J=7.2Hz, OCH 2CH 3-5 "), 3.85 (6H, s, OCH 3-3 ', 5 '), 1.43 (3H, t, J=7.2Hz, OCH 2CH 3-5 "), 1.32 (3H, t, J=7.2Hz, OCH 2CH 3-1); ESI-MSm/z[M+H] +413.
Compound I-b: yield: 19.3%; White solid; Mp 103-105 ℃; Rf (n-hexane/ethyl acetate 5: 2) 0.28; 1H NMR (400MHz, CDCl 3): δ 7.87 (1H, dd, J=15.2,11.6Hz, H-3), 7.40 (2H, d, J=8.4Hz, H-3 ", 7 "), 6.87 (2H, d, J=8.4Hz, H-4 "; 6 "), 6.73 (1H, d, J=11.6Hz, H-5), 6.54 (2H, s, H-2 ', 6 '), 6.33 (1H, t, J=11.6Hz, H-4), 6.02 (1H, d, J=15.2Hz, H-2), 4.97 (2H, s, H-1 "), 4.20 (2H, q, J=7.2Hz, OCH 2CH 3-1), 4.03 (2H, q, J=7.2Hz, OCH 2CH 3-5 "), 3.85 (6H, s, OCH 3-3 ', 5 '), 1.41 (3H, t, J=7.2Hz, OCH 2CH 3-5 "), 1.34 (3H, t, J=7.2Hz, OCH 2CH 3-1); ESI-MSm/z[M+H] +413.
Compound I-c: yield: 12.1%; White solid; Mp 75-77 ℃; Rf (n-hexane/ethyl acetate 5: 2) 0.31; 1H NMR (400MHz, CDCl 3): δ 7.46 (1H, t, J=11.6Hz, H-3), 7.39 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.07 (1H, t, J=11.6Hz, H-5), 6.86 (2H, d, J=8.4Hz, H-4 ", 6 "), 6.83 (1H, t, J=11.6Hz, H-4), 6.50 (2H, s, H-2 ', 6 '), 5.78 (1H, d, J=11.6Hz, H-2), 4.98 (2H, s, H-1 "), 4.22 (2H, q, J=7.2Hz, OCH 2CH 3-1), 4.04 (2H, q, J=7.2Hz, OCH 2CH 3-5 "), 3.82 (6H, s, OCH 3-3 ', 5 '), 1.43 (3H, t, J=7.2Hz, OCH 2CH 3-5 "), 1.33 (3H, t, J=7.2Hz, OCH 2CH 3-1); ESI-MSm/z[M+H] +413.
Embodiment 2: Compound I I-a promptly (2E, 4E)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2, the preparation of 4-diene-1-alcohol
Figure C20071015691000091
This example relate to a class suc as formula the 5-shown in (II) with cytotoxic activity (4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl) penta-2, the general synthetic method of 4-diene-1-alcohol derivatives.Be specifically related to 5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diene-1-alcohol synthetic.Under the ice bath, with (160 milligrams of lithium aluminum hydrides, 4.2 mmole) and (196 milligrams of aluminum chlorides, 1.4 mmole) join in the anhydrous tetrahydro furan, stirred 5 minutes, again with (486 milligrams of raw material I-a, 1.2 anhydrous tetrahydrofuran solution mmole) is added drop-wise in this reaction system, controlled temperature is lower than 10 ℃, stirs 2 hours, drips less water cancellation reaction.The tetrahydrofuran (THF) diluting reaction system after-filtration that add to reclaim again, filtrate concentrate crude product, get the Compound I I-a of respective configuration through column chromatography purification.
Compound I I-a: yield: 52.4%; White solid; Mp 108-109 ℃; Rf (n-hexane/ethyl acetate 5: 2) 0.15; 1H NMR (400MHz, CDCl 3): δ 7.37 (2H, d, J=8.4Hz, H-3 ", 7 "), 6.84 (2H, d, J=8.4Hz, H-4 ", 6 "), 6.68 (1H, t, J=15.6Hz, H-3), 6.59 (2H, s, H-2 ', 6 '), 6.46 (1H d, J=15.6Hz, H-5), 6.46 (1H d, J=15.6Hz, H-4), 5.95 (1H, dt, J=15.6,5.2Hz, H-2), 4.93 (2H, s, H-1 "), 4.25 (2H, d; J=5.2Hz, H-1), 4.02 (2H, q, J=7.2Hz, OCH 2CH 3-5 "), 3.85 (6H, s, OCH 3-3 ', 5 '), 1.23 (3H, t, J=7.2Hz, OCH 2CH 3-5 "); ESI-MS m/z[M+H] +371.
Embodiment 3: the preparation of Compound I I-b, II-c and II-d
According to the method for embodiment 2, be raw material with formula (I) compound of respective configuration, having obtained conjugated diene compound II-b and II-c through reduction, also obtained the product II-d that one of them two key is reduced.
Compound I I-b: yield: 51.3%; White solid; Mp 93-95 ℃; Rf (n-hexane/ethyl acetate 5: 2) 0.18; 1H NMR (400MHz, CDCl 3): δ 7.00 (2H, d, J=8.4Hz, H-3 ", 7 "), 6.90 (1H, d, J=15.2Hz, H-3), 6.74 (1H, d, J=8.8Hz, H-4 ", 6 "), 6.56 (2H, s, H-2 ', 6 '), 6.39 (1H, d, J=11.2Hz, H-5), 6.18 (1H, d, J=11.2Hz, H-4), 5.91 (1H, dt, J=15.2Hz, H-2), 5.65 (2H, s, H-1 '), 4.12 (2H, d, J=7.6Hz, H-1), 3.95 (2H, q, J=7.6Hz, OCH 2CH 3-5 "), 3.87 (6H, s, OCH 3-3 ', 5 '), 1.36 (3H, t, J=7.2Hz, OCH 2CH 3-5 "); ESI-MS m/z[M+H] +371.
Compound I I-c: yield: 43.4%; White solid; Mp 66-68 ℃; Rf (n-hexane/ethyl acetate 5: 2) 0.20; 1H NMR (400MHz, (CD 3) 2CO): δ 7.38 (2H, d, J=8.4Hz, H-3 ", 7 "), 6.83 (2H, d, J=8.4Hz, H-4 ", 6 "), 6.67 (2H, s, H-2 ', 6 '), 6.53 (1H, d, J=10.8Hz, H-5), 6.43 (1H, dd, J=12.0,11.2Hz, H-3), 5.63 (1H, dt, J=12.0,5.2Hz, H-2), 4.84 (1H, dd, J=11.2,10.8Hz, H-4), 4.83 (2H, s, H-1 "), 4.16 (2H; d, J=5.2Hz, H-1), 4.03 (2H, q, J=7.2Hz, OCH 2CH 3-5 "), 3.83 (6H, s, OCH 3-3 ', 5 '), 1.36 (3H, t, J=7.2Hz, OCH 2CH 3-5 "); ESI-MS m/z[M+H] +371.
Compound I I-d: yield: 13.7%; White solid; Mp 60-62 ℃; Rf (n-hexane/ethyl acetate 5: 2) 0.22; 1H NMR (400MHz, (CD 3) 2CO): δ 7.40 (2H, d, J=8.4Hz, H-3 ", 7 "), 6.88 (2H, d, J=8.4Hz, H-4 ", 6 "), 6.54 (2H, s, H-2 ', 6 '), 6.53 (1H, dt, J=11.2,6.8Hz, H-3), 5.59 (1H, m, H-2), 4.83 (2H, s, H-1 '), 4.24 (2H, d, J=5.2Hz, H-1), 4.03 (2H, q, J=6.8Hz, OCH 2CH 3-5 '), 3.80 (6H, s, OCH 3-3 ', 5 '), 2.41 (1H, t, J=7.6Hz, H-5), 2.22 (1H, m, H-4), 1.36 (3H, t, J=6.8Hz, OCH 2CH 3-5 "); ESI-MS m/z[M+H] +373.
In order to understand essence of the present invention better, embodiment further specifies the present invention below by pharmacology.Pharmacology embodiment has provided synthetic and the dependency structure appraising datum and the part activity data of representative compounds.Mandatory declaration, following pharmacology 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.
Embodiment 4:Compound I I-c 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/ milliliter 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, the dimethyl sulfoxide solution of the Compound I I-c that will newly join joins in each hole with concentration gradient respectively, make that the compound ultimate density is respectively 100 mcg/ml in the hole, 33.3 mcg/ml, 11.1 mcg/ml and 3.7 mcg/ml.After 72 hours, the phosphate buffered saline buffer that adds 10 microlitre MTT (5 mg/ml), continue 37 ℃ of cultivations after 4 hours again, removed unconverted MTT in centrifugal 5 minutes, add 200 microlitre 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 I-c is to A549 cell 503nhibiting concentration IC 50Obtain by dose effect curve.The IC of Compound I I-c 50Be 62 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of people's lung cancer A549 cell with an antitumor line medication cis-platinum (DDP) in this test 50Be 18.7 μ M.
This experiment show this type of 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives has stronger cytotoxicity to people's lung cancer A549 cell, might develop into the new medicine with effect of anti-lung cancer.
Embodiment 5:Compound I-b is to the chronic myelogone leukemia cell's of people (K562) cytotoxic activity
The chronic myelogone leukemia cell of people (K562) contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10 4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO 2Cultivated 24 hours in the incubator of damp atmosphere.
The measuring method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I-b that will newly join joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again 2Cultivated 3 hours in the incubator of damp atmosphere, add 150 milliliters of methyl-sulphoxides in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein Compound I-b is to the half-inhibition concentration (IC of K562 cell 50) obtain by dose effect curve.
The mensuration of cell survival rate is with improveing mtt assay, and concrete grammar is with embodiment 4.
To the chronic myelogone leukemia K 562 of people cell 503nhibiting concentration IC 50Obtain by dose effect curve.The IC of Compound I-b 50For: 52.8 μ M.
As positive control, DDP is to the chronic myelogone leukemia cell's of people 503nhibiting concentration IC with an antitumor line medication cis-platinum (DDP) in this test 50Be 19.1 μ M.
This experiment show this type of 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives has stronger cytotoxicity to the chronic myelogone leukaemia cancer cell of people K562 cell, might develop into the new medicine with anti-chronic myelogone leukemia effect.
Embodiment 6: Compound I I-c is to the cytotoxic activity of people's promyelocytic leukemia cell HL-60
HL-60 (people's promyelocytic leukemia cell) contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10 4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO 2Cultivated 24 hours in the incubator of damp atmosphere.
The measuring method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, the dimethyl sulfoxide solution of the Compound I I-c that will newly join joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 milligrams/microlitre), continue at 37 ℃ 5%CO again 2Cultivated 3 hours in the incubator of damp atmosphere, add 150 microlitre methyl-sulphoxides in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein Compound I I-c is to the half-inhibition concentration (IC of HL-60 cell 50) obtain by dose effect curve.
To human leukemia HL-60 cell's 503nhibiting concentration IC 50Obtain by dose effect curve.The IC of Compound I I-c 50For: 22.2 μ M.
This test with an antitumor line medication cis-platinum (DDP) as positive control, DDP to HL-60 cell growth 503nhibiting concentration IC 50Be 6.6 μ M.
This experiment show this type of 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives has stronger cytotoxicity to HL-60 (people's promyelocytic leukemia cell), might develop into the new medicine with leukemia resisting action.
Embodiment 7: Compound I-b is to the cytotoxic activity of mouse lymph sample knurl P388D1 cell
Mouse lymph sample knurl P388D1 cell contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10 3Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO 2Cultivated 24 hours in the incubator of damp atmosphere.
The measuring method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I-b that will newly join joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again 2Cultivated 3 hours in the incubator of damp atmosphere, add 150 microlitre methyl-sulphoxides in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein Compound I-b is to the half-inhibition concentration (IC of P388D1 cell 50) obtain by dose effect curve.
To mouse lymph sample knurl P388D1 cell 503nhibiting concentration IC 50Obtain by dose effect curve.The IC of Compound I-b 50For: 8.98 μ M.
This test with an antitumor line medication cis-platinum (DDP) as positive control, DDP to mouse leukemia P388D1 cell growth 503nhibiting concentration IC 50Be 14.8 μ M.
This experiment show this type of 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives demonstrates stronger cytotoxicity to having mouse lymph sample knurl P388D1 cell, might develop into the new medicine with leukemia resisting action.

Claims (8)

1. one kind 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives, and their pharmacologically acceptable salt, have following general structure:
Figure C2007101569100002C1
Formula (1)
Wherein: R 1, R 2, R 3, R 4And R 5Identical or different, select hydrogen for use, nitro, hydroxyl, halogen contains the saturated or unsaturated alkyl or the alkoxyl group of 1～8 carbon or contains the alkylamino radical of 1～8 carbon;
R is-COOH-CH 2OH ,-CHO ,-COOR 6,-CONHNH 2,-CONH 2,-CONHR 6,-CON (R 6) 2, R wherein 6It is the alkyl group that contains 1～8 carbon;
R 1, R 2, R 3, R 4And R 5Can not be hydrogen simultaneously.
2. according to claim 14 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives, it is characterized in that: substituent R is COOCH in formula (1) 2CH 3The time, be following formula (I) compound:
Figure C2007101569100002C2
Wherein: radicals R 1, R 2, R 3, R 4And R 5Definition and formula (1) in identical.
3. according to claim 24 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives, it is characterized in that formula (I) compound is:
I-a:(2E, 4E)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diolefinic acid ethyl ester;
I-b:(2E, 4Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diolefinic acid ethyl ester;
I-c:(2Z, 4Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diolefinic acid ethyl ester.
4. according to claim 14 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives, it is characterized in that: substituent R is CH in formula (1) 2During OH, be following formula (II) compound:
Wherein: radicals R 1, R 2, R 3, R 4And R 5Definition and formula (1) in identical.
5. according to claim 44 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives, it is characterized in that formula (II) compound is:
II-a:(2E, 4E)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diene-1-alcohol;
II-b:(2E, 4Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diene-1-alcohol;
II-c:(2Z, 4Z)-5-(4 '-to oxyethyl group benzyloxy base-3 ', 5 '-Dimethoxyphenyl) penta-2,4-diene-1-alcohol.
6. according to claim 24 '-substituted benzyloxy-3 ', 5 '-preparation method of Dimethoxyphenyl-butadiene derivatives, it is characterized in that realizing by following scheme: with 4 '-substituted benzyloxy-3 ', 5 '-dimethoxy benzaldehyde and bromo ethyl crotonate triphenylphosphine salt prepare formula (I) compound, and reaction formula is:
Figure C2007101569100003C2
Wherein: radicals R 1, R 2, R 3, R 4And R 5Definition and formula (1) in identical.
7. according to claim 44 '-substituted benzyloxy-3 ', 5 '-preparation method of Dimethoxyphenyl-butadiene derivatives, it is characterized in that realizing by following scheme: the reduction of formula (I) compound process lithium aluminum hydride-aluminum chloride mixture is obtained corresponding formula (II) compound, and reaction formula is:
Figure C2007101569100003C3
Wherein: radicals R 1, R 2, R 3, R 4And R 5Definition and formula (1) in identical.
8. according to claim 14 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives and the application of their pharmacologically acceptable salt in preparation control tumor disease medicine.
CN200710156910A 2007-11-20 2007-11-20 4'-substituted benzyloxy-phenyl butadiene derivatives and preparation and uses thereof Expired - Fee Related CN100596294C (en)

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