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 in the purposes of preparing in Antitubulin.
Background technology
Combretastatins series compound extracts to separate at first and obtains from the Combretum caffrum trunk of South Africa.It has anti-tumor activity, can directly act on endotheliocyte, the endothelial cell apoptosis of induction propagation, thus suppress tumor neovasculature generation, reach the object of tumors destroyed.Combretastatins series compound has cis stilbene structure.Wherein combretastatin A-4[CA-4, Combretastatin, cis-1-(3,4,5-trimethoxy) phenyl-2-(3 '-hydroxyl-4 '-methoxyl group) phenyl ethene] there is the strongest inhibition microtubule polymerization effect (Pettit G R, etal.J.Med.Chem (1995) 38 1666-1672).Recently, because CA-4 is as tumor vascular targeting reagent, demonstrates it and block 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 to be 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 the hydroxyl of 3 of CA-4 ' position is transformed into after amino, at present common CA-4 is transformed into its phosphatic method inapplicable.Although Japanese Ajincomoto Co., Inc modifies amino CA-4 with amino acid, increase that it is water-soluble, becoming 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 the each position of whole body by blood-transmitted, various tumours is had to 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 logical formula I represents that contain below:
(Ⅰ)
Wherein
R
1independently selected from C
1-C
3alkyl, haloalkyl;
R
2independently 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 there is general formula II (a) or II (b) compound:
Ⅱa
Ⅱb
Wherein
R
1independently selected from C
1-C
3alkyl, haloalkyl;
R
2independently selected from hydrogen, methyl, ethyl, halogen;
R
4independently selected from hydrogen, C
1-C
3alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic aryl, Heterocyclylalkyl, alkyloyl, carbalkoxy;
R
5independently 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
brespectively independently selected from hydrogen, alkyl, cycloalkyl, or can form heterocycle or the Heterocyclylalkyl of one 5,6 or 7 yuan with N, O, S atom;
R
cindependently selected from alkyl, cycloalkyl, aryl, heterocyclic aryl, Heterocyclylalkyl;
R
dindependently 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 more groups: 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)-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)-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) the fluoro-1-of-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.
Pharmaceutically acceptable salt of formula I compound of the present invention, or containing 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.In the time there is multiple basic group, can generate polyacid additive salt.
Compound of the present invention and pharmacy acceptable salt also comprise the form of solvate or hydrate.In general, the form of solvate or hydrate and form non-solvated or non-hydrated are equal to, and contain in the lump within the scope of the invention.Likely there is polycrystal or unbodied form in some compound in the present invention.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 separating very particularly.Racemic form can split by physical method, and described physical method is such as diastereomer derivative being carried out to fractional crystallization, separation or separating by chiral column chromatogram.Can follow crystallization and obtain independent optical isomer from racemic modification by for example optical activity acid form salify of ordinary method.
In addition, the present invention also provides the method for synthetic formula I compound.Its technological process is as follows:
Ⅱa Ⅱb
Synthetic method of the present invention obtains corresponding microcosmic salt by the bromo of compound VII, after reacting with triphenylphosphine, then microcosmic salt is reacted to the toluylene structure (IV) that obtains cis by wittig with compound VIII.Toluylene becomes amino as reductive agent by the nitroreduction in structure with samarium metal powder with dibromo dioctyl dipyridyl, has just obtained amino compete A-4 (III).Then taking amino compete A-4 as raw material, (b), last and sour salify obtains final product for structure II a or II to connect into acid amides with pyridine carboxylic acid or piperidine carboxylic acid by the method for acyl chlorides or active ester.
The invention still further relates to the pharmaceutical composition of acceptable carrier in the formula I compound that comprises significant quantity and pharmacology, that said composition is applicable to is local, in intestines or intestines outside administration, can be inorganic or organic, solid-state or liquid.For oral, especially with tablet or capsule.This tablet or capsule comprise activeconstituents and thinner (as lactose, glucose, sucrose, mannitol, sorbyl alcohol, Mierocrystalline cellulose, glycerol), lubricant (as talcum, stearate), polyoxyethylene glycol.Tablet also can comprise tackiness agent, starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone, also can comprise disintegrator (as starch, agar, alginic acid and salt thereof), effervescent mixture, or sorbent material if desired, 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 case of the lyophilised compositions being only made up of activeconstituents and a kind of carrier (as N.F,USP MANNITOL), this type of solution can be prepared 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 in the medicine of the disease that formula I compound causes at the improper new vessel of preparation treatment.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, villous vessels knurl, chorioepithelium knurl, chorioblastoma, osteosarcoma, osteoblastoma, osteoclastoma, osteochondrofibroma, osteochondrosarcoma, 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 formula I compound in the application of preparing in tubulin aggregation inhibitor.
The present invention also provides a kind of zooperal method, can verify by this method compound (I) absorption in animal body and the inhibition ability to tumour.
Embodiment
To describe exemplary of the present invention below in detail.But these embodiments only for the purpose of illustration, are not intended to limit the scope of the invention.
It is below 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 to described group or the term in the whole text at specification sheets, 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 the alkyl with one or more carbon-carbon double bonds, as vinyl, propenyl, 1,3-butadiene, maleic, anti-butylene etc.
Term " alkynyl " refers to the alkyl with multiple carbon carbon triple bonds, 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 aromatic series ring-type group of optional replacement, wherein at least contains a carbon atom and is replaced by other heteroatoms, and heteroatoms comprises nitrogen, oxygen, sulphur.This nitrogen and sulfur heteroatom also can be optionally oxidized, and nitrogen heteroatom also can be optionally 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 the ring that has one or more aromatic nucleus and condense (having a common key), has the cycloalkyl that one or more aromatic nucleus condense to 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, 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, wherein R
6refer to alkyl.
Term " alkoxyl group " refers to group-OR
7, wherein R
7refer to alkyl.
Term " acyloxy " refers to group-OC (=O) R
8, wherein R
8refer to alkyl.
" optionally " means that subsequently event or the situation described can occur or not occur, described description the parade one's wealth example that wherein said event or situation occur and the example that wherein it does not occur.
" pharmaceutically acceptable carrier " used herein comprise the whole solvent of any core, dispersion medium, dressing, antibacterium and antifungal medicine, etc. blend absorption delay agent etc.Such medium and medicament are well known in the art for pharmaceutically active substances.Unless any conventional media or medicament and activeconstituents are incompatible, expected when its application in therapeutic composition.Supplementary activeconstituents also can be incorporated in composition.
Embodiment 1
(Z) synthesizing of-1-(3,4,5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene
Step 1: bromination trimethoxy benzyl triphenylphosphine synthetic
3,4,5-Trimethoxybenzaldehyde 4Kg is dissolved in to dehydrated alcohol, stirs, repeatedly add on a small quantity below sodium borohydride 1.4Kg at 35 DEG C.Adding rear reaction spends the night.After having reacted, rotary evaporation is removed ethanol.Add ethyl acetate (10L × 4) extraction, combined ethyl acetate layer, anhydrous magnesium sulfate drying, filters, and pressure reducing and steaming ethyl acetate, obtains 3200ml product.
3,4,5-trimethoxy benzylalcohol 3200ml is dissolved in 20L toluene, stirs, cool to-5-0 DEG C, drip phosphorus tribromide 1L, temperature control is at-5-0 DEG C 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, point 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, more than stirring 48h, have solid to separate out, filter, obtain 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 chemosynthesis device, under argon shield, bromination trimethoxyphenyl methylene radical triphen Phosphonium 15g (28.7mmol.) is suspended in 300ml THF, be cooled to-15 DEG C of left and right.Splash into the n-Butyl Lithium cyclohexane solution 22ml of 1.6mol/L, react 1 hour.Then,, by 5.7 grams of (29mmol.) 4-oxyethyl group-3-nitrobenzaldehyde 24ml THF solution, be slowly added dropwise in reaction.TLC follows the tracks of, and stirring is spent the night, and temperature of reaction is raised to room temperature.Next day, drops to solution temperature-5 DEG C, adds saturated aqueous common salt stopped reaction.Separate organic layer, except desolventizing.Often pressure column chromatography (silicagel column, 4: 1 n-hexane/ethyl acetate) separate obtain 6.5 grams of pale yellow crystals, be (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-nitro-4-ethoxyl phenenyl) ethene, productive rate 63%.
In dry 5L four-necked bottle, add 3.5L newly to steam Virahol, dibromo dioctyl dipyridyl 50g, samarium metal powder 120g, finally add (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-nitro-4-ethoxyl phenenyl) ethene 50g, stir, be heated to reflux.TLC point plate is followed the tracks of, until reaction finishes.After having reacted, suction filtration, concentrated, column chromatography separates, 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 100ml thionyl chloride, stirs, and reflux 12h, cooling, pressure reducing and steaming thionyl chloride, obtains off-white color solid.Add the THF that 50ml is dry, solvent evaporated, then repeat this operation 2 times, the solid obtaining is directly used in next step reaction.
Previous step is reacted to the solid obtaining and is dissolved in 100ml pyridine, add amino CA-4(12.2g, 37mmol), stir, be heated to 60 DEG C, reaction 6h.After reaction finishes; reaction solution is poured in 500ml water; add NaOH solution to regulate pH value to 9; there is solid to separate out; filter, the solid obtaining obtains product (Z)-1-(3,4 after post (eluent: chloroform/methanol=9/0.3) is purified; 5-trimethoxyphenyl)-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
By (Z)-1-(3; 4; 5-trimethoxyphenyl)-2-(3-(N-methyl piperidine-4-formyl radical) amino-4-ethoxyl phenenyl) ethene 20g joins in 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 title after ethyl alcohol recrystallization.
Utilize different raw materials, by the similar method of embodiment 1, synthesized respectively following various compounds:
Embodiment 31 pharmaceutical preparation formulas
The invention provides the formula of the pharmaceutical composition of several diseases relevant to new vessel paraplasm, its pharmaceutical composition mainly contains the oral preparations such as tablet, capsule.Represent compound shown in the present with " active compound " below.
The anti-tumor activity test of the tumour cell of embodiment 32 to vitro culture
Cell is cultivated with the nutrient solution containing 10% foetal calf serum, makes cell always in logarithmic phase.Cell is inoculated in 96 culture plates, density 4-7 × 10
4/ ml(HUVEC density 3 × 10
4/ ml) .37 DEG C, 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.After drug effect finishes, use trichoroacetic acid(TCA) fixed cell, after cleaning, add SRB working fluid, after 15min, with 1% acetum washing, with Tris base dissolving and protein bound SRB, under NOCOstar microplate reader 545nm wavelength, measure the OD value of each aperture.Positive control drug is selected CA-4.
According to 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 different concns, calculate IC with Logitech method
50value.
The anti-tumor activity of table 1 active compound to cultured tumor cells in vitro
Note: EACA is compound described in the embodiment of the present invention 1.
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 is also had to significant restraining effect; EACA restraining effect is significantly better than positive control CA-4.
The efficacy experiment of embodiment 32 Nude Mice
BALB/cA-nude nude mouse, in 6-7 week, ♀, purchased 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, by animal random packet (d0).Survey weekly 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 are the gross tumor volume of testing while end;
Gross tumor volume when T0, C0 are experiment beginning.
Institute's test agent is all become to desired concn with 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, the curative effect of the Nude Mice of compound shown in 23 to people's liver cancer Bel-7402, colon cancer cell line HT-29, SGC-7901 cell and Non-small Cell Lung Cancer A 549 is tested, and its result is as shown in table 2.
The curative effect of the multiple cancer cells Nude Mice of table 2 active compound
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.