CN102329327A - Furan derivatives and preparation method and application thereof - Google Patents
Furan derivatives and preparation method and application thereof Download PDFInfo
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- CN102329327A CN102329327A CN201110319870A CN201110319870A CN102329327A CN 102329327 A CN102329327 A CN 102329327A CN 201110319870 A CN201110319870 A CN 201110319870A CN 201110319870 A CN201110319870 A CN 201110319870A CN 102329327 A CN102329327 A CN 102329327A
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- cancer
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Abstract
The invention belongs to the technical field of medicines and provides furan derivatives with a structure shown as a general formula I and medicinal salts of the furan derivatives. R1, R2 and R3 are shown in the specification. The invention also relates to a method for preparing the compounds, and discloses a medical composition in which the compounds or pharmaceutically acceptable salts of the compounds are taken as active ingredients, and use of the compounds and the pharmaceutically acceptable salts of the compounds as antitumor medicines.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to one type and have antineoplastic compound and preparation method thereof, contain their pharmaceutical composition and as the purposes of antitumor drug.
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 become the second largest killer who is only second to cardiovascular disorder at present.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 furan derivatives and the pharmaceutical salts thereof of one type of novel texture.
Another object of the present invention is, discloses the preparation method of one type of furan derivatives and pharmaceutical salts thereof.
A further object of the present invention is that open is the pharmaceutical composition of main active ingredient with one type of furan derivatives and pharmaceutical salts thereof.
A further object of the invention is, open furan derivatives and pharmaceutical salts thereof be as the application of medicine for resisting malignant tumors, particularly in the purposes that is used to prepare aspect treatment mammary cancer, lung cancer, the cancer of the stomach medicine.
Combine the object of the invention at present, content of the present invention is set forth in detail.
The present invention is specifically related to the compound and the pharmacy acceptable salt thereof of formula I structure:
Wherein:
R
1, R
2For: hydrogen, C
1-C
4The straight or branched alkyl, the substituted C of hydroxyl
1-C
4The straight or branched alkyl, halogen, nitro, substituted-phenyl, saturated five-membered ring.
R
3For: hydrogen, C
1-C
4The straight or branched alkyl.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
R
1, R
2For: hydrogen, methyl, ethyl, methylol, chlorine, bromine, nitro, oil of mirbane, tetramethyleneimine;
R
3For: hydrogen, methyl, ethyl, propyl group, sec.-propyl.
More preferably following compound and pharmacy acceptable salt thereof:
(6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl) (5-ethyl furan-2-yl) ketoxime also for I-1
(6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl) ketone-O-methyloxime also for I-2 (4-bromine furans-2-yl)
(6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl) ketoxime also for I-3 (5-chlorine furans-2-yl)
(6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl) (5-nitrofuran-2-yl) ketoxime also for I-4
(6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl) (furans-2-yl) ketone-O-sec.-propyl oxime also for I-5
(6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl) (5-(methylol) furans-2-yl) ketone-O-ethyl oxime also for I-6
(6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl) (5-(4-nitrophenyl) furans-2-yl) MIBK-O-methyloxime also for I-7
(6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl) (5-(tetramethyleneimine-1-yl) furans-2-yl) ketone-O-propyl group oxime also for I-8
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, PHENRAMINE MALEATE, benzoate, SUMATRIPTAN SUCCINATE, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts.
The preparation route of formula I compound is following:
Substituted furan-2-benzaldehyde 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 hydrogencarbonate, saleratus, sodium hydroxide or Pottasium Hydroxide ,-30～85 ℃ of reactions make key intermediate III.Intermediate III again with halogenating agent-10～110 ℃ of reactions in methylene dichloride, trichloromethane or toluene such as bromine, NBS or NCS, generate intermediate compound IV.Intermediate compound IV and 4; 5; 6, the 7-THTP also [3,2-c] pyridine in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium hydrogencarbonate, saleratus, sodium hydroxide or Pottasium Hydroxide; With methyl alcohol, ethanol, ETHYLE ACETATE, methylene dichloride, trichloromethane or toluene etc. is solvent, and 0～120 ℃ of reaction makes compound I.
Reaction makes all cpds or products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol or the DMSO dropping inorganic acid, organic acid processes pharmacy acceptable salt.
Specifically be that all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, the dripping hydrochloric acid ether is processed hydrochloride to pH=2 under ice-water bath; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE 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, ETHYLE ACETATE or the DMSO, drips the vitriol oil down to pH=3, process 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 prepn, and route of administration can be non-enteron aisle approach (like vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions of The compounds of this invention is following: use standard and conventional technology; Acceptable solid or liquid vehicle are combined, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.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, Ucar 35, 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-s 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 compsn.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 products, 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 ltd.
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 100 μ g/mL Vetstreps, places 37 ℃, 100% relative humidity, contains 5%CO
2Incubator in, it is subsequent use 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 is with blood cell counts plate numeration viable cell.(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 (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 ELIASA 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 control group OD average)/(control group OD average-blank control group OD average)] * 100%.According to inhibitory rate of cell growth, calculate IC with the straight-line regression method
50Value.
(4) experimental result:
The IC of the tumour cell of table 1 pair vitro culture
50(μ g/mL)
(5) conclusion:
According to above-mentioned in vitro tests result, we can find out that the compound with formula I structure has stronger restraining effect to above-mentioned 3 kinds of human tumor cells.
Embodiment
Below in conjunction with embodiment the present invention is done further explanation, it is indicative that embodiment is merely, and means that never it limits scope of the present invention by any way.Described compound is through performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as ir spectra (IR), nuclear magnetic resonance spectrum (
1H NMR,
13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Reference implementation example 1:
Synthesizing of intermediate III-1
In the reaction flask that stirring, condensing surface, TM are housed, add 12.4g 5-ethyl furan-2-formaldehyde, it is dissolved, stir adding sodium hydroxide 8.0g down with the 50mL absolute ethyl 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 absolute ethyl alcohol evaporate to dryness, with 3 * 30mL water washing reaction solution, use dichloromethane extraction, the SODIUM SULPHATE ANHYDROUS 99PCT thorough drying is filtered, and methylene dichloride is to the greatest extent steamed in decompression, promptly gets white solid (HPLC:97.6%).Rf=0.55 [single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=7: 1].
With reference to the method for reference implementation example 1, can synthetic intermediate III-2～III-8.
Table 2 intermediate III-2～III-8 tabulation
Reference implementation example 2:
Synthesizing of intermediate compound IV-1
In the reaction flask that stirring, condensing surface, TM are housed, add 13.9g intermediate III-1, it is dissolved, stir adding NBS 17.8g down with the 50mL 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 SODIUM SULPHATE ANHYDROUS 99PCT thorough drying is filtered, and methylene dichloride is to the greatest extent steamed in decompression, promptly gets light yellow oily product (HPLC:96.7%).Rf=0.50 [single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=7: 1].
With reference to the method for reference implementation example 2, can synthetic intermediate IV-2～IV-8.
Table 3 intermediate compound IV-2～IV-8 tabulation
Embodiment 1:
(6, the 7-dihydro-thiophene is synthesizing of [3,2-c] pyridines-5 (4H)-yl) (5-ethyl furan-2-yl) ketoximes (compound I-1) also
In the reaction flask that stirring, condensing surface, TM are housed, add 10.9g intermediate compound IV-1, it is dissolved, stir adding Anhydrous potassium carbonate 6.5g down with the 30mL anhydrous methanol.With 4,5,6,7-THTP also [3,2-c] pyridine 7.0g adds reaction system in batches.Add, continue reaction 3.5h (the flaggy demonstration reacts completely) in refluxing down.The filtering solid matter is with the anhydrous methanol evaporate to dryness, with 3 * 30mL water washing reaction solution; Use dichloromethane extraction, the SODIUM SULPHATE ANHYDROUS 99PCT thorough drying is filtered; 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)=8: 1]; Rf=0.59 gets light yellow solid (HPLC:99.3%).
With reference to the method for embodiment 1, can obtain target compound I-2～I-8.
Table 4 compound I-2～I-8 tabulation
Embodiment 2:
Compound I-1 one-tenth hydrochloride: get compound I-1 white solid product 2.0g, be dissolved in the 10mL absolute ethyl 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 3:
Compound I-2 one-tenth taurate: get compound I-2 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 under room temperature, leaves standstill 24h.Separate out transparent crystallization, filter vacuum-drying.
Embodiment 4:
Compound I-4 one-tenth vitriol: get compound I-4 light yellow solid product 2.0g, be dissolved in 12mL 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 oxime compounds of furans of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, said embodiment only is used for explanation, rather than is used to limit scope of the present invention.Said 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 1-4.
Embodiment 5:
Prepare hard gelatin capsule with following compositions:
Preparation technology: supplementary material is dry in advance, and it is subsequent use to cross 100 mesh sieves.After pressing recipe quantity mentioned component being mixed, be packed in the hard gelatin capsule.
Embodiment 6:
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, and it is subsequent use 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 midbody content, mix compressing tablet on tabletting machine.
Embodiment 7:
The preparation of injection liquid:
Preparing method: get activeconstituents and join in the water for injection that dissolves polysorbate and Ucar 35, 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 8:
The preparation of injection lyophilized powder:
The taurate 100mg of compound I-2
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparing 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, filtrating is carried out packing, adopts freeze-drying, makes loose block, seals, and promptly gets.
Claims (8)
1. the compound and the pharmacy acceptable salt thereof that have formula I structure:
Wherein:
R
1, R
2For: hydrogen, methyl, ethyl, methylol, chlorine, bromine, nitro, oil of mirbane, tetramethyleneimine;
R
3For: hydrogen, methyl, ethyl, propyl group, sec.-propyl.
2. compound as claimed in claim 1 and pharmacy acceptable salt thereof, its Chinese style I compound is:
3. compound as claimed in claim 1 and pharmacy acceptable salt thereof, pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
4. compound as claimed in claim 3 and pharmacy acceptable salt thereof, pharmacy acceptable salt refers to: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, PHENRAMINE MALEATE, benzoate, SUMATRIPTAN SUCCINATE, tartrate, Citrate trianion, fumarate, taurate, gluconate.
5. the preparation method of claim 1 Chinese style I compound is characterized in that: intermediate compound IV and 4,5; 6; 7-THTP also [3,2-c] pyridine is a solvent with methyl alcohol, ethanol, ETHYLE ACETATE, methylene dichloride, trichloromethane or toluene in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium hydrogencarbonate, saleratus, sodium hydroxide or Pottasium Hydroxide; 25～120 ℃ of reactions make compound I
R wherein
1, R
2, R
3According to claim 1.
6. antitumor medicine composition, it comprise the treatment significant quantity like each described formula I compound of claim 1～2 or its pharmacy acceptable salt and one or more pharmaceutical carriers.
7. each described formula I compound of claim 1～2 and pharmacy acceptable salt thereof are 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.
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Citations (3)
| 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 |
| CN101817834A (en) * | 2010-05-13 | 2010-09-01 | 天津药物研究院 | Pyrazole derivatives and preparation method and application thereof |
-
2011
- 2011-10-20 CN CN201110319870.1A patent/CN102329327B/en active Active
Patent Citations (3)
| 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 |
| CN101817834A (en) * | 2010-05-13 | 2010-09-01 | 天津药物研究院 | Pyrazole derivatives and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 成碟,等: "含有取代哌嗪及哌啶结构的噻吩并吡啶类化合物的合成及活性研究", 《中国药学杂志》, vol. 44, no. 22, 30 November 2009 (2009-11-30), pages 1752 - 1754 * |
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