CN104926804B - One kind has compound, the preparation method and use of antitumor action - Google Patents
One kind has compound, the preparation method and use of antitumor action Download PDFInfo
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- CN104926804B CN104926804B CN201510303912.0A CN201510303912A CN104926804B CN 104926804 B CN104926804 B CN 104926804B CN 201510303912 A CN201510303912 A CN 201510303912A CN 104926804 B CN104926804 B CN 104926804B
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- 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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Abstract
The invention discloses compounds and its pharmaceutically acceptable salt that one kind with structure shown in formula I has antitumor action, in which: X O, S, N；R1, R2 are simultaneously or separately are as follows: hydrogen, C1‑C4Alkyl；R3 are as follows: simultaneously or separately by C1‑C4Alkyl, halogen, nitro, phenyl, trifluoromethyl, C1‑C4Alkoxy carbonyl group, C1‑C4Alkoxy list or two or trisubstituted thiophene -2- base or thiene-3-yl.The invention also discloses the preparation methods of above compound, and it also discloses using the compound or its pharmaceutically acceptable salt as the pharmaceutical composition of active ingredients, and they are in the application as anti-tumor drug, in terms for the treatment of breast cancer medicines especially for preparation.
Description
Technical field
The invention belongs to pharmaceutical technology fields, more precisely, be related to a kind of compound with antitumor action and
Preparation method and use.
Background technique
Cancer has become the big chronic disease for seriously endangering human health at present.Cancer year number of the infected in China's is on 1,200,000 left sides
The right side, the number for dying of cancer are up to 900,000 or more, and patient to be treated is more than 1,500,000, and has the tendency that rising year by year.Therefore cancer
Disease has become the second largest killer for being only second to cardiovascular disease.Clinical treatment tumour is general to use operation, radiotherapy, chemotherapy
Three big therapies.Though embolic chemotherapy is more quick, cure rate is very low.The many anticancer drugs of clinical discovery exist apparent right simultaneously
The damage and toxic side effect of normal body, such as mutagenesis and genetoxic.Therefore, it finds effectively and there is smaller body injury
The hot spot of new drug research is had become with the anticancer drug of toxic side effect.
Summary of the invention
It is an object of the present invention to open a kind of with its pharmaceutical salts of the compound of antitumor action.
It is another object of the present invention to the preparations of open a kind of compound with antitumor action and its pharmaceutical salts
Method.
Another object of the present invention is, it is open using a kind of its pharmaceutical salts with antitumor action as chief active at
The pharmaceutical composition divided.
A further object of the invention is that open a kind of compound with antitumor action and its pharmaceutical salts are as anti-
Application in terms of malignant tumor medicine, the purposes in terms for the treatment of breast cancer medicines especially for preparation.
Now in conjunction with the object of the invention, the content of present invention is described in detail.
Present invention relates particularly to the compound of structure shown in formula I and its pharmaceutically acceptable salts:
Wherein:
X is O, S, N；
R1, R2 are simultaneously or separately are as follows: hydrogen, C1-C4Alkyl；
R3 are as follows: simultaneously or separately by C1-C4Alkyl, halogen, nitro, phenyl, trifluoromethyl, C1-C4Alkoxy carbonyl group, C1-C4
Alkoxy list or two or trisubstituted thiophene -2- base or thiene-3-yl.
It is preferred that following compound and its pharmaceutically acceptable salt:
Wherein:
X is O；
R1, R2 are simultaneously or separately are as follows: hydrogen, methyl, ethyl；
R3 are as follows: simultaneously or separately by methyl, chlorine, bromine, nitro, phenyl, trifluoromethyl, methoxycarbonyl group, methoxyl group list or two
Or trisubstituted thiophene -2- base or thiene-3-yl.
Its pharmaceutically acceptable salt of more preferable following compound:
Type I compound pharmaceutically acceptable salt refers to: compound and inorganic acid, organic acid are at salt.Wherein preferably: hydrochloric acid
Salt, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate, methylsulphur
Hydrochlorate, tosilate, maleate, benzoate, succinate, tartrate, citrate, fumarate, ox sulphur
Hydrochlorate, gluconate, amino-acid salt.
The preparation route of type I compound is as follows:
X, R1, R2, R3 are defined as described above.
Compound (2), in aprotic solvent, with substituted thiophene sulfonic acid chloride (3) under the catalysis of alkaline acid binding agent, 0~
40 DEG C of reactions are made.
Aprotic solvent is methylene chloride, chloroform, ethyl acetate, N,N-dimethylformamide, acetonitrile or acetone etc..
Alkaline acid binding agent is triethylamine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or potassium tert-butoxide etc..0
Reaction, which is made various compounds or products therefrom is dissolved in dropwise addition inorganic acid, organic acid in DMF, DMSO, is made pharmacy
Upper acceptable salt.
Various compounds are specifically dissolved in one of DMF, DMSO, ethereal HCI are added dropwise under ice-water bath to pH=2,
Hydrochloride is made；Or various compounds are dissolved in one of DMF or DMSO, equimolar taurine is added, heating stirring obtains it
Taurate；Or various compounds are dissolved in one of DMF or DMSO, the concentrated sulfuric acid is added dropwise under ice-water bath to pH=3, system
At sulfate etc..
Such compound is effective for treatment human malignancies.Although the compound of the present invention can be without any
It prepares and is directly administered, but the various compounds preferably use in the form of a pharmaceutical preparation, administration route can be non-bowel
Approach (such as vein, intramuscular delivery) and oral administration.
The pharmaceutical composition preparation of the compounds of this invention is as follows: using standard and conventional technique, makes the compounds of this invention
In conjunction with solid acceptable on galenic pharmacy or liquid-carrier, and be allowed to arbitrarily with adjuvant acceptable on galenic pharmacy and
Excipient combines and is prepared into particle 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 substance, can serve as diluent, flavouring agent, solubilizer, lubricant, suspending agent, glue
Mixture, disintegrating agent 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, diagnosis the case where be specifically applied, the amount or concentration of compound used are in a wider range
It adjusts, in general, the amount range of reactive compound is 0.5%~90% (weight) of composition.Another preferred range is
0.5%-70%.
Compound or its pharmaceutically acceptable salt with structure shown in formula I of the invention, in vitro has significantly tumour
Inhibiting effect.
External antitumor action
(1) experimental method:
Using classical cytotoxic activity vitro detection method mtt assay, the human tumour of invention Compounds in vitro culture is detected
The cell Proliferation toxicity of cell.
(2) experimental material:
Laboratory sample: type I compound is made by oneself by inventor and is provided.Sample is when experiment with DMSO hydrotropy, serum-free DMEM training
Feeding base is diluted to required concentration, and sample segment solution is in suspension.
Main agents: the packing of MTT, Amresco company, lot number: 04M0904；Complete DMEM culture medium, Gibco company produce
Product, lot number: 1290007；Calf serum, Lanzhou people's marine growth, lot number: 20060509；Trypsase, the packing of Amresco company,
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 company, model:
HERACell150；Inverted microscope, Carl Zeiss company, model: Axiovert 200；Enzyme-linked immunosorbent assay instrument, TECAN
Company, model: Sunrise；Centrifuge, Kerdro company, model: Heraeus.
Cell strain: MCF7 human breast cancer cell is purchased from Chinese Academy of Sciences Shanghai cell research institute.
(3) experimental procedure:
Cell culture: tumor cell inoculation is containing 10% calf serum, 100IU/ml penicillin G sodium salt and 100 μ g/ml sulphur
In the DMEM culture solution of sour streptomysin, it is placed in 37 DEG C, 100% relative humidity, contains 5%CO2Incubator in, pass on 3 standby
With.
Mtt assay measurement: the cell of logarithmic growth phase, (suspension cell need not disappear after 0.25% trypsin digestion
Change), it is suspended in the DMEM culture solution containing 10% calf serum, gently blows and beats into single cell suspension, microscope with glass dropper
Lower blood cell counts plate numeration living cells.(cell concentration is adjusted to 6~10 to the every 90 μ L of hole inoculating cell suspension of 96 well culture plates
×104A/ml), 37 DEG C, 100% relative humidity, contain 5%CO2, 95% air incubator culture for 24 hours after, every hole adds 10 μ L
Medical fluid (final concentration is set as: 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 dense
Degree sets negative control (isoconcentration DMSO) and blank background (cell is not added), and each group is all provided with 6 multiple holes.It is continuous again to cultivate for 24 hours, so
The 10 μ L of MTT solution of 5mg/ml is added in every hole afterwards, continues after cultivating 4h, carefully suck supernatant (suspension cell, need first from
The heart, then suck supernatant).100 μ LDMSO are added in every hole, set micro oscillator concussion 5min and are completely dissolved so as to crystallize, microplate reader
492nm Single wavelength colorimetric measures OD value.Inhibitory rate of cell growth is calculated as evaluation index using following methods.
Inhibiting rate (%)=[1- (experimental group OD mean value-blank group OD mean value)/(control group OD mean value-blank group OD is equal
Value)] × 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 as a result, we can see that the compound with structure shown in formula I is thin to above-mentioned human tumor
Born of the same parents have stronger inhibiting effect.
Detailed description of the invention
Attached drawing is the general structure figure of the compound with structure shown in formula I.
Specific embodiment
The present invention will be further explained with reference to the examples below, and the examples are merely illustrative, is in no way intended to it
It limits the scope of the invention in any way.The compound is carried out through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC)
Detection.Then can use such as infrared spectroscopy (IR), nuclear magnetic resoance spectrum (1H NMR,13C NMR), high resolution mass spectrum (HRMS)
Deng further confirming its structure.
The preparation of embodiment 1: I -1
Equipped with stirring, condenser, thermometer reaction flask in, addition 24.5g (0.10mol) compound a and 280ml bis-
10~30 DEG C, 18.3g 3- thiophenesulfonyl chloride (b), 41.3g (0.25mol) triethylamine and 100ml bis- is added dropwise in chloromethanes, stirring
The mixed solution of chloromethanes, after being added dropwise, back flow reaction 4h, TLC show fully reacting, solvent evaporated, residue 410ml
Methylene chloride dissolution, saturated salt solution (200ml × 3) washing, is evaporated off solvent, and residue acetone recrystallization obtains yellow solid, receives
Rate 76.6%, ESI-MS (m/z): 391.0660.
Referring to the method for embodiment 1, chemical compounds I -2~I -10 can be synthesized.
The preparation of embodiment 2: I -2
It is prepared by the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride 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
It is prepared by the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride into 2- methoxycarbonyl group 3- thiophenesulfonyl chloride.
Yellow solid, yield 61.3%, HRMS (m/z) [M+H]+: 449.0715.
The preparation of embodiment 4: I -4
The preparation of the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride into 2,5- bis- chloro- 4- nitro -3- thiophenesulfonyl chloride.
Yellow solid, yield 67.8%, HRMS (m/z) [M+H]+: 503.9732.
The preparation of embodiment 5: I -5
The preparation of the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride into 4- phenyl -5- trifluoromethyl -3- thiophenesulfonyl
Chlorine.
Yellow solid, yield 70.7%, HRMS (m/z) [M+H]+: 535.0847.
The preparation of embodiment 6: I -6
The preparation of the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride into 5- bromo- 2- thiophenesulfonyl chloride.
Yellow solid, yield 69.1%, HRMS (m/z) [M+H]+: 468.9766.
The preparation of embodiment 7: I -7
The preparation of the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride into 4- nitro -5- chloro- 2- thiophenesulfonyl chloride.
Yellow solid, yield 54.3%, HRMS (m/z) [M+H]+: 470.0122.
The preparation of embodiment 8: I -8
The preparation of the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride into 3- methoxyl group -5- chloro- 2- thiophenesulfonyl chloride.
Yellow solid, yield 63.4%, HRMS (m/z) [M+H]+: 479.0821.
The preparation of embodiment 9: I -9
The preparation of the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride into 5- chloro- 2- thiophenesulfonyl chloride.
Yellow solid, yield 80.8%, HRMS (m/z) [M+H]+: 425.0271.
The preparation of embodiment 10: I -10
The preparation of the similar method of embodiment 1, changes 3- thiophenesulfonyl chloride into 3- methyl -5- methoxycarbonyl group -2- thiophenesulfonyl
Chlorine.
Pale solid, yield 66.6%, HRMS (m/z) [M+H]+: 463.0872.
Embodiment 11:
- 1 hydrochloric acid salt of chemical compounds I: -1 solid 5.0g of chemical compounds I is taken, 10mlDMF is dissolved in.Ice-water bath is cooled to 5 DEG C, drop
Add 11.1% ethereal HCI solution to pH be 2, continue at stir about 1h under ice-water bath.Filtering, vacuum drying, obtains white solid powder
End.
Embodiment 12:
- 6 one-tenth lactate of chemical compounds I: I -6 solid 4.6g is taken, 22mLDMSO is dissolved in.Equimolar cream is added after being heated to reflux
Acid continues at stirred at reflux reaction about 2h.End of reaction stands 8h at room temperature.Light yellow crystals, filtering, vacuum is precipitated
It is dry.
In order to which the pharmaceutical composition of the compound of the invention containing benzazepine is more fully explained, it is provided below down
Series preparation embodiment, the embodiment are merely to illustrate, rather than for limiting the scope of the invention.The preparation can be used
Any reactive compound and its salt in the compounds of this invention.
Embodiment 13:
Hard gelatin capsule is prepared with following compositions:
Preparation process: supplementary material is pre-dried, and is sieved with 100 mesh sieve spare.After mentioned component is mixed by recipe quantity, filling
Enter in hard gelatin capsule.
Embodiment 14:
Tablet is prepared with following compositions:
Preparation process: supplementary material is pre-dried, and is sieved with 100 mesh sieve spare.First the auxiliary material of recipe quantity is mixed well.It will be former
Material medicine is added in auxiliary material with being incremented by dilution method, and each added-time mixes well 2-3 times, is guaranteed that medicine is mixed well with auxiliary material, is crossed 20 mesh
Sieve, dry 2h, dry particl cross 16 mesh sieves in 55 DEG C of ventilated drying ovens, measure intermediates content, are uniformly mixed, in tablet press machine
Upper tabletting.
Embodiment 17:
The preparation of injection freeze-dried powder:
The hydrochloride 600mg of chemical compounds I -1
Mannitol 55-85%
Preparation method: taking active constituent that water for injection is added, and is made it dissolve with medicinal basic adjusting pH value to 4-8.It adds
Mannitol carries out high pressure sterilization by the requirement of injection, active carbon is added, using filtering with microporous membrane, filtrate is dispensed, and is adopted
With freeze-drying, be made loose block, sealing to get.
Claims (8)
1. compound or its pharmaceutically acceptable salt with structure shown in formula I:
Wherein:
X is O, S, N；
R1, R2 are simultaneously or separately are as follows: hydrogen, C1-C4Alkyl；
R3 are as follows: simultaneously or separately by C1-C4Alkyl, halogen, nitro, phenyl, trifluoromethyl, C1-C4Alkoxy carbonyl group, C1-C4Alcoxyl
Base list or two or trisubstituted thiophene -2- base or thiene-3-yl.
2. compound or its pharmaceutically acceptable salt with structure shown in formula I, preferred compound are as follows:
3. type I compound as described in claim 1 or its pharmaceutically acceptable salt, pharmaceutically acceptable salt are as follows: Formulas I
Compound and inorganic acid, organic acid are at salt.
4. compound of formula I as claimed in claim 3 or its pharmaceutically acceptable salt, pharmaceutically acceptable salt are as follows: salt
Hydrochlorate, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, butyrate, lactate, mesylate,
Tosilate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurate.
5. the preparation method of type I compound in claim 1, it is characterised in that: compound 2, in aprotic solvent, with substitution
Under the catalysis of alkaline acid binding agent, 0~40 DEG C of reaction is made thiophenesulfonyl chloride 3,
X, R1, R2, R3 definition are as described in claim 1.
6. a kind of antitumor medicine composition, it include any one of claim 1~2 of therapeutically effective amount compound or its
Pharmaceutically acceptable salt and one or more pharmaceutical carriers.
7. the compound or its pharmaceutically acceptable salt of any one of claim 1~2 are in terms of being used to prepare anti-tumor drug
Application.
8. the use as claimed in claim 7, the purposes in terms of being used to prepare treatment breast cancer medicines.
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| WO2019193161A1 (en) | 2018-04-06 | 2019-10-10 | Universität Wien | Bumetanide derivatives for the therapy of stroke and other neurological diseases/disorders involving nkccs |
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| EP2110374A1 (en) * | 2008-04-18 | 2009-10-21 | Merck Sante | Benzofurane, benzothiophene, benzothiazol derivatives as FXR modulators |
| GB0808282D0 (en) * | 2008-05-07 | 2008-06-11 | Medical Res Council | 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 |
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