CN104230611B - A kind of 4-(1-substituted-phenyl vinyl) biphenyl derivatives and its preparation method and application - Google Patents

A kind of 4-(1-substituted-phenyl vinyl) biphenyl derivatives and its preparation method and application Download PDF

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CN104230611B
CN104230611B CN201410400569.7A CN201410400569A CN104230611B CN 104230611 B CN104230611 B CN 104230611B CN 201410400569 A CN201410400569 A CN 201410400569A CN 104230611 B CN104230611 B CN 104230611B
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salt
substituted
phenyl vinyl
biphenyl derivatives
biphenyl
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CN104230611A (en
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周有骏
孙囡囡
朱驹
吕加国
郑灿辉
蒋骏航
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Second Military Medical University SMMU
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Abstract

The present invention relates to a kind of 4-(1-substituted-phenyl vinyl) biphenyl derivatives and its preparation method and application.Described 4-(1-substituted-phenyl vinyl) biphenyl derivatives general structure is:

Description

A kind of 4-(1-substituted-phenyl vinyl) biphenyl derivatives and its preparation method and application
Technical field
The present invention relates to medical art, specifically, is a kind of 4-(1-substituted-phenyl vinyl) biphenyl derivatives and its preparation method and application.
Background technology
In recent years, malignant tumour has become the first cause of the death of urban and rural residents of China, and mortality ratio shows a rising trend.Current chemotherapeutics is the main method for the treatment of tumour, and wherein, molecular targeted agents has the feature clearer and more definite than traditional cell toxicant series antineoplastic medicament mechanism of action, specificity is higher, toxicity is low, is the Main way of current antitumor drug research.Due to tumour be polygene participate in, multi-signal impact multistage negotiation complex disease, in clinical therapy of tumor process, single target spot antitumor drug show tumor suppression spectrum single, easily there is the problems such as resistance.And the antitumor drug acting on multiple target spot effectively can cut off many tumorigenic pathways, there is better treatment advantage, single target drug can be avoided easily to produce the problems such as resistance simultaneously, become the hot fields of current antitumor drug research.
Tubulin is the important target of target treatment to tumor blood vessel.In three key agents binding sites of tubulin, colchicine site is because of the small volume of binding cavity, and the structure of corresponding inhibitor is simple, is more suitable for compared to taxol site and vinealeucoblastine(VLB) site the research carrying out micromolecular inhibitor.
Along with intracellular signal transduction pathway is revealed gradually, research finds that targeting can in breeding relevant path to Tumor Differentiation effectively grow and reduce Normocellular injury by Tumor suppression, therefore the protein kinase playing keying action in path has become the important target spot of drug screening, for finding that anti-tumor drugs targeting research that is efficient, low toxicity specifies direction.
Antitubulin and kinases inhibitor are two large hot fields of current antitumor drug research.The research experience of Antitubulin and multiple protein kinase inhibitor shows, the different inhibitor of some mechanism of action has similar structure, and even some Antitubulin demonstrates certain kinase inhibiting activity.Therefore design finds not only to act on tubulin but also kinase whose antineoplastic compound can be suppressed to be possible, and the exploitation multiple inhibiting agent with tubulin and protein kinase that is brand-new, efficient, low toxicity is also very necessary.
Summary of the invention
The object of the invention is for deficiency of the prior art, a kind of 4-(1-substituted-phenyl vinyl) biphenyl derivatives is provided.
Of the present invention again one object be that the pharmacy acceptable salt of described 4-(1-substituted-phenyl vinyl) biphenyl derivatives, solvate, precursor compound or polymorphic form are provided.
Another object of the present invention provides the preparation method of described 4-(1-substituted-phenyl vinyl) biphenyl derivatives.
4th object of the present invention, provides a kind of pharmaceutical composition.
5th object of the present invention, what provide described 4-(1-substituted-phenyl vinyl) biphenyl derivatives, its pharmacy acceptable salt, solvate, prodrug or polymorphic form is preparing the purposes in medicine.
For achieving the above object, the technical scheme that the present invention takes is:
A kind of 4-(1-substituted-phenyl vinyl) biphenyl derivatives, its general structure is:
Wherein, substituent R 1be positioned at 2,3,4,5,6, can be do not replace, monosubstituted, two replacement or polysubstituted, substituent R 1be selected from the one in following groups, two or more: hydrogen, halogen, itrile group, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 alkoxyl group, work as R 1during for two or three replacements, substituting group can be identical or different;
Preferably, substituent R 1be positioned at 2, 3, 4, 5 or 6, can be unsubstituted, mono-substituted, disubstituted, or it is polysubstituted, described substituting group is selected from the one in following groups, two or more: nitro, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, fluorine, chlorine, bromine, iodine, cyano group, amino, hydroxyl, single methyl fluoride, difluoromethyl, trifluoromethyl, monochloro methyl, dichloromethyl, trichloromethyl, single brooethyl, two brooethyls, trisbromomethyl, work as R 1during for two or three replacements, substituting group can be identical or different.
More excellent, substituent R 1being positioned at 2,3,4,5,6, is mono-substituted, two replacements or polysubstituted, described substituting group be selected from one in following groups, two or more: 2-NO 2, 3-NO 2, 4-NO 2, 2-CH 3, 3-CH 3, 4-CH 3, 2-OCH 3, 3-OCH 3, 4-OCH 3, 2-F, 3-F, 4-F, 2-CF 3, 3-CF 3, 4-CF 3, 2-CN, 3-CN, 4-CN, 2-NH 2, 3-NH 2, 4-NH 2, 2-OH, 3-OH, 4-OH, work as R 1during for two or three replacements, substituting group can be identical or different;
Most preferred, substituent R 1being positioned at 2,3,4,5 or 6, is mono-substituted, two replacements or polysubstituted, described substituting group be selected from one in following groups, two or more: 2-NO 2, 3-NO 2, 4-NO 2, 2-CH 3, 3-CH 3, 4-CH 3, 2-OCH 3, 3-OCH 3, 4-OCH 3, 2-F, 3-F, 4-F, 2-CF 3, 3-CF 3, 4-CF 3, 2-CN, 3-CN, 4-CN, 2-NH 2, 3-NH 2, 4-NH 2, 2-OH, 3-OH, 4-OH, 3,5-OCH 3, 2,4-F, 2,4-CH 3, 2,5-F, 3,5-F, 2,5-OCH 3, 2,3-CH 3;
Substituent R 2be positioned at 2 ', 3 ', 4 ', 5 ', 6 ' position, be do not replace, monosubstituted, two replacement or polysubstituted, substituent R 2be selected from the one in following groups, two or more: hydrogen, halogen, itrile group, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 alkoxyl group, work as R 2during for two or three replacements, substituting group can be identical or different;
Preferably, R 2be positioned at 2 ', 3 ', 4 ', 5 ', 6 ' position, be do not replace, monosubstituted, two replacement or polysubstituted, described substituting group be selected from one in following groups, two or more: straight or branched alkoxyl group, amino, hydroxyl, straight or branched acyloxy, straight or branched amido, work as R 2during for two replacement or three replacements, substituting group can be identical or different;
More excellent, substituent R 2being positioned at 2 ', 3 ', 4 ', 5 ', 6 ' position, is monosubstituted, two replacements or polysubstituted, described substituting group be selected from one in following groups, two or more: methoxyl group, hydroxyl, amino, acetoxyl group, kharophen, glycyl oxygen base, work as R 2during for two or three replacements, substituting group can be identical or different.
Most preferred, substituent R 2being positioned at 2 ', 3 ', 4 ', 5 ', 6 ' position, is monosubstituted, two replacements or polysubstituted, described substituting group be selected from one in following groups, two or more: 4-OCH 3, 2-NH 2, 3-NH 2, 4-NH 2, 3-OH-4-OCH 3, 2-NCOCH 3, 3-NCOCH 3, 4-NCOCH 3, 3-OCOCH 3-4-OCH 3, 3-OCOCH 2nH 2-4-OCH 3.
Except as otherwise noted, the straight or branched alkoxyl group of C1-8 of the present invention refers to the alkoxyl group containing 1-8 carbon atom, include but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, hexyloxy, heptan oxygen base or octyloxy.
Except as otherwise noted, the straight or branched alkyl of C1-8 of the present invention refers to and includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl or octyl group by the alkyl containing 1-8 carbon atom.
Except as otherwise noted, term halogen is haloid element substituting group, includes but not limited to fluorine, chlorine, bromine or iodine.
Wherein, the term " polysubstituted " in the present invention and " multiple " refer to three kinds or more, and what below occur is also identical meanings.
As one of the embodiment of the best, 4-of the present invention (1-substituted-phenyl vinyl) biphenyl derivatives is the particular compound as following table 1:
Table 14-(1-substituted-phenyl vinyl) biphenyl derivatives
For realizing above-mentioned second object, the technical scheme that the present invention takes is:
The pharmacy acceptable salt of described 4-(1-substituted-phenyl vinyl) biphenyl derivatives, solvate, precursor compound or polymorphic form.
Described pharmacy acceptable salt is inorganic salt, organic salt or amino acid salts.
Wherein, the example of inorganic salt comprises: hydrochloride, vitriol, phosphoric acid salt, diphosphate, hydrobromate or nitrate.
Wherein, the example of organic salt comprises: acetate, maleate, fumarate, tartrate, succinate, lactic acid salt, tosilate, salicylate, oxalate.
Wherein, the example of amino acid salts comprises: arginic acid salt, ornithine salt, lysine salt, leucine salt, Isoleucine salt, glycinate, cystine salt, cysteine salt, tyrosine salt, L-Ala salt, phenylalanine salt, Histidine salt, Serine salt, Threonine salt, methionine salt, tryptophane salt, glutaminate, aspartate, α-amino-isovaleric acid salt, methionine(Met) salt, proline salt or oxyproline salt.
For realizing above-mentioned 3rd object, the technical scheme that the present invention takes is:
Described 4-(1-substituted-phenyl vinyl) biphenyl derivatives preparation method, comprises the steps:
(1) 4-ethanoyl-1,1 '-biphenyl is prepared
Will to phenyl methyl ketone boric acid and bromobenzene be water-soluble and dioxane, add two (triphenyl phosphorus) Palladous chloride, cesium carbonate, backflow, reaction generates 4-ethanoyl-1,1 '-biphenyl.
(2) 4-ethanoyl-1,1 '-biphenyl Tosylhydrazone is prepared
4-ethanoyl-1,1 '-biphenyl and p-toluene sulfonyl hydrazide are refluxed in dehydrated alcohol, lets cool and separate out 4-ethanoyl-1,1 '-biphenyl Tosylhydrazone.
(3) 4-(1-substituted-phenyl vinyl) biphenyl is prepared
By 4-ethanoyl-1; 1 '-biphenyl Tosylhydrazone and bromobenzene are dissolved in dioxane; add two (acetonitrile) chlorination, two (diphenylphosphine) propane of 3-and cesium carbonate, nitrogen protection stirring and refluxing, generates 4-(1-substituted-phenyl vinyl) biphenyl.
Wherein, the preparation method of 4-(1-substituted-phenyl vinyl) biphenyl derivatives pharmacy acceptable salt can be prepared according to this area ordinary method, such as, carry out under normal conditions reacting with inorganic salt, organic salt or amino acid salts and obtain.
For realizing above-mentioned 4th object, the technical scheme that the present invention takes is:
A kind of pharmaceutical composition, it comprises the arbitrary described 4-of a) claims 1-5 (1-substituted-phenyl vinyl) biphenyl derivatives, the pharmacy acceptable salt of 4-according to claim 6 (1-substituted-phenyl vinyl) biphenyl derivatives, solvate, precursor compound or polymorphic form, and b) its pharmaceutically acceptable carrier.
Described pharmaceutical composition can be the pharmaceutical preparation of solid form or liquid form, and described pharmaceutical dosage form includes but not limited to tablet, capsule, powder agent, granule, suspensoid or injection.
For realizing above-mentioned 5th object, the technical scheme that the present invention takes is:
Described 4-(1-substituted-phenyl vinyl) biphenyl derivatives, its pharmacy acceptable salt, solvate, prodrug, polymorphic form or pharmaceutical composition are preparing the purposes in medicine, and described medicine is used for:
A) tubulin is suppressed;
B) arrestin kinases;
C) cancer that cytotoxic activity responds is treated;
D) treatment generates relevant disease with abnormal vascular;
E) colorectal carcinoma, lung cancer, mammary cancer or leukemia is treated.
Except as otherwise noted, in the present invention, said protein kinase is the protein kinase that tumor growth is relevant, includes but not limited to AKT, C-met or GSK3 β.
The present invention is by analyzing the character of binding site in colchicine crystalline complex structure and carry out docking simulation experiment, find that 4-of the present invention (1-substituted-phenyl vinyl) biphenyl derivatives has tubulin inhibit activities, and demonstrate it, to kinds of tumor cells, there is biological activity.
Further, present invention also offers described 4-(1-substituted-phenyl vinyl) biphenyl derivatives or the application of its pharmacologically acceptable salts in the medicine preparing the cancer that treatment cytotoxic activity responds.
Further, present invention also offers described 4-(1-substituted-phenyl vinyl) biphenyl derivatives or its pharmacologically acceptable salts and to generate application in the medicine of relevant disease in preparation treatment with abnormal vascular.
Further, present invention also offers described 4-(1-substituted-phenyl vinyl) biphenyl derivatives or the application of its pharmacologically acceptable salts in the medicine of preparation treatment tumor type disease.
Best, present invention also offers described 4-(1-substituted-phenyl vinyl) biphenyl derivatives or its pharmacologically acceptable salts for the preparation of the application in treatment colorectal carcinoma, lung cancer, mammary cancer or leukemia medicament.
In addition, present invention also offers the cancer that described 4-(1-substituted-phenyl vinyl) biphenyl derivatives or its pharmacologically acceptable salts be used for the treatment of and include but not limited to the cancer that the positions such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain and central nervous system occur and thyroid carcinoma, leukemia, Huo Jie king's evil and myelomatosis etc.
The invention has the advantages that:
Provide a kind of efficient, low toxicity, have multiple inhibiting effect antitumor, especially for the medicine of colorectal carcinoma knurl strain.Compound 4-of the present invention (1-substituted-phenyl vinyl) biphenyl derivatives can not only suppress tubulin, again can arrestin kinases, has better treatment advantage.
Embodiment
The present invention sets forth the present invention further by following examples and experimental example, but the present invention is not limited to this.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition of manufacturer's suggestion.
the preparation (in table 1 compound 1) of embodiment 14'-(1-(4-p-methoxy-phenyl) vinyl)-2 nitro biphenyl
(1) intermediate is prepared: 2-nitro-4 '-ethanoyl-1,1 '-biphenyl (II)
To phenyl methyl ketone boric acid (0.23g; 1.4mmol), 2-Nitrobromobenzene (I) (0.20g; 1mmol), cesium carbonate (0.489g; 1.5mmol) water-soluble (0.75ml) and dioxane (2.2ml); add two (triphenyl phosphorus) Palladous chloride (0.02g, 0.03mmol) again, nitrogen protection; 100 DEG C of return stirring 1hr, reaction solution is brown clear liquid.Reaction solution is slowly added in trash ice (400g), then stirs 1h.Add 15ml water, with ethyl acetate (10ml × 3) extraction, merge organic phase, anhydrous sodium sulfate drying, after filtering, underpressure distillation concentrates, and column chromatography for separation (PE:EtOAc=20:1), obtains white solid, yield 86%.Obtain intermediate (II);
(2) intermediate is prepared: 2-nitro-4 '-ethanoyl-1,1 '-biphenyl Tosylhydrazone (III)
Intermediate (II) (0.25g, 1.28mmol) and p-toluene sulfonyl hydrazide (0.2g, 1.53mmol) are dissolved in dehydrated alcohol (10ml), nitrogen protection, 110 DEG C of backflows.TLC detection reaction.Letting cool after reaction terminates, is white solid, yield 89%.Obtain intermediate (III);
(3) target product is prepared: 2-nitro-4 '-(1-(4-p-methoxy-phenyl)-1-vinyl) biphenyl (V)
By intermediate (III) (0.49g; 1.2mmol), two (acetonitrile) Palladous chloride (0.013g, 0.05mmol) and 1,3-two (diphenylphosphine) propane (0.04g, 10mol%) are dissolved in the dioxane of 10ml drying; nitrogen protection, stirring at room temperature 5 minutes.Add concentrated hydrochloric acid cesium carbonate (0.98g, 3mmol), nitrogen protection, in stirred at ambient temperature 1 minute.Add methoxybromobenzene (IV) (0.1g, 0.5mmol), nitrogen protection, 90 DEG C of reflux, stir.TLC detection reaction, question response terminates, and lets cool to room temperature, and add ethyl acetate and filter, underpressure distillation concentrates, and column chromatography for separation (PE:EtOAc=5:1), obtains white solid, productive rate 71%.Obtain title compound (V).
embodiment 2-7
Repeat embodiment 1, difference is: use different raw materials, thus obtained compound 2-7.Specific as follows:
By 3-methyl bromobenzene, 2-methoxybromobenzene, 3-methoxybromobenzene, 4-Nitrobromobenzene, 3-Nitrobromobenzene, 2-methyl bromobenzene respectively to phenyl methyl ketone boric acid is prepared into corresponding replacement to acetyl biphenyl; corresponding replacement 4 '-ethanoyl-1 is made again with p-toluene sulfonyl hydrazide; 1 '-biphenyl Tosylhydrazone, finally generates compound 2,3,4,5,6,7 in table 1 respectively again and to methoxybromobenzene reaction.
the preparation (in table 1 compound 8) of embodiment 8:4'-(1-(3-acetoxyl group-4-p-methoxy-phenyl) vinyl)-3,5-dimethoxy-biphenyls
(1) intermediate is prepared: 3,5-dimethoxy-4 ' '-ethanoyl-1,1 '-biphenyl (VII)
To phenyl methyl ketone boric acid (0.23g; 1.4mmol), 3; 5-dimethoxy bromobenzene (VI) (0.22g; 1mmol), cesium carbonate (0.489g, 1.5mmol) water-soluble (0.75ml) and dioxane (2.2ml), then add two (triphenyl phosphorus) Palladous chloride (0.02g; 0.03mmol); nitrogen protection, 100 DEG C of return stirring 1hr, reaction solution is brown clear liquid.Reaction solution is slowly added in trash ice (400g), then stirs 1h.Add 15ml water, with ethyl acetate (10ml × 3) extraction, merge organic phase, anhydrous sodium sulfate drying, after filtering, underpressure distillation concentrates, and column chromatography for separation (PE:EtOAc=20:1), obtains white solid, yield 86%.Obtain intermediate (VII);
(2) intermediate is prepared: 3,5-dimethoxy-4 ' '-ethanoyl-1,1 '-biphenyl Tosylhydrazone (VIII)
Intermediate (VII) (0.25g, 1.28mmol) and p-toluene sulfonyl hydrazide (0.2g, 1.53mmol) are dissolved in dehydrated alcohol (10ml), nitrogen protection, 110 DEG C of backflows.TLC detection reaction.Letting cool after reaction terminates, is white solid, yield 89%.Obtain intermediate (VIII);
(3) target product is prepared: 3,5-dimethoxy-4 ' '-(1-(3-acetoxyl group-4-p-methoxy-phenyl)-1-vinyl) biphenyl (Ⅹ)
By intermediate (VIII) (0.49g; 1.2mmol), two (acetonitrile) Palladous chloride (0.013g, 0.05mmol) and 1,3-two (diphenylphosphine) propane (0.04g, 10mol%) are dissolved in the dioxane of 10ml drying; nitrogen protection, stirring at room temperature 5 minutes.Add concentrated hydrochloric acid cesium carbonate (0.98g, 3mmol), nitrogen protection, in stirred at ambient temperature 1 minute.Add 3-acetoxyl group-4 methoxybromobenzene (Ⅸ) (0.1g, 0.5mmol), nitrogen protection, 90 DEG C of reflux, stir.TLC detection reaction, question response terminates, and lets cool to room temperature, and add ethyl acetate and filter, underpressure distillation concentrates, and column chromatography for separation (PE:EtOAc=5:1), obtains white solid, productive rate 31%.Obtain title compound (Ⅹ).
embodiment 9-35:
Repeat embodiment 8, difference is: use different raw materials, thus obtained compound 9-35.Specific as follows:
By 2-Nitrobromobenzene, 2,4-difluoro bromobenzene, 4-trifluoro-methoxyl bromobenzene, 3-methyl bromobenzene, 2-methoxybromobenzene, 4-methoxybromobenzene, 2,4-dimethyl bromobenzene, 2-cyano group bromobenzene, 3-trifluoro-methoxyl bromobenzene, 2,5-difluoro bromobenzene, 3,5-difluoro bromobenzene, 2-trifluoro-methoxyl bromobenzene, 3-cyano group bromobenzene, 3-methoxybromobenzene, 4-Nitrobromobenzene, 3-Nitrobromobenzene, 2,5-dimethoxy bromobenzene, 4-methyl bromobenzene, 3-bromofluorobenzene, 4-bromofluorobenzene, 2-methyl bromobenzene, the amino bromobenzene of 2-, the amino bromobenzene of 3-, the amino bromobenzene of 4-, 2,3-dimethyl bromobenzene, 2-methyl bromobenzene trifluoride, 4-cyano group bromobenzene respectively to phenyl methyl ketone boric acid is prepared into corresponding replacement to acetyl biphenyl, corresponding replacement 4 '-ethanoyl-1 is made again with p-toluene sulfonyl hydrazide, 1 '-biphenyl Tosylhydrazone, finally generates compound 9 in table 1 with the reaction of 3-acetoxyl group-4 methoxybromobenzene respectively again, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35.
the preparation (in table 1 compound 36) of embodiment 36:4'-(1-(3-hydroxyl-4-p-methoxy-phenyl) vinyl)-3,5-dimethoxy-biphenyls
(1) intermediate is prepared: 3,5-dimethoxy-4 ' '-ethanoyl-1,1 '-biphenyl (VII)
To phenyl methyl ketone boric acid (0.23g; 1.4mmol), 3; 5-dimethoxy bromobenzene (VI) (0.22g; 1mmol), cesium carbonate (0.489g, 1.5mmol) water-soluble (0.75ml) and dioxane (2.2ml), then add two (triphenyl phosphorus) Palladous chloride (0.02g; 0.03mmol); nitrogen protection, 100 DEG C of return stirring 1hr, reaction solution is brown clear liquid.Reaction solution is slowly added in trash ice (400g), then stirs 1h.Add 15ml water, with ethyl acetate (10ml × 3) extraction, merge organic phase, anhydrous sodium sulfate drying, after filtering, underpressure distillation concentrates, and column chromatography for separation (PE:EtOAc=20:1), obtains white solid, yield 86%.Obtain intermediate (VII);
(2) intermediate is prepared: 3,5-dimethoxy-4 ' '-ethanoyl-1,1 '-biphenyl Tosylhydrazone (VIII)
Intermediate (VII) (0.25g, 1.28mmol) and p-toluene sulfonyl hydrazide (0.2g, 1.53mmol) are dissolved in dehydrated alcohol (10ml), nitrogen protection, 110 DEG C of backflows.TLC detection reaction.Letting cool after reaction terminates, is white solid, yield 89%.Obtain intermediate (VIII);
(3) target product is prepared: 3,5-dimethoxy-4 ' '-(1-(3-acetoxyl group-4-p-methoxy-phenyl)-1-vinyl) biphenyl (Ⅺ)
By intermediate (VIII) (0.49g, 1.2mmol), two (acetonitrile) Palladous chloride (0.013g, 0.05mmol) and 1; two (diphenylphosphine) propane (0.04g of 3-; 10mol%) be dissolved in the dioxane of 10ml drying, nitrogen protection, stirring at room temperature 5 minutes.Add concentrated hydrochloric acid cesium carbonate (0.98g, 3mmol), nitrogen protection, in stirred at ambient temperature 1 minute.Add 3-acetoxyl group-4 methoxybromobenzene (Ⅸ) (0.1g, 0.5mmol), nitrogen protection, 90 DEG C of reflux, stir.TLC detection reaction, question response terminates, and lets cool to room temperature, and add ethyl acetate and filter, underpressure distillation concentrates, and column chromatography for separation (PE:EtOAc=5:1), obtains white solid, productive rate 37%.Obtain title compound (Ⅺ).
embodiment 37-67:
Repeat embodiment 36, difference is: use different raw materials, thus obtained compound 37-67.Specific as follows:
By 2-Nitrobromobenzene, 2,4-difluoro bromobenzene, 4-trifluoro-methoxyl bromobenzene, 4-methyl bromobenzene trifluoride, 3-methyl bromobenzene, 2-methoxybromobenzene, 3-methyl bromobenzene trifluoride, 4-methoxybromobenzene, 2,4-dimethyl bromobenzene, 2-cyano group bromobenzene, 3-trifluoro-methoxyl bromobenzene, 2,5-difluoro bromobenzene, 3,5-difluoro bromobenzene, 2-trifluoro-methoxyl bromobenzene, 3-cyano group bromobenzene, 3-methoxybromobenzene, 4-Nitrobromobenzene, 3-Nitrobromobenzene, 2,5-dimethoxy bromobenzene, 4-methyl bromobenzene, 3-bromofluorobenzene, 4-bromofluorobenzene, 2-methyl bromobenzene, the amino bromobenzene of 2-, the amino bromobenzene of 3-, the amino bromobenzene of 4-, 2,3-dimethyl bromobenzene, 2-methyl bromobenzene trifluoride, 4-cyano group bromobenzene, 3-bromophenol, 4-bromophenol respectively to phenyl methyl ketone boric acid is prepared into corresponding replacement to acetyl biphenyl, corresponding replacement 4 '-ethanoyl-1 is made again with p-toluene sulfonyl hydrazide, 1 '-biphenyl Tosylhydrazone, finally generates compound 36 in table 1 with the reaction of 3-acetoxyl group-4 methoxybromobenzene respectively again, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67.
the preparation (in table 1 compound 68) of embodiment 68:4'-(1-(4-aminophenyl) vinyl)-4-trifluoromethyl-biphenyl
By table 1 compound 37 (0.57g; 1.82mmol) be dissolved in 20ml methylene dichloride; 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.76g is added under condition of ice bath; 4.00mmol) with N-methylmorpholine (0.65ml; 6.00ml), Boc-glycine (0.35g; 2.01mmol), nitrogen protection, stirring at room temperature.Reaction in 3 hours terminates, and adds 100ml methylene dichloride, washing (50ml × 3), saturated sodium-chloride is washed (50ml × 3), anhydrous sodium sulfate drying, underpressure distillation, column chromatography for separation (PE:EtOAc=20:1), obtains compound (XVIII).
Added by saturated salt acid ether in compound (XVIII), stirring at room temperature, dissolve, separate out yellow solid after 10 minutes, add anhydrous diethyl ether and filter, solid is the compound (XIX) as shown in title.Yield 78%.
embodiment 69-75
Repeat embodiment 68, difference is: use different raw materials, thus obtained compound 69-75.Specific as follows:
With compound in table 1 41,56,44,52,53,54,59 respectively with Boc-glycine reactant, then carry out de-Boc reaction, generate compound 69,70,71,72,73,74,75 in table 1.
the preparation (in table 1 compound 76) of embodiment 76:4'-(1-(4-aminophenyl) vinyl)-4-trifluoromethyl-biphenyl
Compound (XVI) (0.2g, 0.5mmol) and potassium hydroxide (0.35g, 6mmol) are dissolved in 5ml water and 10ml methyl alcohol, 55 DEG C of stirrings, TLC monitors reaction, to reacting end, underpressure distillation, adds 15ml water, extracts by ethyl acetate (10ml × 3), merge organic phase, anhydrous sodium sulfate drying, underpressure distillation after filtering, obtains white solid, be as topic compound, yield 90%.
embodiment 77-90:
Repeat embodiment 76, difference is: use different raw materials, thus obtained compound 77-90.Specific as follows:
Be hydrolyzed with methyl alcohol respectively by compound in table 1 92,93,94,95,96,97,98,99,100,101,102,103,104,105, reacting phase should generate compound 77,78,79,80,81,82,83,84,85,86,87,88,89,90 in table 1.
the preparation (in table 1 compound 91) of embodiment 91:4'-(1-(4-acetylamino phenyl) vinyl)-4-trifluoromethyl-biphenyl
(1) intermediate is prepared: 4-trifluoromethyl-4 '-ethanoyl-1,1 '-biphenyl (XIII)
To phenyl methyl ketone boric acid (0.23g; 1.4mmol), 3; 5-dimethoxy bromobenzene (XII) (0.22g; 1mmol), cesium carbonate (0.489g, 1.5mmol) water-soluble (0.75ml) and dioxane (2.2ml), then add two (triphenyl phosphorus) Palladous chloride (0.02g; 0.03mmol); nitrogen protection, 100 DEG C of return stirring 1hr, reaction solution is brown clear liquid.Reaction solution is slowly added in trash ice (400g), then stirs 1h.Add 15ml water, with ethyl acetate (10ml × 3) extraction, merge organic phase, anhydrous sodium sulfate drying, after filtering, underpressure distillation concentrates, and column chromatography for separation (PE:EtOAc=20:1), obtains white solid, yield 86%.Obtain intermediate (XIII);
(2) intermediate is prepared: 4-trifluoromethyl-4 '-ethanoyl-1,1 '-biphenyl Tosylhydrazone (XIV)
Intermediate (XIII) (0.25g, 1.28mmol) and p-toluene sulfonyl hydrazide (0.2g, 1.53mmol) are dissolved in dehydrated alcohol (10ml), nitrogen protection, 110 DEG C of backflows.TLC detection reaction.Letting cool after reaction terminates, is white solid, yield 89%.Obtain intermediate (XIV);
(3) target product is prepared: 4-trifluoromethyl-4 '-(1-(2-acetylamino phenyl)-1-vinyl) biphenyl (Ⅺ)
By intermediate (XIV) (0.49g, 1.2mmol), two (acetonitrile) Palladous chloride (0.013g, 0.05mmol) and 1; two (diphenylphosphine) propane (0.04g of 3-; 10mol%) be dissolved in the dioxane of 10ml drying, nitrogen protection, stirring at room temperature 5 minutes.Add concentrated hydrochloric acid cesium carbonate (0.98g, 3mmol), nitrogen protection, in stirred at ambient temperature 1 minute.Add 3-acetoxyl group-4 methoxybromobenzene (XV) (0.1g, 0.5mmol), nitrogen protection, 90 DEG C of reflux, stir.TLC detection reaction, question response terminates, and lets cool to room temperature, and add ethyl acetate and filter, underpressure distillation concentrates, and column chromatography for separation (PE:EtOAc=5:1), obtains white solid, productive rate 70%.Obtain title compound (XVI).
embodiment 92-95:
Repeat embodiment 91, difference is: use different raw materials, thus obtained compound 92-95, specific as follows:
By 2-methyl bromobenzene, the amino bromobenzene of 2-, 2-methyl bromobenzene trifluoride, 3-methyl bromobenzene trifluoride respectively to phenyl methyl ketone boric acid is prepared into corresponding replacement to acetyl biphenyl; corresponding replacement 4 '-ethanoyl-1 is made again with p-toluene sulfonyl hydrazide; 1 '-biphenyl Tosylhydrazone, finally generates compound 92,93,94,95 in table 1 with the reaction of 2-kharophen bromobenzene respectively again.Obtain white solid, productive rate 70%.Obtain title compound (XVI).
embodiment 96-100:
Repeat embodiment 91, difference is: use different raw materials, thus obtained compound 96-100.Specific as follows:
By 4-methyl bromobenzene trifluoride, 2-methyl bromobenzene, the amino bromobenzene of 2-, 2-methyl bromobenzene trifluoride, 3-methyl bromobenzene trifluoride respectively to phenyl methyl ketone boric acid is prepared into corresponding replacement to acetyl biphenyl; corresponding replacement 4 '-ethanoyl-1 is made again with p-toluene sulfonyl hydrazide; 1 '-biphenyl Tosylhydrazone, finally generates compound 96,97,98,99,100 in table 1 with the reaction of 3-kharophen bromobenzene respectively again.
embodiment 101-105:
Repeat embodiment 91, difference is: use different raw materials, thus obtained compound 101-105.Specific as follows:
By 4-methyl bromobenzene trifluoride, 2-methyl bromobenzene, the amino bromobenzene of 2-, 2-methyl bromobenzene trifluoride, 3-methyl bromobenzene trifluoride respectively to phenyl methyl ketone boric acid is prepared into corresponding replacement to acetyl biphenyl; corresponding replacement 4 '-ethanoyl-1 is made again with p-toluene sulfonyl hydrazide; 1 '-biphenyl Tosylhydrazone, finally generates compound 101,102,103,104,105 in table 1 with the reaction of 4-kharophen bromobenzene respectively again.
The chemical structure of the target product that the present invention has synthesized is in table 1.Nucleus magnetic hydrogen spectrum, mass spectrometer system characterize the chemical structure of target product, the part of compounds chemical structure of synthesis and 1h-NMR data are in table 2, and mass spectrum, melting point data are in table 3.
The chemical structure of table 2 part of compounds and 1h-NMR data
NT=undetermined;
Compound 1-105 is respectively the compound prepared in embodiment 1-105.
The chemical structure of table 3 part of compounds and mass spectrum, melting point data
embodiment 106: the Inhibiting enzyme activity biological assay of the compounds of this invention
1. experiment material
Table 4 experiment material
2. testing method:
Utilize the method for MobilityShiftAssay when KmATP, AKT1, GSK3 β, c-MET kinases screens compound.
Test compounds concentration is inhibiting rate when 20 μMs.
Experimental technique and result provide by the wise and farsighted chemistry in Shanghai.
3. kinase activity test result:
Table 5 kinase activity test result
embodiment 107: the suppression tubulin activity experiment of the compounds of this invention
One, experiment material and method
1. experiment material: ox tubulin (manufacturer: Cytoskeleton).Damping fluid GeneralTubulinBuffer:80mMPIPESpH=6.9,2mMMgCl 2, 0.5mMEGTA.TubulinGlycerolBuffer:60%glycerol。GTP:100mM。DMSO(Merck)。96 hole half area culture plates.Instrument: the full-automatic microplate reader of Synergy4 type (production firm: BioTek).
2. experimental technique:
Step one: use DMSO sample dissolution, adds damping fluid GeneralTubulinBuffer and is made into the solution that concentration is 40 μMs.
Step 2: added by the testing compound prepared in 96 well culture plates, every hole 10 μ L, puts in microplate reader, equilibrium temperature to 37 DEG C.
Step 3: tubulin is dissolved in polymerization damping fluid, adds in testing compound, every hole 100 μ L, duplicate hole, 37 DEG C, and per minute surveys 340nmOD value.Draw absorbance curve.
Step 4: calculate IC 50, tubulin polymerization inhibiting rate %=(blank well OD max-test hole OD max)/blank well OD max× 100%.
Two, experimental result
Table 6 suppresses tubulin activity test result
Above-mentioned experimental result display, this compounds has tubulin polymerization inhibit activities 40 μMs time, can further investigate as antitumor drug.
embodiment 108: this series compound inhibition tumor cell proliferation experiment
One, test method
1. sample preparation:
With DMSO(Merck) dissolve after, add PBS (-) and be made into the solution of 1000mg/ml or uniform suspension, then dilute with the PBS (-) containing DMSO.Positive control drug adopts Zorubicin (DOX).
2. cell strain
1) A549(human lung carcinoma cell);
2) HCT116(human colon cancer cell);
3) MDA-MB-23(human breast cancer cell);
Test tumor cell line provides by Shanghai Institute of Pharmaceutical Industry's Pharmacology Lab.
3. nutrient solution
DMEM+5-10%FBS+ is dual anti-.
4. other materials
Full-automatic microplate reader:
Model: WellscanMK-2.
Production firm: Labsystems.
Import 96 well culture plate etc.
5. test method
Mtt assay.It is 4 ~ 5 × 10 that the 96 every holes of orifice plate add concentration 4the cell suspension 100ml of individual/ml, puts 37 DEG C, 5%CO 2in incubator.After 24h, add sample liquid, 10ml/ hole, if duplicate hole, 37 DEG C, 5%CO 2effect 72h.Every hole adds the MTT solution 20ml of 5mg/ml, adds lysate, 100ml/ hole, put in incubator after effect 4h, surveys 570nmOD value after dissolving by the full-automatic microplate reader of MK-2.
Two, activity data
Table 7 compound on tumor cyto-inhibition
As known from Table 7, compound of the present invention has inhibit activities to lung cell A549, colon cancer cell HCT116, breast cancer cell MDA-MB-23, particularly to colon cancer cell HCT116, shows good anti-tumor activity.Specific value obtains it is noted that part of compounds shows in-vitro multiplication restraining effect that is higher, wide spectrum as 20,59,60 and 64, and this is be developed as antitumor drug that is efficient, novel, high specificity to lay a good foundation, and has good Development volue.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.

Claims (5)

1. 4-(1-substituted-phenyl vinyl) biphenyl derivatives, is characterized in that, shown in described derivant structure general formula following (I):
Described 4-(1-substituted-phenyl vinyl) biphenyl derivatives be following in one:
2. the pharmacy acceptable salt of 4-according to claim 1 (1-substituted-phenyl vinyl) biphenyl derivatives.
3. pharmacy acceptable salt according to claim 2, is characterized in that,
Described pharmacy acceptable salt is inorganic salt, organic salt or amino acid salts;
Wherein inorganic salt are: hydrochloride, vitriol, phosphoric acid salt, diphosphate, hydrobromate or nitrate;
Wherein organic salt is: acetate, maleate, fumarate, tartrate, succinate, lactic acid salt, tosilate, salicylate, oxalate;
Wherein amino acid salts is: arginic acid salt, ornithine salt, lysine salt, leucine salt, Isoleucine salt, glycinate, cystine salt, cysteine salt, tyrosine salt, L-Ala salt, phenylalanine salt, Histidine salt, Serine salt, Threonine salt, methionine salt, tryptophane salt, glutaminate, aspartate, α-amino-isovaleric acid salt, methionine(Met) salt, proline salt or oxyproline salt.
4. a pharmaceutical composition, it is characterized in that, it comprises one or more of the pharmacy acceptable salt of a) 4-described in claims 1 (1-substituted-phenyl vinyl) biphenyl derivatives, 4-according to claim 2 (1-substituted-phenyl vinyl) biphenyl derivatives, and b) its pharmaceutically acceptable carrier.
5. 4-according to claim 1 (1-substituted-phenyl vinyl) biphenyl derivatives, the pharmacy acceptable salt of 4-according to claim 2 (1-substituted-phenyl vinyl) biphenyl derivatives, or pharmaceutical composition according to claim 4 is preparing the purposes in medicine, it is characterized in that, described medicine is used for:
A) tubulin is suppressed;
B) arrestin kinases;
C) cancer that cytotoxic activity responds is treated;
D) colorectal carcinoma, lung cancer, mammary cancer or leukemia is treated;
Described b) middle kinases is AKT1, GSK3 β, c-MET kinases; Described c) middle cell is lung cell A549, colon cancer cell HCT116 or breast cancer cell MDA-MB-23.
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Citations (1)

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US4613208A (en) * 1982-11-29 1986-09-23 Hoffmann-La Roche Inc. Coloring substance-containing liquid crystal mixtures

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Publication number Priority date Publication date Assignee Title
US4613208A (en) * 1982-11-29 1986-09-23 Hoffmann-La Roche Inc. Coloring substance-containing liquid crystal mixtures

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Kwan, Man Lung等.A convenient one-pot organoaluminum mediated vinylsilane synthesis from non-enolizable ketones via the Peterson protocol.《Tetrahedron Letters》.2002, *
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