CN104292210A - Pyridine-containing nitric oxide donor compound and preparation method and use thereof - Google Patents
Pyridine-containing nitric oxide donor compound and preparation method and use thereof Download PDFInfo
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- CN104292210A CN104292210A CN201310295541.7A CN201310295541A CN104292210A CN 104292210 A CN104292210 A CN 104292210A CN 201310295541 A CN201310295541 A CN 201310295541A CN 104292210 A CN104292210 A CN 104292210A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
Abstract
The invention discloses a pyridine-containing nitric oxide donor derivative having a structure shown as a formula I, and a pharmaceutically-acceptable salt thereof. In the formula I, n=1, 2 or 3; R1 is alkyl or a naphthenic base having 1-4 carbon atoms; R2 and R3 are hydrogen and alkyl having 1-4 carbon atoms simultaneously or separately; and R4 is hydrogen or alkyl having 1-4 carbon atoms. The invention further discloses a preparation method of the derivative, and discloses a medicinal composition taking the derivative or the pharmaceutically-acceptable salt thereof as an active effective component, and an application of the medicinal composition as an antitumor medicament, particularly application of the medicinal composition to preparation of medicaments for treating the breast cancer, the lung cancer and the stomach cancer.
Description
Technical field
The invention belongs to medical art, or rather, relate to class compound with antitumor action and preparation method thereof, containing their pharmaceutical composition and the purposes as antitumor drug.
Background technology
In nitrogen protoxide (NO) molecule, atom N skin has 5 electronics, and O atoms outermost has 6 electronics, after forming covalent linkage, molecular orbital(MO) also has a unpaired electron, unstable chemcial property, the transformation period is short, by force fat-soluble, easy disperse, by cytolemma, is diffused in adjacent tissue, with the chemical property that it is active, very fast with the effect of target material, generation biological effect.NO is connected with some drugs, not only can strengthen drug effect, increases new adaptability, and significantly can reduce untoward reaction.
The nitrogen protoxide source of organism comprises endogenous, exogenous two aspects.Endogenous refers to using L-arginine as substrate, by the effect of NO synthetic enzyme, generates NO and Cit.Exogenous NO donor refers to the compound of the different structure of release NO character, and their chemically reactive depends on the state of oxidation of relevant nitrogen-atoms, controls speed and degree that physiological transforms NO.Desirable NO donor medicine spontaneously stably can discharge NO in vivo, and release is simple, and without the need to cellular metabolism, long-time application not easily produces tolerance, has the kind of different action time and different action intensity for selecting.
The important sources of exogenous NO donor is NO donor, namely discharges the compound of NO in vivo.Chemically according to and NO discharge the different of the atom that position is connected, NO donor is divided into six classes: C-NO donor, N-NO donor, O-NO donor, S-NO donor, heterocycle-NO donor and transition metal-NO donor.Current most study is also the most deep is O-NO donor, consists predominantly of machine nitric ether and organic sub-nitrate.
Cancer has become a large chronic disease of serious harm human health at present.The people of annual suffers from cancer has 9,000,000 in the world according to statistics, and the patient dying from cancer is 6,000,000, has become the second largest killer being only second to cardiovascular disorder.Clinical treatment tumour, generally adopts operation, radiotherapy, the large therapy of chemotherapy three.Though embolic chemotherapy is comparatively quick, curative ratio is very low.The many cancer therapy drugs of clinical discovery exist significantly to damage and the toxic side effect of normal body simultaneously.Therefore, introduce nitric oxide donors, one of exploitation good effect, the novel cpd direction becoming research that toxic side effect is low.
Summary of the invention
One object of the present invention is, discloses nitric oxide donors derivative and pharmaceutical salts thereof that a class contains pyridine.
Another object of the present invention is, the pharmaceutical composition that to disclose with a class be main active ingredient containing the nitric oxide donors derivative of pyridine and pharmaceutical salts thereof.
Another object of the present invention is, discloses the preparation method of nitric oxide donors derivative containing pyridine and pharmaceutical salts thereof.
A further object of the invention is, discloses containing the application as antitumor drug aspect of the nitric oxide donors derivative of pyridine and pharmaceutical salts thereof.
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:
N=1,2 or 3;
R
1for C1-C4 alkyl, cycloalkyl;
R
2, R
3be hydrogen at the same time or separately, C1-C4 alkyl;
R
4for hydrogen, C1-C4 alkyl.
More can preferred following compound and pharmacy acceptable salt thereof:
I-1) 3-(cyclopropylcarbamoyl)-2-((4-(1-oxo-2-nitric ether) ethyl)-3-methylpiperazine-1-yl) pyridine;
I-2) 3-(cyclopropylcarbamoyl)-2-((4-(1-oxo-3-nitric ether) ethyl) piperazine-1-base) pyridine;
I-3) 3-(cyclopropylcarbamoyl)-2-((4-(1-oxo-3-nitric ether) ethyl)-3,3-lupetazin-1-bases) pyridine;
I-4) 3-(cyclopropylcarbamoyl)-2-((4-(1-oxo-2-nitric ether) butyl) piperazine-1-base) pyridine;
I-5) 3-(cyclopropylcarbamoyl)-2-((4-(1-oxo-5-nitric ether) amyl group) piperazine-1-base) pyridine;
The compound with structure shown in formula I of the present invention, its pharmacy acceptable salt means: the compounds of this invention and mineral acid, organic acid salify.Wherein particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate, maleate; benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, amino acid salts, gluconate, etc.
The syntheti c route of type I compound is as follows:
X is chlorine, bromine; N, R
1, R
2, R
3, R
4definition as previously mentioned.
By 1-(3-substituent pyridine-2-base) piperazine (II) is dissolved in methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), acetone, ethyl acetate, methyl alcohol, in ethanol or DMF equal solvent, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide, control temperature, at-10 DEG C ~ 30 DEG C, reacts to obtain intermediate III with halogen carboxylic acid halides, intermediate III and Silver Nitrate are in methylene dichloride, trichloromethane, acetonitrile or toluene equal solvent, and 30 ~ 120 DEG C of lucifuge reactions finally obtain chemical compounds Is.Wherein each substituent definition is the same.
Obtained for reaction various intermediate or products therefrom are dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip mineral acid or organic acid, make pharmacy acceptable salt.
Specifically various compound is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drips ethereal HCI to pH=2, make hydrochloride; Or various compound is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, the molar glucose saccharic acid such as to add, heated and stirred obtains its gluconate; Or various compound is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drips the vitriol oil to pH=3, make vitriol, etc.
This compounds is effective in treatment human cancerous disease.Although compound of the present invention can without the direct administration of any configuration, described various compounds preferably use in the form of a pharmaceutical preparation, and route of administration can be parenteral route (as vein, intramuscular delivery) and oral administration.
The pharmaceutical composition preparation method 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 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 such as injection, pulvis etc.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, and the amount of compound used or concentration regulate in a wider scope.Usually, the weight range of active compound is 0.5% ~ 90% (weight) of composition, and another preferred scope is 0.5% ~ 70%.
Compound and the pharmacy acceptable salt thereof with structure shown in formula I of the present invention, has obvious effect at anti-tumor aspect.
The antitumor action of the compounds of this invention is further illustrated below by pharmacodynamic experiment.
External antitumor action
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the cell proliferation toxicity of the human tumor cells that invention Compounds in vitro is cultivated.
(2) experiment material:
Laboratory sample: type I compound is made by oneself by contriver and provided.During experiment, sample is with DMSO hydrotropy, and plasma-free DMEM medium is diluted to desired concn, and sample segment solution is suspension.
Main agents: the packing of MTT, Amresco company, lot number: 04M0904; Complete DMEM substratum, Gibco 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 KingYork Amino Acid Co., Ltd..
Laboratory apparatus: Bechtop, Suzhou Decontamination Equipment Plant; CO
2incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
Cell strain: SPCA1 human lung adenocarcinoma cell line, MCF7 human breast cancer cell, SGC-7901 gastric carcinoma cells, all purchased from Shanghai cell research institute of the Chinese Academy of Sciences.
(3) experimental procedure:
Cell cultures: tumor cell inoculation containing 10% calf serum, in the DMEM nutrient solution of 100IU/ml penicillin G sodium salt and 100 μ g/ml Vetstreps, be placed in 37 DEG C, 100% relative humidity, containing 5%CO
2incubator in, go down to posterity for subsequent use after 3 times.
Mtt assay measures: the cell in vegetative period of taking the logarithm, after 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution containing 10% calf serum, blow and beat into single cell suspension gently with glass dropper, with blood cell counts plate numeration viable cell under microscope.96 well culture plate every hole inoculating cell suspension 90 μ L(cell concns are adjusted to 6 ~ 10 × 10
4individual/ml), 37 DEG C, 100% relative humidity, containing 5%CO
2, 95% air incubator cultivate after 24h, every hole adds 10 μ L liquids (final concentration is set to: 40 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml and 2.5 μ g/ml, five concentration).In addition, each concentration establishes negative control (isoconcentration DMSO) and blank background (not adding cell), all establishes 6 multiple holes for each group.Cultured continuously 24h again, then every hole adds the MTT solution 10 μ L of 5mg/ml, after continuing to cultivate 4h, carefully sucks supernatant liquor (suspension cell needs first centrifugal, then sucks supernatant).Every hole adds 100 μ L DMSO, and put micro oscillator concussion 5min and dissolve completely to make crystallization, microplate reader 492nm Single wavelength colorimetric, measures OD value.Inhibitory rate of cell growth is calculated as evaluation index using 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 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 structure shown in formula I has stronger restraining effect to above-mentioned 3 kinds of human tumor cells.
Embodiment
Below in conjunction with example, the present invention is described further.Example is only indicative, never means that it limits the scope of the invention by any way.
reference example 1:
Intermediate III-1
2.60g(0.01mol is added in the reaction flask that stirring, condenser, thermometer are housed) N-cyclopropyl-2-(3-methylpiperazine-1-yl) niacinamide, dissolved with 10mL DMF, add triethylamine 2.5g, control temperature is at-10 DEG C ~ 2 DEG C, drip chloroacetyl chloride 1.70g(0.15mol), drip off rear holding temperature reaction 6h, naturally reaction solution is poured in 30mL distilled water after rising to room temperature, stir, filtering solids, vacuum-drying, obtains intermediate III-1(HPLC:84.5%).HRMS(m/z)：337.1426。
Method with reference to reference example 1 conveniently can prepare compound: intermediate III-2 ~ III-5.
Table 2 intermediate III-2 ~ III-5
embodiment 1:
3-(cyclopropylcarbamoyl)-2-((4-(1-oxo-2-nitric ether) ethyl)-3-methylpiperazine-1-yl) pyridine (chemical compounds I-1)
Intermediate III-1 (3.2g is added in the reaction flask that stirring, condenser, thermometer are housed, 0.01mo1), anhydrous acetonitrile (20m1) dissolves, add Silver Nitrate (2.0g, anhydrous acetonitrile (10m1) 0.012mo1), lucifuge refluxes under stirring after 5h, TLC display reacts completely and is cooled to room temperature, evaporated under reduced pressure solvent.Add methylene dichloride (20m1) in residuum, stir 10min, filter, filtrate decompression solvent evaporated.Add dehydrated alcohol (30m1), evaporated under reduced pressure after activated carbon decolorizing, reduced pressure at room temperature is spent the night, and obtains pale yellow transparent oily matter I-1 (3.1g, yield 90%), purity 98.9% (HPLC method).HRMS（m/z）：364.1615。
Method with reference to embodiment 1 conveniently can prepare compound: chemical compounds I-2 ~ I-5.
Table 3 chemical compounds I-2 ~ I-5
embodiment 2:
Chemical compounds I-3 becomes hydrochloride: get the faint yellow oil product 2.0g of chemical compounds I-3, be dissolved in 10mL anhydrous diethyl ether.Ice-water bath is cooled to 0 DEG C, and dripping 25% ethereal HCI solution is 2 to pH, continues at stir about 1h under ice-water bath.Filter, obtain white solid.
embodiment 3:
Chemical compounds I-4 becomes gluconate: get chemical compounds I-4 yellow oil product 2.0g, be dissolved in 10mL dehydrated alcohol.To add etc. molar glucose saccharic acid after being heated to backflow, continue at stirred at reflux and react about 2h.React complete, in left at room temperature 24h.Filter, obtain light yellow solid.
embodiment 4:
Chemical compounds I-5 becomes vitriol: get the faint yellow oil product 2.0g of chemical compounds I-5, be dissolved in 10mL anhydrous methanol.Ice-water bath is cooled to 5 DEG C, and dripping concentrated sulfuric acid solution is 3 to pH, continues at stir about 0.5h under ice-water bath.Filter, obtain light yellow solid.
In order to the pharmaceutical composition of nitric oxide donors compounds of the present invention is described more fully, provide following example of formulations below, described embodiment only for illustration of, instead of for limiting the scope of the invention.Described preparation can use any active compound in the compounds of this invention, preferably uses the compound implemented described in 1-4.
embodiment 5:
Hard gelatin capsule is prepared by following compositions:
After mentioned component is mixed, be packed in hard gelatin capsule with 460mg.
embodiment 6:
Tablet is prepared by following compositions:
Supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.First the auxiliary material of recipe quantity is fully mixed.Be added in auxiliary material by bulk drug to increase progressively dilution method, each added-time fully mixes 2-3 time, ensures that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 DEG C of ventilated drying ovens, dry particle crosses the whole grain of 16 mesh sieve, measure intermediates content, mix, compressing tablet on tabletting machine.
embodiment 7:
The preparation of injection liquid:
Get activeconstituents to join in the water for injection dissolving sorbyl alcohol and propylene glycol, add medicinal basic adjust ph and make it dissolve to 4-8.Add gac, whip attachment 30 minutes, carbon removal, essence filter, embedding, sterilizing.
embodiment 8:
The preparation of injection lyophilized powder:
The gluconate 100mg of chemical compounds I-4
Medicinal basic 0.1-7%
N.F,USP MANNITOL 55-85%
Get activeconstituents and add water for injection, make it dissolve by medicinal basic adjust ph to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving, add gac by the requirement of injection, adopt filtering with microporous membrane, filtrate carries out packing, adopts freeze-drying, and obtained loose block, sealing, to obtain final product.
Claims (9)
1. there is compound or its pharmacy acceptable salt of structure shown in formula I:
Wherein n=1,2 or 3;
R
1for C1-C4 alkyl, cycloalkyl;
R
2, R
3be hydrogen at the same time or separately, C1-C4 alkyl;
R
4for hydrogen, C1-C4 alkyl.
2. there is compound or its pharmacy acceptable salt of structure shown in formula I as claimed in claim 1, be selected from:
3. have compound or its pharmacy acceptable salt of structure shown in formula I as claimed in claim 1 or 2, its pharmacy acceptable salt is: formula I and mineral acid, organic acid salify.
4. type 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, amino acid salts, gluconate.
5. there is the preparation method of the compound of structure shown in formula I as claimed in claim 1 or 2, it is characterized in that:
-the 2-of 1-(3-substituent pyridine shown in formula II base) piperazine acid binding agent exist under, react to obtain intermediate III with alkyl acyl halide; Intermediate III and Silver Nitrate react 30 ~ 120 DEG C of lucifuges, obtained type I compound, and reaction formula is as follows:
X is chlorine, bromine; N, R
1, R
2, R
3, R
4definition as claimed in claim 1.
6. preparation method as claimed in claim 5, is characterized in that: described acid binding agent is triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide.
7. a pharmaceutical composition, it comprises the compound with structure shown in formula I according to any one of claim 1 ~ 2 or its pharmacy acceptable salt and one or more pharmaceutical carriers for the treatment of significant quantity.
8. the compound with structure shown in formula I according to any one of claim 1 ~ 2 or its pharmacy acceptable salt are for the preparation of the application in antitumor drug.
9. apply as claimed in claim 8, for the preparation for the treatment of mammary cancer, lung cancer, application in gastric cancer medicament.
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Cited By (1)
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| CN107602522A (en) * | 2017-08-28 | 2018-01-19 | 暨南大学 | A kind of Xanthone NO compound donators and preparation method thereof and the application in antineoplastic is prepared |
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| CN107602522A (en) * | 2017-08-28 | 2018-01-19 | 暨南大学 | A kind of Xanthone NO compound donators and preparation method thereof and the application in antineoplastic is prepared |
| CN107602522B (en) * | 2017-08-28 | 2019-12-24 | 暨南大学 | Xanthone-NO donor compound, preparation method thereof and application thereof in preparation of antitumor drugs |
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