CN103304556A - Schiff base compound containing benzopyran, preparation method and use thereof - Google Patents
Schiff base compound containing benzopyran, preparation method and use thereof Download PDFInfo
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- CN103304556A CN103304556A CN2013102484404A CN201310248440A CN103304556A CN 103304556 A CN103304556 A CN 103304556A CN 2013102484404 A CN2013102484404 A CN 2013102484404A CN 201310248440 A CN201310248440 A CN 201310248440A CN 103304556 A CN103304556 A CN 103304556A
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- LEVDMLXWNRQECJ-KZZDLZNXSA-N CC/C=N/C(/C)=N/N(C)C(C)O Chemical compound CC/C=N/C(/C)=N/N(C)C(C)O LEVDMLXWNRQECJ-KZZDLZNXSA-N 0.000 description 1
- FGBBUIKZQWSUAN-SSDVNMTOSA-N Cc1ccc(C(CSCc2nnc(/N=C/c3ccccc3)[o]2)=CC(O2)=O)c2c1 Chemical compound Cc1ccc(C(CSCc2nnc(/N=C/c3ccccc3)[o]2)=CC(O2)=O)c2c1 FGBBUIKZQWSUAN-SSDVNMTOSA-N 0.000 description 1
- PFVRGTHLCXEOBV-UHFFFAOYSA-N Cc1ccc(C(CSCc2nnc(N)[o]2)=CC(O2)=O)c2c1 Chemical compound Cc1ccc(C(CSCc2nnc(N)[o]2)=CC(O2)=O)c2c1 PFVRGTHLCXEOBV-UHFFFAOYSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N O=Cc1ccccc1 Chemical compound O=Cc1ccccc1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a Schiff base compound containing benzopyran having a structure as shown in formula I, and a pharmaceutically acceptable salt thereof, wherein R represents one of hydrogen and C1-C4 alkyls; X represents S or SO2; R1 represents H, halogen, alkyl of C1-C4 or alkoxy; and R2 represents H, halogen, alkyl of C1-C4 or alkoxy. The invention also discloses a preparation method of the compound, and simultaneously, a pharmaceutical composition with the compound or the pharmaceutically acceptable salt thereof as an active effective constituent, as well as an application thereof as an antitumor drug, especially application in the aspect of preparing drugs for treating breast cancer, lung cancer and stomach cancer.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to a class and have compound of antitumor action and its production and use.
Background technology
Cancer has become a big chronic disease of serious harm human health at present.The annual people who suffers from cancer has 9,000,000 in the world according to statistics, and the patient who dies from cancer is 6,000,000, and cancer patients's death is almost just arranged p.s..China's cancer year number of the infected is died from the number of cancer up to more than 900,000 about 1,200,000, patient to be treated surpasses 1,500,000, and the trend that rises is year by year arranged.Therefore cancer has now become the second largest killer who is only second to cardiovascular disorder.Treat tumour clinically, generally adopt operation, radiotherapy, chemotherapy three big therapies.Though embolic chemotherapy is comparatively quick, curative ratio is very low.The many cancer therapy drugs of clinical discovery exist tangible damage and toxic side effect to normal body, for example mutagenesis and genetoxic simultaneously.Therefore, seek effectively and cancer therapy drug with less body injury and toxic side effect has become the focus of new drug research.
Summary of the invention
One object of the present invention is, discloses the schiff bases compounds and the pharmaceutical salts thereof that contain chromene of a class novel texture.
Another object of the present invention is, discloses a class and contains the schiff bases compounds of chromene and the preparation method of pharmaceutical salts thereof.
A further object of the present invention is, open schiff bases compounds and the pharmaceutical salts thereof that contains chromene with a class is the pharmaceutical composition of main active ingredient.
A further object of the invention is, discloses a class and contains the schiff bases compounds of chromene and pharmaceutical salts thereof as the application of medicine for resisting malignant tumors, particularly in the purposes aspect medicines such as treatment mammary cancer, lung cancer, cancer of the stomach.
Now in conjunction with the object of the invention, content of the present invention is described in detail.
The present invention is specifically related to compound and the pharmacy acceptable salt thereof of formula I structure:
Wherein: R is hydrogen, the C1-C4 alkyl;
X is S or SO2;
R
1Be H, halogen, C1-C4 alkyl or alkoxyl group.
R
2Be H, halogen, C1-C4 alkyl or alkoxyl group.
Preferred following compound and pharmacy acceptable salt thereof:
Formula I compound pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.Wherein preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts.
The preparation route of formula I compound is as follows:
X, R, R1 and R2 are described as defined above.
Primary amine (II) is dissolved in methylene dichloride, trichloromethane, ethanol, methyl alcohol, benzene or the toluene, add an acidic catalyst such as Glacial acetic acid, tosic acid etc., or add basic catalyst such as sodium hydroxide etc., or do not add catalyzer, method with siccative such as reflux water-dividing or adding anhydrous magnesium sulfates is removed the water (or not dewatering) that generates in the reaction process, contains the schiff bases compounds (I) of chromene 20-100 ℃ of following prepared in reaction.
Wherein (Indian Journal of Chemistry, 2006(45B): 258-266) the general Study personnel of this research field all can conveniently make the people's such as synthesized reference Alawandi of compound (II) method.Concrete preparation route is as follows:
Wherein: i is NH
2CSNH
2/ EtOH:Ether; Ii is ClCHCOC
2H
5/ anhydrous/K
2CO
3/ EtOH;
Iii is H
2O
2/ CH
3CO
2H; Iv is N
2H
4H
2O(99%)/EtOH;
V is CNBr/CH
3OH/60 ℃.
According to aforesaid method, can prepare compound ii-1～II-4:
Raw material (III) is commercially available analytical pure product, can directly buy.
Reaction makes all cpds or oxide compound or oxyhydroxide that products therefrom is dissolved in dropping inorganic acid, organic acid, basic metal, alkaline-earth metal in DMF, acetone, methyl alcohol, ethanol, DMSO or the ether is made pharmacy acceptable salt.
Specifically be that all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, the dripping hydrochloric acid ether is made hydrochloride to pH=2 under ice-water bath; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, and adding and wait a mole taurine, heated and stirred gets its taurate; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, under ice-water bath, drips the vitriol oil to pH=3, make vitriol, etc.
This compounds is effective for the treatment human malignancies.Although compound of the present invention can be without the direct administration of any preparation, described all cpds preferably uses with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions of The compounds of this invention is as follows: use standard and conventional technology; The compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis etc.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, the amount of used compound or concentration are regulated in a wideer scope, usually, the weight range of active compound is 0.5%～90%(weight of composition).Another preferred range is 0.5%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention has the obvious suppression effect external to tumour.
External antitumor action
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the invention compound to the cell proliferation toxicity of the human tumor cells of vitro culture.
(2) experiment material:
Laboratory sample: formula I compound is provided by contriver's self-control.Sample is with the DMSO hydrotropy during experiment, and serum-free DMEM substratum is diluted to desired concn, and sample segment solution is suspension.
Main agents: MTT, the packing of Amresco company, lot number: 04M0904; Complete DMEM substratum, Gibco company product, lot number: 1290007; Calf serum, Lanzhou people's marine life, lot number: 20060509; Trypsinase, the packing of Amresco company, lot number: 016B0604.
Laboratory apparatus: Bechtop, Suzhou Decontamination Equipment Plant; CO
2Incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
Cell strain: SPCA1 human lung adenocarcinoma cell line, MCF7 human breast cancer cell, SGC-7901 gastric carcinoma cells, all available from Shanghai cell research institute of the Chinese Academy of Sciences.
(3) experimental procedure:
Cell cultures: tumor cell inoculation is containing 10% calf serum, in the DMEM nutrient solution of 100IU/ml penicillin G sodium salt and 100 μ g/ml Vetstreps, places 37 ℃, 100% relative humidity, contains 5%CO
2Incubator in, it is standby after 3 times to go down to posterity.
Mtt assay is measured: the cell in the vegetative period of taking the logarithm, behind 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution that contains 10% calf serum, blow and beat into single cell suspension gently with the glass dropper, microscopically blood cell counts plate numeration viable cell.Inoculating cell suspension 90 μ L(cell concns in the every hole of 96 well culture plates are adjusted into 6～10 * 10
4Individual/ml), at 37 ℃, 100% relative humidity, contain 5%CO
2, 95% air incubator cultivate 24h after, every hole adds 10 μ L soups (final concentration is made as: 40 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml and five concentration of 2.5 μ g/ml).In addition, each concentration is established negative control (isoconcentration DMSO) and blank background (not adding cell), and each group is all established 6 multiple holes.Cultured continuously 24h again, every hole adds the MTT solution 10 μ L of 5mg/ml then, and after continuing to cultivate 4h, the careful suction removed supernatant liquor (suspension cell needs earlier centrifugally, inhales and removes supernatant).Every hole adds 100 μ L DMSO, puts micro oscillator concussion 5min so that crystallization is dissolved fully, and the single wavelength colorimetric of microplate reader 492nm is measured the OD value.Calculate inhibitory rate of cell growth as evaluation index with following method.
Inhibiting rate (%)=[1-(experimental group OD average-blank group OD average)/(control group OD average-blank group OD average)] * 100%.According to inhibitory rate of cell growth, calculate IC with the straight-line regression method
50Value.
(4) experimental result:
IC to the tumour cell of vitro culture
50(μ g/ml)
(5) conclusion:
According to above-mentioned in vitro tests result, the compound that we have formula I structure as can be seen has stronger restraining effect to above-mentioned 3 kinds of human tumor cells.
Embodiment
The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1H NMR,
13C NMR), high resolution mass spectrum (HRMS) etc. is further proved conclusively its structure.
Embodiment 1:
The preparation of intermediate I-1
Add II-1(2g in the reaction flask, 6.6mmol), add the 30ml methylene dichloride, the control temperature is at 20 ℃.Add an amount of anhydrous magnesium sulfate afterwards, stirring slowly drips III-1(0.7g after fully dissolving, and 6.6mmol), is warming up to backflow under nitrogen protection, keeps 12 hours.Reaction removes by filter sal epsom after finishing, and the evaporate to dryness solvent obtains light brown oily thing.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 1.9g, yield 73.3%, purity 97.5%(HPLC normalization method), ESI-MS (m/z): 392.1.
Embodiment 2:
The preparation of intermediate I-2
Add II-1(2g in the reaction flask, 6.6mmol), add 20ml ethanol, stir and make its dissolving.Add an amount of molecular sieve afterwards, be warming up to 50 ℃, slowly drip III-2(0.93g, ethanolic soln 6.6mmol) is warming up to backflow under nitrogen protection, reacts 8 hours.Reaction removes molecular sieve after finishing, and the evaporate to dryness solvent obtains light brown oily thing.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 1.8g, yield 62.7%, purity 96.9%(HPLC normalization method), ESI-MS (m/z): 426.1.
Embodiment 3:
The preparation of intermediate I-3
Add II-1(2g in the reaction flask, 6.6mmol), add 40ml benzene, stir and make its dissolving.The NaOH that adds catalytic amount afterwards is warming up to 50 ℃, slowly drips III-3(1.1g, and toluene solution 6.6mmol) is to reduce the harm of benzene toxicity.Under nitrogen protection, be warming up to backflow, reacted 2 hours.Remove the water that produces in the reaction process with water trap.After reaction finishes, filter the evaporate to dryness solvent, obtain reddish-brown oily matter.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 1.6g, yield 55.3%, purity 98.0%(HPLC normalization method), ESI-MS (m/z): 448.2.
Embodiment 4:
The preparation of intermediate I-4
Add II-1(2g in the reaction flask, 6.6mmol), add 40ml benzene, stir and make its dissolving.The Glacial acetic acid that adds catalytic amount afterwards is warming up to 50 ℃, slowly drips III-4(1.0g, and toluene solution 6.6mmol) is to reduce the harm of benzene toxicity.Under nitrogen protection, be warming up to backflow, reacted 2 hours.Remove the water that produces in the reaction process with water trap.Reaction finishes back evaporate to dryness solvent, obtains reddish-brown oily matter.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 2.0g, yield 68.0%, purity 97.3%(HPLC normalization method), ESI-MS (m/z): 444.1.
Embodiment 5:
The preparation of intermediate I-5
Add II-1(2g in the reaction flask, 6.6mmol), add 30ml ethanol, stir and make its dissolving.Add the tosic acid monohydrate of catalytic amount, excessive anhydrous sodium sulphate is warming up to 50 ℃, slowly drips III-5(1.0g, and ethanolic soln 6.6mmol) is warming up to backflow under nitrogen protection, reacted 4 hours.Reaction finishes after-filtration and removes insolubles, and the evaporate to dryness solvent obtains light brown oily thing.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 1.6g, yield 56.6%, purity 97.5%(HPLC normalization method), ESI-MS (m/z): 436.1.
Embodiment 6:
The preparation of intermediate I-6
Add II-2(2g in the reaction flask, 6.6mmol), add the 30ml methylene dichloride, the control temperature is at 20 ℃.Add an amount of anhydrous magnesium sulfate afterwards, stirring slowly drips III-1(0.7g after fully dissolving, and 6.6mmol), is warming up to backflow under nitrogen protection, keeps 12 hours.Reaction removes by filter sal epsom after finishing, and the evaporate to dryness solvent obtains light brown oily thing.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 2.1g, yield 81.7%, purity 97.0%(HPLC normalization method), ESI-MS (m/z): 392.1.
Embodiment 7:
The preparation of intermediate I-7
Add II-2(2g in the reaction flask, 6.6mmol), add 20ml ethanol, stir and make its dissolving.Add an amount of molecular sieve afterwards, be warming up to 50 ℃, slowly drip III-2(0.93g, ethanolic soln 6.6mmol) is warming up to backflow under nitrogen protection, reacts 8 hours.Reaction removes molecular sieve after finishing, and the evaporate to dryness solvent obtains light brown oily thing.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 1.9g, yield 68.0%, purity 97.5%(HPLC normalization method), ESI-MS (m/z): 426.1.
Embodiment 8:
The preparation of intermediate I-8
Add II-2(2g in the reaction flask, 6.6mmol), add 40ml benzene, stir and make its dissolving.The NaOH that adds catalytic amount afterwards is warming up to 50 ℃, slowly drips III-3(1.1g, and toluene solution 6.6mmol) is to reduce the harm of benzene toxicity.Under nitrogen protection, be warming up to backflow, reacted 2 hours.Remove the water that produces in the reaction process with water trap.After reaction finishes, filter the evaporate to dryness solvent, obtain reddish-brown oily matter.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 1.6g, yield 54.0%, purity 97.6%(HPLC normalization method), ESI-MS (m/z): 448.2.
Embodiment 9:
The preparation of intermediate I-9
Add II-2(2g in the reaction flask, 6.6mmol), add 40ml benzene, stir and make its dissolving.The Glacial acetic acid that adds catalytic amount afterwards is warming up to 50 ℃, slowly drips III-4(1.0g, and toluene solution 6.6mmol) is to reduce the harm of benzene toxicity.Under nitrogen protection, be warming up to backflow, reacted 2 hours.Remove the water that produces in the reaction process with water trap.Reaction finishes back evaporate to dryness solvent, obtains reddish-brown oily matter.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 1.9g, yield 64.2%, purity 97.0%(HPLC normalization method), ESI-MS (m/z): 444.1.
Embodiment 10:
The preparation of intermediate I-10
Add II-2(2g in the reaction flask, 6.6mmol), add 30ml ethanol, stir and make its dissolving.Add the tosic acid monohydrate of catalytic amount, excessive anhydrous sodium sulphate is warming up to 50 ℃, slowly drips III-5(1.0g, and ethanolic soln 6.6mmol) is warming up to backflow under nitrogen protection, reacted 4 hours.Reaction finishes after-filtration and removes insolubles, and the evaporate to dryness solvent obtains light brown oily thing.Gained oily matter is dissolved in dehydrated alcohol, and putting coldly has solid to separate out.Filter, obtain product 1.5g, yield 53.0%, purity 96.5%(HPLC normalization method), ESI-MS (m/z): 436.1.
Embodiment 11:
The preparation of intermediate I-11
Add II-3(2g in the reaction flask, 6.0mmol), add the 30ml dehydrated alcohol, add III-1(0.6g then, 6.0mmol), under nitrogen protection, be warming up to backflow, kept 10 hours.After reaction finishes, put the cold-draw filter, evaporate to dryness obtains light brown oily thing.Gained oily matter is dissolved in acetonitrile, and putting coldly has solid to separate out.Filter, obtain product 1.9g, yield 69.5%, purity 98.6%(HPLC normalization method), ESI-MS (m/z): 424.1.
Embodiment 12:
The preparation of intermediate I-12
Add II-3(2g in the reaction flask, 6.0mmol), add the dissolving of 30ml absolute ethyl alcohol and stirring, add III-2(0.8g then, 6.0mmol), under nitrogen protection, be warming up to backflow, kept 10 hours.After reaction finishes, put the cold-draw filter, evaporate to dryness obtains light brown oily thing.Gained oily matter is dissolved in acetonitrile, and putting coldly has solid to separate out.Filter, obtain product 2.0g, yield 72%, purity 97.2%(HPLC normalization method), ESI-MS (m/z): 458.1.
Embodiment 13:
The preparation of intermediate I-13
Add II-4(2g in the reaction flask, 6.0mmol), add the dissolving of 30ml absolute ethyl alcohol and stirring, add the Glacial acetic acid of catalytic amount, add III-3(1.0g then, 6.0mmol), under nitrogen protection, be warming up to backflow, kept 8 hours.After reaction finishes, put the cold-draw filter, evaporate to dryness obtains light brown oily thing.Gained oily matter is dissolved in acetonitrile, and putting coldly has solid to separate out.Filter, obtain product 1.7g, yield 58.2%, purity 96.7%(HPLC normalization method), ESI-MS (m/z): 480.2.
Embodiment 14:
The preparation of intermediate I-14
Add II-4(2g in the reaction flask, 6.0mmol), add the dissolving of 30ml absolute ethyl alcohol and stirring, add the p-methylbenzoic acid (moisture) of catalytic amount, add III-5(0.9g then, 6.0mmol), under nitrogen protection, be warming up to backflow, kept 9 hours.After reaction finishes, put the cold-draw filter, evaporate to dryness obtains light brown oily thing.Gained oily matter is dissolved in acetonitrile, and putting coldly has solid to separate out.Filter, obtain product 1.8g, yield 63%, purity 97.0%(HPLC normalization method), ESI-MS (m/z): 468.1.
Embodiment 15:
Chemical compounds I-1 one-tenth hydrochloride: get chemical compounds I-1 white solid product 2.0g, be dissolved in the 8ml dehydrated alcohol.Ice-water bath is cooled to 5 ℃, drip 11.1% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under the ice-water bath.Filter, vacuum-drying gets the white solid powder.
Embodiment 16:
Chemical compounds I-3 one-tenth taurate: get chemical compounds I-3 white solid product 2.0g, be dissolved in the 10ml anhydrous methanol.Be heated to the back adding that refluxes and wait a mole taurine, continue at the about 1.5h of stirring reaction down that refluxes.Reaction finishes, and leaves standstill 24h under room temperature.Separate out light yellow crystallization, filter vacuum-drying.
Embodiment 17:
Chemical compounds I-5 one-tenth vitriol: get chemical compounds I-5 white solid product 2.0g, be dissolved in 15ml acetone.Ice-water bath is cooled to 0 ℃, drip concentrated sulfuric acid solution to pH be 3, continue at stir about 1h under the ice-water bath.Filter, get white solid.
For the pharmaceutical composition that contains the schiff bases compounds of chromene of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, described embodiment only is used for explanation, rather than is used for limiting the scope of the invention.Described preparation can use any active compound and the salt thereof in the The compounds of this invention, preferably uses the compound described in the embodiment 1-14.
Embodiment 18:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule
Chemical compounds I-8 40mg
Dry starch 400mg
Magnesium Stearate 20mg
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.After pressing recipe quantity mentioned component being mixed, be packed in the hard gelatin capsule.
Embodiment 19:
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the whole grain of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 20:
The preparation of injection liquid:
The hydrochloride 200mg of chemical compounds I-1
Propylene glycol 100mg
Polysorbate 80 is an amount of
Distilled water 300ml
Preparation method: get activeconstituents and join in the water for injection that dissolves polysorbate and propylene glycol, add medicinal basic adjusting pH value to 4～8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 21:
The preparation of injection lyophilized powder:
The taurate 100mg of chemical compounds I-3
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, regulate the pH value with medicinal basic and make its dissolving to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, seals, namely.
Claims (9)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
R is hydrogen, the C1-C4 alkyl;
X is S or SO2;
R
1Be H, halogen, C1-C4 alkyl or alkoxyl group.
R
2Be H, halogen, C1-C4 alkyl or alkoxyl group.
2. compound or its pharmacy acceptable salt according to claim 1, described compound is:
3. formula I compound as claimed in claim 1 or its pharmacy acceptable salt, its pharmacy acceptable salt is: formula I compound and mineral acid or organic acid salify.
4. formula I compound as claimed in claim 3 or its pharmacy acceptable salt; its pharmacy acceptable salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate.
5. the preparation method of formula I compound according to claim 1, it is characterized in that: in organic solvent, compound ii and the reaction of compound III obtain chemical compounds I.
X, R, R1 and R2 are described as defined above.
6. preparation method as claimed in claim 5 is characterized in that, described organic solvent is selected from methylene dichloride, trichloromethane, ethanol, methyl alcohol, benzene or toluene.
7. antitumor medicine composition, it comprises each compound or its pharmacy acceptable salt and one or more pharmaceutical carriers of claim 1～2 for the treatment of significant quantity.
In the claim 1 each compound or its pharmacy acceptable salt in the application aspect antitumor drug.
9. application as claimed in claim 7 is characterized in that described tumour is mammary cancer, lung cancer and cancer of the stomach.
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| CN103936683A (en) * | 2014-03-06 | 2014-07-23 | 陕西科技大学 | 4-amino-5-substituted-1,2,4-triazole-3-thione Schiff base and preparation method thereof |
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