CN102276625B - Thiadiazole derivative - Google Patents
Thiadiazole derivative Download PDFInfo
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- CN102276625B CN102276625B CN 201110242765 CN201110242765A CN102276625B CN 102276625 B CN102276625 B CN 102276625B CN 201110242765 CN201110242765 CN 201110242765 CN 201110242765 A CN201110242765 A CN 201110242765A CN 102276625 B CN102276625 B CN 102276625B
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Abstract
The invention belongs to the technical field of anti-tumor medicaments, and provides a thiadiazole derivative with a structure of a formula I. In the formula I, R<1> is hydrogen, methyl and ethyl, and R<2> is the hydrogen, chlorine, bromine, the methyl, methylmercapto, ethylthio, methoxy carbonyl, carbethoxy, methoxyphenyl, bromophenyl and phenoxymethyl. The invention also relates to a preparation method for the compound, and discloses a medicinal composition in which a compound or a pharmaceutically-acceptable salt thereof are taken as active ingredients and application of the compound or the pharmaceutically-acceptable salt of the compound which serve as the anti-tumor medicaments.
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 thiadiazoles derivative and the pharmaceutical salts thereof of a class novel texture.
Another object of the present invention is, discloses the preparation method of a class thiadiazoles derivative and pharmaceutical salts thereof.
A further object of the present invention is that disclosing with a class thiadiazoles derivative and pharmaceutical salts thereof is the pharmaceutical composition of main active ingredient.
A further object of the invention is, discloses thiadiazoles derivative and pharmaceutical salts thereof, as the application of antitumor drug aspect, particularly in the purposes aspect treatment lung cancer, mammary cancer, prostate cancer medicine.
The present invention is specifically related to compound and the pharmacy acceptable salt thereof of formula I structure:
Wherein:
R
1For: hydrogen, C
1-C
4The straight or branched alkyl.
R
2For: hydrogen, halogen, C
1-C
4The straight or branched alkylthio, C
1-C
4The straight or branched alkoxyphenyl radical, benzene oxygen alkyl, halogeno-benzene, C
1-C
4The straight or branched carbalkoxy.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
R
1For: hydrogen, methyl, ethyl;
R
2For: hydrogen, chlorine, bromine, methyl, methylthio group, ethylmercapto group, methoxycarbonyl, ethoxycarbonyl, methoxyphenyl, bromophenyl, Phenoxymethyl.
More preferably following compound and pharmacy acceptable salt thereof:
(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl)-N-(5-(ethylmercapto group)-1,3,4-thiadiazoles-2-yl) ethanamide also for 2-;
N-(5-bromo-1,3,4-thiadiazoles-2-yl)-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) ethanamide also for 2-;
(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl)-N-(1,3,4-thiadiazoles-2-yl) ethanamide also for 2-;
5-(2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) kharophen also)-2-methoxycarbonyl-1,3,4-thiadiazoles;
(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl)-N-(5-(4-p-methoxy-phenyl)-1,3,4-thiadiazoles-2-yl) ethanamide also for 2-;
N-(5-(4-bromophenyl)-1,3,4-thiadiazoles-2-yl)-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl) ethanamide also for 2-;
(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl)-N-(5-(Phenoxymethyl)-1,3,4-thiadiazoles-2-yl) butyramide also for 2-.
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, etc.
The preparation route of formula I compound is as follows:
Wherein X is Cl or Br; R
1～R
2Definition as described above.
Thiadiazole compound (II), in DMF, with 2-halogen acyl halide compounds under triethylamine catalysis ,-20-15 ℃ of reaction makes key intermediate III.Intermediate III again with 4,5,6,7-tetramethylene sulfide and pyridine in the presence of triethylamine, be solvent with the acetonitrile, 70～90 ℃ of reactions make compound I.
Reaction makes all cpds or products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol, Virahol, ether or the DMSO dropping inorganic acid, organic acid makes pharmacy acceptable salt.
Specifically be that products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol or the DMSO, dripping hydrochloric acid ethanol is made hydrochloride to pH2.Or products therefrom is dissolved in DMF, acetone, methyl alcohol or ethanol, molar lactic acid such as adding get its lactic acid salt.
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 to tumour cell.
External antitumor action experiment
(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; 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: HERACell150; 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, PC-3M Human Prostate Cancer 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 with the glass dropper, microscopically 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 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:
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, 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: the preparation of intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 16.1g 5-(ethylmercapto group)-1,3,4-thiadiazoles-2-amino adds the 20.2g triethylamine with 50ml DMF with its dissolving back, and-10 ℃～5 ℃ are stirred down, drip the mixed solution of chloroacetyl chloride (16.9g) and methylene dichloride (30ml), behind low-temp reaction 3h (the flaggy demonstration reacts completely) the stirring at room 1h, reaction solution is poured in the 100ml cold water, fully stirred, filter, namely get brown solid (HPLC:88.5%).The Rf=0.72[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=3: 2].
Method with reference to reference example 1 can conveniently prepare compound: intermediate III-2～III-6 replaces chloroacetyl chloride to get III-7 (the compound tabulation sees Table 2) with 2-bromo butyryl bromide.
Table 2 intermediate III-2～III-7 tabulation
Embodiment 1:
(6,7-dihydro-thiophene is the preparation of [3,2-c] pyridine-5 (4H)-yl)-N-(5-(ethylmercapto group)-1,3,4-thiadiazoles-2-yl) ethanamide (compound I-1) also for 2-
In the reaction flask that stirring, condenser, thermometer are housed, add 23.7g intermediate III-1,100mL acetonitrile successively, 20.2g triethylamine, with 17.5g 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride, under room temperature, stir 5h, with 3 * 50mL saturated aqueous common salt washing reaction liquid, use ethyl acetate extraction, anhydrous sodium sulphate is fully dry, filter, ethyl acetate is to the greatest extent steamed in decompression, namely gets sorrel oily matter, and post separates [moving phase: v (sherwood oil): v (ethyl acetate)=3: 2], Rf=0.51 gets white solid (HPLC:99.4%).
1H?NMR(CDCl
3，400MHz)δ：1.311-1.347(t，3H，-CH
3)，2.481-2.499(m，2H，-CH
2CH
2-)，2.819-2.888(m，2H，-CH
2CH
2-)，3.184-3.239(q，2H，-CH
2CO-)，3.546(s，2H，-CH
2-)，3.628(s，2H，-CH
2-)，6.773-6.785(d，1H，-CH＝)，7.253-7.266(d，1H，＝CHS-)，12.463(s，1H，-NH)。HRMS(m/z)[M+H]
+：341.0559。
Method with reference to embodiment 1 can conveniently prepare compound I-2～I-7 (the compound tabulation sees Table 3).
Table 3 compound I-2～I-7 tabulation
Embodiment 2:
1 one-tenth hydrochloride of compound: get compound 1 white solid product 2.0g, be dissolved in the 10mL anhydrous diethyl ether.Ice-water bath is cooled to 0 ℃, drip 25% hydrochloric acid diethyl ether solution to pH be 2, continue at stir about 1h under the ice-water bath.Filter, get white solid.
For the pharmaceutical composition of thiadiazoles derivative 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.
Embodiment 3:
Prepare hard gelatin capsule with following compositions:
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 4:
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 arrangement of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Claims (8)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
R
1For: hydrogen, methyl, ethyl;
R
2For: hydrogen, chlorine, bromine, methyl, methylthio group, methoxycarbonyl, ethoxycarbonyl, methoxyphenyl, bromophenyl, Phenoxymethyl.
2. the compound with formula I structure or its pharmacy acceptable salt described in claim 1, described compound is:
Ⅰ-2
Ⅰ-3
Ⅰ-4
Ⅰ-5
Ⅰ-6
Ⅰ-7
3. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1 or 2, its pharmacy acceptable salt is: formula I compound and mineral acid, 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 claim 1 Chinese style I compound is characterized in that: thiadiazole compound (II), in DMF, with 2-halogen acyl halide compounds under triethylamine catalysis ,-20-15 ℃ of reaction makes the key intermediate III, the intermediate III is again with 4,5,6,7-tetramethylene sulfide and pyridine are solvent with the acetonitrile in the presence of triethylamine, 70～90 ℃ of reactions, make chemical compounds I, wherein X is Cl or Br, R
1～R
2As claim 1 definition,
6. pharmaceutical composition with antitumor action, it comprises compound or its pharmacy acceptable salt and one or more pharmaceutical carriers with formula I structure as claimed in claim 1 or 2 for the treatment of significant quantity.
7. have the compound of formula I structure and pharmacy acceptable salt thereof in the claim 1 or 2 in the application aspect antitumor drug.
8. application as claimed in claim 7 is in the purposes aspect treatment lung cancer, mammary cancer, prostate cancer medicine.
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| CN101974016A (en) * | 2010-10-14 | 2011-02-16 | 天津药物研究院 | Amide compound and preparation method and applications thereof |
Non-Patent Citations (2)
| Title |
|---|
| Zhi Shuang，等.N-(5-Ethylsulfanyl-1,3,4-thiadiazol-2-yl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetamide.《Acta Crystallographica, Section E: Structure Reports Online》.2011,第67卷(第6期),第o1490页. * |
| 周云松,等.噻吩并四氢吡啶衍生物的合成及其抗血小板聚集活性研究.《药学学报》.2011,第46卷(第1期),第70-74页. * |
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