CN101845052B - Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof - Google Patents
Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof Download PDFInfo
- Publication number
- CN101845052B CN101845052B CN2010101977307A CN201010197730A CN101845052B CN 101845052 B CN101845052 B CN 101845052B CN 2010101977307 A CN2010101977307 A CN 2010101977307A CN 201010197730 A CN201010197730 A CN 201010197730A CN 101845052 B CN101845052 B CN 101845052B
- Authority
- CN
- China
- Prior art keywords
- compound
- salt
- formula
- cancer
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 *CN(CCC1S2)CC1=CC2=O Chemical compound *CN(CCC1S2)CC1=CC2=O 0.000 description 1
Abstract
The invention provides a nitrogen-containing heterocyclic ring thienopyridine ketone derivative with a structure as the first formula and salts thereof, which belong to the technical field of anti-malignant-tumor medicine, wherein R is a nitrogen-containing six-membered heterocyclic ring or a benzene nitrogen-containing six-membered heterocyclic ring. The invention also relates to the preparation method of the compound, and simultaneously discloses a medicine composition using the compound or pharmaceutically acceptable salts thereof as active ingredients, and the application thereof in the aspect that the compound or pharmaceutically acceptable salts as anti-malignant-tumor medicine.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to one type and have compound of anticarcinogenesis and preparation method thereof.
Background technology
Cancer is one of main killer of human health, and its mortality ratio ranked second the position in China position of ranking forefront in the world.According to World Health Organization statistics, global cancer mortality number in 2007 reaches 7,900,000 (account for all death tolls 13%), and lung cancer, cancer of the stomach, liver cancer, colorectal carcinoma and mammary cancer are the arch-criminals of annual most of cancer mortalities.In recent years, because the cancer risk factors such as abuse of urban air pollution, overweight or obesity, alcohol tobacco are on the rise, cause the sickness rate of cancer to rise year by year.In developing country, along with the reduction of transmissible disease death and child mortality, more people's life-time dilatations, the burden of cancer also increases thereupon.Pharmacological agent is one of main treatment means of cancer, and the searching of cancer therapy drug is the popular domain of scientists study always.At present being used for anticancer medicine clinically has hundreds of; Prolong cancer patients's life effectively or improved cancer patients's life quality; But most drug is a cell toxicity medicament, and selectivity is not high, when eliminating tumour cell, normal cell is also had major injury; Cause the intensive toxic side effects, and have the resistance problem.In addition, existing chemicals is unsatisfactory to the result of treatment of most solid tumors.Therefore, seeking the new type anticancer medicine shoulders heavy responsibilities.
Summary of the invention
One object of the present invention is, discloses one type of nitrogenous heterocyclic Thienopyridinone derivatives and pharmaceutical salts thereof.
Another object of the present invention is that disclosing with one type of nitrogenous heterocyclic Thienopyridinone derivatives and salt thereof is the pharmaceutical composition of main active ingredient.
A further object of the present invention is, discloses the preparation method of one type of nitrogenous heterocyclic Thienopyridinone derivatives and salt thereof.
A further object of the invention is; One type of nitrogenous heterocyclic Thienopyridinone derivatives and pharmaceutical salts thereof are disclosed; As the application of medicine for resisting malignant tumors, particularly in the purposes that is used to prepare aspect treatment lung cancer, mammary cancer, liver cancer, the cancer of the stomach medicine.
The present invention is specifically related to the compound and the salt thereof of general formula I structure:
Wherein:
R is (a) nitrogenous hexa-member heterocycle;
(b) the nitrogenous hexa-member heterocycle of benzo.
The nitrogenous hexa-member heterocycle of nitrogenous hexa-member heterocycle of the present invention and benzo is specifically represented pyridine, quinoline etc.
The compound that the present invention relates to formula I structure, wherein part of compounds is:
I-15-(pyridine-2-base-methyl)-5,6,7, the 7a-THTP is [3,2-c] pyridines-2 (4H)-ketone also;
I-25-(quinoline-2-base-methyl)-5,6,7, the 7a-THTP is [3,2-c] pyridines-2 (4H)-ketone also.
The compound with formula I structure or its pharmacy acceptable salt among the present invention mean: the salt that The compounds of this invention is become with mineral acid, organic acid.Wherein preferred especially salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, PHENRAMINE MALEATE, benzoate, SUMATRIPTAN SUCCINATE, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts or the like.
The preparation route of formula I compound:
Wherein X is bromine or chlorine.
5; 6; 7, the 7a-THTP also [3,2-c] pyridines-2 (4H)-ketone and brooethyl or the substituted nitrogenous hexa-member heterocycle of chloromethyl or the nitrogenous hexa-member heterocycle of benzo in methylene dichloride, trichloromethane, acetonitrile or toluene equal solvent; In the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium hydrogencarbonate, saleratus, sodium hydroxide or Pottasium Hydroxide ,-10 ℃~105 ℃ reactions make formula I compound.
Reaction is made various midbodys or products therefrom be dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, dropping inorganic acid or organic acid solution are processed pharmacy acceptable salt.
Specifically be that all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, the dripping hydrochloric acid diethyl ether solution is processed hydrochloride to pH=2 under ice-water bath; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, and adding and wait a mole taurine, heated and stirred gets its taurate; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, drips concentrated sulfuric acid solution down to pH=3, process vitriol in ice-water bath, or the like.
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 prepn, and route of administration can be non-enteron aisle approach (like vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions method of The compounds of this invention is following: use standard and conventional technology; Acceptable solid or liquid vehicle are combined, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.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, Ucar 35, 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-s for example injection, pulvis or the like.
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, and the amount of used compound or concentration are regulated in the scope of a broad.Usually, the weight range of active compound is 0.5%~90% (weight) of compsn, and another preferred range is 0.5%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention all has the obvious suppression effect to tumour in external, body.
External antitumor action
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the cell proliferation toxicity of invention compound the human tumor cells of vitro culture.
(2) experiment material:
Laboratory sample: nitrogenous heterocyclic Thienopyridinone derivatives 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 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 gold credit amino acid 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: lung cancer A-549 cell, liver cancer SMMC-7721 cell, mammary cancer MCF-7 cell, adenocarcinoma of stomach SGC-7901 cell, 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 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 single cell suspension gently with the glass dropper, microscopically is with 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 then hole adds the MTT solution 10 μ L of 5mg/mL, and after continuing to cultivate 4h, the careful suction removed supernatant (suspension cell needs earlier centrifugally, inhales and removes supernatant).Every hole adds DMSO 100 μ L, puts micro oscillator concussion 5min so that crystallization is dissolved fully, and the single wavelength colorimetric of ELIASA 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 control group OD average)/(control group OD average-blank control group OD average)] * 100%.According to inhibitory rate of cell growth, calculate IC with the straight-line regression method
50Value.
(4) experimental result: see table 1.
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 general formula I structure has stronger restraining effect to above-mentioned 4 kinds of human tumor cells.
Intravital antitumor action
(1) experiment material:
Sample: I-1 is provided by contriver's self-control.
Cell strain: liver cancer H22 cell, available from Shanghai cell research institute of the Chinese Academy of Sciences.
Positive control drug: endoxan, lot number: 07020121, Hengrui Medicine Co., Ltd., Jiangsu Prov..
Instrument: PB303-N type per mille electronic balance, Mettler Toledo Inc. produces.
Animal: Kunming mouse, the SPF level, male and female half and half, body weight 18-22g purchases in Institute of Radiation Medicine, Chinese Academy of Medical Sciences, conformity certification number: SCXK (Tianjin) 2005-0001.
(2) experimental technique:
Get abdominal cavity inoculation knurl strain 9 days, tumor growth is good, the tangible tumor-bearing mice of abdominal tympanites; Ascites is drawn in aseptic technique down; Be made into the cancer cells suspension by saline water dilution in 1: 3, in all experiment mice right fore armpit subcutaneous vaccinations (0.2mL/ mouse), all operations is accomplished in 30min.To inoculate knurl liquid mouse next day by the body weight random packet, i.e. lotus knurl control group, endoxan group (25mg/kg), I-1 organizes (100mg/kg, 50mg/kg).The equal intraperitoneal injection of each administration group, once a day, control group gives with volume saline water.Mouse successive administration 10 days behind the last administration 24h, takes off cervical vertebra and puts to death, and peels off tumour, takes by weighing knurl and weighs, and calculates and respectively organizes heavy MV of mouse tumor and inhibiting rate.
Inhibiting rate=[(the average knurl of the average knurl weight-experimental group of control group is heavy)/average knurl of control group is heavy] * 100%
(3) result:
(4) conclusion:
Can find out that from above-mentioned animal vivo test result I-1 has certain restraining effect to the tumor growth of H22 tumor-bearing mice.During two dose groups intraperitoneal injections, inhibition rate of tumor growth all is better than positive control.
Embodiment
Below in conjunction with embodiment the present invention is done further explanation, it is indicative that embodiment is merely, and means that never it limits scope of the present invention by any way.Described compound is through performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as ir spectra (IR), nuclear magnetic resonance spectrum (
1H NMR,
13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Embodiment 1:
5-(pyridine-2-base-methyl)-5,6,7, the 7a-THTP is [3,2-c] pyridines-2 (4H)-ketone (compound I-1) also
In the reaction flask that stirring, condensing surface, TM are housed, add 5,6,7, the 7a-THTP is [3,2-c] pyridines-2 (4H)-ketone 15.5g (0.1mol) also, with the 70mL acetonitrile it is dissolved, and is cooled to-10 ℃ under stirring, and adds Anhydrous potassium carbonate 41.5g (0.3mol).2-(brooethyl) pyridine 17.2g (0.1mol) is added in the reaction system in batches, finish and be warming up to 45 ℃ of continuation reaction 6h (the flaggy demonstration reacts completely).Filter, filtrating solvent evaporated acetonitrile adds the 80mL methylene dichloride, with 3 * 80mL water washing reaction solution; Obtain dichloromethane layer, use the SODIUM SULPHATE ANHYDROUS 99PCT thorough drying, filter; Methylene dichloride is to the greatest extent steamed in decompression, promptly gets light yellow wax shape product 14.3g (HPLC:98.1%), yield 58.1%.Rf=0.51 [single-point, developping agent: v (sherwood oil): v (ETHYLE ACETATE)=1: 2].
1H?NMR(DMSO-d6,400MHz)δ:3.072~3.101(t,2H),3.578~3.607(t,2H),4.248(s,2H),4.284~4.301(t,1H),4.617(s,2H),6.577(s,1H),7.530~7.561(m,1H),7.836~7.855(d,1H),7.982~8.025(m,1H),8.692~8.703(d,1H)。MS,m/Z:246.0(M)。
Embodiment 2:
5-(quinoline-2-base-methyl)-5,6,7, the 7a-THTP is [3,2-c] pyridines-2 (4H)-ketone (compound I-2) also
In the reaction flask that stirring, condensing surface, TM are housed, add 5,6,7, the 7a-THTP is [3,2-c] pyridines-2 (4H)-ketone 15.5g (0.1mol) also, with 80mL toluene it is dissolved, and is cooled to 0 ℃ under stirring, and adds triethylamine 30.4g (0.3mol).2-chloromethyl quinoline 17.8g (0.1mol) is added in the reaction system in batches, finish and be warming up to 100 ℃ of reaction 1h (the flaggy demonstration reacts completely).With 3 * 80mL water washing reaction solution, obtain toluene layer, use the SODIUM SULPHATE ANHYDROUS 99PCT thorough drying, to filter, toluene is to the greatest extent steamed in decompression, promptly gets white wax shape product 17.8g (HPLC:97.8%), yield 60.3%.。Rf=0.53 [single-point, developping agent: v (sherwood oil): v (ETHYLE ACETATE)=1: 2].MS,m/Z:296.0(M)。
Embodiment 3:
Compound I-1 one-tenth hydrochloride: get I-1 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.
Embodiment 4:
Compound I-2 one-tenth taurate: get I-2 solid product 2.0g, be dissolved in the 15mL absolute ethyl alcohol.Be heated to the back adding that refluxes and wait a mole taurine, continue at the about 2h of stirring reaction down that refluxes.Reaction finishes, and under room temperature, leaves standstill 24h.Filter, get white solid.
For the pharmaceutical composition of nitrogenous heterocyclic Thienopyridinone derivatives of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, said embodiment only is used for explanation, rather than is used to limit scope of the present invention.Said preparation can use any active compound and the salt thereof in the The compounds of this invention, preferably uses the compound described in the embodiment 1~4.
Embodiment 5:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule
Compound I-1 75mg
Pregelatinized Starch 100mg
Prist 4mg
Sodium starch glycolate 10mg
Magnesium Stearate 20mg
10% polyvidone ethanolic soln is an amount of
Preparation technology: supplementary material is dry in advance, and it is subsequent use to cross 100 mesh sieves.Press recipe quantity with the mentioned component mixing, cross 60 mesh sieves three times, add an amount of 10% polyvidone ethanol (95%) solution system softwood, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed the whole grain of 16 mesh sieves, are packed in the hard gelatin capsule.
Embodiment 6:
Prepare tablet with following compositions:
Consumption/sheet
Compound I-2 75mg
Starch 45mg
Microcrystalline Cellulose 40mg
CMS sodium salt 4.5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Prist 3mg
Preparation technology: supplementary material is dry in advance, and it is subsequent use 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 midbody content, mix compressing tablet on tabletting machine.
Embodiment 7:
The preparation of injection liquid:
The hydrochloride 45mg of compound I-1
Ucar 35 100mg
Polysorbate 80 is an amount of
Zero(ppm) water 300mL
Preparing method: get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and Ucar 35, 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 8:
The preparation of injection lyophilized powder:
The taurate 50mg of compound I-2
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-80%
Preparing method: get activeconstituents and add water for injection, regulate pH value to 4~8 with medicinal basic and make its dissolving.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrating is carried out packing, adopts freeze-drying, makes loose block, seals, and promptly gets.
Claims (8)
1. the compound and the salt thereof that have formula I structure:
Wherein:
R is (a) pyridine;
(b) quinoline.
2. the compound of Formula I described in claim 1, represent following compound:
(I-1) 5-(pyridine-2-base-methyl)-5,6,7, the 7a-THTP is [3,2-c] pyridines-2 (4H)-ketone also;
(I-2) 5-(quinoline-2-base-methyl)-5,6,7, the 7a-THTP is [3,2-c] pyridines-2 (4H)-ketone also.
3. compound as claimed in claim 1, its pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
4. the salt of formula I compound as claimed in claim 3, preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, PHENRAMINE MALEATE, benzoate, SUMATRIPTAN SUCCINATE, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts.
5. the preparation method of claim 1 Chinese style I compound is characterized in that: 5,6; 7; The 7a-THTP also [3,2-c] pyridines-2 (4H)-ketone and the substituted nitrogenous hexa-member heterocycle of monochloromethyl or the nitrogenous hexa-member heterocycle of benzo in methylene dichloride, trichloromethane, acetonitrile or toluene, in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium hydrogencarbonate, saleratus, sodium hydroxide or Pottasium Hydroxide;-10 ℃~105 ℃ reactions make formula I compound
Wherein X is bromine or chlorine.
6. the pharmaceutical composition of an anti-malignant tumor, it comprises compound or its salt and one or more pharmaceutical excipients of the formula I structure shown in claim 1 of treating significant quantity.
7. claim 1~4 Chinese style I compound and salt thereof are in the application that is used to prepare medicine for resisting malignant tumors.
8. application as claimed in claim 7 is in the purposes that is used to prepare aspect treatment lung cancer, liver cancer, mammary cancer, the cancer of the stomach medicine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010101977307A CN101845052B (en) | 2010-06-11 | 2010-06-11 | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010101977307A CN101845052B (en) | 2010-06-11 | 2010-06-11 | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101845052A CN101845052A (en) | 2010-09-29 |
CN101845052B true CN101845052B (en) | 2012-01-11 |
Family
ID=42769884
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010101977307A Expired - Fee Related CN101845052B (en) | 2010-06-11 | 2010-06-11 | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101845052B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102127091B (en) * | 2010-12-30 | 2012-11-21 | 天津药物研究院 | Heterocyclic ring-containing schiff base compound |
CN115073489B (en) * | 2021-03-15 | 2023-11-28 | 同济大学 | Thienopyridone compound, preparation method and antifungal drug |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4740510A (en) * | 1985-01-31 | 1988-04-26 | Sanofi (S.A.) | Derivatives of alpha-(2-oxo 2,4,5,6,7,7a-hexahydro thieno[3,2-c]5-pyridyl) phenyl acetic acid, and their use as platelet and thrombotic aggregation inhibitors |
CN1217186A (en) * | 1991-09-09 | 1999-05-26 | 三共株式会社 | Preparation method for medicinal composition containing hydrogenated pyridine derivative as active components |
-
2010
- 2010-06-11 CN CN2010101977307A patent/CN101845052B/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4740510A (en) * | 1985-01-31 | 1988-04-26 | Sanofi (S.A.) | Derivatives of alpha-(2-oxo 2,4,5,6,7,7a-hexahydro thieno[3,2-c]5-pyridyl) phenyl acetic acid, and their use as platelet and thrombotic aggregation inhibitors |
CN1217186A (en) * | 1991-09-09 | 1999-05-26 | 三共株式会社 | Preparation method for medicinal composition containing hydrogenated pyridine derivative as active components |
Also Published As
Publication number | Publication date |
---|---|
CN101845052A (en) | 2010-09-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104411701B (en) | Substituted cycloalkenopyrazoles as bub1 inhibitors for the treatment of cancer | |
CN101845051B (en) | Nitrogen-containing heterocyclic thienopyridine compounds and preparation method and application thereof | |
CN101361741B (en) | New anti-tumor use of iso-oxazoline derivates | |
CN101863901B (en) | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof | |
CN101845052B (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof | |
CN101519423B (en) | Betulinic acid analogue and preparation method and application thereof | |
CN103864765B (en) | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use | |
CN101974016A (en) | Amide compound and preparation method and applications thereof | |
CN102911118A (en) | Benzo-azepine type derivative and preparation method and purpose thereof | |
CN101805355B (en) | Thienopyridone derivative, preparation method and uses thereof | |
CN111821303B (en) | Application of vortioxetine and salts thereof in preparation of antitumor drugs | |
CN104926804B (en) | One kind has compound, the preparation method and use of antitumor action | |
CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
CN102276626B (en) | Isoxazole-containing compound | |
CN101863898B (en) | Thieno pyridinone derivative containing piperazidine and preparation method and applications thereof | |
CN102329327B (en) | Furan derivatives and preparation method and application thereof | |
CN105541696B (en) | A kind of antitumor compound and its preparation method and application | |
CN102417514B (en) | Pyridine derivatives, preparation method thereof, and purpose thereof | |
CN101885726A (en) | New compound structure and preparation method and application thereof | |
CN101967154B (en) | Oxime compounds, preparation method and application thereof | |
CN102838652B (en) | A kind of oleanolic acid derivate with anticarcinogenesis and its production and use | |
CN102358742B (en) | Thiazole compound with antitumor activity | |
CN102276625A (en) | Thiadiazole derivative | |
CN101774976B (en) | Sulfonyl isoxazoline derivative and anti-tumor application | |
CN105037345A (en) | Antitumor compound as well as preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120111 Termination date: 20210611 |
|
CF01 | Termination of patent right due to non-payment of annual fee |