CN104292210B - Nitric oxide donors class compound containing pyridine, preparation method and the usage - Google Patents
Nitric oxide donors class compound containing pyridine, preparation method and the usage Download PDFInfo
- Publication number
- CN104292210B CN104292210B CN201310295541.7A CN201310295541A CN104292210B CN 104292210 B CN104292210 B CN 104292210B CN 201310295541 A CN201310295541 A CN 201310295541A CN 104292210 B CN104292210 B CN 104292210B
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- formula
- alkyl
- 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.)
- Active
Links
- 0 **C(C1=*C=CCN=C1N1CCNCC1)=O Chemical compound **C(C1=*C=CCN=C1N1CCNCC1)=O 0.000 description 4
Classifications
-
- 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
-
- 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 kind of the nitric oxide donors derivative and its pharmaceutically acceptable salt containing pyridine with structure shown in formula I, wherein：Wherein n=1,2 or 3；R1For C1 C4 alkyl, cycloalkyl；R2、R3It is hydrogen at the same time or separately, C1 C4 alkyl；R4For hydrogen, C1 C4 alkyl.The invention also discloses the preparation method of said derivative, and also disclose using the analog derivative or its pharmaceutically acceptable salt and be used as the pharmaceutical composition of active ingredients, and they are as antineoplastic, the application particularly in terms of for preparing treatment breast cancer, lung cancer, gastric cancer medicament.
Description
Technical field
The invention belongs to pharmaceutical technology field, more precisely, be related to a kind of compound with antitumor action and
Its preparation method, the pharmaceutical composition containing them and the purposes as antineoplastic.
Background technology
Nitric oxide（NO）In molecule, N atoms outermosts have 5 electronics, and O atom outer layer has 6 electronics, forms covalent bond
Afterwards, there is a unpaired electron on molecular orbit, unstable chemcial property, half-life short, fat-soluble strong, easy disperse is led to
Cell membrane, it is diffused into adjacent tissue, with its active chemical property, is acted on quickly with target substance, produce biological effect.
NO is connected with some drugses, can not only strengthen drug effect, increases new adaptability, and can significantly reduce adverse reaction.
The nitric oxide source of organism includes endogenous, exogenous two aspects.Endogenous refers to make with L-arginine
For substrate, by the effect of NO synzyme, NO and Cit are generated.Exogenous NO donors refer to the different knots for discharging NO properties
The compound of structure, their chemism depend on the state of oxidation of related nitrogen-atoms, control physiological conversion NO speed
And degree.Preferable NO donor medicines are spontaneous stably to discharge NO in vivo, and are discharged simply, long without cell metabolism
Time application is not likely to produce tolerance, has the kind of different action times and different action intensities for selecting.
The important sources of exogenous NO donors are NO donors, i.e., discharge NO compound in vivo.Chemically basis and NO
The difference of the connected atom in position is discharged, NO donors are divided into six classes：C-NO donors, N-NO donors, O-NO donors, S-NO are supplied
Body, heterocycle-NO donors and transition metal-NO donors.It is O-NO donors that most study is also most deep at present, consists predominantly of machine
Nitrate and organic sub-nitrate.
Cancer turns into the big chronic disease for seriously endangering human health at present.Suffer from cancered people every year in the world according to statistics
Have 9,000,000, the patient for dying from cancer is 6,000,000, it has also become is only second to the second largest killer of angiocardiopathy.Clinical treatment swells
Knurl is general using operation, radiotherapy, three big therapy of chemotherapy.Though embolic chemotherapy is more quick, cure rate is very low.Clinical hair simultaneously
Damage and the toxic side effect significantly to normal body be present in existing many cancer therapy drugs.Therefore, nitric oxide donors, exploitation are introduced
The low new compound of good effect, toxic side effect turns into one of direction of research.
The content of the invention
It is an object of the present invention to disclose a kind of nitric oxide donors derivative and its pharmaceutical salts containing pyridine.
It is another object of the present invention to disclose with nitric oxide donors derivative of the one kind containing pyridine and its medicinal
Salt is the pharmaceutical composition of main active.
Another object of the present invention is, discloses the system of nitric oxide donors derivative and its pharmaceutical salts containing pyridine
Preparation Method.
A further object of the invention is, discloses the nitric oxide donors derivative containing pyridine and its pharmaceutical salts conduct
Application in terms of antineoplastic.
In conjunction with the object of the invention, present invention is described in detail.
Present invention relates particularly to the compound of Formulas I structure and its pharmaceutically acceptable salt：
Wherein：
N=1,2 or 3；
R1For C1-C4 alkyl, cycloalkyl；
R2、R3It is hydrogen at the same time or separately, C1-C4 alkyl；
R4For hydrogen, C1-C4 alkyl.
More preferable following compound and its pharmaceutically acceptable salt：
Ⅰ-1）3- (cyclopropylcarbamoyl) -2-（（4-（1- oxo -2- nitrates）Ethyl）- 3- methyl piperazines -1-
Base) pyridine；
Ⅰ-2）3- (cyclopropylcarbamoyl) -2-（（4-（1- oxo -3- nitrates）Ethyl）Piperazine -1- bases) pyridine；
Ⅰ-3）3- (cyclopropylcarbamoyl) -2-（（4-（1- oxo -3- nitrates）Ethyl）- 3,3- lupetazin-
1- yls) pyridine；
Ⅰ-4）3- (cyclopropylcarbamoyl) -2-（（4-（1- oxo -2- nitrates）Butyl）Piperazine -1- bases) pyridine；
Ⅰ-5）3- (cyclopropylcarbamoyl) -2-（（4-（1- oxo -5- nitrates）Amyl group）Piperazine -1- bases) pyridine；
The compound with structure shown in formula I of the present invention, its pharmaceutically acceptable salt are meant：The compounds of this invention with it is inorganic
Acid, organic acid are into salt.Wherein particularly preferred salt is：Hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, phosphorus
Hydrochlorate, hydrophosphate, acetate, propionate, butyrate, lactate, mesylate, tosilate, maleate, benzene first
Hydrochlorate, succinate, tartrate, citrate, fumarate, taurate, amino-acid salt, gluconate, etc..
The syntheti c route of type I compound is as follows：
X is chlorine, bromine；n、R1、R2、R3、R4It is defined as described above.
By 1-（3- substituent pyridine -2- bases）Piperazine (II) is dissolved in dichloromethane, chloroform, acetonitrile, tetrahydrofuran, and third
In ketone, ethyl acetate, methanol, ethanol or DMF equal solvents, in triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium acid carbonate, hydrogen-oxygen
Under the catalysis for changing the acid binding agent such as sodium or potassium hydroxide, control temperature reacts to obtain intermediate III at -10 DEG C~30 DEG C with halogen carboxylic acid halides,
For intermediate III with silver nitrate in dichloromethane, chloroform, acetonitrile or toluene equal solvent, 30~120 DEG C of lucifuge reactions are final
Chemical compounds I is made.Wherein each substituent is as defined above.
Will reaction be made various intermediates or products therefrom be dissolved in ether, DMF, acetone, methanol, ethanol, ethyl acetate or
One kind in DMSO, inorganic acid or organic acid is added dropwise, pharmaceutically acceptable salt is made.
Various compounds are specifically dissolved in one kind in ether, DMF, acetone, methanol, ethanol, ethyl acetate or DMSO,
Ethereal HCI is added dropwise under ice-water bath to pH=2, hydrochloride is made；Or by various compounds be dissolved in ether, DMF, acetone, methanol,
One kind in ethanol, ethyl acetate or DMSO, adds equimolar gluconic acid, and heating stirring obtains its gluconate；Or will
Various compounds are dissolved in one kind in ether, DMF, acetone, methanol, ethanol, ethyl acetate or DMSO, are added dropwise under ice-water bath dense
Sulfate, etc. is made to pH=3 in sulfuric acid.
Such compound is effective in terms of human cancerous disease is treated.Although the present invention compound can without appoint
What configuration is directly administered, but described various compounds preferably use in the form of a pharmaceutical preparation, and method of administration can be non-enteric
Road approach (such as vein, intramuscular delivery) and oral administration.
The pharmaceutical composition preparation method of the compounds of this invention is as follows：Using standard and conventional technique, make of the present inventionization
Compound is combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily with acceptable auxiliary on galenic pharmacy
Agent and excipient, which combine, is prepared into particulate or microballoon.Solid dosage forms includes tablet, discrete particles, capsule, sustained release tablets, sustained release pellet
Etc..Solid carrier can be at least one material, its can serve as diluent, flavouring agent, solubilizer, lubricant, suspending agent,
Adhesive, disintegrant and coating agent.Inert solid carrier includes magnesium phosphate, magnesium stearate, smoothers sugar, lactose, pectin, the third two
Alcohol, polyoxyethylene sorbitan monoleate, dextrin, starch, gelatin, cellulose substances such as methylcellulose, microcrystalline cellulose, low melting point stone
Wax, polyethylene glycol, mannitol, cocoa butter etc..Liquid dosage form includes 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 can be according to patient
The state of an illness, the situation of diagnosis be specifically applied, the amount or concentration of compound used are in a wider scope
Regulation.Generally, the amount scope of reactive compound is 0.5%~90% (weight) of composition, and another preferable scope is 0.5%
~70%.
The compound and its pharmaceutically acceptable salt with structure shown in formula I of the present invention, has significantly in anti-tumor aspect
Effect.
The antitumor action of the compounds of this invention is further illustrated below by pharmacodynamic experiment.
External antitumor action
（1）Experimental method：
Using the cytotoxic activity vitro detection method mtt assay of classics, the human tumour of detection invention Compounds in vitro culture
The cell propagation toxicity of cell.
（2）Experiment material：
Laboratory sample：Type I compound is made by oneself by inventor and provided.Sample is with DMSO hydrotropies, serum-free DMEM trainings during experiment
Foster base is diluted to required concentration, and sample segment solution is in suspension.
Main agents：MTT, Amresco company dispense, lot number：04M0904；Complete DMEM culture mediums, the production of Gibco companies
Product, lot number：1290007；Calf serum, Lanzhou people's marine growth, lot number：20060509；Trypsase, the packing of Amresco companies,
Lot number：016B0604；Fluorouracil Injection, 0.25g/10ml (branch), lot number：0512022, the Tianjin gold credit limited public affairs of amino acid
Department.
Laboratory apparatus：Superclean bench, Suzhou Decontamination Equipment Plant；CO2Incubator, Thermo companies, model：HERA
Cell150；Inverted microscope, Carl Zeiss companies, model：Axiovert200；Enzyme-linked immunosorbent assay instrument, TECAN companies,
Model：Sunrise；Centrifuge, Kerdro companies, model：Heraeus.
Cell line：SPCA1 human lung adenocarcinoma cell lines, MCF7 human breast cancer cells, SGC-7901 gastric carcinoma cells, are purchased from
Shanghai cell research institute of the Chinese Academy of Sciences.
（3）Experimental procedure：
Cell culture：Tumor cell inoculation is containing 10% calf serum, 100IU/ml penicillin G sodium salts and 100 μ g/ml sulphur
In the DMEM nutrient solutions of sour streptomysin, be placed in 37 DEG C, 100% relative humidity, containing 5%CO2Incubator in, passage 3 times after it is standby.
Mtt assay determines：Take the logarithm the cell in growth period, after 0.25% Trypsin Induced（Suspension cell need not digestion）,
It is suspended in the DMEM nutrient solutions containing 10% calf serum, gently blows and beats into single cell suspension with glass dropper, blood is used under microscope
Cell count plate numeration living cells.96 well culture plates are per the μ L of hole inoculating cell suspension 90（Cell concentration is adjusted to 6~10 × 104
Individual/ml）, 37 DEG C, 100% relative humidity, containing 5%CO2, 95% air incubator culture 24h after, add 10 μ L decoctions per hole（Eventually
Concentration is set to：Five 40 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml and 2.5 μ g/ml concentration）.In addition, each concentration sets the moon
Property control（Isoconcentration DMSO）And blank background（It is not added with cell）, each group is all provided with 6 multiple holes.24h is continuously cultivated again, then per hole
The 5mg/ml μ L of MTT solution 10 are added, continues after cultivating 4h, carefully sucks supernatant（Suspension cell is, it is necessary to first centrifuge, then inhale
Remove supernatant）.100 μ L DMSO are added per hole, put micro oscillator concussion 5min so that crystallization is completely dissolved, ELIASA 492nm is mono-
Wavelength colorimetric, determine OD values.Inhibitory rate of cell growth, which is calculated, in following methods is used as evaluation index.
Inhibiting rate (%)=[1-（Experimental group OD averages-blank group OD averages）/（Control group OD averages-blank group OD averages）]
×100%.According to inhibitory rate of cell growth, IC is calculated in linear regression method50Value.
（4）Experimental result：
IC of the table 1 to the tumour cell of in vitro culture50(μg/ml)
（5）Conclusion：
According to above-mentioned in vitro test result, we can see that the compound with structure shown in formula I is to above-mentioned 3 kinds of human tumors
Cell has stronger inhibitory action.
Embodiment
The present invention is described further with reference to example.Example is only explanatory, is in no way intended to it to appoint
Where formula limits the scope of the present invention.
Reference implementation example 1：
Intermediate III -1
Equipped with stirring, condenser, thermometer reaction bulb in add 2.60g（0.01mol）N- cyclopropyl -2- (3- first
Base piperazine -1- bases) niacinamide, dissolved with 10mL DMF, add triethylamine 2.5g, control temperature at -10 DEG C~2 DEG C,
Chloracetyl chloride 1.70g is added dropwise（0.15mol）, thermotonus 6h is maintained after dripping off, pours into reaction solution after being warmed to room temperature naturally
In 30mL distilled water, stirring, filter solid is crossed, vacuum drying, produces intermediate III -1（HPLC：84.5%）.HRMS(m/z)：
337.1426。
It can facilitate prepare compound with reference to the method for reference implementation example 1：Intermediate III -2~III -5.
The intermediate III -2~III -5 of table 2
Embodiment 1：
3- (cyclopropylcarbamoyl) -2-（（4-（1- oxo -2- nitrates）Ethyl）- 3- methylpiperazine-1-yls) pyrrole
Pyridine（Chemical compounds I -1）
Equipped with stirring, condenser, thermometer reaction bulb in add intermediate III -1 (3.2g, 0.01mo1), anhydrous second
Nitrile (20m1) dissolves, and adds the anhydrous acetonitrile (10m1) of silver nitrate (2.0g, 0.012mo1), backflow 5h under lucifuge stirring,
Room temperature, evaporated under reduced pressure solvent are cooled to after TLC display reactions completely.Dichloromethane (20m1), stirring are added in residue
10min, filtering, filtrate decompression solvent evaporated.Absolute ethyl alcohol (30m1), the evaporated under reduced pressure after activated carbon decolorizing are added, room temperature subtracts
Pressure is dried overnight, and obtains pale yellow transparent grease I -1 (3.1g, yield 90%), purity 98.9% (HPLC methods).HRMS（m/z）：
364.1615。
It can facilitate prepare compound with reference to the method for embodiment 1：Chemical compounds I -2~I -5.
The chemical compounds I -2~I -5 of table 3
Embodiment 2：
The hydrochloric acid salt of chemical compounds I -3：The faint yellow oil product 2.0g of chemical compounds I -3 is taken, is dissolved in 10mL absolute ethers.Frozen water
Bath is cooled to 0 DEG C, and it is 2 that 25% ethereal HCI solution, which is added dropwise, to pH, continues at stir about 1h under ice-water bath.Filtering, is obtained white solid
Body.
Embodiment 3：
The one-tenth gluconate of chemical compounds I -4：The yellow oil product 2.0g of chemical compounds I -4 is taken, is dissolved in 10mL absolute ethyl alcohols.Add
Heat adds equimolar gluconic acid to after flowing back, and continues at stirred at reflux reaction about 2h.Reaction finishes, and stands at room temperature
24h.Filtering, obtains light yellow solid.
Embodiment 4：
The one-tenth sulfate of chemical compounds I -5：The faint yellow oil product 2.0g of chemical compounds I -5 is taken, is dissolved in 10mL absolute methanols.Frozen water
Bath is cooled to 5 DEG C, and it is 3 that concentrated sulfuric acid solution, which is added dropwise, to pH, continues at stir about 0.5h under ice-water bath.Filtering, obtains light yellow solid.
In order to which the pharmaceutical composition of the nitric oxide donors class compound of the present invention is more fully explained, it is provided below following
Example of formulations, the embodiment are merely to illustrate, rather than for limiting the scope of the present invention.The preparation can use this
Any reactive compound in invention compound, preferably using the compound implemented described in 1-4.
Embodiment 5：
Hard gelatin capsule is prepared with following compositions：
After mentioned component is mixed, it is packed into 460mg in hard gelatin capsule.
Embodiment 6：
Tablet is prepared with following compositions：
Supplementary material is pre-dried, it is standby to cross 100 mesh sieves.First the auxiliary material of recipe quantity is fully mixed.By bulk drug to pass
Increase dilution method to be added in auxiliary material, each added-time fully mixes 2-3 times, ensures that medicine fully mixes with auxiliary material, 20 mesh sieves is crossed, 55
2h is dried in DEG C ventilated drying oven, dry particl crosses 16 mesh sieve whole grains, determines intermediates content, is well mixed, the tabletting on tablet press machine.
Embodiment 7：
The preparation of parenteral solution：
Take active component to be added in the water for injection for having dissolved sorbierite and propane diols, add medicinal basic adjust pH value to
4-8 makes its dissolving.Add activated carbon, stirring and adsorbing 30 minutes, carbon removal, refined filtration, embedding, sterilizing.
Embodiment 8：
The preparation of injection freeze-dried powder：
The gluconate 100mg of chemical compounds I -4
Medicinal basic 0.1-7%
Mannitol 55-85%
Take active component to add water for injection, make its dissolving with medicinal basic regulation pH value to 4-8.Mannitol is added, is pressed
The requirement of injection carries out autoclaving, adds activated carbon, and using filtering with microporous membrane, filtrate is dispensed, dry using freezing
Dry method, loose block is made, sealing, produces.
Claims (9)
1. compound or its pharmaceutically acceptable salt with structure shown in formula I：
Wherein n=1,2 or 3；
R1For C1-C4 alkyl, cycloalkyl；
R2、R3It is hydrogen at the same time or separately, C1-C4 alkyl；
R4For hydrogen, C1-C4 alkyl.
2. compound or its pharmaceutically acceptable salt with structure shown in formula I：
It is selected from：
Ⅰ-1)
Ⅰ-2)
Ⅰ-3)
Ⅰ-4)
Ⅰ-5)
3. type I compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, its pharmaceutically acceptable salt are：
Compound of formula I and inorganic acid, organic acid into salt.
4. type I compound as claimed in claim 3 or its pharmaceutically acceptable salt, its pharmaceutically acceptable salt are：Salt
Hydrochlorate, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate, first
Sulfonate, tosilate, maleate, benzoate, succinate, tartrate, citrate, fumarate, ox
Sulfonate, amino-acid salt, gluconate.
5. the preparation method of the compound with structure shown in formula I as claimed in claim 1, it is characterised in that：
1- shown in formula II (3- substituent pyridine -2- bases) piperazine in the presence of acid binding agent, reacts to obtain intermediate with alkyl acyl halide
Ⅲ；Intermediate III reacts with silver nitrate in 30~120 DEG C of lucifuges, and type I compound is made, represents as follows with reaction equation：
X is chlorine, bromine；n、R1、R2、R3、R4Definition is as claimed in claim 1.
6. preparation method as claimed in claim 5, it is characterised in that：The acid binding agent is triethylamine, pyridine, potassium carbonate, carbon
Sour sodium, sodium acid carbonate, sodium hydroxide or potassium hydroxide.
7. a kind of pharmaceutical composition, it has the knot of formula I comprising therapeutically effective amount as according to any one of claims 1 to 2
The compound of structure or its pharmaceutically acceptable salt and one or more pharmaceutical carriers.
8. as the compound according to any one of claims 1 to 2 with structure shown in formula I or its pharmaceutically acceptable salt with
Application in terms of antineoplastic is prepared.
9. application as claimed in claim 8, the application in terms of for preparing treatment breast cancer, lung cancer, gastric cancer medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310295541.7A CN104292210B (en) | 2013-07-15 | 2013-07-15 | Nitric oxide donors class compound containing pyridine, preparation method and the usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310295541.7A CN104292210B (en) | 2013-07-15 | 2013-07-15 | Nitric oxide donors class compound containing pyridine, preparation method and the usage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104292210A CN104292210A (en) | 2015-01-21 |
| CN104292210B true CN104292210B (en) | 2017-11-10 |
Family
ID=52312198
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310295541.7A Active CN104292210B (en) | 2013-07-15 | 2013-07-15 | Nitric oxide donors class compound containing pyridine, preparation method and the usage |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104292210B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796040A (en) * | 2012-08-23 | 2012-11-28 | 天津药物研究院 | 1,4-disubstituted piperazine derivatives and their preparation method and use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101245061B (en) * | 2007-02-13 | 2012-09-19 | 天津天士力集团有限公司 | N-(5-amido-2-methyl phenyl)-4-(3-pyridinyl)-2-aminopyrimidine nitric oxide donating derivant, production method and uses thereof |
| CN101613393A (en) * | 2009-05-25 | 2009-12-30 | 中国药科大学 | Synthetic and the application in medication preparation of ursolic acid derivative |
| CN105237611B (en) * | 2011-06-17 | 2018-11-13 | 上海医药工业研究院 | Asiatic acid amino butanetriol salt crystal form and preparation method thereof |
-
2013
- 2013-07-15 CN CN201310295541.7A patent/CN104292210B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796040A (en) * | 2012-08-23 | 2012-11-28 | 天津药物研究院 | 1,4-disubstituted piperazine derivatives and their preparation method and use |
Non-Patent Citations (1)
| Title |
|---|
| 一氧化氮供体/一氧化氮供体型化合物在肿瘤治疗中的研究进展;崔冉 等;《临床合理用药》;20120630;第5卷(第6B期);175-177 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104292210A (en) | 2015-01-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103044395B (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| CN107556361A (en) | Driffractive ring lupinane derivative and its anticancer usage | |
| CN101869560A (en) | Isoalantolactone amino derivative and application of salt thereof in preparing anti-tumor medicament | |
| CN102911118B (en) | Benzo-azepine type derivative and preparation method and purpose thereof | |
| CN103183682A (en) | C-10 site carbamido substituted artemisinin derivative, preparation method and application | |
| CN107141284B (en) | Coptisine analog derivative, preparation method, pharmaceutical composition and anticancer usage | |
| CN104292210B (en) | Nitric oxide donors class compound containing pyridine, preparation method and the usage | |
| CN103864765B (en) | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use | |
| CN104926804B (en) | One kind has compound, the preparation method and use of antitumor action | |
| CN104292211A (en) | Desloratadine nitric oxide donor, and preparation method and application thereof | |
| CN101974016A (en) | Amide compound and preparation method and applications thereof | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN105037345B (en) | Antitumoral compounds, preparation method and use | |
| CN104119295B (en) | Phenothiazines nitric oxide donors, preparation method and use | |
| CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
| CN101845052B (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof | |
| CN107129497A (en) | The Sophoridine analog derivative of one class containing mustargen and its production and use | |
| CN103880793B (en) | Containing furan imine compound and its production and use | |
| CN102276625B (en) | Thiadiazole derivative | |
| CN103012394A (en) | Rhodanine derivative and preparation method thereof | |
| CN102276626B (en) | Isoxazole-containing compound | |
| CN103288805B (en) | Pyrimidines containing benzofuran and its production and use | |
| CN102417514B (en) | Pyridine derivatives, preparation method thereof, and purpose thereof | |
| CN101805355B (en) | Thienopyridone derivative, preparation method and uses thereof | |
| CN104829629B (en) | Thiophane simultaneously [2,3 c] pyridine derivate, Preparation Method And The Use containing sulfoamido |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |