CN101967154A - Oxime compounds, preparation method and application thereof - Google Patents
Oxime compounds, preparation method and application thereof Download PDFInfo
- Publication number
- CN101967154A CN101967154A CN201010502996.8A CN201010502996A CN101967154A CN 101967154 A CN101967154 A CN 101967154A CN 201010502996 A CN201010502996 A CN 201010502996A CN 101967154 A CN101967154 A CN 101967154A
- Authority
- CN
- China
- Prior art keywords
- compound
- pyridine
- tetramethylene sulfide
- ketone
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention discloses oxime compounds with a structure as shown in formula I and pharmaceutically acceptable salt thereof. In the formula I, R1 is halogen; R2, R3 and R4 are simultaneously or respectively hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitryl, nitrile and phyenyl; R5 is hydrogen, C1 to C4 straight-chain or branch chain alkyl, and phenyl substituted by halogen, nitryl, nitrile, C1 to C4 alkyl, C1 to C4 alkoxy, amido and alkanolamide. The invention also discloses a preparation method for the compounds, a medicinal composition using the compounds or the pharmaceutically acceptable salt thereof as an active effective component, and application of the compounds or the pharmaceutically acceptable salt thereof in serving as anti-tumor medicament, particularly in preparing medicament for treating breast cancer, lung cancer and gastric 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 in the world according to statistics people who suffers from cancer has 9,000,000, 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 about 1,200,000, and the number of dying from cancer is up to more than 900,000, and 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 its pharmaceutical salts of oxime compounds of a class novel texture.
Another object of the present invention is, discloses the preparation method of a class oxime compounds and pharmaceutical salts thereof.
A further object of the present invention is that open is the pharmaceutical composition of main active ingredient with a class oxime compounds and pharmaceutical salts thereof.
A further object of the invention is, discloses the application as medicine for resisting malignant tumors of a class oxime compounds and pharmaceutical salts thereof, particularly in the purposes that is used to prepare aspect treatment mammary cancer, lung cancer, the cancer of the stomach medicine.
Now, content of the present invention is described in detail in conjunction with the object of the invention.
The present invention is specifically related to the compound and the pharmacy acceptable salt thereof of formula I structure:
Wherein:
R
1Be halogen;
R
2, R
3, R
4Be at the same time or separately: hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen, nitro, itrile group, phenyl;
R
5For: hydrogen, C
1-C
4The straight or branched alkyl is by halogen, nitro, itrile group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, C
1-C
4The phenyl that alkyl amide replaces.
Wherein preferred its pharmacy acceptable salt of following compound:
(1) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2-chloro-phenyl-) ketoxime;
(2) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(4-fluorophenyl)-O-methyl ketone oxime;
(3) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2, the 5-dichlorophenyl)-O-ethyl ketone oxime;
(4) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2, the 6-dichlorophenyl)-O-propyl ketone oxime;
(5) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,4, the 6-trichlorophenyl)-O-isopropyl ketoxime;
(6) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,3,5,6-tetrafluoro phenyl) ketoxime;
(7) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,3-dichloro-4,4-aminomethyl phenyl)-O-methyl ketone oxime.
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:
Wherein compound 2, and reference literature (EP0342118, EP0465358, the JP62103088) synthetic method in, the researcher in this field all can make.
Substituted benzoyl aldehyde compound (II), in methyl alcohol, ethanol or acetone equal solvent, with N-substituted hydroxylamine hydrochloride compounds under the catalysis of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide ,-30～85 ℃ of reactions make the key intermediate III.The intermediate III again with halogenating agent-10～110 ℃ of reactions in methylene dichloride, trichloromethane or toluene such as bromine, NBS or NCS, generate the intermediate IV.Intermediate IV and 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone is in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, with methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene etc. is solvent, and 0～120 ℃ of reaction makes chemical compounds I.
Reaction makes all cpds or products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol or the DMSO dropping inorganic acid, organic acid makes 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, drips the vitriol oil down to pH=3, make vitriol in ice-water bath, or the like.
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; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.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 or the like.
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 the scope of a broad, 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 cell proliferation toxicity of invention compound 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; Fluorouracil Injection, 0.25g/10ml (propping up), lot number: 0512022, Tianjin gold credit amino acid company limited.
Laboratory apparatus: Bechtop, Suzhou Decontamination Equipment Plant; CO
2Incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert 200; 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 100ug/ml Vetstrep, 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, microscopically blood cell counts plate numeration viable cell with the glass dropper.(cell concn is adjusted into 6～10 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ L
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 then hole adds the MTT solution 10 μ L of 5mg/mL, 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), mass spectrum (MS) etc. is further proved conclusively its structure.
Reference example 1:
Intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 12.4g 2-chlorobenzaldehyde, it is dissolved, stir adding sodium hydroxide 8.0g down with the 35mL dehydrated alcohol.The 6.9g oxammonium hydrochloride is added reaction system in batches.Add, under room temperature, continue reaction 5h (the flaggy demonstration reacts completely).With the dehydrated alcohol evaporate to dryness, with 3 * 30mL water washing reaction solution, use dichloromethane extraction, the anhydrous sodium sulphate thorough drying is filtered, and methylene dichloride is to the greatest extent steamed in decompression, promptly gets white solid (HPLC:99.8%).The Rf=0.42[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=6: 1].
1H?NMR(DMSO-d
6，400MHz)δ：2.448(s，1H，-OH)，7.546～7.932(m，4H，phenyl-H)，8.31(s，1H，-CH＝N-)。
With reference to the method for reference example 1, can synthetic intermediate III-2～III-7.
Reference example 2:
Intermediate IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add 13.9g intermediate III-1, it is dissolved, stir adding NBS 17.8g down with the 40mL methylene dichloride.Room temperature reaction 6h under the illumination (the flaggy demonstration reacts completely).With 3 * 30mL 35%Na
2S
2O
3The solution washing reaction solution, dichloromethane layer anhydrous sodium sulphate thorough drying is filtered, and methylene dichloride is to the greatest extent steamed in decompression, promptly gets light yellow oily product (HPLC:97.2%).The Rf=0.35[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=6: 1].
1H?NMR(DMSO-d
6，400MHz)δ：2.324(s，1H，-OH)，7.572～7.961(m，4H，phenyl-H)。
With reference to the method for reference example 2, can synthetic intermediate IV-2～IV-7.
Embodiment 1:
(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2-chloro-phenyl-) ketoxime (compound 1)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.2g intermediate IV-1, it is dissolved, stir adding Anhydrous potassium carbonate 2.76g down with the 10mL anhydrous methanol.With 1.6g 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone adds reaction system in batches.Add, continue reaction 3.5h (the flaggy demonstration reacts completely) in refluxing down.The filtering solid matter, with the anhydrous methanol evaporate to dryness, with 3 * 10mL water washing reaction solution, use dichloromethane extraction, the anhydrous sodium sulphate thorough drying, filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets the dark oil thing, and post separates [moving phase: v (methylene dichloride): v (methyl alcohol)=9: 1], Rf=0.45 gets light yellow solid (HPLC:99.3%).
1H?NMR(DMSO-d
6，400MHz)δ：2.336(s，1H，-OH)，2.732～2.781(s，2H，-CH
2-)，2.942～2.985(m，2H，-CH
2-)，3.688～3.703(dd，2H，-CH
2-)，4.173(m，1H，-CH-)，6.28(s，1H，-CH＝O)，7.486～7.833(m，4H，phenyl-H)。
Embodiment 2:
(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(4-fluorophenyl)-O-methyl ketone oxime (compound 2)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.32g intermediate IV-2, it is dissolved, stir adding triethylamine 2.18g down with the 10mL dehydrated alcohol.With 1.6g 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone adds reaction system in batches.Add, continue reaction 4h (the flaggy demonstration reacts completely) in 70 ℃.With the dehydrated alcohol evaporate to dryness, with 3 * 10mL water washing reaction solution, use chloroform extraction, the anhydrous sodium sulphate thorough drying is filtered, and trichloromethane is to the greatest extent steamed in decompression, promptly get pale brown look oily matter, post separates [moving phase: v (methylene dichloride): v (methyl alcohol)=6: 1], and Rf=0.52 gets white solid (HPLC:99.0%).
Embodiment 3:
(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2, the 5-dichlorophenyl)-O-ethyl ketone oxime (compound 3)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.2g intermediate IV-3, it is dissolved, stir adding sodium hydroxide 1.0g down with the 20mL ethyl acetate.With 1.6g 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone adds reaction system in batches.Add, continue reaction 8h (the flaggy demonstration reacts completely) in refluxing down.The filtering solid matter is with 3 * 20mL water washing reaction solution, anhydrous sodium sulphate thorough drying, filter, ethyl acetate is to the greatest extent steamed in decompression, promptly gets yellow oil, post separates [moving phase: v (methylene dichloride): v (methyl alcohol)=6: 1], and Rf=0.50 gets white solid (HPLC:99.8%).
Embodiment 4:
(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2, the 6-dichlorophenyl)-O-propyl ketone oxime (compound 4)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.8g intermediate IV-4, it is dissolved, stir adding anhydrous sodium carbonate 1.31g down with the 15mL trichloromethane.With 1.6g 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone adds reaction system in batches.Add, continue reaction 10h (the flaggy demonstration reacts completely) in refluxing down.The filtering solid matter is with 3 * 15mL water washing reaction solution, anhydrous sodium sulphate thorough drying, filter, trichloromethane is to the greatest extent steamed in decompression, promptly gets yellow oil, post separates [moving phase: v (methylene dichloride): v (methyl alcohol)=8: 1], and Rf=0.58 gets white solid (HPLC:99.5%).
Embodiment 5:
(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,4, the 6-trichlorophenyl)-O-isopropyl ketoxime (compound 5)
In the reaction flask that stirring, condenser, thermometer are housed, add 3.0g intermediate IV-5, it is dissolved, stir adding pyridine 1.65g down with the 10mL methylene dichloride.With 1.6g 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone adds reaction system in batches.Add, continue reaction 7h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 10mL water washing reaction solution, anhydrous sodium sulphate thorough drying, filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets red-brown oily matter, and post separates [moving phase: v (methylene dichloride): v (methyl alcohol)=7: 1], Rf=0.55 gets white solid (HPLC:99.8%).
Embodiment 6:
(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,3,5,6-tetrafluoro phenyl) ketoxime (compound 6)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.7g intermediate IV-6, it is dissolved, stir adding sodium bicarbonate 1.73g down with 20mL toluene.With 1.6g 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone adds reaction system in batches.Add, continue reaction 6h (the flaggy demonstration reacts completely) in 95 ℃.The filtering solid matter is with 3 * 20mL water washing reaction solution, anhydrous sodium sulphate thorough drying, filter, toluene is to the greatest extent steamed in decompression, promptly gets blackyellow oily matter, post separates [moving phase: v (methylene dichloride): v (methyl alcohol)=8: 1], and Rf=0.60 gets light yellow solid (HPLC:99.2%).
Embodiment 7:
(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,3-dichloro-4,4-aminomethyl phenyl)-O-methyl ketone oxime (compound 7)
In the reaction flask that stirring, condenser, thermometer are housed, add 2.6g intermediate IV-7, it is dissolved, stir adding potassium hydroxide 1.3g down with the 10mL anhydrous methanol.With 1.6g 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone adds reaction system in batches.Add, continue reaction 3h (the flaggy demonstration reacts completely) in refluxing down.The filtering solid matter, with the anhydrous methanol evaporate to dryness, with 3 * 10mL water washing reaction solution, use dichloromethane extraction, the anhydrous sodium sulphate thorough drying, filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets pale brown look oily matter, and post separates [moving phase: v (methylene dichloride): v (methyl alcohol)=7: 1], Rf=0.46 gets white solid (HPLC:99.5%).
Embodiment 8:
1 one-tenth hydrochloride of compound: get compound 1 light yellow 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 9:
5 one-tenth taurates of compound: get compound 5 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 10:
7 one-tenth vitriol of compound: get compound 7 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 of oxime compounds of the present invention is described more fully, following example of formulations is provided below, described embodiment only is used for explanation, rather than is used to limit 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 1-10.
Embodiment 11:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule
Compound 2 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 12:
Prepare tablet with following compositions:
Consumption/sheet
Compound 4 10mg
Starch 45mg
Carboxymethyl starch sodium salt 4.5mg
Magnesium Stearate 0.5mg
Talcum powder 1mg
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 13:
The preparation of injection liquid:
The hydrochloride 200mg of compound 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 14:
The preparation of injection lyophilized powder:
The taurate 100mg of compound 5
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, promptly.
Claims (8)
1. the compound and the pharmacy acceptable salt thereof that have formula I structure:
Wherein:
R
1Be halogen;
R
2, R
3, R
4Be at the same time or separately: hydrogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halogen, nitro, itrile group, phenyl;
R
5For: hydrogen, C
1-C
4The straight or branched alkyl is by halogen, nitro, itrile group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, C
1-C
4The phenyl that alkyl amide replaces.
2. the formula I compound described in claim 1 is following compound:
(1) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2-chloro-phenyl-) ketoxime;
(2) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(4-fluorophenyl)-O-methyl ketone oxime;
(3) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2, the 5-dichlorophenyl)-O-ethyl ketone oxime;
(4) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2, the 6-dichlorophenyl)-O-propyl ketone oxime;
(5) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,4, the 6-trichlorophenyl)-O-isopropyl ketoxime;
(6) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,3,5,6-tetrafluoro phenyl) ketoxime;
(7) (5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridine-2-(4H)-ketone group also)-(2,3-dichloro-4,4-aminomethyl phenyl)-O-methyl ketone oxime.
3. as the described formula I of claim 1～2 compound, pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
4. formula I compound pharmacy acceptable salt as claimed in claim 3 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, gluconate, amino acid salts.
5. the preparation method of claim 1 Chinese style I compound, it is characterized in that: intermediate IV and 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2-(4H)-ketone in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, be solvent with methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene, 25～120 ℃ of reactions make chemical compounds I.
6. antitumor medicine composition, it comprises each formula I compound or its pharmacy acceptable salt and one or more pharmaceutical carriers of claim 1～2 for the treatment of significant quantity.
Claim 1～2 each formula I compound and pharmacy acceptable salt in the application that is used to prepare aspect the antitumor drug.
8. application as claimed in claim 7 is in the purposes that is used to prepare aspect treatment mammary cancer, lung cancer, the cancer of the stomach medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010502996A CN101967154B (en) | 2010-10-11 | 2010-10-11 | Oxime compounds, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010502996A CN101967154B (en) | 2010-10-11 | 2010-10-11 | Oxime compounds, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101967154A true CN101967154A (en) | 2011-02-09 |
| CN101967154B CN101967154B (en) | 2011-12-28 |
Family
ID=43546387
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010502996A Expired - Fee Related CN101967154B (en) | 2010-10-11 | 2010-10-11 | Oxime compounds, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101967154B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225420A (en) * | 1991-02-14 | 1993-07-06 | Elf-Sanofi | Use of tetrahydrothienopyridine derivatives as angiogenesis inhibitors |
| CN101402641A (en) * | 2008-11-20 | 2009-04-08 | 天津药物研究院 | Oxime derivatives containing thienopyridine, preparation method and application thereof |
-
2010
- 2010-10-11 CN CN201010502996A patent/CN101967154B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225420A (en) * | 1991-02-14 | 1993-07-06 | Elf-Sanofi | Use of tetrahydrothienopyridine derivatives as angiogenesis inhibitors |
| CN101402641A (en) * | 2008-11-20 | 2009-04-08 | 天津药物研究院 | Oxime derivatives containing thienopyridine, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101967154B (en) | 2011-12-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103044395B (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| CN104163823A (en) | Camptothecin and artesunate conjugate, preparation method and application thereof | |
| CN102911118B (en) | Benzo-azepine type derivative and preparation method and purpose thereof | |
| CN101845051B (en) | Nitrogen-containing heterocyclic thienopyridine compounds and preparation method and application thereof | |
| CN101974016A (en) | Amide compound and preparation method and applications thereof | |
| CN101863901B (en) | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof | |
| CN103864765B (en) | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use | |
| CN104292211A (en) | Desloratadine nitric oxide donor, and preparation method and application thereof | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN104926804B (en) | One kind has compound, the preparation method and use of antitumor action | |
| CN101967154B (en) | Oxime compounds, preparation method and application thereof | |
| CN101845052B (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof | |
| CN102276626B (en) | Isoxazole-containing compound | |
| CN102796140A (en) | Phosphate-containing isoxazoline derivatives and their preparation method and use | |
| CN102417514B (en) | Pyridine derivatives, preparation method thereof, and purpose thereof | |
| CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
| CN102276625B (en) | Thiadiazole derivative | |
| CN102329327B (en) | Furan derivatives and preparation method and application thereof | |
| CN101805355B (en) | Thienopyridone derivative, preparation method and uses thereof | |
| CN103880793B (en) | Containing furan imine compound and its production and use | |
| CN103804367B (en) | Benzazepine derivant, Preparation Method And The Use | |
| CN105037345A (en) | Antitumor compound as well as preparation method and application thereof | |
| CN102358742B (en) | Thiazole compound with antitumor activity | |
| CN103288805A (en) | Benzofuran-containing pyrimidine compound, its preparation method and use | |
| CN104829629B (en) | Thiophane simultaneously [2,3 c] pyridine derivate, Preparation Method And The Use containing sulfoamido |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20111228 Termination date: 20211011 |