CN102329327B - Furan derivatives and preparation method and application thereof - Google Patents
Furan derivatives and preparation method and application thereof Download PDFInfo
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- CN102329327B CN102329327B CN201110319870.1A CN201110319870A CN102329327B CN 102329327 B CN102329327 B CN 102329327B CN 201110319870 A CN201110319870 A CN 201110319870A CN 102329327 B CN102329327 B CN 102329327B
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- cancer
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- 0 *N=CC1=CCCO1 Chemical compound *N=CC1=CCCO1 0.000 description 3
- HIMNXJAVIZINRN-VMPITWQZSA-N CCc1ccc(/C=N/O)[o]1 Chemical compound CCc1ccc(/C=N/O)[o]1 HIMNXJAVIZINRN-VMPITWQZSA-N 0.000 description 2
- OGUWOLDNYOTRBO-UHFFFAOYSA-N C(CNC1)c2c1cc[s]2 Chemical compound C(CNC1)c2c1cc[s]2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 1
- OGPSEYDRTCOHND-CLFYSBASSA-N CCc1ccc(/C(/Br)=N/O)[o]1 Chemical compound CCc1ccc(/C(/Br)=N/O)[o]1 OGPSEYDRTCOHND-CLFYSBASSA-N 0.000 description 1
- BOQNBJCFILUPHH-UHFFFAOYSA-N O=Cc1ccc(CI)[o]1 Chemical compound O=Cc1ccc(CI)[o]1 BOQNBJCFILUPHH-UHFFFAOYSA-N 0.000 description 1
- HYBBIBNJHNGZAN-UHFFFAOYSA-N O=Cc1ccc[o]1 Chemical compound O=Cc1ccc[o]1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
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, the pharmaceutical composition that relates to a class and there is antineoplastic compound and preparation method thereof, contain them and as the purposes of antitumor drug.
Background technology
Cancer has become a large chronic disease of serious harm human health at present.Suffering from every year in the world according to statistics cancered people has 9,000,000, and the patient who dies from cancer is 6,000,000, almost just has cancer patients's death p.s..China's cancer year number of the infected, in 1,200,000 left and right, is died from the number of cancer up to more than 900,000, and patient to be treated surpasses 1,500,000, and has the trend rising year by year.Therefore cancer has now become the second largest killer who is only second to cardiovascular disorder.Treat clinically tumour, generally adopt operation, radiotherapy, the large therapy of chemotherapy three.Though embolic chemotherapy is comparatively quick, curative ratio is very low.The many cancer therapy drugs existence of clinical discovery are simultaneously obvious to the damage of normal body and toxic side effect, for example mutagenesis and genetoxic.Therefore, find effectively and the 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 furan derivatives and the pharmaceutical salts thereof of a class novel texture.
Another object of the present invention is, discloses the preparation method of a class furan derivatives and pharmaceutical salts thereof.
A further object of the present invention is, openly take the pharmaceutical composition that a class furan derivatives and pharmaceutical salts thereof be main active ingredient.
A further object of the invention is, discloses furan derivatives and pharmaceutical salts thereof as the application of medicine for resisting malignant tumors, particularly in the purposes aspect treatment mammary cancer, lung cancer, cancer of the stomach medicine.
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
1, R
2for: hydrogen, C
1-C
4straight or branched alkyl, the C that hydroxyl replaces
1-C
4straight or branched alkyl, halogen, nitro, substituted-phenyl, saturated five-membered ring.
R
3for: hydrogen, C
1-C
4straight 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:
I-1 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (5-ethyl furan-2-yl) ketoxime
I-2 (4-bromine furans-2-yl) (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) ketone-O-methyloxime
I-3 (5-chlorine furans-2-yl) (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) ketoxime
I-4 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (5-nitrofuran-2-yl) ketoxime
I-5 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (furans-2-yl) ketone-O-sec.-propyl oxime
I-6 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (5-(methylol) furans-2-yl) ketone-O-ethyl oxime
I-7 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (5-(4-nitrophenyl) furans-2-yl) methyl ketone-O-methyloxime
I-8 (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (5-(pyrrolidin-1-yl) furans-2-yl) ketone-O-propyl group 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 syntheti c route of formula I compound is as follows:
Substituted furan-2-benzaldehyde compound (II), in methyl alcohol, ethanol or acetone equal solvent, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide ,-30～85 ℃ of reactions make key intermediate III with N-substituted hydroxylamine hydrochloride compounds.Intermediate III again with the halogenating agent such as bromine, NBS or NCS in methylene dichloride, trichloromethane or toluene-10～110 ℃ react, generate intermediate compound IV.Intermediate compound IV and 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine is under the acid binding agent such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exists, take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene etc. is solvent, and 0～120 ℃ of reaction makes Compound I.
Reaction make various compounds or products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol or DMSO drip mineral acid, organic acid is made pharmacy acceptable salt.
Specifically various compounds are dissolved in to a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drip salt acid ether to pH=2, make hydrochloride; Or various compounds are dissolved in to a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, and mole taurine such as adding, heated and stirred obtains its taurate; Or various compounds are dissolved in to a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drip the vitriol oil to pH=3, make vitriol, etc.
This compounds is effective for treatment human malignancies.Although compound of the present invention can be without the direct administration of any preparation, described various compounds are preferably used with the form of pharmaceutical preparation, and route of administration can be parenteral route (as vein, muscle administration) and oral administration.
The pharmaceutical composition of the compounds of this invention is prepared 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 one 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 such as 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 containing in pharmaceutical composition and unit dosage form (the compounds of this invention) can specifically be applied according to the situation of patient's the state of an illness, diagnosis, the amount of compound used or concentration regulate in a wider scope, conventionally, 0.5%～90% (weight) that the weight range of active compound is composition.Another preferred scope is 0.5%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention, has obvious restraining effect to tumour in vitro.
External antitumor action
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the cell proliferation toxicity of invention compound to the human tumor cells of vitro culture.
(2) experiment material:
Laboratory sample: formula I compound is provided by contriver's self-control.During experiment, sample is with DMSO hydrotropy, 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 Jin Yao 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 purchased 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, is placed in 37 ℃, 100% relative humidity, containing 5%CO
2incubator in, go down to posterity standby after 3 times.
Mtt assay is measured: the cell in the vegetative period of taking the logarithm, after 0.25% tryptic digestion (suspension cell need not digest), be suspended in containing in the DMEM nutrient solution of 10% calf serum, with glass dropper, blow and beat into gently single cell suspension, under microscope, use blood cell counts plate numeration viable cell.(cell concn is adjusted into 6～10 * 10 to the 96 every hole of well culture plate inoculating cell suspension 90 μ L
4individual/mL), at 37 ℃, 100% relative humidity, containing 5%CO
2, 95% air incubator cultivate after 24h, every hole adds 10 μ L liquids (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, then every hole adds the MTT solution 10 μ L of 5mg/mL, continues to cultivate after 4h, carefully suck supernatant liquor (suspension cell, need first centrifugal, then suck supernatant).Every hole adds 100 μ L DMSO, puts micro oscillator concussion 5min so that crystallization is dissolved completely, and the mono-wavelength colorimetric of microplate reader 492nm, measures OD value.The following method of usining is calculated inhibitory rate of cell growth as evaluation index.
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, with straight-line regression method, calculate IC
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 described further, and embodiment is only indicative, never means that 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 confirmed its structure.
reference example 1:
Synthesizing of intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 12.4g 5-ethyl furan-2-formaldehyde, with 50mL dehydrated alcohol, dissolved, under stirring, add sodium hydroxide 8.0g.6.9g oxammonium hydrochloride is added to reaction system in batches.Add, under room temperature, continue reaction 5h (flaggy demonstration reacts completely).By dehydrated alcohol evaporate to dryness, with 3 * 30mL water washing reaction solution, with dichloromethane extraction, anhydrous sodium sulphate is fully dry, filters, and methylene dichloride is to the greatest extent steamed in decompression, obtains 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 example 1, can synthetic intermediate III-2～III-8.
Table 2 intermediate III-2～III-8 list
reference example 2:
Synthesizing of intermediate compound IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add 13.9g intermediate III-1, with 50mL methylene dichloride, dissolved, under stirring, add NBS 17.8g.Room temperature reaction 6h under illumination (flaggy demonstration reacts completely).With 3 * 30mL 35%Na
2s
2o
3solution washing reaction solution, dichloromethane layer anhydrous sodium sulphate is fully dry, filters, and methylene dichloride is to the greatest extent steamed in decompression, obtains 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 example 2, can synthetic intermediate IV-2～IV-8.
Table 3 intermediate compound IV-2～IV-8 list
embodiment 1:
Synthesizing of (6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also) (5-ethyl furan-2-yl) ketoxime (Compound I-1)
In the reaction flask that stirring, condenser, thermometer are housed, add 10.9g intermediate compound IV-1, with 30mL anhydrous methanol, dissolved, under stirring, add Anhydrous potassium carbonate 6.5g.By 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine 7.0g add reaction system in batches.Add, in the lower reaction 3.5h (flaggy demonstration reacts completely) that continues that refluxes.Filtering solid matter, by anhydrous methanol evaporate to dryness, with 3 * 30mL water washing reaction solution, with dichloromethane extraction, anhydrous sodium sulphate is fully dry, filter, methylene dichloride is to the greatest extent steamed in decompression, obtains dark oil thing, post separated [moving phase: v (methylene dichloride): v (methyl alcohol)=8: 1], Rf=0.59, obtains 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 list
embodiment 2:
Compound I-1 one-tenth hydrochloride: get Compound I-1 white solid product 2.0g, be dissolved in 10mL 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 ice-water bath.Filter, vacuum-drying, obtains white solid powder.
embodiment 3:
Compound I-2 one-tenth taurate: get Compound I-2 white solid product 2.0g, be dissolved in 10mL anhydrous methanol.After being heated to reflux, add and wait mole taurine, continue at time about 1.5h of stirring reaction that refluxes.React complete, standing 24h under room temperature.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 ice-water bath.Filter, obtain white solid.
For the pharmaceutical composition of the oxime compounds containing furans of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, described embodiment is only for explanation, rather than for limiting the scope of the invention.Described preparation can be used any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 1-4.
embodiment 5:
By following compositions, prepare hard gelatin capsule:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.Press recipe quantity by after mentioned component mixing, be packed in hard gelatin capsule.
embodiment 6:
By following compositions, prepare tablet:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.First the auxiliary material of recipe quantity is fully mixed.Bulk drug is added in auxiliary material to increase progressively dilution method, and each added-time fully mixes 2-3 time, guarantees that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dry particle is crossed the whole grain of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
embodiment 7:
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves polysorbate and propylene glycol, add medicinal basic to regulate pH value to 4～8 to make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilizing.
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%
Preparation method: get activeconstituents and add water for injection, regulate pH value to make its dissolving to 4-8 with medicinal basic.Add N.F,USP MANNITOL again, by the requirement of injection, carry out autoclaving, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, and sealing, obtains.
Claims (8)
1. compound and the pharmacy acceptable salt thereof with formula I structure:
Wherein:
R
1, R
2for: hydrogen, methyl, ethyl, methylol, chlorine, bromine, nitro, nitrophenyl, pyrrolidyl;
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, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate.
5. the preparation method of claim 1 Chinese style I compound, it is characterized in that: intermediate IV and 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine, under triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exist, be take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene as solvent, 25～120 ℃ of reactions make chemical compounds I
Wherein X is Cl, Br; R
1, R
2, R
3as claimed in claim 1.
6. an antitumor medicine composition, it comprises the formula I compound as described in claim 1～2 any one or its pharmacy acceptable salt and one or more pharmaceutical carriers for the treatment of significant quantity.
7. the formula I compound described in claim 1～2 any one and pharmacy acceptable salt thereof are in the application aspect antitumor drug.
8. application as claimed in claim 7, in the purposes aspect treatment mammary cancer, lung cancer, cancer of the stomach medicine.
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| CN102329327B true CN102329327B (en) | 2014-04-09 |
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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 (2)
| Title |
|---|
| 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;成碟,等;《中国药学杂志》;20091130;第44卷(第22期);第1752-1754页 * |
| 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》.2009,第44卷(第22期),第1752-1754页. |
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