CN103044395A - Desloratadine-containing amino acid derivative as well as preparation method and application thereof - Google Patents
Desloratadine-containing amino acid derivative as well as preparation method and application thereof Download PDFInfo
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- CN103044395A CN103044395A CN2012105924346A CN201210592434A CN103044395A CN 103044395 A CN103044395 A CN 103044395A CN 2012105924346 A CN2012105924346 A CN 2012105924346A CN 201210592434 A CN201210592434 A CN 201210592434A CN 103044395 A CN103044395 A CN 103044395A
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- 0 *CC(N(CC1)CCC1=C1c2ncccc2CCc2cc(Cl)ccc12)=O Chemical compound *CC(N(CC1)CCC1=C1c2ncccc2CCc2cc(Cl)ccc12)=O 0.000 description 2
- ZZWPOYPWQTUZDY-UHFFFAOYSA-N CCC(C(OC)=O)N Chemical compound CCC(C(OC)=O)N ZZWPOYPWQTUZDY-UHFFFAOYSA-N 0.000 description 1
- CIHREYRWKLEYNE-UHFFFAOYSA-N COC(C(CCl)NCCCC(N(CC1)CCC1=C1c2ncccc2CCc2cc(Cl)ccc12)=O)=O Chemical compound COC(C(CCl)NCCCC(N(CC1)CCC1=C1c2ncccc2CCc2cc(Cl)ccc12)=O)=O CIHREYRWKLEYNE-UHFFFAOYSA-N 0.000 description 1
- TZJVWRXHKAXSEA-UHFFFAOYSA-N COC(CCCCCN)=O Chemical compound COC(CCCCCN)=O TZJVWRXHKAXSEA-UHFFFAOYSA-N 0.000 description 1
- BVAIKEUTJRYIPH-UHFFFAOYSA-N Cc(cc1CCc2cccnc22)ccc1C2=C(CC1)CCN1C(CNCCCCCC(OC)=O)=O Chemical compound Cc(cc1CCc2cccnc22)ccc1C2=C(CC1)CCN1C(CNCCCCCC(OC)=O)=O BVAIKEUTJRYIPH-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a desloratadine-containing amino acid compound with a structure of formula I and a pharmaceutically acceptable salt thereof. In the formula, n is 1, 2 or 3, m is 0, 1, 2, 3, 4, 5 or 6, and R is hydrogen, methyl, ethyl, isopropyl, fluorine-substituted C1-C4 alkyl or chloromethyl. The invention further discloses a preparation method for the compound and a pharmaceutical composition taking the compound or the pharmaceutically acceptable salt of the compound as an active ingredient at the same time, as well as the application of the compound, the pharmaceutically acceptable salt of the compound and the pharmaceutical composition serving as anti-tumor drugs, especially the application in preparation of drugs 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 large chronic disease of serious harm human health at present.Suffering from the world according to statistics cancered people every year 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 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 clinically tumour, generally adopt operation, radiotherapy, chemotherapy three large therapies.Though embolic chemotherapy is comparatively quick, curative ratio is very low.The many cancer therapy drugs of clinical discovery exist obvious 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 amino acids that contains Desloratadine and the pharmaceutical salts thereof of a class novel texture.
Another object of the present invention is, discloses a class and contains the amino acids of Desloratadine and the preparation method of pharmaceutical salts thereof.
A further object of the present invention is, openly contains the amino acids of Desloratadine and pharmaceutical salts thereof as the pharmaceutical composition of main active ingredient take a class.
A further object of the invention is, discloses a class and contains the amino acids of Desloratadine 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:
N=1,2 or 3; M=0,1,2,3,4,5 or 6;
R is: hydrogen, C
1-C
4The straight or branched alkyl, C
1-C
4The straight or branched dialkyl group, halogen, haloalkyl, phenyl, substituted-phenyl, alkoxyl group.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
N=1,2 or 3; M=0,1,2,3,4,5 or 6;
R is: hydrogen, methyl, ethyl, sec.-propyl, the C that fluorine replaces
1-C
4Alkyl, chloromethyl.
More preferably following compound:
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.As described salt, they can also be the salt that forms with conventional alkali, for example basic metal (for example sodium salt or sylvite), alkaline-earth metal (for example calcium salt and magnesium salts) or derived from the ammonium salt of ammonia or organic amine.
The syntheti c route of formula I compound is as follows:
Compound (b) wherein, those skilled in the art all can conveniently make by compound (a).
M, n, R are described as defined above.
Desloratadine (II) is dissolved in methylene dichloride, trichloromethane, N, in dinethylformamide or the acetonitrile equal solvent, at N, under the catalysis of N-dicyclohexylcarbodiimide and DMAP (DCC/DMAP), make the intermediate III with the hydroxycarboxylic acid of slow adding-30 ~ 30 ℃ of reactions.Intermediate III and Tosyl chloride are in methylene dichloride, trichloromethane, ethyl acetate, acetonitrile, pyridine, acetone, benzene or toluene, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide or potassium tert.-butoxide ,-20 ~ 30 ℃ of reactions generate the intermediate IV.The intermediate IV is at methyl alcohol, ethanol, methylene dichloride, trichloromethane, acetone, N, in dinethylformamide, ethyl acetate, acetonitrile, pyridine, benzene or the toluene equal solvent, with (b) compounds under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, 0 ~ 130 ℃ of reaction obtains the intermediate V, and the hydrolysis of intermediate V namely gets the end product chemical compounds I.
Reaction makes various compounds or products therefrom is dissolved in the oxide compound or the oxyhydroxide that drip mineral acid, Organic Acid and Base metal, alkaline-earth metal in DMF, acetone, methyl alcohol, ethanol, DMSO or the ether makes pharmacy acceptable salt.
Specifically various compounds are dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, under ice-water bath, drip the salt acid ether to pH=2, make hydrochloride; Or various compounds are 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 various compounds are dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, under ice-water bath, drip the vitriol oil to pH=3, make vitriol, etc.
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 various compounds preferably use with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (such as vein, muscle administration) and oral administration.
The pharmaceutical composition of the compounds of this invention is prepared as follows: Application 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 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 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 wider scope, usually, the weight range of active compound is 0.5%～90%(weight of 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 external to tumour.
External antitumor action
(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: 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 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 the incubator of 5%CO2, and it is for 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 gently single cell suspension with the glass dropper, microscopically blood cell counts plate numeration viable cell.The every hole of 96 well culture plates inoculating cell suspension 90 μ L(cell concns be adjusted into 6～10 * 104/ml), at 37 ℃, 100% relative humidity, contain 5%CO
2, 95% air incubator cultivate 24h after, 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, after continuing to cultivate 4h, carefully sucks supernatant liquor (suspension cell needs first centrifugally, sucks supernatant again).Every hole adds 100 μ LDMSO, 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, 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
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), high resolution mass spectrum (HRMS) etc. is further proved conclusively its structure.
Reference example 1:
The preparation of intermediate III-1
Stirring is being housed, condenser, in the reaction flask of thermometer, add 3.10g (10mmol) Desloratadine (II) and 30ml methylene dichloride, stir, the control temperature is at 0 ℃, add DCC2.5g(12mmol in batches) and the DMAP of catalytic amount, after stirring 1h, slowly drip oxyacetic acid 0.76g(10mmol), 0 ℃ of reaction 3h filters insolubles, and filtrate is used 10% dilute hydrochloric acid (15ml * 3) successively, 10% sodium bicarbonate aqueous solution (15ml * 3), saturated aqueous common salt (15ml * 3) washing, the elimination insolubles, filtrate with anhydrous sodium sulfate drying after, the decompression steam solvent, residue separates with silica gel column chromatography, get white solid, yield 77.5%, purity 95.5%(HPLC normalization method), ESI-MS (m/z): 368.1.
Reference example 2:
The preparation of intermediate III-2
Stirring is being housed, condenser, in the reaction flask of thermometer, add 3.10g (10mmol) Desloratadine (II) and 30ml methylene dichloride, stir, the control temperature is at 0 ℃, add DCC2.5g(12mmol in batches) and the DMAP of catalytic amount, after stirring 1h, slowly drip 4 hydroxybutyric acid 1.04g(10mmol), 0 ℃ of reaction 3h filters insolubles, and filtrate is used 10% dilute hydrochloric acid (15ml * 3) successively, 10% sodium bicarbonate aqueous solution (15ml * 3), saturated aqueous common salt (15ml * 3) washing, the elimination insolubles, filtrate with anhydrous sodium sulfate drying after, the decompression steam solvent, residue separates with silica gel column chromatography, get white solid, yield 75.8%, purity 97.5%(HPLC normalization method), ESI-MS (m/z): 396.2.
Reference example 3:
The preparation of intermediate IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add 3.68g(10mmol) intermediate III-1, the 50ml pyridine stirs and makes its dissolving, solution is controlled at below-5 ℃, add 2.28g(12mmol in batches) Tosyl chloride, 0 ℃ of reaction 10h, the TLC demonstration reacts completely, and reaction solution is poured in the cold water, there is solid to separate out, filter, filter cake after saturated aqueous common salt (50ml * 3) washing, vacuum-drying, obtain white solid, yield 92.2%, purity 98.0%(HPLC normalization method), ESI-MS (m/z): 522.1.
Reference example 4:
The preparation of intermediate IV-2
Stirring is being housed, condenser, in the reaction flask of thermometer, add 3.96g(10mmol) intermediate III-2,50ml N, dinethylformamide and 2.52g(25mmol) triethylamine, stirring makes its dissolving, solution is controlled at below-5 ℃, adds 2.28g(12mmol in batches) Tosyl chloride, 0 ℃ of reaction 10h, the TLC demonstration reacts completely, reaction solution is poured in the cold water, had solid to separate out, filter, filter cake is after saturated aqueous common salt (50ml * 3) washing, vacuum-drying obtains faint yellow solid, yield 90.6%, purity 97.5%(HPLC normalization method), ESI-MS (m/z): 550.2.
Reference example 5:
The preparation of intermediate V-1
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.22g(10mmol) intermediate IV-1,1.68g(20mmol) sodium bicarbonate, 30ml acetonitrile and 1.03g(10mmol) 3-alanine methyl esters, back flow reaction 6h, the TLC demonstration reacts completely the elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtains compound V-1: white solid, yield 76%, purity 99.6%(HPLC normalization method), ESI-MS (m/z): 453.2.
Reference example 6:
The preparation of intermediate V-2
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.51g(10mmol) intermediate IV-2,2.76g(20mmol) salt of wormwood, 30ml tetrahydrofuran (THF) and 1.03g(10mmol) 3-alanine methyl esters, back flow reaction 7h, the TLC demonstration reacts completely the elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtains compound V-2: white solid, yield 82%, purity 99.4%(HPLC normalization method), ESI-MS (m/z): 481.2.
Reference example 7:
The preparation of intermediate V-3
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.22g(10mmol) intermediate IV-1,2.00g(20mmol) saleratus, 30ml tetrahydrofuran (THF) and 1.45g(10mmol) 3-amino-4-methylvaleric acid methyl esters, back flow reaction 7h, the TLC demonstration reacts completely, the elimination insolubles, steaming desolventizes, residue obtains compound V-3 with the silica gel column chromatography separation: white solid, yield 80%, purity 99.5%(HPLC normalization method), ESI-MS (m/z): 495.2.
Reference example 8:
The preparation of intermediate V-4
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.51g(10mmol) intermediate IV-2,2.00g(20mmol) saleratus, 30mlN, dinethylformamide and 1.45g(10mmol) 3-amino-4-methylvaleric acid methyl esters, 80 ℃ of reaction 6h reflux, the TLC demonstration reacts completely, the elimination insolubles, remove solvent under reduced pressure, residue separates with silica gel column chromatography, obtain compound V-4: white solid, yield 80%, purity 99.4%(HPLC normalization method), ESI-MS (m/z): 523.3.
Reference example 9:
The preparation of intermediate V-5
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.22g(10mmol) intermediate IV-1,2.00g(20mmol) saleratus, 30ml methylene dichloride and 1.45g(10mmol) the 6-ACA 6-aminocaproic acid methyl esters, back flow reaction 10h, the TLC demonstration reacts completely the elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtains compound V-5: white solid, yield 85%, purity 99.4%(HPLC normalization method), ESI-MS (m/z): 495.2.
Reference example 10:
The preparation of intermediate V-6
In the reaction flask that stirring, condenser, thermometer are housed, add successively 3.88g(10mmol) intermediate IV-2,2.02g(20mmol) triethylamine, 30ml N, dinethylformamide and 1.45g(10mmol) the 6-ACA 6-aminocaproic acid methyl esters, 80 ℃ of reaction 5h, the TLC demonstration reacts completely, the elimination insolubles, filtrate is poured in the 100ml cold water, there is solid to separate out, filters, filter cake sherwood oil and re-crystallizing in ethyl acetate, obtain compound V-6: white crystal, yield 81%, purity 99.5%(HPLC normalization method), ESI-MS (m/z): 523.3.
Reference example 11:
The preparation of intermediate V-7
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.22g(10mmol) intermediate IV-1,2.02g(20mmol) triethylamine, 30ml acetonitrile and 1.85g(10mmol) 2-amino-5,5,5-trifluoromethyl methyl valerate, back flow reaction 8h, the TLC demonstration reacts completely, the elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtains compound V-7: white solid, yield 85%, purity 99.3%(HPLC normalization method), ESI-MS (m/z): 535.2.
Reference example 12:
The preparation of intermediate V-8
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.51g(10mmol) intermediate IV-2,2.00g(20mmol) saleratus, 30ml acetonitrile and 1.85g(10mmol) 2-amino-5,5,5-trifluoromethyl methyl valerate, back flow reaction 8h, the TLC demonstration reacts completely, the elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtains compound V-8: white solid, yield 83%, purity 99.5%(HPLC normalization method), ESI-MS (m/z): 563.2.
Reference example 13:
The preparation of intermediate V-9
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.22g(10mmol) intermediate IV-1,2.00g(20mmol) saleratus, 30ml acetonitrile and 1.38g(10mmol) 2-amino-3-methyl chloropropionate, back flow reaction 8h, the TLC demonstration reacts completely the elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtains compound V-8: white solid, yield 81%, purity 99.5%(HPLC normalization method), ESI-MS (m/z): 487.1.
Reference example 14:
The preparation of intermediate V-10
In the reaction flask that stirring, condenser, thermometer are housed, add successively 5.51g(10mmol) intermediate IV-2,2.02g(20mmol) triethylamine, 30ml acetonitrile and 1.38g(10mmol) 2-amino-3-methyl chloropropionate, back flow reaction 8h, the TLC demonstration reacts completely elimination insolubles, solvent evaporated, the silica gel column chromatography separation obtains compound V-7: white solid, yield 77%, purity 99.4%(HPLC normalization method), ESI-MS (m/z): 515.2.
Embodiment 1:
The preparation of chemical compounds I-1
In the reaction flask that stirring, condenser, thermometer are housed, add 4.53g(10mmol) intermediate V-1,60ml ethanol, stir and make its dissolving, drip 10% aqueous sodium hydroxide solution, to pH8, stir 2h, drip 10% aqueous hydrochloric acid, regulate pH6, stir, the solid that filtration is separated out, filter cake are used respectively 15ml distilled water, the cold ethanol of 10ml, 15ml distilled water wash, vacuum-drying, obtain white solid, yield 95%, purity 99.2%(HPLC normalization method), HRMS (m/z) [M+H]
+: 440.1735.
With reference to the method for embodiment 1, can synthetic compound I-2～I-10.
Table 2 chemical compounds I-2～I-10
Embodiment 2:
Chemical compounds I-1 one-tenth hydrochloride: get chemical compounds I-1 white 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 3:
Chemical compounds I-2 one-tenth taurate: get chemical compounds I-2 white solid product 2.0g(m.p.184.1 ~ 185.9 ℃, HPLC97.6%), be dissolved in the 10ml anhydrous methanol.Adding waits a mole taurine after being heated to backflow, continues at the lower about 1.5h of stirring reaction of backflow.React complete, under room temperature, leave standstill 24h.Separate out light yellow crystallization, filter vacuum-drying.
Embodiment 4:
Chemical compounds I-5 one-tenth vitriol: get chemical compounds I-5 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.
Embodiment 5:
Chemical compounds I-8 one-tenth sylvite: get I-8 white solid product 3.3g, be dissolved in the 10mL dehydrated alcohol.Ice-water bath is cooled to 5 ℃, stir lower drip 20% potassium hydroxide aqueous solution to pH be 9, continue at stir about 1h under the ice-water bath.Under room temperature, leave standstill 24h.Separate out white crystals, filter vacuum-drying.
Embodiment 6:
Chemical compounds I-10 one-tenth sodium salt: get the white solid product 4.0g of I-10, be dissolved in 20mL acetone.Ice-water bath is cooled to 5 ℃, stir lower drip 15% aqueous sodium hydroxide solution to pH be 10, continue at stir about 1h under the ice-water bath.Under room temperature, leave standstill 24h.Separate out yellow crystal, filter vacuum-drying.
For the pharmaceutical composition that contains the amino acids of Desloratadine of the present invention is described more fully, the below provides following example of formulations, and described embodiment only is used for explanation, rather than is used for limiting the scope of the invention.Described preparation can use any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in the embodiment 1-6.
Embodiment 7:
Prepare hard gelatin capsule with following compositions:
Preparation technology: supplementary material is dry in advance, and it is for subsequent use to cross 100 mesh sieves.After pressing recipe quantity mentioned component being mixed, be packed in the hard gelatin capsule.
Embodiment 8:
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, and it is for subsequent use to cross 100 mesh sieves.First 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 9:
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 adjusting pH value to 4 ~ 8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 10:
The preparation of injection lyophilized powder:
The taurate 100mg of chemical compounds I-2
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, sealing, and get final product.
Claims (10)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
N=1,2 or 3; M=0,1,2,3,4,5 or 6;
R is: hydrogen, C
1-C
4The straight or branched alkyl, C
1-C
4The straight or branched dialkyl group, halogen, haloalkyl, phenyl, substituted-phenyl, alkoxyl group.
2. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1:
Wherein:
N=1,2 or 3; M=0,1,2,3,4,5 or 6;
R is: hydrogen, methyl, ethyl, sec.-propyl, the C that fluorine replaces
1-C
4Alkyl, chloromethyl.
3. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1 or 2, described compound is:
4. 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; Oxide compound, oxyhydroxide salify with basic metal, alkaline-earth metal.
5. formula I compound as claimed in claim 4 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, sodium salt, sylvite, calcium salt, magnesium salts.
6. the preparation method of the compound of formula I structure as claimed in claim 1 or 2, it is characterized in that: at methylene dichloride, trichloromethane, N, in dinethylformamide or the acetonitrile solvent, N, under the catalysis of N-dicyclohexylcarbodiimide and DMAP, Loratadine (II) makes the intermediate III with hydroxycarboxylic acid-30 ~ 30 ℃ of reactions; Intermediate III and Tosyl chloride are in methylene dichloride, trichloromethane, ethyl acetate, acetonitrile, pyridine, acetone, benzene or toluene, and under the catalysis of acid binding agent ,-20 ~ 30 ℃ of reactions generate the key intermediate IV; The intermediate IV is at methyl alcohol, ethanol, methylene dichloride, trichloromethane, acetone, N, in dinethylformamide, ethyl acetate, acetonitrile, pyridine, benzene or the toluene solvant, with (b) compounds under the catalysis of acid binding agent, 0 ~ 130 ℃ of reaction obtains the intermediate V; The hydrolysis of intermediate V namely gets the end product chemical compounds I;
M, n, R define as claimed in claim 1.
7. preparation method as claimed in claim 6, it is characterized in that: described acid binding agent is triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide or potassium tert.-butoxide.
8. pharmaceutical composition, it comprises each compound or its pharmacy acceptable salt and one or more pharmaceutical carriers of formula I structure of claim 1～2 for the treatment of significant quantity.
Claim 1～2 each the compound of formula I structure or its pharmacy acceptable salt in the application aspect antitumor drug.
10. application as claimed in claim 9 is in the purposes aspect treatment mammary cancer, lung cancer, cancer of the stomach medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN109651459A (en) * | 2019-01-24 | 2019-04-19 | 江苏八巨药业有限公司 | A kind of preparation method of gemcitabine intermediate methylsulfonyl ester |
| CN110755431A (en) * | 2019-11-08 | 2020-02-07 | 暨南大学 | Application of desloratadine in preparation of anti-liver cancer drugs |
| WO2021076033A3 (en) * | 2019-10-18 | 2021-05-27 | Hakmed Ab | Desloratadine for the treatment and/or prophylaxis of cancers |
| CN113628677A (en) * | 2021-08-04 | 2021-11-09 | 辽宁大学 | Application of desloratadine in preparation of medicine taking TGF-beta type I receptor as target |
| CN115141229A (en) * | 2022-07-21 | 2022-10-04 | 华创合成制药股份有限公司 | Antihistaminic compound and preparation method and application thereof |
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| WO2024016638A1 (en) * | 2022-07-21 | 2024-01-25 | 华创合成制药股份有限公司 | Antihistamine compound, preparation method therefor and use thereof |
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