CN103012248A - Synthesis of amino combretastatin derivative and application of amino combretastatin derivative as oral antitumour drug - Google Patents

Synthesis of amino combretastatin derivative and application of amino combretastatin derivative as oral antitumour drug Download PDF

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CN103012248A
CN103012248A CN2013100110609A CN201310011060A CN103012248A CN 103012248 A CN103012248 A CN 103012248A CN 2013100110609 A CN2013100110609 A CN 2013100110609A CN 201310011060 A CN201310011060 A CN 201310011060A CN 103012248 A CN103012248 A CN 103012248A
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acid
amino
trimethoxyphenyl
ethene
formyl radical
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CN103012248B (en
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王建平
王建国
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Zhejiang Dade Pharmaceutical Group Co Ltd
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Zhejiang Dade Pharmaceutical Group Co Ltd
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses a compound which is shown as a formula (I) and used for inhibiting generation of tumour neovascularization as well as officinal salt or a configurational isomer thereof, wherein substituent groups R1, R2 and R3 are defined in the specification. The invention also discloses a preparation method of the compound in the formula (I), a pharmaceutical composition and an application of the compound as a microtubulin inhibitor in the aspect of inhibiting the tumour neovascularization, especially an application as an oral preparation.

Description

Amino combretastatin derivative synthetic and as the application of oral antitumor drug
Technical field
The invention belongs to medical technical field, relate to a series of Combretastatin (Combretastatin) A4 derivative and preparation method thereof, and the purposes in the preparation Antitubulin.
Background technology
The Combretastatins series compound extracts to separate from the Combretum caffrum trunk of South Africa at first and obtains.It has anti-tumor activity, can directly act on endotheliocyte, induces the endothelial cell apoptosis of propagation, thereby suppresses tumor neovasculature generation, reaches the purpose of tumors destroyed.The Combretastatins series compound has cis stilbene structure.Combretastatin A-4[CA-4 wherein, Combretastatin, cis-1-(3,4, the 5-trimethoxy) phenyl-2-(3 '-hydroxyl-4 '-methoxyl group) phenyl ethene] have a strongest inhibition microtubule polymerization effect (Pettit G R, etal.J.Med.Chem (1995) 38 1666-1672).Recently, because CA-4 as tumor vascular targeting reagent, demonstrates it and blocks tumor vascular good characteristic (Thorpe PE.Clin Cancer Res.2004Jan 15,10 (2): 415-27; West CM, Price P.Anticancer Drugs.2004 Mar, 15 (3): 179-87; Young SL, Chaplin DJ.Expert Opin Investig Drugs.2004Sep, 13 (9): 1171-82.).U.S. Oxigene, Inc. company as anti-cancer agent, has entered the clinical study of III phase with CA-4.The people such as the T.Hatanaka of Japanese Ajincomoto Co., Inc (Ajinomoto Co.) in 1997 find the hydroxyl of 3 of CA-4 ' position is transformed into amino, and its antitumour activity improves (USP5674906) greatly.
But Combretastatins series compound water-soluble very poor is very restricted its clinical application.And after the hydroxyl of 3 of CA-4 ' position is transformed into amino, at present common CA-4 is transformed into its phosphatic method and inapplicable.Although Japanese Ajincomoto Co., Inc modifies amino CA-4 with amino acid, increased that it is water-soluble, making it become injection can use cancer patient.But its using method still has inconvenience.Therefore, the present invention will provide a kind of new amino CA-4 derivative, and this compound absorbs by digestive tube, and arrives each position of whole body by blood-transmitted, various tumours is had certain curative effect, especially liver cancer and colorectal carcinoma.
Summary of the invention
The invention provides a kind of compound or its pharmacy acceptable salt that following logical formula I represents that contain:
Figure BDA00002729490000021
(Ⅰ)
Wherein
R 1Be independently selected from C 1-C 3Alkyl, haloalkyl;
R 2Be independently selected from hydrogen, methyl, ethyl, halogen;
R 3Be can be optionally substituted contain one or more heteroatomic heterocycles or Heterocyclylalkyl, wherein having a heteroatoms at least is N.
In formula I compound of the present invention, preferably have general formula II (a) or II (b) compound:
Figure BDA00002729490000022
Ⅱa
Figure BDA00002729490000023
Ⅱb
Wherein
R 1Be independently selected from C 1-C 3Alkyl, haloalkyl;
R 2Be independently selected from hydrogen, methyl, ethyl, halogen;
R 4Be independently selected from hydrogen, C 1-C 3Alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic aryl, Heterocyclylalkyl, alkyloyl, carbalkoxy;
R 5Be independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyano group, NR aR b, NR dC (O) R c, C (O) NR aR b, S (O) 2NR aR b, NR dS (O) 2R c, NR d(CH 2) nR c, (CH 2) nNR aR b, NHC (O) NH R c, (CH 2) nNHC (O) R c, NHC (NH) R c
R a, R bBe independently selected from respectively hydrogen, alkyl, cycloalkyl, or can form one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl with N, O, S atom;
R cBe independently selected from alkyl, cycloalkyl, aryl, heterocyclic aryl, Heterocyclylalkyl;
R dBe independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclic aryl;
Above-described alkyl, cycloalkyl, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical, Heterocyclylalkyl can be replaced by following any one or a plurality of group: halogen, amino, alkylamino, dialkylamine, acid amides, aryl, heterocyclic radical, nitro, cyano group, carboxyl, carbalkoxy, hydroxyl, alkoxyl group, acyloxy,=O ,=S ,=NH.
Formula I compound of the present invention or its pharmacy acceptable salt, wherein said compound more preferably from:
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-difluoro-methoxy phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-trifluoro ethoxy phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-hydroxymethyl piperidine-4-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-and 1-(3,4,5-trimethoxyphenyl)-2-(3-(2-pyrryl piperidines-4-formyl radical)) amino-4-methoxyl phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(pyridine-3-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(2-kharophen pyridine-5-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-and 1-(3,4,5-trimethoxyphenyl)-2-(3-(2-5-flumethiazine-5-formyl radical)) amino-4-methoxyl phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(2-fluorine pyridine-5-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-1-fluoro-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-1-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-methoxyl phenyl) ethene.
Formula I compound of the present invention is acceptable salt pharmaceutically, or contain at least one alkaline salt forming group, with the acid of its salify can be mineral acid or the organic acid of pharmaceutically commonly using, comprise mineral acid: hydrochloric acid, sulfuric acid, phosphoric acid; Organic carboxyl acid: acetic acid, propionic acid, trifluoroacetic acid, oxyacetic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, oxalic acid, various natural or synthetic amino acid, phenylformic acid, Whitfield's ointment, 4-ASA, amygdalic acid, styracin, nicotinic acid, γ-picolinic acid; Organic sulfonic acid: methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, 2-naphthene sulfonic acid.When having a plurality of basic group, can generate the polyacid additive salt.
Compound of the present invention and pharmacy acceptable salt also comprise the form of solvate or hydrate.In general, the form form of solvate or hydrate and non-solvent or non-hydrated is equal to, and contains within the scope of the invention in the lump.Some compound among the present invention might exist polycrystal or unbodied form.Generally speaking, all physical form have equal purposes, and contain within the scope of the invention.
All steric isomers of the compounds of this invention that is form of mixtures or is pure form are contained in the present invention.The definition of the compounds of this invention comprises all possible steric isomer and composition thereof.It comprises racemic form and the optical isomer with given activity that separates very particularly.Racemic form can split by physical method, and described physical method is such as the diastereomer derivative being carried out fractional crystallization, separation or separating by the chiral column chromatogram.Can by ordinary method for example optical activity acid form salify follow crystallization and obtain independent optical isomer from racemic modification.
In addition, the present invention also provides the method for synthetic formula I compound.Its technological process is as follows:
Figure BDA00002729490000051
Ⅱa Ⅱb
Synthetic method of the present invention obtains corresponding microcosmic salt after reacting by the bromo of compound VII, with triphenylphosphine, again microcosmic salt and compound VIII is reacted the toluylene structure (IV) that obtains cis by wittig.Toluylene becomes amino as reductive agent with the nitroreduction in the structure with the samarium metal powder with dibromo dioctyl dipyridyl, has just obtained amino compete A-4 (III).Then take amino compete A-4 as raw material, connect into acid amides (structure II a or II b) with pyridine carboxylic acid or the piperidine carboxylic acid method by acyl chlorides or active ester, obtain final product with sour salify at last.
The invention still further relates to the pharmaceutical composition of acceptable carrier on the formula I compound that comprises significant quantity and the pharmacology, that said composition is applicable to is local, in the intestines or the outer administration of intestines, can be inorganic or organic, solid-state or liquid.For oral, especially with tablet or capsule.This tablet or capsule comprise activeconstituents and thinner (such as lactose, glucose, sucrose, mannitol, sorbyl alcohol, Mierocrystalline cellulose, glycerol), lubricant (such as talcum, stearate), polyoxyethylene glycol.Tablet also can comprise tackiness agent, starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone also can comprise disintegrator (such as starch, agar, alginic acid and salt thereof), effervescent mixture, or sorbent material in case of necessity, dyestuff, seasonings, sweetener.These compositions can also administered parenterally form or be suitable for the form of injection.The preferred isotonic aqueous solution of this type of formulation or emulsion, as in the situation of the lyophilised compositions that only is comprised of activeconstituents and a kind of carrier (such as N.F,USP MANNITOL), this type of solution can prepare before use.These pharmaceutical compositions can be aseptic, or comprise vehicle, or the salt of solubilizing agent, adjusting osmotic pressure.
The invention still further relates to the application of formula I compound in the medicine of the disease that the improper new vessel of preparation treatment causes.The disease that improper new vessel causes comprises various tumours, mainly contains: lung cancer, small cell lung cancer, liver cancer, carcinoma of the pancreas, cancer of the stomach, osteocarcinoma, esophagus cancer, mastocarcinoma, kidney, cholangiocarcinoma, prostate cancer, carcinoma of testis, colorectal carcinoma, ovarian cancer, bladder cancer, cervical cancer, bronchogenic carcinoma, melanoma, gland cancer, syringocarcinoma, papillary carcinoma, papillary carcinoma, squamous cell carcinoma, rodent cancer, adenocarcinoma cystic, glioma, astrocytoma, medulloblastoma, neuroblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, oligodendroglioma, meningioma, neurofibroma, fibrosarcoma, fibroblastoma, fibroma, myxosarcoma, myxocystoma, lipoma, lipoadenoma, chondrosarcoma, chondroma, chondromyoma, chordoma, chorioadenoma, the villous vessels knurl, the chorioepithelium knurl, chorioblastoma, osteosarcoma, osteoblastoma, osteoclastoma, osteochondrofibroma, osteochondrosarcoma, the thigh cystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, vascular tumor, angiosarcoma, lymphangiosarcoma, lymphangioma, lymphoma, endothelioma, synovioma, synovial sarcoma, mesothelioma, mesocytoma, ewing's tumor, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdosarcoma, kemia, acute myelogenous leukemia, chronic leukemia, polycyth(a)emia, multiple myeloma.
The disease that improper new vessel causes also comprises: rheumatic arthritis, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, psoriasis, acne erythematosa, kaposi's sarcoma, specific reaction keratitis, epidemic keratoconjunctivitis, neovascular glaucoma, bacterial canker, mycotic ulcer, herpes-ness progenitalis infection, zoster infects, protozoal infections, mycobacterium infects, polyarteritis, sarcoid, scleritis, flush, the dry sacroiliitis syndromes of dry eye, systemic lupus erythematosus, AIDS, syphilis.
The invention still further relates to the application of formula I compound in preparation tubulin aggregation inhibitor.
The present invention also provides a kind of zooperal method, can verify by this method compound (I) in animal body absorption and to the inhibition ability of tumour.
Embodiment
The below will describe exemplary of the present invention in detail.Yet these embodiments are not intended to limit the scope of the invention only for the purpose of illustration.
It below is the definition of the term that can use in this manual.Except as otherwise noted, the original definition that this patent provides with regard to group or term is applicable at described group or the term of specification sheets in the whole text, uses separately or uses as the part of another group no matter be.
Term " alkyl " refers to unsubstituted alkyl straight chain or side chain, it has 1-20 carbon atom, preferably 1-6 carbon atom refers in particular to methyl, ethyl, propyl group (comprising n-propyl and sec.-propyl), butyl (comprising normal-butyl, isobutyl-, the tertiary butyl) etc.
Term " thiazolinyl " refers to have the alkyl of one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, maleic, anti-butylene etc.
Term " alkynyl " refers to have the alkyl of a plurality of carbon carbon triple bonds, such as ethynyl, proyl etc.
Term " halogen " or " halo " refer to fluorine (fluoro), chlorine (chloro), bromine (bromo), iodine (iodo).
Term " aryl " refers to the aromatic hydrocarbons of monocycle or many rings, such as benzene, naphthalene, anthracene, phenanthrene etc.
Term " heterocyclic aryl " refers to the optional aromatic series ring-type group that replaces, and wherein contains at least a carbon atom and is replaced by other heteroatoms, and heteroatoms comprises nitrogen, oxygen, sulphur.This nitrogen and sulfur heteroatom also can be chosen wantonly oxidized, and nitrogen heteroatom also can be chosen wantonly quaternized.This heterocyclic group can connect at any heteroatoms or carbon atom place.Preferred heterocyclic aryl includes but not limited to pyridine, pyrazine, pyrimidine, pyridazine, triazine, furans, thiophene, imidazoles, triazole, tetrazolium, thiazole, isothiazole, pyrroles, pyrazoles, oxazole, isoxazole, cumarone, benzothiazole, thionaphthene, indoles, quinoline, isoquinoline 99.9, purine, carbazole, benzoglyoxaline, pyrrolopyridine, pyrrolopyrimidine etc.
Term " cycloalkyl " refers to the carbocyclic ring of non-aromatic, comprises monocycle, condensed ring or volution.Cycloalkyl also comprises having the ring that one or more aromatic nucleus condense (a common key is namely arranged), and the cycloalkyl that has one or more aromatic nucleus to condense can be connected with other groups by aromatic nucleus or non-aromatic ring part.
Term " Heterocyclylalkyl " refers to nonaromatic heterocycles, and wherein one or more become annular atoms is heteroatoms, such as oxygen, nitrogen, sulphur atom.Heterocyclylalkyl can comprise monocycle or many ring (if any 2,3,4 fused rings), volution.Preferred Heterocyclylalkyl comprises aziridine, azetidine, tetrahydrofuran (THF), tetramethylene sulfide, tetramethyleneimine, oxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidines etc.Heterocyclylalkyl also comprises having the heterocycle that one or more aromatic nucleus condense, for example 2, and 3-Dihydrobenzofuranes, 1,3-benzo dioxolane, phendioxin, 4-diox, benzenedicarboxamide etc.Having the Heterocyclylalkyl that one or more aromatic nucleus condense can be connected with other group by aromatic nucleus or non-aromatic ring part.
Term " cyano group " refers to group-CN.
Term " nitro " refers to group-NO 2
Term " sulfydryl " refers to group-SH.
Term " alcoxyl carbon back " refers to group-C (=O) OR 6, R wherein 6Refer to alkyl.
Term " alkoxyl group " refers to group-OR 7, R wherein 7Refer to alkyl.
Term " acyloxy " refers to group-OC (=O) R 8, R wherein 8Refer to alkyl.
" optionally " means that subsequently event or the situation described can occur or not occur, described description parade one's wealth example that wherein said event or situation occur and its example of not occuring wherein.
" pharmaceutically acceptable carrier " used herein comprise the whole solvent of any nuclear, dispersion medium, dressing, antibacterium and antifungal medicine, etc. blend absorption delay agent etc.Such medium and medicament are used for pharmaceutically active substances and are well known in the art.Unless any conventional media or medicament and activeconstituents are incompatible, expected during its application in therapeutic composition.The activeconstituents that replenishes also can be incorporated in the composition.
Embodiment 1
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene synthetic
Step 1: bromination trimethoxy benzyl triphenylphosphine synthetic
3,4,5-Trimethoxybenzaldehyde 4Kg is dissolved in dehydrated alcohol, stirs, repeatedly adding on a small quantity sodium borohydride 1.4Kg below 35 ℃.Adding afterreaction spends the night.After reaction was finished, rotary evaporation was removed ethanol.Add ethyl acetate (10L * 4) extraction, the combined ethyl acetate layer, anhydrous magnesium sulfate drying filters, and the pressure reducing and steaming ethyl acetate obtains the 3200ml product.
3,4,5-trimethoxy benzylalcohol 3200ml is dissolved in the 20L toluene, stirs, cool to-5-0 ℃, drip phosphorus tribromide 1L, temperature control is at-5-0 ℃ simultaneously.After being added dropwise to complete, low-temp reaction 2h returns to room temperature, and reaction is spent the night.
Add purified water 14L termination reaction, stir 30min, separatory, minute water-yielding stratum.Organic layer washs Ph value 7.5-8 with saturated sodium bicarbonate solution, and anhydrous magnesium sulfate drying filters, and obtains the toluene solution of trimethoxy benzyl bromine.
In this solution, add triphenyl phosphorus 5.6Kg, stir more than the 48h, have solid to separate out, filter, namely obtain the product crude product, weight in wet base 13Kg.Product dehydrated alcohol recrystallization.
Step 2:(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-methoxyl phenyl) ethene synthetic
In the chemosynthesis device, under the argon shield, bromination trimethoxyphenyl methylene radical triphen Phosphonium 15g (28.7mmol.) is suspended among the 300ml THF, be cooled to about-15 ℃.Splash into the n-Butyl Lithium cyclohexane solution 22ml of 1.6mol/L, reacted 1 hour.Then, with 5.7 gram (29mmol.) 4-oxyethyl group-3-nitrobenzaldehyde 24ml THF solution, slowly be added dropwise in the reaction.TLC follows the tracks of, and stirring is spent the night, and temperature of reaction is raised to room temperature.Drop to solution temperature-5 ℃ next day, adds the saturated aqueous common salt stopped reaction.Tell organic layer, desolventizing.Often pressure column chromatography (silicagel column, 4: 1 n-hexane/ethyl acetate) separation obtains 6.5 gram pale yellow crystals, is (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-nitro-4-ethoxyl phenenyl) ethene, productive rate 63%.
In the 5L of drying four-necked bottle, add 3.5L and newly steam Virahol, dibromo dioctyl dipyridyl 50g, samarium metal powder 120g, add at last (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-nitro-4-ethoxyl phenenyl) ethene 50g, stir, be heated to backflow.TLC point plate is followed the tracks of, until reaction finishes.After reaction is finished, suction filtration, concentrated, column chromatography is separated, eluent petrol ether/ethyl acetate=4/1.Yield 30～40%.
Step 3:(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene synthetic
1-methyl piperidine-4-formate hydrochlorate (10g, 55.6mmol) adds the 100ml thionyl chloride, stirs, and reflux 12h, cooling, the pressure reducing and steaming thionyl chloride obtains the off-white color solid.The THF that adds the 50ml drying, solvent evaporated repeats this operation 2 times again, and the solid that obtains is directly used in next step reaction.
The solid that the previous step reaction is obtained is dissolved in the 100ml pyridine, adds amino CA-4(12.2g, 37mmol), stir, be heated to 60 ℃, reaction 6h.After reaction finishes; reaction solution is poured in the 500ml water; add NaOH solution and regulate pH value to 9; there is solid to separate out; filter, the solid that obtains is through post (eluent: chloroform/methanol=9/0.3) obtain product (Z)-1-(3,4 after the purification; the 5-trimethoxyphenyl)-and 2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene 14g, yield 83%.MS(M+1)=455.5。
Embodiment 2
(Z)-preparation of 1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene Citrate trianion
With (Z)-1-(3; 4; the 5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene 20g joins in the 200ml acetone; heating for dissolving; add citric acid 10g; continue reflux 3h, the precipitation that cooled and filtered is separated out, and with obtaining compound shown in the title behind the ethyl alcohol recrystallization.
Utilize different raw materials, by embodiment 1 similar method, synthesized respectively following various compounds:
Figure BDA00002729490000101
Figure BDA00002729490000111
Figure BDA00002729490000131
Figure BDA00002729490000141
Embodiment 31 pharmaceutical preparation prescriptions
The invention provides the prescription of the pharmaceutical composition of several diseases relevant with the new vessel paraplasm, its pharmaceutical composition mainly contains the oral preparations such as tablet, capsule.Below with " active compound " expression compound shown in the present.
Figure BDA00002729490000163
The anti-tumor activity test of the tumour cell of 32 pairs of vitro culture of embodiment
Cell is cultivated with the nutrient solution that contains 10% foetal calf serum, makes cell be in logarithmic phase always.Cell is inoculated in 96 culture plates, density 4-7 * 10 4/ ml(HUVEC density 3 * 10 4/ ml) .37 ℃, 5%CO 2The dosing in 24 hours of incubator preculture, medicine is established 6 concentration, and each concentration is established two multiple holes, continuous action 72 hours.Drug effect is used the trichoroacetic acid(TCA) fixed cell after finishing, and adds the SRB working fluid after cleaning, and behind the 15min, with the washing of 1% acetum, with Tris base dissolving and protein bound SRB, measures the OD value of each aperture under the NOCOstar microplate reader 545nm wavelength.Positive control drug is selected CA-4.
According to the OD value, calculate inhibitory rate of cell growth.
Inhibiting rate (%)=(control group OD value-medication group OD value)/control group OD value 100
According to the inhibiting rate of medicine cell growth under the different concns, calculate IC with the Logitech method 50Value.
Table 1 active compound is to the anti-tumor activity of cultured tumor cells in vitro
Annotate: EACA is the embodiment of the invention 1 described compound.
Conclusion: compound shown in the present all has obvious anti-tumor activity to the tumour cell of multiple vitro culture; Cell proliferation of human umbilical vein also there is significant restraining effect; The EACA restraining effect significantly is better than positive control CA-4.
The efficacy experiment of embodiment 32 Nude Mice
The BALB/cA-nude nude mouse, in 6-7 week, ♀ is available from Shanghai Slac Experimental Animal Co., Ltd..Subcutaneous Human hepatocarcinoma Bel-7402 cell, colon cancer cell line HT-29, SGC-7901 cell and the Non-small Cell Lung Cancer A 549 inoculated respectively of nude mouse treats that tumor growth is to 100-250mm 3After, with animal random packet (d0).Survey weekly the knurl volume 2-3 time, claim mouse heavy, record data.Gross tumor volume (V) calculation formula is:
V=1/2 * a * b2 wherein a, b represents respectively length and width;
T/C (%)=(T-T0)/(C-C0) * 100 wherein T, C is the gross tumor volume of testing when finishing;
Gross tumor volume when T0, C0 begin for experiment.
Institute's test agent is all become desired concn with the 50%PEG400 distilled water diluting.Application method is administration every day 1 time, and gastric infusion is used in conjunction 21 days.Respectively to embodiment 1,3,4,17, compound shown in 23 is tested the curative effect of the Nude Mice of people's liver cancer Bel-7402, colon cancer cell line HT-29, SGC-7901 cell and Non-small Cell Lung Cancer A 549, and its result is as shown in table 2.
The curative effect of the multiple cancer cells Nude Mice of table 2 active compound
Figure BDA00002729490000181
Conclusion: compound shown in the present can obviously suppress the growth of people's liver cancer Bel-7402, colon cancer cell line HT-29, SGC-7901 cell and Non-small Cell Lung Cancer A 549 Nude Mice under the condition of gastric infusion.

Claims (11)

1. one kind contains compound or its pharmacy acceptable salt that following logical formula I represents:
Figure FDA00002729489900011
Wherein
R 1Be independently selected from C 1-C 3Alkyl, haloalkyl;
R 2Be independently selected from hydrogen, methyl, ethyl, halogen;
R 3Be can be optionally substituted contain one or more heteroatomic heterocycles or Heterocyclylalkyl, wherein having a heteroatoms at least is N.
2. compound according to claim 1 has following general formula II (a) or II (b):
Wherein
R 1Be independently selected from C 1-C 3Alkyl, haloalkyl;
R 2Be independently selected from hydrogen, methyl, ethyl, halogen;
R 4Be independently selected from hydrogen, C 1-C 3Alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic aryl, Heterocyclylalkyl, alkyloyl, carbalkoxy;
R 5Be independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxyl group, thiazolinyl, alkynyl, hydroxyl, sulfydryl, amino, nitro, cyano group, NR aR b, NR dC (O) R c, C (O) NR aR b, S (O) 2NR aR b, NR dS (O) 2R c, NR d(CH 2) nR c, (CH 2) nNR aR b, NHC (O) NH R c, (CH 2) nNHC (O) R c, NHC (NH) R c
R a, R bBe independently selected from respectively hydrogen, alkyl, cycloalkyl, or can form one 5,6 or 7 yuan heterocycle or Heterocyclylalkyl with N, O, S atom;
R cBe independently selected from alkyl, cycloalkyl, aryl, heterocyclic aryl, Heterocyclylalkyl;
R dBe independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclic aryl;
Above-described alkyl, cycloalkyl, alkoxyl group, thiazolinyl, alkynyl, heterocyclic radical, Heterocyclylalkyl can be replaced by following any one or a plurality of group: halogen, amino, alkylamino, dialkylamine, acid amides, aryl, heterocyclic radical, nitro, cyano group, carboxyl, carbalkoxy, hydroxyl, alkoxyl group, acyloxy,=O ,=S ,=NH.
According to claim 2 shown in compound, wherein
R 1Methyl, ethyl, difluoromethyl, 2,2,2-trifluoroethyl;
R 2Hydrogen, fluorine, methyl, ethyl;
R 4Hydrogen, methyl, ethyl, chloromethyl, cyclohexyl, phenyl, pyridyl, thienyl, furyl, pyrryl, piperidyl, tetrahydrofuran base, piperazinyl, ethanoyl, tertbutyloxycarbonyl;
R 5Be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, sec.-propyl, cyclopropyl, methoxyl group, oxyethyl group, hydroxyl, sulfydryl, amino, nitro, cyano group, amine formyl.
4. according to claim 1-3 each described compound or its pharmacy acceptable salt, wherein said compound preferably from:
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-difluoro-methoxy phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-trifluoro ethoxy phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-hydroxymethyl piperidine-4-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-and 1-(3,4,5-trimethoxyphenyl)-2-(3-(2-pyrryl piperidines-4-formyl radical)) amino-4-methoxyl phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(pyridine-3-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(2-kharophen pyridine-5-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-and 1-(3,4,5-trimethoxyphenyl)-2-(3-(2-5-flumethiazine-5-formyl radical)) amino-4-methoxyl phenyl) ethene;
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-(2-fluorine pyridine-5-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-1-fluoro-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-methoxyl phenyl) ethene;
(Z)-1-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-methoxyl phenyl) ethene.
5. described compound acceptable salt pharmaceutically according to claim 1-4, or contain at least one alkaline salt forming group, with the acid of its salify can be mineral acid or the organic acid of pharmaceutically commonly using, comprise mineral acid: hydrochloric acid, sulfuric acid, phosphoric acid; Organic carboxyl acid: acetic acid, propionic acid, trifluoroacetic acid, oxyacetic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, oxalic acid, various natural or synthetic amino acid, phenylformic acid, Whitfield's ointment, 4-ASA, amygdalic acid, styracin, nicotinic acid, γ-picolinic acid; Organic sulfonic acid: methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, 2-naphthene sulfonic acid.When having a plurality of basic group, can generate the polyacid additive salt.
6. a pharmaceutical composition is characterized in that, it contain the treatment significant quantity such as the described compound of claim 1-5 and pharmaceutically acceptable carrier.
7. described according to claim 6, pharmaceutically acceptable carrier mainly comprises the employed thinner of oral preparations, lubricant, polyoxyethylene glycol.Tablet also can comprise tackiness agent, starch, and gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone also can comprise disintegrator in case of necessity, effervescent mixture, or sorbent material, dyestuff, seasonings, sweetener.
8. one kind such as the application of the described compound of claim 1-5 in preparation tubulin aggregation inhibitor.
9. one kind such as the application of the described compound of claim 1-5 in the medicine of the disease that the improper new vessel of preparation treatment causes.
10. described according to claim 9, the disease that improper new vessel causes comprises various tumours, mainly contains: lung cancer, small cell lung cancer, liver cancer, carcinoma of the pancreas, cancer of the stomach, osteocarcinoma, esophagus cancer, mastocarcinoma, kidney, cholangiocarcinoma, prostate cancer, carcinoma of testis, colorectal carcinoma, ovarian cancer, bladder cancer, cervical cancer, bronchogenic carcinoma, melanoma, gland cancer, syringocarcinoma, papillary carcinoma, papillary carcinoma, squamous cell carcinoma, rodent cancer, adenocarcinoma cystic, glioma, astrocytoma, medulloblastoma, neuroblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, oligodendroglioma, meningioma, neurofibroma, fibrosarcoma, fibroblastoma, fibroma, myxosarcoma, myxocystoma, lipoma, lipoadenoma, chondrosarcoma, chondroma, chondromyoma, chordoma, chorioadenoma, the villous vessels knurl, the chorioepithelium knurl, chorioblastoma, osteosarcoma, osteoblastoma, osteoclastoma, osteochondrofibroma, osteochondrosarcoma, the thigh cystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, vascular tumor, angiosarcoma, lymphangiosarcoma, lymphangioma, lymphoma, endothelioma, synovioma, synovial sarcoma, mesothelioma, mesocytoma, ewing's tumor, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdosarcoma, kemia, acute myelogenous leukemia, chronic leukemia, polycyth(a)emia, multiple myeloma.
11. described according to claim 9, the disease that improper new vessel causes also comprises: rheumatic arthritis, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, psoriasis, acne erythematosa, kaposi's sarcoma, specific reaction keratitis, epidemic keratoconjunctivitis, neovascular glaucoma, bacterial canker, mycotic ulcer, herpes-ness progenitalis infection, zoster infects, protozoal infections, mycobacterium infects, polyarteritis, sarcoid, scleritis, flush, the dry sacroiliitis syndromes of dry eye, systemic lupus erythematosus, AIDS, syphilis.
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