CN104119295B - Phenothiazines nitric oxide donors, preparation method and use - Google Patents
Phenothiazines nitric oxide donors, preparation method and use Download PDFInfo
- Publication number
- CN104119295B CN104119295B CN201310152346.9A CN201310152346A CN104119295B CN 104119295 B CN104119295 B CN 104119295B CN 201310152346 A CN201310152346 A CN 201310152346A CN 104119295 B CN104119295 B CN 104119295B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- chain
- straight
- hydrogen
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/30—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with acyl radicals attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of Nitric oxidedonating compounds containing phenthazine with structure shown in formula I, wherein：N=0,1 or 2；R1For：Hydrogen, halogen, C1 C4 branched-chain or straight-chain alkyl, halo C1 C4 branched-chain or straight-chain alkyl；R2For：Hydrogen, C1 C4 branched-chain or straight-chain alkyl.The invention also discloses the preparation method of above-claimed cpd, and also disclose the pharmaceutical composition using the compound as 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
Preparation method and use.
Background technology
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, almost just there is a cancer death each second.Fall ill in China's cancer year people
Number is 1,200,000 or so, and the number for dying from cancer is up to more than 900,000, and patient to be treated has what is risen year by year more than 1,500,000
Trend.Therefore cancer turns into the second largest killer for being only second to angiocardiopathy.Clinical treatment tumour, typically using hand
Art, radiotherapy, three big therapy of chemotherapy.Though embolic chemotherapy is more quick, cure rate is very low.The many cancer therapy drugs of clinical discovery simultaneously
In the presence of the damage significantly to normal body and toxic side effect, such as mutagenesis and genetoxic.
NO is messenger molecule and effector molecule important in organism, the regulation of different physiological roles is participated in, in intestines and stomach
Have the function that to protect gastric mucosa in system.NO donors include nitrate（R-ONO2）, nitrous acid ester（R-ONO）, nitrous acid sulphur
Alcohol（R-SNO）Deng most common of which is exactly nitrate.The new antitumoral compounds of the present invention are a kind of nitrates, are had
Good researching value.
The content of the invention
It is an object of the present invention to the nitric oxide donors class compound containing phenthazine of a kind of new structure is disclosed
And its pharmaceutical salts.
It is another object of the present invention to, open a kind of nitric oxide donors class compound containing phenthazine and its medicinal
The preparation method of salt.
Another object of the present invention is, open with nitric oxide donors class compound and its medicine of the one kind containing phenthazine
With the pharmaceutical composition that salt is main active.
A further object of the invention is, open a kind of nitric oxide donors class compound containing phenthazine and its medicinal
Application of the salt as medicine for resisting malignant tumors, particularly in terms of for preparing treatment breast cancer, lung cancer, gastric cancer medicament
Purposes.
In conjunction with the object of the invention, present invention is described in detail.
Present invention relates particularly to the compound of structure shown in formula I and its pharmaceutically acceptable salt：
Wherein：
N=0,1 or 2.
R1For：Hydrogen, halogen, C1-C4Branched-chain or straight-chain alkyl, halo C1-C4Branched-chain or straight-chain alkyl；
R2For：Hydrogen, C1-C4Branched-chain or straight-chain alkyl.
The compound of structure shown in formula I and its structural formula of pharmaceutically acceptable salt are preferably：
Wherein：
N=0,1 or 2；
R1For：Hydrogen, chlorine, halo C1-C4 straight chained alkyl；
R2For：Hydrogen, C1-C4 straight chained alkyl.
The syntheti c route of type I compound is as follows：
n、R1、R2It is defined as described above.
Substituted phenothiazine compound（Ⅱ）, in dichloromethane, chloroform, acetone, DMF, first
In the solution such as benzene or acetonitrile, with substituted 2- halogen acetyl halide compounds（Ⅲ）In triethylamine, pyridine, potassium carbonate, sodium carbonate, bicarbonate
Under the catalysis of the acid binding agents such as sodium, saleratus, sodium hydroxide or potassium hydroxide, -30~50 DEG C of reaction generation intermediates IV are middle
With silver nitrate in dichloromethane, chloroform, acetonitrile or toluene equal solvent, 30~120 DEG C of lucifuge reactions are final to be made body IV
Chemical compounds I.
Such compound is effective for treatment human malignancies.Although the compound of the present invention can be without any
Prepare and be directly administered, but described various compounds preferably use in the form of a pharmaceutical preparation, and method of administration can be non-bowel
Approach（Such as vein, intramuscular delivery）And it is administered orally.
The pharmaceutical composition of the compounds of this invention prepares as follows：Using standard and conventional technique, make the compounds of this invention
Combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily with acceptable adjuvant on galenic pharmacy and
Excipient combines and is prepared into particulate or microballoon.Solid dosage forms includes tablet, discrete particles, capsule, sustained release tablets, sustained release pellet etc.
Deng.Solid carrier can be at least one material, and it can serve as diluent, flavouring agent, solubilizer, lubricant, suspending agent, viscous
Mixture, 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 active ingredient contained in pharmaceutical composition and unit dosage form（The compounds of this invention）Amount 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 are the 0.5%~90% of composition（Weight）.Another preferable scope is 0.5%-
70%。
The compound with structure shown in formula I of the present invention, there is obvious inhibitory action to tumour.
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：
To the IC of 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
With reference to embodiment, the present invention is described further, and embodiment is only explanatory, is in no way intended to it
The scope limiting the invention in any way.Described compound is through high performance liquid chromatography（HPLC）, thin-layer chromatography（TLC）Carry out
Detection.Such as infrared spectrum can then be used（IR）, nuclear magnetic resoance spectrum（1H NMR,13C NMR）, high resolution mass spectrum（HRMS）
Deng further confirming its structure.
Embodiment 1：
Intermediate VI -1
Equipped with stirring, 1.99g (0.01mo1) phenthazine being added in the reaction bulb of condenser, addition contains 2.5g
（0.025mol）The DMF of triethylamine（30ml）Stirring and dissolving, -10 DEG C~0 DEG C is slowly added dropwise chloracetyl chloride 1.68g
（0.015mol）, react 3h.After being stored at room temperature half an hour, it is poured into 200ml distilled water water, stirs, filtering, obtains yellow and consolidate
Body, without purifying, direct plunge into and react in next step.
With reference to the method for embodiment 1, you can synthetic intermediate VI -2~VI -9.
Embodiment 2：
2- oxygen -2- (10H- phenthazine -10- bases) acetyl nitrate salt（Chemical compounds I -1）
2.75g is added in the reaction bulb equipped with stirring, thermometer and condenser（0.01mol）Intermediate VII -1 and 30ml
Anhydrous acetonitrile, the anhydrous acetonitrile (10m1) of silver nitrate (2.0g, 0.012mo1) is added, backflow 5h, TLC show under lucifuge stirring
Room temperature, evaporated under reduced pressure solvent are cooled to after showing reaction completely.Dichloromethane (20m1) is added in residue, stirs 10min, mistake
Filter, filtrate decompression solvent evaporated.Absolute ethyl alcohol (30m1), the evaporated under reduced pressure after activated carbon decolorizing are added, silica gel column chromatography obtains
Pale yellow transparent grease I -1 (2.62g, yield 87%), purity 99.7% (HPLC methods).HRMS(m/z)[M+H]+：
303.0434。
With reference to the method for embodiment 1, you can synthesis chemical compounds I -2~I -9.
In order to which the pharmaceutical composition of the nitric oxide compound containing phenthazine of the present invention is more fully explained, carry below
For following example of formulations, the embodiment is merely to illustrate, rather than for limiting the scope of the present invention.The preparation can be with
Using any reactive compound and its salt in the compounds of this invention, preferably using the compound described in embodiment 1-4.
Embodiment 3：
Hard gelatin capsule is prepared with following compositions：
Preparation technology：Supplementary material is pre-dried, it is standby to cross 100 mesh sieves.After by recipe quantity, mentioned component is mixed, filling
Enter in hard gelatin capsule.
Embodiment 4：
Tablet is prepared with following compositions：
Preparation technology：Supplementary material is pre-dried, it is standby to cross 100 mesh sieves.First the auxiliary material of recipe quantity is fully mixed.By original
Material medicine is added in auxiliary material with incremental dilution method, and each added-time fully mixes 2-3 times, is ensured that medicine fully mixes with auxiliary material, is crossed 20 mesh
Sieve, 2h is dried in 55 DEG C of ventilated drying ovens, dry particl crosses 16 mesh sieve whole grains, determines intermediates content, is well mixed, in tablet press machine
Upper tabletting.
Embodiment 5：
The preparation of parenteral solution：
Preparation method：Take active component to be added in the water for injection of solubilized solution polysorbate and propane diols, add medicinal
Alkali, which adjusts pH value, makes its dissolving to 4~8.Add activated carbon, stirring and adsorbing 30min, carbon removal, refined filtration, embedding, sterilizing.
Embodiment 6：
The preparation of injection freeze-dried powder：
Compound I-9 sulfate 100mg
Medicinal basic 0.1-7.0%
Mannitol 55-85%
Preparation method：Take active component to add water for injection, make its dissolving with medicinal basic regulation pH value to 4-8.Add
Mannitol, autoclaving is carried out by the requirement of injection, adds activated carbon, using filtering with microporous membrane, filtrate is dispensed, and is adopted
With freeze-drying, loose block is made, sealing, produces.
Claims (12)
1. the compound with structure shown in formula I：
Wherein：
N=0,1 or 2；
R1For：Hydrogen, halogen, C1-C4 branched-chain or straight-chain alkyl, halo C1-C4 branched-chain or straight-chain alkyl；
R2For：Hydrogen, C1-C4 branched-chain or straight-chain alkyl.
2. compound according to claim 1, it is characterised in that：
Wherein：
N=0,1 or 2；
R1For：Hydrogen, chlorine, halo C1-C4 straight chained alkyl；
R2For：Hydrogen, C1-C4 straight chained alkyl.
3. structure shown in formula I compound described in claim 1, is selected from：
Ⅰ-1.
Ⅰ-2.
Ⅰ-3.
Ⅰ-4.
Ⅰ-5.
Ⅰ-6.
Ⅰ-7.
Ⅰ-8.
Ⅰ-9.
4. the preparation method of type I compound in claim 1, it is characterised in that the preparation method is prepared by following two step：
(1) phenothiazine compound II in a solvent, with substituted 2- halogen acyl halides compound III under acid binding agent catalysis, reacts
Generate intermediate IV；
(2) intermediate IV reacts to obtain chemical compounds I in a solvent with silver nitrate；
N, R1、R2Definition is as claimed in claim 1.
5. preparation method according to claim 4, it is characterised in that solvent is selected from dichloromethane, three chloromethanes in step (1)
Alkane, acetone, DMF, toluene or acetonitrile.
6. preparation method according to claim 4, it is characterised in that the reaction temperature in step (1) is -30~50 DEG C.
7. preparation method according to claim 4, it is characterised in that the acid binding agent in step (1) is selected from triethylamine, pyrrole
Pyridine, potassium carbonate, sodium carbonate, sodium acid carbonate, saleratus, sodium hydroxide or potassium hydroxide.
8. preparation method according to claim 4, it is characterised in that the solvent in step (2) is selected from dichloromethane, trichlorine
Methane, acetonitrile or toluene.
9. preparation method according to claim 4, it is characterised in that the reaction temperature in step (2) is 30~120 DEG C.
10. a kind of antitumor medicine composition, it include any one of claims 1 to 3 of therapeutically effective amount compound and
One or more pharmaceutical carriers.
11. application of the compound of any one of claims 1 to 3 in terms of for preparing antineoplastic.
12. application according to claim 11, it is characterised in that the compound is preparing treatment breast cancer, lung cancer, stomach cancer
Purposes in terms of medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310152346.9A CN104119295B (en) | 2013-04-27 | 2013-04-27 | Phenothiazines nitric oxide donors, preparation method and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310152346.9A CN104119295B (en) | 2013-04-27 | 2013-04-27 | Phenothiazines nitric oxide donors, preparation method and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104119295A CN104119295A (en) | 2014-10-29 |
| CN104119295B true CN104119295B (en) | 2018-04-10 |
Family
ID=51764960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310152346.9A Active CN104119295B (en) | 2013-04-27 | 2013-04-27 | Phenothiazines nitric oxide donors, preparation method and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104119295B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1335841A (en) * | 1998-09-23 | 2002-02-13 | 科学研究与运用咨询公司 | N-(iminomethyl) amine derivatives, their preparation, their use as medicines and compositions containing them |
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| WO2011011186A2 (en) * | 2009-07-22 | 2011-01-27 | The Board Of Trustees Of The University Of Illinois | Hdac inhibitors and therapeutic methods using the same |
-
2013
- 2013-04-27 CN CN201310152346.9A patent/CN104119295B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1335841A (en) * | 1998-09-23 | 2002-02-13 | 科学研究与运用咨询公司 | N-(iminomethyl) amine derivatives, their preparation, their use as medicines and compositions containing them |
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| WO2011011186A2 (en) * | 2009-07-22 | 2011-01-27 | The Board Of Trustees Of The University Of Illinois | Hdac inhibitors and therapeutic methods using the same |
Non-Patent Citations (2)
| Title |
|---|
| 吩噻嗪类药物潜在抗肿瘤作用机制研究;齐鲁等;《中国科学：生命科学》;20131130;第43卷(第11期);939-946 * |
| 抗肿瘤一氧化氮供体药物研究进展;王兰等;《中国新药杂志》;20061130;第15卷(第21期);1818-1836 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104119295A (en) | 2014-10-29 |
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 | |
| CN102911118B (en) | Benzo-azepine type derivative and preparation method and purpose thereof | |
| CN103864765B (en) | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use | |
| CN110857295B (en) | Flavone-ligustrazine compound CH-X with selective anti-liver cancer effect and preparation method and application thereof | |
| 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 | |
| CN104119295B (en) | Phenothiazines nitric oxide donors, preparation method and use | |
| CN101974016A (en) | Amide compound and preparation method and applications thereof | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN104292210B (en) | Nitric oxide donors class compound containing pyridine, preparation method and the usage | |
| CN110590778B (en) | 3, 10 di-p-methoxyphenyl 6, 12 diaza tetracubane compound, synthetic method and pharmaceutical composition | |
| CN105037345B (en) | Antitumoral compounds, preparation method and use | |
| CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
| CN103880793B (en) | Containing furan imine compound and its production and use | |
| CN103804367B (en) | Benzazepine derivant, Preparation Method And The Use | |
| CN103288805B (en) | Pyrimidines containing benzofuran and its production and use | |
| CN107129497A (en) | The Sophoridine analog derivative of one class containing mustargen and its production and use | |
| CN102417514B (en) | Pyridine derivatives, preparation method thereof, and purpose thereof | |
| CN102276626B (en) | Isoxazole-containing compound | |
| CN101805355B (en) | Thienopyridone derivative, preparation method and uses thereof | |
| CN102796140A (en) | Phosphate-containing isoxazoline derivatives and their preparation method and use | |
| CN102276625B (en) | Thiadiazole derivative | |
| CN102838652B (en) | A kind of oleanolic acid derivate with anticarcinogenesis and its production and use | |
| CN101845052A (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, 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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |