CN104926804A - Compounds with anti-tumor effect, and preparation method and application of compounds - Google Patents
Compounds with anti-tumor effect, and preparation method and application of compounds Download PDFInfo
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- CN104926804A CN104926804A CN201510303912.0A CN201510303912A CN104926804A CN 104926804 A CN104926804 A CN 104926804A CN 201510303912 A CN201510303912 A CN 201510303912A CN 104926804 A CN104926804 A CN 104926804A
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- compound
- acceptable salt
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- pharmacy acceptable
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- 0 *c1c[s]cc1 Chemical compound *c1c[s]cc1 0.000 description 1
- SJMRUQKOWLBVHX-UHFFFAOYSA-N NC(c1c[o]c(cc2)c1cc2N(CC1)CCN1S(c1c[s]cc1)(=O)=O)=O Chemical compound NC(c1c[o]c(cc2)c1cc2N(CC1)CCN1S(c1c[s]cc1)(=O)=O)=O SJMRUQKOWLBVHX-UHFFFAOYSA-N 0.000 description 1
- QPUCUKSIUJTUPB-UHFFFAOYSA-N NC(c1c[o]c(cc2)c1cc2N1CCNCC1)=O Chemical compound NC(c1c[o]c(cc2)c1cc2N1CCNCC1)=O QPUCUKSIUJTUPB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a class of compounds with an anti-tumor effect and with structures as formula I shown in the description, and pharmaceutically acceptable salts of the compounds. In formula I, X is O, S or N; R1 and R2 can be hydrogen and C1-C4 alkyl groups simultaneously or separately; R3 is a thiophene-2-yl or thiophen-3-yl simultaneously or separately monosubstituted/disubstituted/trisubstituted by C1-C4 alkyl, halogen, nitro, phenyl, trifluoromethyl, C1-C4 alkoxycarbonyl, C1-C4 alkoxy. The invention further discloses a preparation method for the compounds, and further discloses pharmaceutical compositions using the compounds or the pharmaceutically acceptable salts of the compounds as active ingredients, and application of the compounds as anti-tumor drugs, especially to the preparation of drugs for treatment of breast cancer.
Description
Technical field
The invention belongs to medical art, or rather, relate to class compound with antitumor action and its production and use.
Background technology
Cancer has become a large chronic disease of serious harm human health at present.China's cancer year number of the infected, about 1,200,000, dies from the number of cancer up to more than 900,000, and patient to be treated more than 1,500,000, and has the trend risen year by year.Therefore cancer has now 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, such as mutagenesis and genetoxic.Therefore, to 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 its pharmaceutical salts of compound that a class has antitumor action.
Another object of the present invention is, discloses a class and has the compound of antitumor action and the preparation method of pharmaceutical salts thereof.
Another object of the present invention is, open have with a class pharmaceutical composition that its pharmaceutical salts of antitumor action is main active ingredient.
A further object of the invention is, discloses a class and has the application as medicine for resisting malignant tumors of the compound of antitumor action and pharmaceutical salts thereof, particularly for the preparation of the purposes in treatment breast cancer medicines.
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 structure shown in formula I:
Wherein:
X is O, S, N;
R1, R2 are at the same time or separately: hydrogen, C
1-C
4alkyl;
R3 is: at the same time or separately by C
1-C
4alkyl, halogen, nitro, phenyl, trifluoromethyl, C
1-C
4carbalkoxy, C
1-C
4alkoxyl group list or two or trisubstituted thiophene-2-base or thiene-3-yl-.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
X is O;
R1, R2 are at the same time or separately: hydrogen, methyl, ethyl;
R3 is: at the same time or separately by methyl, chlorine, bromine, nitro, phenyl, trifluoromethyl, methoxycarbonyl, methoxyl group list or two or trisubstituted thiophene-2-base or thiene-3-yl-.
More preferably its pharmacy acceptable salt of following compound:
Type 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 type I compound is as follows:
X, R1, R2, R3 definition as previously mentioned.
Compound (2), in aprotic solvent, with substituted thiophene SULPHURYL CHLORIDE (3) under the catalysis of alkaline acid binding agent, 0 ~ 40 DEG C of reaction is obtained.
Aprotic solvent is methylene dichloride, trichloromethane, ethyl acetate, DMF, acetonitrile or acetone etc.
Alkalescence acid binding agent is triethylamine, salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide or potassium tert.-butoxide etc.0
The obtained various compound of reaction or products therefrom is dissolved in DMF, DMSO drip mineral acid, pharmacy acceptable salt made by organic acid.
Specifically various compound is dissolved in DMF, the one in DMSO, under ice-water bath, drips ethereal HCI to pH=2, make hydrochloride; Or the one various compound is dissolved in DMF or DMSO, mole taurine such as to add, heated and stirred obtains its taurate; Or the one be dissolved in by various compound in DMF or DMSO, drips the vitriol oil to pH=3, makes vitriol etc. under ice-water bath.
This compounds is effective for treatment human malignancies.Although compound of the present invention can without the direct administration of any preparation, 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 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 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, 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.Another preferred scope is 0.5%-70%.
Compound or its pharmacy acceptable salt with structure shown in formula I 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 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: Axiovert 200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
Cell strain: MCF7 human breast cancer cell, 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, single cell suspension is blown and beaten into gently, with blood cell counts plate numeration viable cell under microscope with glass dropper.(cell concn is adjusted to 6 ~ 10 × 10 to 96 well culture plate every hole inoculating cell suspension 90 μ L
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:
To the IC of the tumour cell of 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 human tumor cell.
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.Such as infrared spectra (IR) can be adopted subsequently, nuclear magnetic resonance spectrum (
1h NMR,
13c NMR), high resolution mass spectrum (HRMS) etc. further confirms its structure.
The preparation of embodiment 1: I-1
Stirring is being housed, condenser, in the reaction flask of thermometer, add 24.5g (0.10mol) compound a and 280ml methylene dichloride, stir, 10 ~ 30 DEG C, drip 18.3g 3-thiophenesulfonyl chloride (b), the mixing solutions of 41.3g (0.25mol) triethylamine and 100ml methylene dichloride, after dropwising, back flow reaction 4h, TLC display reacts completely, solvent evaporated, residue 410ml methylene dichloride dissolves, saturated aqueous common salt (200ml × 3) washs, steaming desolventizes, residue acetone recrystallization, obtain yellow solid, yield 76.6%, ESI-MS (m/z): 391.0660.
With reference to the method for embodiment 1, can synthetic compound I-2 ~ I-10.
The preparation of embodiment 2: I-2
By the method preparation that embodiment 1 is similar, 3-thiophenesulfonyl chloride is changed into 2,5-dimethyl 3-thiophenesulfonyl chloride.
Faint yellow solid, yield 79.6%, HRMS (m/z) [M+H]
+: 419.0973.
The preparation of embodiment 3: I-3
By the method preparation that embodiment 1 is similar, 3-thiophenesulfonyl chloride is changed into 2-methoxycarbonyl 3-thiophenesulfonyl chloride.
Yellow solid, yield 61.3%, HRMS (m/z) [M+H]
+: 449.0715.
The preparation of embodiment 4: I-4
The method preparation that embodiment 1 is similar, changes the chloro-4-nitro of 2,5-bis--3-thiophenesulfonyl chloride into by 3-thiophenesulfonyl chloride.
Yellow solid, yield 67.8%, HRMS (m/z) [M+H]
+: 503.9732.
The preparation of embodiment 5: I-5
The method preparation that embodiment 1 is similar, changes 4-phenyl-5-trifluoromethyl-3-thiophenesulfonyl chloride into by 3-thiophenesulfonyl chloride.
Yellow solid, yield 70.7%, HRMS (m/z) [M+H]
+: 535.0847.
The preparation of embodiment 6: I-6
The method preparation that embodiment 1 is similar, changes the bromo-2-thiophenesulfonyl chloride of 5-into by 3-thiophenesulfonyl chloride.
Yellow solid, yield 69.1%, HRMS (m/z) [M+H]
+: 468.9766.
The preparation of embodiment 7: I-7
The method preparation that embodiment 1 is similar, changes the chloro-2-thiophenesulfonyl chloride of 4-nitro-5-into by 3-thiophenesulfonyl chloride.
Yellow solid, yield 54.3%, HRMS (m/z) [M+H]
+: 470.0122.
The preparation of embodiment 8: I-8
The method preparation that embodiment 1 is similar, changes the chloro-2-thiophenesulfonyl chloride of 3-methoxyl group-5-into by 3-thiophenesulfonyl chloride.
Yellow solid, yield 63.4%, HRMS (m/z) [M+H]
+: 479.0821.
The preparation of embodiment 9: I-9
The method preparation that embodiment 1 is similar, changes the chloro-2-thiophenesulfonyl chloride of 5-into by 3-thiophenesulfonyl chloride.
Yellow solid, yield 80.8%, HRMS (m/z) [M+H]
+: 425.0271.
The preparation of embodiment 10: I-10
The method preparation that embodiment 1 is similar, changes 3-methyl-5-methoxycarbonyl-2-thiophenesulfonyl chloride into by 3-thiophenesulfonyl chloride.
Pale solid, yield 66.6%, HRMS (m/z) [M+H]
+: 463.0872.
embodiment 11:
Chemical compounds I-1 becomes hydrochloride: get chemical compounds I-1 solid 5.0g, be dissolved in 10mlDMF.Ice-water bath is cooled to 5 DEG C, and dripping 11.1% ethereal HCI solution is 2 to pH, continues at stir about 1h under ice-water bath.Filter, vacuum-drying, obtains white solid powder.
embodiment 12:
Chemical compounds I-6 becomes lactic acid salt: get I-6 solid 4.6g, be dissolved in 22mLDMSO.To add etc. molar lactic acid after being heated to backflow, continue at stirred at reflux and react about 2h.React complete, in left at room temperature 8h.Separate out Light yellow crystals, filter, vacuum-drying.
In order to the pharmaceutical composition of the compound containing benzazepine 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 and salt thereof.
embodiment 13:
Hard gelatin capsule is prepared by following compositions:
Preparation technology: supplementary material is dry in advance, crosses 100 mesh sieves for subsequent use.After mentioned component being mixed by recipe quantity, be packed in hard gelatin capsule.
embodiment 14:
Tablet is prepared by following compositions:
Preparation technology: supplementary material is dry in advance, crosses 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 15:
The preparation of injection lyophilized powder:
The hydrochloride 600mg of chemical compounds I-1
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, makes 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 (8)
1. there is compound or its pharmacy acceptable salt of structure shown in formula I:
Wherein:
X is O, S, N;
R1, R2 are at the same time or separately: hydrogen, C
1-C
4alkyl;
R3 is: at the same time or separately by C
1-C
4alkyl, halogen, nitro, phenyl, trifluoromethyl, C
1-C
4carbalkoxy, C
1-C
4alkoxyl group list or two or trisubstituted thiophene-2-base or thiene-3-yl-.
2. have compound or its pharmacy acceptable salt of structure shown in formula I, described compound is:
3. type I compound as claimed in claim 1 or its pharmacy acceptable salt, its pharmacy acceptable salt is: formula I and mineral acid, organic acid salify.
4. formula I as claimed in claim 3 or its pharmacy acceptable salt; its pharmacy acceptable salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, butyrates, lactic acid salt, mesylate; tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate.
5. the preparation method of type I compound in claim 1, is characterized in that: compound (2), and in aprotic solvent, with substituted thiophene SULPHURYL CHLORIDE (3) under the catalysis of alkaline acid binding agent, 0 ~ 40 DEG C of reaction is obtained.
X, R1, R2, R3 definition as previously mentioned.
6. an antitumor medicine composition, it comprises the compound of any one of claim 1 ~ 2 for the treatment of significant quantity or its pharmacy acceptable salt and one or more pharmaceutical carriers.
7. the compound of any one of claim 1 ~ 2 or its pharmacy acceptable salt are for the preparation of the application in antitumor drug.
8. apply as claimed in claim 7, for the preparation for the treatment of breast cancer medicines in purposes.
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|---|---|---|---|
| CN201510303912.0A CN104926804B (en) | 2015-06-04 | 2015-06-04 | One kind has compound, the preparation method and use of antitumor action |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019193161A1 (en) | 2018-04-06 | 2019-10-10 | Universität Wien | Bumetanide derivatives for the therapy of stroke and other neurological diseases/disorders involving nkccs |
| WO2019193159A1 (en) | 2018-04-06 | 2019-10-10 | Universität Wien | Bumetanide derivatives for the therapy of hyperhidrosis |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT201900000687A1 (en) * | 2019-01-16 | 2020-07-16 | Fondazione St Italiano Tecnologia | COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF CYSTIC FIBROSIS |
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| US20110059953A1 (en) * | 2008-05-07 | 2011-03-10 | Frank Boeckler | Compounds for use in stabilizing p53 mutants |
| CN101990535A (en) * | 2008-04-18 | 2011-03-23 | 默克专利有限公司 | Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators |
| WO2013175499A2 (en) * | 2012-04-20 | 2013-11-28 | Cadila Healthcare Limited | Polymorphic form of 5-(4-[4-(5-cyano-1h-indol-3- yl)butyl]piperazin-1-yl) benzofuran-2-carboxamide |
| WO2014006637A3 (en) * | 2012-07-02 | 2014-05-22 | Symed Labs Limited | Improved process for preparing benzofuran-2-carboxamide derivatives |
-
2015
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Patent Citations (5)
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|---|---|---|---|---|
| WO2005115983A1 (en) * | 2004-04-07 | 2005-12-08 | Kalypsys, Inc. | Aryl sulfonamide and sulfonyl compounds as modulators of ppar and methods of treating metabolic disorders |
| CN101990535A (en) * | 2008-04-18 | 2011-03-23 | 默克专利有限公司 | Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators |
| US20110059953A1 (en) * | 2008-05-07 | 2011-03-10 | Frank Boeckler | Compounds for use in stabilizing p53 mutants |
| WO2013175499A2 (en) * | 2012-04-20 | 2013-11-28 | Cadila Healthcare Limited | Polymorphic form of 5-(4-[4-(5-cyano-1h-indol-3- yl)butyl]piperazin-1-yl) benzofuran-2-carboxamide |
| WO2014006637A3 (en) * | 2012-07-02 | 2014-05-22 | Symed Labs Limited | Improved process for preparing benzofuran-2-carboxamide derivatives |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019193161A1 (en) | 2018-04-06 | 2019-10-10 | Universität Wien | Bumetanide derivatives for the therapy of stroke and other neurological diseases/disorders involving nkccs |
| WO2019193159A1 (en) | 2018-04-06 | 2019-10-10 | Universität Wien | Bumetanide derivatives for the therapy of hyperhidrosis |
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Granted publication date: 20190125 Termination date: 20190604 |