CN101654401B - Asymmetrical biphenyl compounds, medicinal compositions containing same and application of medicinal compositions - Google Patents
Asymmetrical biphenyl compounds, medicinal compositions containing same and application of medicinal compositions Download PDFInfo
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Abstract
The invention relates to asymmetrical biphenyl compounds of formulae (I) and (II), a medicinal compositions containing the same and application of the medicinal compositions, wherein R1-R8 are defined in the description. The compounds of the invention have anti-tumor bioactivity.
Description
Technical field
The present invention relates to have antitumour activity asymmetric biphenol compound, contain the pharmaceutical composition of described compound and for the preparation of the purposes in anti-tumor drug.
Background technology
Malignant tumour is common disease and the frequently-occurring disease of serious threat human health.According to World Health Organization's report, annual because the dead number of tumour reaches 7,000,000 in the whole world 5,000,000,000 populations, and also have the trend that increases every year.In the three large therapies (operation, chemotherapy and radiation) of malignant tumour, pharmacological agent occupies critical role.In recent years along with molecular biological development and the people further understanding to the molecular level mechanism of the generation of cancer, development, antitumor drug research just turns to new type antineoplastic medicine for the too many levels effect of mechanism from traditional cytotoxic drug.Take cell signal conducting molecule as target spot or new vessel as the medicine of inhibitor, anti-metastasis or the anti-drug resistance of target spot, differentiating inducer, targeted therapy, raising or regulate the focus that the number of ways such as body's immunity and gene therapy become the research and development PTS.Wherein the protein tyrosine kinase inhibitor Gefitinib (Gefetinib) take cell signal conducting molecule as target spot has obtained success, becomes the medicine of first nonsmall-cell lung cancer of listing.
Although the cancer therapy drug that uses clinically at present has kind more than 60,, treatment that account for malignant tumour solid tumor 90% or more the most serious to the harm humans life and health fails to reach satisfied effect.Therefore the antitumor drug that continues the new high-efficiency low-toxicity of searching remains the focus of pharmaceutical chemistry area research.
Couplet benzene ring octadiene system lignans extensively is present in Schisandraceae Plant, is the characteristic component of this section.This lignans skeleton is unique, and stereochemistry is complicated, and biological activity is extensive.The seventies China clinical discovery shizandra berry can obviously reduce hepatitis serum glutamic pyruvic transminase SGPT level, thereby has caused the upsurge of the pharmaceutically acceptable plant research of shizandra berry, and has developed thus anti-hepatitis new drug Biphenylylmethylcarbinol.In recent years, people find by research, and the protecting liver, lowering enzymes that lignanoid is known except people also has the biological activity of other side, such as regulating nervus centralis and anti peroxidation of lipid, antitumor [J Org Chem 1997,62,3242; Oncology 1992,49, and 68; Biochem Pharmacol 2006,72,824; Cancer Chemother Pharmacol2006,58,99], anti-HIV[Bioorg.Med.Chem.1997,5,1715] etc.
Therefore, seek the new biphenyl compound with anti-tumor activity, might satisfy unsatisfied medical requirement clinically.
Summary of the invention
One object of the present invention is to provide simple in structure and has the asymmetric biphenyl compound of antitumour activity.
Another object of the present invention is to provide the pharmaceutical composition that comprises described asymmetric biphenyl compound and one or more pharmaceutical excipients.
A further object of the present invention is to provide described asymmetric biphenyl compound for the preparation of the purposes in the medicine for the treatment of tumour.
On the one hand, the present invention relates to have asymmetric biphenyl compound or its pharmacy acceptable salt of following general formula (I),
Wherein:
R
1, R
2, R
3, R
4, R
5And R
6Be H, halogen, C independently of one another
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, CH
3(CH
2)
mCO ,-NO
2,-CN ,-NH
2,-CF
3,-COOH ,-SO
3H ,-CONH
2,-CONHR ' or-COOR ';
Perhaps, R
1With R
2, R
2With R
3, R
4With R
5Or R
5With R
6Can form together-OCH
2O-;
R
7And R
8Be independently-(CH
2)
mCHO ,-(CH
2)
mCH
2OH ,-(CH
2)
mCOOH ,-(CH
2)
mOR ' ,-CH=N-OH ,-CH=C (NO
2)-CH
3,-CH=CH-CO-CH
3Or-CH=CHR ';
M is 0 to 6 integer;
R ' is camphoroyl or alkyl, diamantane acyl group or alkyl, the acyl group that contains the tropine ring or alkyl, C
1-C
6Fatty acyl group, benzoyl group, C
1-C
4Alkyl replaces or the Multi substituted benzenes acyl group, by carboxyl, hydroxyl, nitro, cyano group or amino benzoyl group, the C that replaces
6-C
10Aroyl, five yuan or the hexa-atomic O of containing or contain N hetero-aromatic ring acyl group, the optional C that contains two keys or triple bond
1-C
10Aliphatic group or the optional C that contains two keys or triple bond
1-C
10Fatty acyl group.
In one embodiment, the present invention relates to have asymmetric biphenyl compound or its pharmacy acceptable salt of following general formula (II),
Wherein:
N=0,1,2 or 3;
R
1, R
2, R
3, R
4, R
5And R
6Be H, halogen, C independently of one another
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, CH
3(CH
2)
mCO ,-NO
2,-CN ,-NH
2,-CF
3,-COOH ,-SO
3H ,-CONH
2,-CONHR ' or-COOR ', m is 0 to 3 integer;
Perhaps, R
1With R
2, R
2With R
3, R
4With R
5Or R
5With R
6Can form together-OCH
2O-; And
R ' is H or C
1-C
6Alkyl.
In further embodiment, the present invention relates to have asymmetric biphenyl compound or its pharmacy acceptable salt of following general formula (II-a),
Wherein:
R
1, R
2, R
3, R
4, R
5And R
6Be H, halogen, C independently of one another
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, CH
3(CH
2)
mCO ,-NO
2,-CN ,-NH
2,-CF
3,-COOH ,-SO
3H ,-CONH
2,-CONHR ' or-COOR ', m is 1 to 3 integer;
Perhaps, R
1With R
2, R
2With R
3, R
4With R
5Or R
5With R
6Can form together-OCH
2O-; And
R ' is H or C
1-C
6Alkyl.
In embodiment further, the present invention relates to have asymmetric biphenyl compound or its pharmacy acceptable salt of above-mentioned general formula (II-a), wherein
R
1, R
2, R
3, R
4, R
5And R
6Be H, halogen, C independently of one another
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
2-C
6Alkenyl, C
3-C
8Cycloalkenyl group, C
2-C
6Alkynyl, C
6-C
10Aryl ,-NO
2,-CN ,-NH
2,-CF
3,-COOH ,-SO
3H ,-CONH
2, C
1-C
6Alkoxyl group, CH
3(CH
2)
mCO ,-CONHR ' or-COOR ', m is 1 to 3 integer;
Perhaps, R
1With R
2, R
2With R
3, R
4With R
5Or R
5With R
6Can form together-OCH
2O-; And
R ' is H or C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
2-C
6Alkenyl, C
3-C
8Cycloalkenyl group, C
2-C
6Alkynyl or C
6-C
10Aryl.
In further embodiment, the present invention relates to have asymmetric biphenyl compound or its pharmacy acceptable salt of following general formula (II-b),
Wherein:
R
1, R
2, R
3, R
4, R
5And R
6Be H, halogen, C independently of one another
1-C
6Alkyl, hydroxyl, C
1-C
6Alkoxyl group, CH
3(CH
2)
mCO ,-NO
2,-CN ,-NH
2,-CF
3,-COOH ,-SO
3H ,-CONH
2,-CONHR ' or-COOR ', m is 1 to 3 integer;
Perhaps, R
1With R
2, R
2With R
3, R
4With R
5Or R
5With R
6Can form together-OCH
2O-; And
R ' is H or C
1-C
6Alkyl.
In embodiment further, the present invention relates to have asymmetric biphenyl compound or its pharmacy acceptable salt of above-mentioned general formula (II-b), wherein
R
1, R
2, R
3, R
4, R
5And R
6Be H, halogen, C independently of one another
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
2-C
6Alkenyl, C
3-C
8Cycloalkenyl group, C
2-C
6Alkynyl, C
6-C
10Aryl ,-NO
2,-CN ,-NH
2,-CF
3,-COOH ,-SO
3H ,-CONH
2, C
1-C
6Alkoxyl group, CH
3(CH
2)
mCO ,-CONHR ' or-COOR ', m is 1 to 3 integer;
Perhaps, R
1With R
2, R
2With R
3, R
4With R
5Or R
5With R
6Can form together-OCH
2O-; And
R ' is H or C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
2-C
6Alkenyl, C
3-C
8Cycloalkenyl group, C
2-C
6Alkynyl or C
6-C
10Aryl.
In further embodiment, the present invention relates to have in following general formula (I-a) to (I-m) asymmetric biphenyl compound or its pharmacy acceptable salt of any one,
Wherein:
X=H, F, Cl, Br or methoxyl group;
R
1And R '
1Can be identical or different, and be H, CHO, CH independently of one another
2OR
2, COOR
3, CH=YR
3R
4, CH
2NH
2, CH
2NHR
2, CONHR
3Or OR
3Perhaps R
1And R '
1Combine and to form six, seven or octatomic ring;
Y=C or N; And
R
2, R
3And R
4Can be respectively H, OH, CN, NO
2, C
6-C
10Aroyl, C
1-
10Alkane acyl group (wherein can contain two keys or three key) or contain 10 carbon atoms with the interior bridged ring acyl group (comprise and contain N, O or the heteroatomic many rings of S or bridged ring) that contains.
In embodiment further, the present invention relates to have general formula in (I-a) to (I-m) any one asymmetric biphenyl compound or its pharmacy acceptable salt, wherein:
X=H, F, Cl, Br or methoxyl group;
R
1And R '
1Can be identical or different, and be H, CHO, CH independently of one another
2OR
2, COOR
3, CH=YR
3R
4, CH
2NH
2, CH
2NHR
2, CONHR
3Or OR
3
Y=C or N; And
R
2, R
3And R
4Can be respectively H, OH, CN, NO
2, C
6-C
10Aroyl, C
1-C
10Alkane acyl group or C
3-C
10Contain the bridged ring acyl group.
In embodiment further, the group that compound of the present invention selects free following compounds to form:
2-phenyl-3,4,5-Trimethoxybenzaldehyde,
3,4,5-trimethoxy-2,2 '-dialdehyde-based biphenyl,
2-aldehyde-5 '-chloro-2 ', 3,4,5-tetramethoxy biphenyl,
2,2 '-dialdehyde-4 ', 5 '-inferior first dioxy-3,4,5-trimethoxy biphenyl,
2-phenyl-4,5-methylenedioxy group phenyl aldehyde,
4,5-methylenedioxy group-2,2 '-dialdehyde biphenyl,
2-aldehyde-5 '-chloro-4,5-methylenedioxy group-2 ' methoxyl biphenyl,
2,2 '-dialdehyde-4,5-dimethoxy 4 ', 5 '-inferior methylenedioxy group biphenyl,
2-phenyl-3-methoxyl group-4,5-methylenedioxy group phenyl aldehyde,
2,2 '-dialdehyde-4,5-methylenedioxy group-6-methoxyl biphenyl,
2,2 '-dialdehyde-5,6-methylenedioxy group-4-methoxyl biphenyl,
5 '-chloro-6,2 '-dimethoxy-4 ', 5-methylenedioxy group biphenyl-2-aldehyde,
2-phenyl-4, the 5-dimethoxy benzaldehyde,
2,2 '-dialdehyde-4, the 5-dimethoxy-biphenyl,
2-aldehyde-5 '-chloro-2 ', 4,5-trimethoxy biphenyl,
2 '-aldehyde radical-4,5,6-trimethoxy biphenyl-2 methyl-formiate,
2 '-aldehyde radical-4-methoxy-5,6-methylenedioxy group biphenyl-2-methyl-formiate,
2 '-aldehyde radical-4,5-first dioxy-6-methoxyl biphenyl 2-methyl-formiate,
2 '-aldehyde radical-3,4-first dioxy-5-methoxyl biphenyl 2-methyl-formiate,
5 '-chloro-5,2 '-dimethoxy-3,4-methylenedioxy group biphenyl-2-methyl-formiate,
5 '-chloro-3,2 '-dimethoxy-4 ', 5-methylenedioxy group biphenyl-2-methyl-formiate,
2,3,4-trimethoxy-2 ', two (the 2-nitro third-1-alkene) biphenyl of 6-,
4 ', 5 '-inferior methylenedioxy group-4,5,6-trimethoxy biphenyl-2,2 '-two camphoroyl methyl esters,
4,5,6-trimethoxy biphenyl-2,2 '-two camphoroyl methyl esters,
4 ', 5 '-inferior methylenedioxy group-4,5,6-trimethoxy biphenyl-2,2 '-the dibenzoyl methyl esters,
4,5,6-trimethoxy-4 ', 5 '-inferior first DOD 4,4′ dioxydiphenyl-2,2 '-the dialdehyde-based azanol,
2-phenyl-4,5-methylenedioxy group benzylalcohol,
5 '-chloro-4,5-first dioxy-2 '-methoxyl biphenyl-2-methyl alcohol,
4 ', 5 ', 5,6-secondary first dioxy-2 '-methylol-4-methoxyl biphenyl-2-methyl-formiate,
2-methoxy-3,4-methoxy-7-hydrogen-dibenzo epoxy heptan-5-ketone,
1,2,3-trimethoxy-9,10-first dioxy-7-hydrogen-dibenzo epoxy heptan-5-ketone,
1,3,8,9,10-pentamethoxyl-dibenzopyrans-6-ketone, and
2,3,8,9,10-pentamethyl--dibenzopyrans-6-ketone.
Again on the one hand, the present invention relates to comprise described formula (I) or (II) pharmaceutical composition of compound and one or more pharmaceutical carriers or vehicle.
Also on the one hand, the present invention relates to described formula (I) or (II) compound for the preparation of the purposes in anti-tumor drug.
Formula of the present invention (I), (II), (II-a) or (II-b) compound can be prepared by the method shown in one of following reaction scheme.
Route A: make the phenyl halides (as the phenyl bromo-derivative) of replacement and the phenylo boric acid compounds reaction that replaces, can obtain asymmetric biphenyl compound I, then to its R
7And R
8The structure of modification such as functional group reduces, oxidation, esterification, nucleophilic addition(Adn) or elimination can obtain more serial asymmetric biphenol compound I,
Substituent R in above-mentioned reaction
1, R
2, R
3, R
4, R
5And R
6Described about formula (I) with preamble, R
7' and R
7" same R
7Definition, R
8' and R
8" same R
8Definition; Perhaps
Route B: the asymmetric biphenyl aldehydo-ester compound that will replace gets Compound I I through sodium borohydride reduction;
Substituent R in above-mentioned reaction
1, R
2, R
3, R
4, R
5, R
6The same formula II is described; Perhaps
Route C: make iodobenzoic acid become ester with the phenol reactant of replacement, then at PdCl
2(PPh
3)
2Catalysis under in molecule coupling obtain Compound I I.
The term that adopts in the present invention " alkyl " comprises alkyl, preferred low alkyl group, for example C
1-C
6Alkyl; Cycloalkyl, preferred C
3-C
8Cycloalkyl; Alkenyl, preferred C
2-C
6Alkenyl; Cycloalkenyl group, preferred C
3-C
8Cycloalkenyl group; Alkynyl, preferred C
2-C
6Alkynyl; And the alkyl that contains simultaneously two keys and triple bond.For example, C
1-C
6Alkyl comprises C
1-C
6Alkyl, C
3-C
8Cycloalkyl or cyclopropane substituted alkyl or alkenyl or alkynyl, C
3-C
8Cycloalkenyl group or alkenyl or alkynyl group, contain simultaneously the C of two keys and three key
2-C
6Alkyl or C
6-C
10Aryl.
Term " the C that adopts in the present invention
6-C
10Aromatic ring yl " refer to contain the single of 6-10 carbon atom or condense aroma system, it includes but not limited to phenyl and naphthyl.
The term that adopts in the present invention " five yuan or six-membered Hetero-aromatic " refers to that in ring system, at least one is selected from heteroatomic five yuan or the hexa-atomic aroma system of O, S, N, and it includes but not limited to pyrroles, pyrazoles, furans, thiophene, pyridine etc.
In the application, alleged " antitumor significant quantity " means the compounds of this invention and is given Mammals (comprising the people) when being used for the treatment of described tumor disease, is enough to realize the amount to the treatment of this tumor disease.
Occur in the application at this undefined term, have the common implication of understanding of those skilled in the art.
Pharmacy acceptable salt of the present invention is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetic acid, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid etc.; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.; Organic bases comprises meglumine, glucosamine etc.; Mineral alkali comprises the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.The pharmacy acceptable salt of the compounds of this invention can make by the ordinary method in this area.
It may be noted that in addition, the compounds of this invention using dosage and using method depend on factors, comprise patient's age, body weight, sex, natural health situation, nutritional status, activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of compound.Preferred using dosage is between 0.01～100mg/kg body weight/day.
The present invention according to the structure design of bioactive natural product synthetic serial asymmetric biphenyl compound at multiple cancer cells as A549 (lung cancer), DU145 (prostate cancer), PC-3 (prostate cancer), KB (nasopharyngeal carcinoma), and all demonstrate the active (ED of stronger inhibition in KB-VIn (anti-drug resistance nasopharyngeal carcinoma) test
50＜10.0 μ g/mL).Wherein part of compounds is at lung carcinoma cell (A549), demonstrate in the inhibition activity test of nasopharyngeal carcinoma cell (KB) with positive control homoharringtonine (Homoharringtonine) and Etoposide (Etoposide, VP-16) and quite or better suppress active.It should be noted that especially the some of them compound has also demonstrated very strong inhibition to the human nasopharyngeal epithelioma 1 (KB-VIN) with resistance active.
Therefore, expect that compound of the present invention can be used for treating kinds cancer, for example lung cancer, prostate cancer, nasopharyngeal carcinoma and drug resistant nasopharyngeal carcinoma.
Embodiment
Provide the following examples to be used to further illustrate the present invention, but do not mean that the present invention only limits to these embodiment.
If no special instructions, the raw material that uses in the application all can be buied from supplier by commercial sources, maybe can prepare by the currently known methods in this area.
Spectroscopic data is by the American AB I API3000 of company (ESI+) type mass spectrograph, and the NEC JNM-ECA-400 of company NMR spectrometer with superconducting magnet records, and is designated as TMS in the nuclear-magnetism sample test, and fusing point is measured with micro-REICHERT melting point apparatus, and temperature is not calibrated.Common agents comes from Beijing chemical reagents corporation, and special reagent is purchased from Acros, Aldrich, Alfa company; Solvent is respectively from the Beijing Chemical Plant, Beijing chemical reagents corporation.The self-control of TLC and PTLC thin layer plate, used silica gel (GF254,200-300 order, 100-200 order) all come from Qingdao Haiyang chemistry company limited.
Embodiment 1:2-phenyl-3,4,5-Trimethoxybenzaldehyde (I-1)
With 2-bromo-3,4,5-Trimethoxybenzaldehyde (A1; 130mg, 0.47mmol), phenylo boric acid (B1,54mg), palladium (11mg), triphenyl phosphorus (38mg), cesium carbonate (709mg) be placed in anhydrous DME; nitrogen protection is stirred.70 ℃ of reaction 7h, the TLC detection reaction is complete, is poured into water, ethyl acetate extraction, crude product after anhydrous magnesium sulfate drying, desolventizing separates (cyclohexane/ethyl acetate) with silicagel column and gets Compound I-1 (91mg, 71%): white solid, mp 88-90 ℃;
1H-NMR (CDCl
3) δ ppm:9.65 (1H, s), 7.43 (3H, m), 7.34 (3H, m), 4.00 (3H, s), 3.97 (3H, s), 3.60 (3H, s).
Embodiment 2:3,4,5-trimethoxy-2,2 '-dialdehyde-based biphenyl (I-2)
Method is with embodiment 1.Bromobenzene A1 (0.55g, 2mmol) gets Compound I-2 (390mg, 65%) with 2-carboxaldehyde radicals phenylo boric acid (B2,600mg) coupling: white solid, mp 71-72 ℃;
1H-NMR (CDCl
3) δ ppm:9.88 (1H, s), 9.60 (1H, s), 8.09 (1H, dd, J=1.6 ﹠amp; 7.6Hz), 7.68 (1H, ddd, J=1.6 ﹠amp; 7.6Hz), 7.60 (1H, dd, J=7.6Hz), 7.42 (1H, s), 7.32 (1H, dd, J=1.6 ﹠amp; 7.6Hz), 4.00 (6H, s), 3.55 (3H, s).
Embodiment 3:2-aldehyde-5 '-chloro-2 ', 3,4,5-tetramethoxy biphenyl (I-3)
Method is with embodiment 1.Bromobenzene A1 (138mg, 0.5mmol) and 5-chloro-2-methoxyphenylboronic acid (B3,186mg), reaction obtains Compound I-3 (104mg, 62%): white solid, mp 111-112 ℃;
1H-NMR (CDCl
3) δ ppm:9.56 (1H, s), 7.38 (2H, m), 7.21 (1H, d, J=2.4Hz), 6.92 (1H, d, J=8.4Hz), 4.00 (3H, s), 3.96 (3H, s), 3.74 (3H, s), 3.66 (3H, s).
Embodiment 4:2,2 '-dialdehyde-4 ', 5 '-inferior first dioxy-3,4,5-trimethoxy biphenyl (I-4)
Method is with embodiment 1.Bromobenzene A1 (137mg, 0.5mmol) and 4,5-time first dioxy-2-carboxaldehyde radicals phenylo boric acid (B4,194mg) reacts to get Compound I-4 (112mg, 65%): white solid, mp 129-130 ℃;
1H-NMR (CDCl
3) δ ppm:9.64 (1H, s), 9.58 (1H, s), 7.51 (1H, s), 7.38 (1H, s), 6.74 (1H, s), 6.15 (2H, s), 4.00 (6H, s), 3.63 (3H, s).
Embodiment 5:2-phenyl-4,5-methylenedioxy group phenyl aldehyde (I-5)
Method is with embodiment 1.2-bromo-4,5-methylenedioxy group phenyl aldehyde (A2,229mg, 1mmol) reacts to get Compound I-5 (181mg, 80%) with phenylo boric acid (B1,122mg): white solid, mp 79-80 ℃;
1H-NMR (CDCl
3) δ ppm:9.74 (1H, s), 7.47 (4H, m), 7.35 (2H, m), 6.85 (1H, s), 6.09 (2H, s).
Embodiment 6:4,5-methylenedioxy group-2,2 '-dialdehyde biphenyl (I-6)
Method is with embodiment 1.Bromobenzene A2 (229mg, 1mmol) reacts to get Compound I-6 (178mg, 70%) with 2-carboxaldehyde radicals phenylo boric acid (B2,300mg): white solid, mp84-85 ℃;
1H-NMR (CDCl
3) δ ppm:9.89 (1H, s), 9.56 (1H, s), 8.04 (1H, d, J=7.6Hz), 7.66 (1H, ddd, J=1.2 ﹠amp; 7.6Hz), 7.59 (1H, dd, J=7.6Hz), 7.50 (1H, s), 7.35 (1H, d, J=7.6Hz), 6.14 (2H, s).
Embodiment 7:2-aldehyde-5 '-chloro-4,5-methylenedioxy group-2 ' methoxyl biphenyl (I-7)
Method is with embodiment 1.Bromobenzene A2 (115mg, 0.5mmol) reacts to get Compound I-7 (100mg, 70%) with 5-chloro-2-methoxyphenylboronic acid (B3,186mg): white solid, mp 122-124 ℃;
1H-NMR (CDCl
3) δ ppm:9.56 (1H, s), 7.45 (1H, s), 7.36 (1H, dd, J=2.4 ﹠amp; 8.4Hz), 7.23 (1H, d, J=2.4Hz), 6.89 (1H, d, J=8.4Hz), 6.75 (1H, s), 6.08 (2H, d, J=6.4Hz), 3.74 (3H, s).
Embodiment 8:2,2 '-dialdehyde-4,5-dimethoxy 4 ', 5 '-inferior methylenedioxy group biphenyl (I-8)
Method is with embodiment 1.Bromobenzene A2 (125mg, 0.51mmol) and 4,5-(methylenedioxy)-2-carboxaldehyde radicals phenylo boric acid (B4,194mg) react to get Compound I-8 (110mg, 70%): white solid, 78 ℃ of mp;
1H-NMR (CDCl
3) δ ppm:9.69 (1H, s), 9.60 (1H, s), 7.54 (1H, s), 7.50 (1H, s), 6.81 (1H, s), 6.77 (1H, s), 6.15 (2H, s), 4.00 (3H, s), 3.95 (3H, s).
Embodiment 9:2-phenyl-3-methoxyl group-4,5-methylenedioxy group phenyl aldehyde (I-9)
Method is with embodiment 1.By 2-bromo-3-methoxyl group-4,5-methylenedioxy group phenyl aldehyde (A3,259mg, 1mmol) reacts to get Compound I-9 (102mg, 40%), white solid, mp 89-91 ℃ with 2-carboxaldehyde radicals phenylo boric acid (B1,244mg);
1H-NMR (CDCl
3) δ ppm:9.52 (1H, s), 7.43 (3H, m), 7.30 (2H, m), 7.24 (1H, s), 6.10 (2H, s), 3.82 (3H, s);
Embodiment 10:2,2 '-dialdehyde-4,5-methylenedioxy group-6-methoxyl biphenyl (I-10)
Method is with embodiment 1.By bromo-3,4-time first dioxy-5-methoxybenzaldehyde (A3,259mg, 1mmol) reacts to get Compound I-10 and I-11 with phenylo boric acid B2 (244mg), gets I-10 after separation:
1H-NMR (CDCl
3) δ ppm:9.86 (1H, s), 9.47 (1H, s), 8.06 (1H, dd, J=1.6﹠amp; 7.6Hz), 7.67 (1H, ddd, J=1.6 ﹠amp; 7.6Hz), 7.64 (1H, dd, J=7.6Hz), 7.27 (1H, s), 7.25 (1H, d, J=7.6Hz), 6.13 (2H, s), 3.83 (3H, s).
Embodiment 11:2,2 '-dialdehyde-5,6-methylenedioxy group-4-methoxyl biphenyl (I-11)
Method is separated to get I-11 with embodiment 10:
1H-NMR (CDCl
3) δ ppm:9.95 (1H, s), 9.68 (1H, s), 8.07 (1H, dd, J=1.6 ﹠amp; 7.6Hz), 7.70 (1H, ddd, J=1.6﹠amp; 7.6Hz), 7.61 (1H, dd, J=7.6Hz), 7.39 (1H, s), 7.37 (1H, dd, J=1.6﹠amp; 7.6Hz), 6.13 (2H, s), 3.83 (3H, s).
Embodiment 12:5 '-chloro-6,2 '-dimethoxy-4 ', 5-methylenedioxy group biphenyl-2-aldehyde (I-12)
Method is with embodiment 1.React to get Compound I-12 (100mg, 32%) by bromobenzene A3 (259mg, 1mmol) with 5-chloro-2-methoxyl group-phenylo boric acid (B3,372mg): white solid, mp98-100 ℃;
1H-NMR (CDCl
3) δ ppm:9.47 (1H, s), 7.36 (1H, dd, J=2.8﹠amp; 8.8Hz), 7.22 (1H, s), 7.15 (1H, d, J=2.8Hz), 6.92 (1H, d, J=8.8Hz), 6.08 (2H, s), 3.85 (3H, s), 3.74 (3H, s).
Embodiment 13:2-phenyl-4,5-dimethoxy benzaldehyde (I-13)
Method is with embodiment 1.By 2-bromo-4,5-dimethoxy phenyl aldehyde (A5,125mg, 0.51mmol), phenylo boric acid (B1,122mg) reacts to get Compound I-13 (103mg, 85%): white solid, mp 132-134 ℃.
1H-NMR(CDCl
3)δppm：9.83(1H，s)，7.54(1H，s)，7.46(5H，m)，6.87(1H，s)，3.99(6H，s)。
Embodiment 14:2,2 '-dialdehyde-4,5-dimethoxy-biphenyl (I-14)
Method is with embodiment 1.Bromobenzene A5 (125mg, 0.51mmol) reacts to get Compound I-14 (101mg, 75%) with 2-carboxaldehyde radicals-phenylo boric acid (150mg): white solid, mp 132-134 ℃;
1H-NMR (CDCl
3) δ ppm:9.87 (1H, s), 9.64 (1H, s), 8.07 (1H, d, J=8Hz), 7.58 (3H, m), 7.41 (1H, d, J=8Hz), 6.78 (1H, s), 4.02 (3H, s), 3.95 (3H, s).
Embodiment 15:2-aldehyde-5 '-chloro-2 ', 4,5-trimethoxy biphenyl (I-15)
Method is with embodiment 1.Bromobenzene A5 (125mg, 0.51mmol) and phenylo boric acid B3 (186mg) react to get Compound I-15 (108mg, 71%): white solid, mp 135-136 ℃;
1H-NMR (CDCl
3) δ ppm:9.62 (1H, s), 7.51 (1H, s), 7.36 (1H, dd, J=8.4﹠amp; 2.4Hz), 7.28 (1H, s), 6.90 (1H, d, J=8.4Hz), 6.76 (1H, s), 3.99 (3H, s), 3.97 (3H, s), 3.74 (3H, s).
Embodiment 16:2 '-aldehyde radical-4,5,6-trimethoxy biphenyl-2 methyl-formiate (I-16)
Method is with embodiment 1.2-bromo-3,4,5-tri-methoxybenzoate (A6,313mg, 1mmol) reacts to get Compound I-16 (222mg, 65%) with phenylo boric acid B2 (308mg): white solid, mp 78-79 ℃;
1H-NMR (CDCl
3) δ ppm:9.82 (1H, s), 8.02 (1H, dd, J=1.2 ﹠amp; 8.0Hz), 7.59 (1H, ddd, J=1.2 ﹠amp; 8.0Hz), 7.50 (1H, dd, J=8.0Hz), 7.38 (1H, s), 7.19 (1H, d, J=8.0Hz), 3.96 (6H, s), 3.52 (6H, s).
Embodiment 17:2 '-aldehyde radical-4-methoxy-5,6-methylenedioxy group biphenyl-2-methyl-formiate (I-17)
Method is with embodiment 1.2-bromo-5-methoxyl group-3,4-methylenedioxy group methyl benzoate (A7,168mg, 0.58mmol) reacts to get Compound I-17 (152mg, 84%) with phenylo boric acid B2 (174mg): mp 121-122 ℃;
1H-NMR (CDCl
3) δ ppm:9.89 (1H, s), 8.02 (1H, dd, J=1.2 ﹠amp; 7.6Hz), 7.63 (1H, ddd, J=1.2 ﹠amp; 7.6Hz), 7.52 (1H, dd, J=7.6Hz), 7.40 (1H, s), 7.27 (1H, d, J=7.6Hz), 6.01 (2H, s), 4.00 (3H, s), 3.58 (3H, s).
Embodiment 18:2 '-aldehyde radical-4,5-first dioxy-6-methoxyl biphenyl 2-methyl-formiate (I-18)
Method is with embodiment 1.2-bromo-4,5-first dioxy-3-methoxyl methyl benzoate (A8,145mg, 0.5mmol) and phenylo boric acid B2 (150mg) react to get Compound I-18 (96mg, 70%): mp 88-90 ℃;
1H-NMR (CDCl
3) δ ppm:9.84 (1H, s), 8.02 (1H, dd, J=1.2 ﹠amp; 7.6Hz), 7.58 (1H, ddd, J=1.2 ﹠amp; 7.6Hz), 7.50 (1H, dd, J=7.6Hz), 7.24 (1H, s), 7.15 (1H, d, J=7.6Hz), 6.10 (2H, s), 3.78 (3H, s), 3.52 (3H, s).
Embodiment 19:2 '-aldehyde radical-3,4-first dioxy-5-methoxyl biphenyl 2-methyl-formiate (I-19)
Method is with embodiment 1.6-iodo-2,3-time first dioxy-4-methoxyl group-methyl benzoate (A9,168mg, 0.5mmol) reacts to get Compound I-19 (97mg, 62%) with phenylo boric acid B2 (150mg): white solid, mp 121-122 ℃;
1H-NMR (CDCl
3) δ ppm:9.88 (1H, s), 7.99 (1H, dd, J=1.2 ﹠amp; 8.0Hz), 7.59 (1H, ddd, J=1.2 ﹠amp; 8.0Hz), 7.50 (1H, dd, J=8.0Hz), 7.25 (1H, d, J=8.0Hz), 6.41 (1H, s), 6.20 (2H, d, J=10.0Hz), 3.92 (3H, s), 3.57 (3H, s).
Embodiment 20:5 '-chloro-5,2 '-dimethoxy-3,4-methylenedioxy group biphenyl-2-methyl-formiate
(I-20)
Method is with embodiment 1.Iodobenzene A9 (84mg, 0.25mmol) and phenylo boric acid B3 (93mg) react to get Compound I-20 (65mg, 68%): mp 128-129 ℃;
1H-NMR (CDCl
3) δ ppm:7.27 (3H, m), 6.84 (1H, d, J=8.8Hz), 6.06 (2H, d, J=2.4Hz), 3.97 (3H, s), 3.72 (3H, s), 3.63 (3H, s).
Embodiment 21:5 '-chloro-3,2 '-dimethoxy-4 ', 5-methylenedioxy group biphenyl-2-methyl-formiate
(I-21)
Method is with embodiment 1.6-bromo-2-methoxyl group-3,4-methylenedioxy group methyl benzoate (A10,145mg, 0.5mmol) reacts to get Compound I-21 (95mg, 55%) with phenylo boric acid B3 (186mg): mp 130-132 ℃; 1H-NMR (CDCl
3) δ ppm:7.27 (2H, m), 7.25 (1H, s), 6.84 (1H, d, J=8.8Hz), 6.07 (2H, m), 3.97 (3H, s), 3.72 (3H, s), 3.63 (3H, s).
Embodiment 22:2,3,4-trimethoxy-2 ', two (the 2-nitro third-1-alkene) biphenyl (I-22) of 6-
Add nitroethane (0.8mL) in toluene (25mL) solution of Compound I-2 (127mg, 0.42mmol), n-Butyl Amine 99 (0.01mL), Glacial acetic acid (0.01mL) connects water trap, and approximately 72h refluxes.Get I-22 (109mg, 63%) through silicagel column (petrol ether/ethyl acetate) purifying: mp 57-58 ℃;
1H-NMR (CDCl
3) δ ppm:7.62 (1H, s), 7.49 (2H, m), 7.47 (2H, m), 7.26 (1H, m), 6.67 (1H, s), 3.95 (3H, s), 3.93 (3H, s), (3.61 3H, s), 2.30 (3H, s), 2.28 (3H, s).
Embodiment 23:4 ', 5 '-inferior methylenedioxy group-4,5,6-trimethoxy biphenyl-2,2 '-two camphoroyl first
Ester (I-23)
Compound I-4 (22mg, 0.06mmol) with excessive sodium borohydride stirring at room in methyl alcohol, add 5%HCl to transfer pH value to 5-6 after the TLC detection reaction is complete, ethyl acetate extraction, desolventizing must be reduced to the product of alcohol, and crude product is not purified, getting 17mg glycol (0.05mmol) after drying is dissolved in methylene dichloride (5mL), add slightly excessive camphor acyl chlorides (60mg) and a small amount of pyridine, stirred overnight at room temperature, it is complete that TLC detects raw material reaction.Add methylene dichloride and water, told layer mutually, and used successively 5%HCl, the saturated common salt water washing, the crude product after desolventizing separates (petrol ether/ethyl acetate) with silicagel column and gets I-23 (20mg, 64%): mp85-86 ℃;
1H-NMR (CDCl
3) δ ppm:6.96 (1H, s), 6.81 (1H, s), 6.69 (1H, s), 6.02 (2H, s), 4.80-5.00 (4H, m), (3.90 6H, s), 3.60 (3H, s), (2.37 2H, m), 1.93 (4H, m), (1.68 2H, brs), 1.10 (6H, s), (1.02 6H, s), 1.01 (6H, s).
Embodiment 24:4 ', 5 '-inferior methylenedioxy group-4,5,6-trimethoxy biphenyl-2,2 '-the dibenzoyl methyl esters
(I-24)
Method is with embodiment 23.The diol compound (50mg, 0.14mmol) of above-mentioned reduction reacts to get I-24 (75mg, 94%) with Benzoyl chloride (0.05mL) in the mixing solutions of methylene dichloride and pyridine:
1H-NMR (CDCl
3) δ ppm:7.96 (4H, m), 7.50 (2H, m), (7.38 4H, m), 7.05 (1H, s), (6.86 1H, s), 6.73 (1H, s), (6.00 2H, d, J=8.8Hz), (5.06-5.03 4H, m), 3.89 (6H, s), 3.66 (3H, s).
Embodiment 25:4,5,6-trimethoxy-4 ', 5 '-inferior first DOD 4,4′ dioxydiphenyl-2,2 '-dialdehyde-based azanol (I-25)
With I-4 (62mg, 0.18mmol) be dissolved in 95% ethanol (8mL), slowly drip the aqueous solution of oxammonium hydrochloride (89mg), it is fully mixed, then slowly add 40% sodium hydroxide (2mL) aqueous solution, after 2h, it is complete that TLC detects raw material reaction, pour in frozen water, then use ethyl acetate extraction.Anhydrous sodium sulfate drying filters, and is concentrated, gets I-25 (54mg, 81%): mp 82-84 ℃;
1H-NMR (DMSO) δ ppm:11.28 (1H, s), 11.15 (1H, s), (7.42 1H, s), 7.40 (1H, s), (7.30 1H, s), 7.23 (1H, s), (6.77 1H, s), 6.14 (2H, d, J=8.0Hz), 3.87 (3H, s), 3.83 (3H, s), 3.53 (3H, s).
Embodiment 26:2-phenyl-4,5-methylenedioxy group benzylalcohol (I-26)
By Compound I-5 (37mg, 0.16mmol) with excessive sodium borohydride stirring at room in methyl alcohol, add 5%HCl to transfer pH value to 5-6 after the TLC detection reaction is complete, ethyl acetate extraction, desolventizing must be reduced to get Compound I-26 (37mg, 99%): white solid, mp92-94 ℃;
1H-NMR (CDCl
3) δ ppm:7.39 (5H, m), 7.04 (1H, s), 6.77 (1H, s), 6.00 (2H, s), 4.50 (2H, d, J=5.2Hz).
Embodiment 27:5 '-chloro-4,5-first dioxy-2 '-methoxyl biphenyl-2-methyl alcohol (I-27)
Compound I-7 (48mg, 0.17mmol) is dissolved in anhydrous methanol, adds sodium borohydride (20mg), stirring at room after the TLC detection reaction is complete, adds 5%HCl to transfer pH value to 5-6, ethyl acetate extraction gets Compound I-2740mg, mp 50-52 ℃ after desolventizing;
1H-NMR (CDCl
3) δ ppm:7.31 (1H, dd, J=4.0 ﹠amp; 8.0Hz), 7.14 (1H, d, J=4.0Hz), 7.03 (1H, s), 6.90 (1H, d, J=8.0Hz), 6.65 (1H, s), 6.10 (2H, d, J=4.0Hz), 4.32 (2H, m), 3.76 (3H, s).
Embodiment 28:4 ', 5 ', 5,6-secondary first dioxy-2 '-methylol-4-methoxyl biphenyl-2-formic acid first
Ester (I-28)
With 2 '-formaldehyde-4 ', 5 ', 5,6-secondary first dioxy-4-methoxyl biphenyl-2-methyl-formiate (70mg, 0.20mmol) is dissolved in and adds NaBH in methyl alcohol
4(38mg, 1mmol) transfers pH value to 5-6 with 5%HCl, ethyl acetate extraction, saturated common salt water washing, anhydrous Na immediately
2SO
4Drying is filtered, and desolventizing gets reduzate I-28,65mg, mp 65-67 ℃;
1H-NMR (CDCl
3) δ ppm:7.25 (1H, s), 7.02 (1H, s), 6.56 (1H, s), 6.01 (4H, m), 4.26 (2H, m), 3.96 (3H, s), 3.69 (3H, s).
Embodiment 29:2-methoxy-3,4-methoxy-7-hydrogen-dibenzo epoxy heptan-5-ketone (II-1a)
With aldehyde radical biphenyl compound (I-19,31mg, 0.1mmol) be dissolved in anhydrous methanol, the sodium borohydride that adds 5 times of equivalents has bubble to emerge, and stirs under room temperature and spends the night, add 5%HCl to transfer pH value to 5-6 after the TLC detection reaction is complete, ethyl acetate extraction, saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and steams under reduced pressure to desolventize, and gets reduzate-biphenyl and seven Yuans cyclic lactone compounds II-1a (20mg, 71%): mp 196-198 ℃;
1H-NMR (CDCl
3) δ ppm:7.57 (1H, d, J=7.6Hz), 7.51 (1H, m), 7.41 (2H, m), (6.72 1H, s), 6.26 (1H, s), 6.15 (1H, s), 5.31 (1H, d, J=12Hz), 4.95 (1H, d, J=12Hz), 4.03 (3H, s).
Embodiment 30:1,2,3-trimethoxy-9,10-first dioxy-7-hydrogen-dibenzo epoxy heptan-5-ketone
(II-2a)
Method is with embodiment 29, by compound 2 '-aldehyde-4 ', 5 '-inferior first dioxy-3,4,5-trimethoxy biphenyl-2-methyl-formiate (76mg, 0.2mmol) reacts to get II-2a (68mg, 98%): mp163-164 ℃;
1H-NMR (CDCl
3) δ ppm:7.26 (1H, s), 6.92 (1H, s), 6.03 (2H, d, J=16Hz), (4.93 1H, d, J=12Hz), 4.81 (1H, d, J=12Hz), (3.99 3H, s), 3.95 (3H, s), 3.66 (3H, s).
Embodiment 31`:1,3,8,9,10-pentamethoxyl-dibenzopyrans-6-ketone (II-1b)
At 3,4,5-trimethoxybenzoic acid (1.25g, 5.9mmol) and chloroform (50mL) solution of trifluoroacetic acid silver (1.36g) in, add iodine (1500mg) in batches, react approximately 8h, TLC detects (dichloromethane/ethyl acetate) and reacts completely, solids removed by filtration.Organic layer 20%Na
2S
2O
3Washing, desolventizing gets product A (1.79g, productive rate 90%).Get its (200mg, 0.59mmol) and be dissolved in CH
2Cl
2(10mL), add successively 3,5-syringol (91mg), DCC (146mg), DMAP (8mg), N
2The lower stirring at room 4h of protection.Solids removed by filtration, removal of solvent under reduced pressure is separated (dichloromethane/ethyl acetate) through silicagel column and is got intermediate C (112mg, 40%).Again with Compound C (70mg, 0.15mmol), PdCl
2(PPh
3)
2(26mg), anhydrous Na OAc (25mg) mixes, drying, then add anhydrous DMA, carry out coupled reaction in molecule at 120 ℃, stir 5h, reaction solution is poured in frozen water, ethyl acetate extraction, concentrated, post separates (dichloromethane/ethyl acetate) purifying and gets Compound I I-1b (36mg, 69%): mp 98-99 ℃;
1H-NMR (CDCl
3) δ ppm:7.62 (1H, s), 6.51 (1H, s), 6.43 (1H, s), 4.00 (3H, s), 3.98 (3H, s), 3.94 (3H, s), 3.87 (3H, s), 3.78 (3H, s).
Embodiment 32:2,3,8,9,10-pentamethyl--dibenzopyrans-6-ketone (II-2b)
Compound 2-iodo-3 by preparation in embodiment 31,4,5-trimethoxy-phenylformic acid (A, 360mg, 1.06mmol) with 3,4-syringol (164mg) makes compound 2 under upper routine similarity condition, 3-dimethoxy benzene-2-iodo-8,9,10-TMB (C, 404mg, 80%): white solid, 96 ℃ of mp; Get its 140mg, 0.3mmol) under upper routine reaction conditions coupling get Compound I I-2b (70mg, 67%), mp 174-176 ℃;
1H-NMR (CDCl
3) δ ppm:8.40 (1H, s), 7.34 (1H, s), 6.88 (1H, s), 4.05 (3H, s), 3.99 (9H, s), 3.96 (3H, s).
Embodiment 33: the anticancer growth test
Carry out this test with reference to the method described in [J.Natl.Cancer Inst.1990,82 (13): 1107-1112].In brief, with human cancer cell used (DU145, PC-3, A549, KB, KB-VIn etc.) be placed in single substratum (RPMI-1640 contains 10% (v/v) calf serum), the morphological specificity in nutrient solution and upgrowth situation check to cell with microscope.Cell is placed in 2.5cm
2Culture dish in, 37 ℃, contain 5%CO
2Cultivate in damp atmosphere.The clone adherent growth.Sample is prepared and is diluted and its process that is inoculated in enchylema be should be aseptic technique.Specimen is usually with DMSO dissolving ,-70 ℃ of preservations.In 96 well culture plates, each hole is placed in the specimen of different concns and about 5000-20000 cell, places 72 hours.The IC of anticancer growth
50Value is determined by SRB (sulforhodamine B) method.Cancer therapy drug homoharringtonine and VP16 are as positive control.
The part antitumour activity test result of the compounds of this invention sees Table 1.
The antitumour activity data of the representational formula I of table 1. and II compound
In table: DU145 and PC-3: prostate cancer cell; A549: lung carcinoma cell; KB: nasopharyngeal carcinoma cell; KB-VIN: drug-fast nasopharyngeal carcinoma cell is arranged.IC
50The effective concentration that suppresses the half growth of cancer cells, the expression antitumour activity.NA: unrestraint is active.This test above-mentioned human cancer cell used buys from U.S. ATCC, or available from the Lineberger Comprehensive Cancer Center of U.S. University of North Carolina (UNC-CH).
Claims (5)
1. have the compound of structure shown in any one in following general formula I-e, I-g, I-j,
Wherein:
X=H, F, Cl, Br or methoxyl group;
R
1And R '
1Can be identical or different, and be H, CHO, CH independently of one another
2OR
2, COOR
3, CH=YR
3R
4
Y＝C；
And
R
2Be H;
R
3Be H, NO
2, methyl;
R
4Be H, NO
2
2. the group that compound or its pharmacy acceptable salt, wherein said compound select free following compounds to form:
4,5,6-trimethoxy-2,2 '-dialdehyde-based biphenyl,
2-aldehyde-5 '-chloro-2 ', 4,5,6-tetramethoxy biphenyl,
2-aldehyde-5 '-chloro-4,5-methylenedioxy group-2 ' methoxyl biphenyl,
2-phenyl-3-methoxyl group-4,5-methylenedioxy group phenyl aldehyde,
2,2 '-dialdehyde-4,5-methylenedioxy group-6-methoxyl biphenyl,
2,2 '-dialdehyde-5,6-methylenedioxy group-4-methoxyl biphenyl,
5 '-chloro-6,2 '-dimethoxy-4 ', 5-methylenedioxy group biphenyl-2-aldehyde,
2-aldehyde-5 '-chloro-2 ', 4,5-trimethoxy biphenyl,
2 '-aldehyde radical-4,5,6-trimethoxy biphenyl-2 methyl-formiate,
2 '-aldehyde radical-4-methoxy-5,6-methylenedioxy group biphenyl-2-methyl-formiate,
2 '-aldehyde radical-4,5-first dioxy-6-methoxyl biphenyl 2-methyl-formiate,
2 '-aldehyde radical-3,4-first dioxy-5-methoxyl biphenyl 2-methyl-formiate,
5 '-chloro-5,2 '-dimethoxy-3,4-methylenedioxy group biphenyl-2-methyl-formiate,
5 '-chloro-3,2 '-dimethoxy-4 ', 5-methylenedioxy group biphenyl-2-methyl-formiate,
4,5,6-trimethoxy-2,2 '-two (2-nitro third-1-alkene) biphenyl,
4 ', 5 '-inferior methylenedioxy group-4,5,6-trimethoxy biphenyl-2,2 '-two camphoroyl methyl esters,
4 ', 5 '-inferior methylenedioxy group-4,5,6-trimethoxy biphenyl-2,2 '-the dibenzoyl methyl esters,
4,5,6-trimethoxy-4 ', 5 '-inferior first DOD 4,4′ dioxydiphenyl-2,2 '-the diformazan aldoxime,
5 '-chloro-4,5-first dioxy-2 '-methoxyl biphenyl-2-methyl alcohol,
4 ', 5 ', 5,6-secondary first dioxy-2 '-methylol-4-methoxyl biphenyl-2-methyl-formiate,
2-methoxy-3,4-methoxy-7-hydrogen-dibenzo epoxy heptan-5-ketone, and
1,3,8,9,10-pentamethoxyl-dibenzopyrans-6-ketone.
3. pharmaceutical composition, it comprises compound according to claim 1 and 2 and one or more pharmaceutical excipients of antitumor significant quantity.
4. the described compound of claim 1 or 2 is for the preparation of the purposes in anti-tumor drug.
5. according to claim 4 purposes, wherein said tumour is lung cancer, prostate cancer or nasopharyngeal carcinoma.
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