CN101161629A - 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 PDFInfo
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- CN101161629A CN101161629A CNA2007101569109A CN200710156910A CN101161629A CN 101161629 A CN101161629 A CN 101161629A CN A2007101569109 A CNA2007101569109 A CN A2007101569109A CN 200710156910 A CN200710156910 A CN 200710156910A CN 101161629 A CN101161629 A CN 101161629A
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- dimethoxyphenyl
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- benzyloxy
- butadiene derivatives
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- GEVWYUUYTOZGRR-UHFFFAOYSA-N 1-phenylbuta-1,3-dienoxymethylbenzene Chemical class C(C1=CC=CC=C1)OC(=CC=C)C1=CC=CC=C1 GEVWYUUYTOZGRR-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 239000003814 drug Substances 0.000 claims abstract description 24
- 125000000051 benzyloxy group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 21
- -1 bromoethylcrotonate-triphenylphosphonium Chemical compound 0.000 claims abstract description 14
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000004494 ethyl ester group Chemical group 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- NROHSTUPCFHVBV-UHFFFAOYSA-N 4,4-dimethoxybuta-1,3-dienylbenzene Chemical class COC(=CC=CC1=CC=CC=C1)OC NROHSTUPCFHVBV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000005998 bromoethyl group Chemical group 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 claims description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 51
- 208000032839 leukemia Diseases 0.000 abstract description 13
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 230000003013 cytotoxicity Effects 0.000 abstract description 8
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 5
- 201000005202 lung cancer Diseases 0.000 abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 abstract description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- 230000002829 reductive effect Effects 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 230000004614 tumor growth Effects 0.000 abstract description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 abstract 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 abstract 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 abstract 1
- 230000004071 biological effect Effects 0.000 abstract 1
- 239000012280 lithium aluminium hydride Substances 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- 230000001472 cytotoxic effect Effects 0.000 description 8
- 230000001684 chronic effect Effects 0.000 description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 description 6
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 6
- 210000002751 lymph Anatomy 0.000 description 6
- 229910052697 platinum Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 5
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
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- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- WWVKQTNONPWVEL-UHFFFAOYSA-N caffeic acid phenethyl ester Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCC1=CC=CC=C1 WWVKQTNONPWVEL-UHFFFAOYSA-N 0.000 description 2
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- 229960005420 etoposide Drugs 0.000 description 2
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- 229960005277 gemcitabine Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
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- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- 229940040145 liniment Drugs 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 201000005296 lung carcinoma Diseases 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- SWUARLUWKZWEBQ-UHFFFAOYSA-N phenylethyl ester of caffeic acid Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-UHFFFAOYSA-N 0.000 description 2
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- RMPQVAAHYOEUJL-UHFFFAOYSA-N COC1=CC(=CC(=C1)C(=CC=C)OCC2=CC=CC=C2)OC Chemical class COC1=CC(=CC(=C1)C(=CC=C)OCC2=CC=CC=C2)OC RMPQVAAHYOEUJL-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241001113317 Farfugium Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 241000241413 Propolis Species 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 229940127089 cytotoxic agent Drugs 0.000 description 1
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- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
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- 229930014626 natural product Natural products 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- LDBPIZIYTBIRPM-VQHVLOKHSA-N phenyl (e)-3-(3,4-dihydroxyphenyl)prop-2-enoate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OC1=CC=CC=C1 LDBPIZIYTBIRPM-VQHVLOKHSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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 such as environmental pollution that I brings in already developing, 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:
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:
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.
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:
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
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 (CDClx) 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; Mp112-114 ℃; 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=8.4 Hz, H-3 ", 7 "), 6.87 (2H, d, J=8.4 Hz, 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=8.4 Hz, H-3 ", 7 "), 7.07 (1H, t, J=11.6 Hz, H-5), 6.86 (2H, d, J=8.4 Hz, H-4 ", 6 "), 6.83 (1H, t, J=11.6 Hz, H-4), 6.50 (2H, s, H-2 ', 6 '), 5.78 (1H, d, J=11.6 Hz, H-2), 4.98 (2H, s, H-1 "), 4.22 (2H, q, J=7.2 Hz, OCH
2CH
3-1), 4.04 (2H, q, J=7.2 Hz, OCH
2CH
3-5 "), 3.82 (6H, s, OCH
3-3 ', 5 '), 1.43 (3H, t, J=7.2 Hz, OCH
2CH
3-5 "), 1.33 (3H, t, J=7.2 Hz, 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
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%C0 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 (9)
1. one kind 4 '-substituted benzyloxy-3 ', 5 '-Dimethoxyphenyl-butadiene derivatives, and their pharmacologically acceptable salt or solvate, have following general structure:
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:
Radicals R wherein
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 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.
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:
Radicals R wherein
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 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.
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:
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:
Radicals R wherein
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 their pharmacologically acceptable salt or the application of solvate in preparation control tumor disease medicine.
9. according to claim 14 '-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.
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