CN105037345A - Antitumor compound as well as preparation method and application thereof - Google Patents
Antitumor compound as well as preparation method and application thereof Download PDFInfo
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- CN105037345A CN105037345A CN201510311971.2A CN201510311971A CN105037345A CN 105037345 A CN105037345 A CN 105037345A CN 201510311971 A CN201510311971 A CN 201510311971A CN 105037345 A CN105037345 A CN 105037345A
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- compound
- acceptable salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a compound with a structure shown in a formula I in the specification and antitumor effects and pharmaceutically acceptable salt thereof. In the formula I, X and Y are O, S and N; R1 and R2 are simultaneously or respectively hydrogen and C1-C4 alkyl; R3 is C1-C4 alkyl, halogen substituted C1-C4 alkyl, C1-C4 carbalkoxy, nitro, phenyl, trifluoromethyl and C1-C4 alkoxy mono-substituted, disubstituted or trisubstituted furan-2-yl, furan-3-yl, thiophene-2-yl and thiophene-3-yl simultaneously or respectively. The invention also discloses a preparation method of the compound, a drug composition with the compound or the pharmaceutically acceptable salt thereof as an active ingredient and an application of the compound, the pharmaceutically acceptable salt thereof and the drug composition as antitumor drugs, especially an application to preparation of drugs for treating lung cancers and gastric cancers.
Description
Technical field
The invention belongs to medical art, or rather, relate to class compound with antitumor action and its production and use.
Background technology
Cancer has become a large chronic disease of serious harm human health at present.Cancer of the stomach ranks first in the various malignant tumour of China, and incidence gastric cancer has obvious region difference, is evident as height in the northwest of China and coastal region in east China incidence gastric cancer rate than southern area.Send out well the age more than 50 years old, the ratio of men and women's sickness rate is 2:1.The person that has following situations should row adjuvant chemotherapy: histological type grade malignancy is high; Cancer cooktop is long-pending is greater than 5 centimetres; Multiple cancer stove; Age was lower than 40 years old.After advanced gastric carcinoma root value criterion, palliative operation, recurrence after radical operation person needs chemotherapy.Conventional chemotherapy of gastric cancer route of administration has oral administration, vein, peritoneal cavity administration, the administration of arterial cannulation regional perfusion etc.Conventional oral chemotherapeutic has Tegafur, Youfuding, Furtulon etc.Conventional intravenous chemotherapy medicine has Fluracil, mitomycin, cis-platinum, Ah mould, Etoposide, calcium leucovorin etc.The chemotherapeutics that taxol, RP-54780, topoenzyme inhibitor, xeloda etc. are new is in recent years used for cancer of the stomach, and other treatment, comprises radiotherapy, thermotherapy, immunotherapy, traditional Chinese medical herbal treatment etc.The immunotherapy of cancer of the stomach comprises non-specific biological response modifier as bacille Calmette-Guerin vaccine, lentinan etc.; Cytokine is as interleukin, Interferon, rabbit etc.; And adoptive immunotherapy is as the clinical application of killer cell after lymphocyte activator (IAK), tumor infiltrating lymphocyte (TIL) etc.Anti-angiogenetic therapy gene studies more gene therapy method, may play a role in the treatment of cancer of the stomach.
It is the fastest that lung cancer is that M & M increases, to one of population health and the maximum malignant tumour of life threat.The many countries of immediate and mid-term all report that the M & M of lung cancer all obviously increases, and male lung cancer M & M all accounts for first of all malignant tumours, and women's sickness rate accounts for second, and mortality ratio accounts for second.The cause of disease of lung cancer is still not exclusively clear and definite so far, and great mass of data shows, long-term a large amount of smoking and lung cancer have very close relationship.Existing research proves: the probability that long-term a large amount of smoker suffers from lung cancer is 10 ~ 20 times of non-smoker, and the age starting smoking is less, and the probability of suffering from lung cancer is higher.In addition, smoking not only directly affects my healthy, also produces detrimentally affect to the health of surrounding population, causes involuntary smoker's lung cancer morbidity obviously to increase.The sickness rate of city resident's lung cancer is higher than rural area, and this may be relevant containing carcinogenic substance with urban atmospheric pollution and flue dust.Therefore should advocate non-smoking, and strengthen city environmental hygiene work.Chemotherapy is the primary treatments of lung cancer, and the lung cancer of more than 90% needs to accept chemotherapeutic treatment.No matter early stage or all comparatively affirm late period chemotherapy to the curative effect of small cell lung cancer, even have an appointment 1% early stage small cell lung cancer cured by chemotherapy.Chemotherapy is also the Main Means for the treatment of nonsmall-cell lung cancer, and the Tumor response rate of chemotherapeutic treatment nonsmall-cell lung cancer is 40% ~ 50%.Chemotherapy generally can not cure nonsmall-cell lung cancer, can only extend survival of patients and quality of making the life better.Chemotherapy is divided into therapeutic chemotherapy and adjuvant chemotherapy.Chemotherapy need select different chemotherapeutics and different chemotherapy regimens according to cancerous lung tissue type difference.Chemotherapy decapacitation is killed outside tumour cell, also has infringement to human normal cell, and therefore chemotherapy needs to carry out under cancer department physician guidance.In recent years the effect of chemotherapy in lung cancer is no longer limited to inoperable Patients with Advanced Lung Cancer, and Chang Zuowei whole body therapeutic lists the comprehensive therapeutic plan of lung cancer in.Chemotherapy can suppress medulla hematopoietic system, mainly white corpuscle and hematoblastic decline, can apply granulocyte colony-stimulating factor and thrombocyte stimulating factor treating.
Though embolic chemotherapy is comparatively quick, curative ratio is very low.The many cancer therapy drugs of clinical discovery exist significantly to damage and the toxic side effect of normal body simultaneously, such as mutagenesis and genetoxic.Therefore, to find effectively and the cancer therapy drug with less body injury and toxic side effect has become the focus of new drug research.
Summary of the invention
One object of the present invention is, discloses its pharmaceutical salts of compound that a class has antitumor action.
Another object of the present invention is, discloses a class and has the compound of antitumor action and the preparation method of pharmaceutical salts thereof.
Another object of the present invention is, open have with a class pharmaceutical composition that its pharmaceutical salts of antitumor action is main active ingredient.
A further object of the invention is, discloses a class and has the application as medicine for resisting malignant tumors of the compound of antitumor action and pharmaceutical salts thereof, particularly for the preparation of the purposes in treatment lung cancer, gastric cancer medicament.
Now in conjunction with the object of the invention, content of the present invention is described in detail.
The present invention is specifically related to compound and the pharmacy acceptable salt thereof of structure shown in formula I:
Wherein:
X, Y are O, S, N;
R1, R2 are at the same time or separately: hydrogen, C
1-C
4alkyl;
R3 is: at the same time or separately by C
1-C
4alkyl, the C of halogen substiuted
1-C
4alkyl, C
1-C
4carbalkoxy, nitro, phenyl, trifluoromethyl, C
1-C
4alkoxyl group list or two or trisubstituted furans-2-base, furans-3-base, thiophene-2-base, thiene-3-yl-.
Preferred following compound and pharmacy acceptable salt thereof:
Wherein:
X is S;
Y is N:
R1, R2 are at the same time or separately: hydrogen, methyl, ethyl;
R3 is: at the same time or separately by methyl, chlorine, bromine, nitro, trifluoromethyl, methoxycarbonyl furans-2-base, furans-3-base, thiophene-2-base, thiene-3-yl-.
More preferably its pharmacy acceptable salt of following compound:
Ⅰ-1.
Ⅰ-2.
Ⅰ-3.
Ⅰ-4.
Ⅰ-5.
Ⅰ-6.
Type I compound pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.Wherein preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts.
The syntheti c route of type I compound is as follows:
X, Y, R1, R2, R3 definition as previously mentioned.
Compound (2), in aprotic solvent, with compound (3) under the catalysis of alkaline acid binding agent ,-10 ~ 30 DEG C of reactions are obtained,
Compound (2) and substituted thiophene SULPHURYL CHLORIDE (3) compounds can be bought and obtain.
Aprotic solvent is methylene dichloride, trichloromethane, acetonitrile etc.
Alkalescence acid binding agent is diisopropylethylamine, salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide or potassium tert.-butoxide etc.
The obtained various compound of reaction or products therefrom is dissolved in DMF, DMSO drip mineral acid, pharmacy acceptable salt made by organic acid.
Specifically various compound is dissolved in DMF, the one in DMSO, under ice-water bath, drips ethereal HCI to pH=2, make hydrochloride; Or the one various compound is dissolved in DMF or DMSO, mole taurine such as to add, heated and stirred obtains its taurate; Or the one be dissolved in by various compound in DMF or DMSO, drips the vitriol oil to pH=3, makes vitriol etc. under ice-water bath.
This compounds is effective for treatment human malignancies.Although compound of the present invention can without the direct administration of any preparation, described various compounds preferably use in the form of a pharmaceutical preparation, and route of administration can be parenteral route (as vein, intramuscular delivery) and oral administration.
The pharmaceutical composition of the compounds of this invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least one material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension such as injection, pulvis etc.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, usually, the weight range of active compound is 0.5% ~ 90% (weight) of composition.Another preferred scope is 0.5%-70%.
Compound or its pharmacy acceptable salt with structure shown in formula I of the present invention, has obvious restraining effect to tumour in vitro.
External antitumor action
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the cell proliferation toxicity of the human tumor cells that invention Compounds in vitro is cultivated.
(2) experiment material:
Laboratory sample: type I compound is made by oneself by contriver and provided.During experiment, sample is with DMSO hydrotropy, and plasma-free DMEM medium is diluted to desired concn, and sample segment solution is suspension.
Main agents: the packing of MTT, Amresco company, lot number: 04M0904; Complete DMEM substratum, Gibco Products, lot number: 1290007; Calf serum, Lanzhou people's marine life, lot number: 20060509; Trypsinase, the packing of Amresco company, lot number: 016B0604; Fluorouracil Injection, 0.25g/10ml (propping up), lot number: 0512022, Tianjin KingYork Amino Acid Co., Ltd..
Laboratory apparatus: Bechtop, Suzhou Decontamination Equipment Plant; CO
2incubator, Thermo company, model: HERACell150; Inverted microscope, CarlZeiss company, model: Axiovert200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
Cell strain: SPCA1 human lung adenocarcinoma cell line, SGC-7901 gastric carcinoma cells, all purchased from Shanghai cell research institute of the Chinese Academy of Sciences.
(3) experimental procedure:
Cell cultures: tumor cell inoculation containing 10% calf serum, in the DMEM nutrient solution of 100IU/ml penicillin G sodium salt and 100 μ g/ml Vetstreps, be placed in 37 DEG C, 100% relative humidity, containing 5%CO
2incubator in, go down to posterity for subsequent use after 3 times.
Mtt assay measures: the cell in vegetative period of taking the logarithm, after 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution containing 10% calf serum, single cell suspension is blown and beaten into gently, with blood cell counts plate numeration viable cell under microscope with glass dropper.(cell concn is adjusted to 6 ~ 10 × 10 to 96 well culture plate every hole inoculating cell suspension 90 μ L
4individual/ml), 37 DEG C, 100% relative humidity, containing 5%CO
2, 95% air incubator cultivate after 24h, every hole adds 10 μ L liquids (final concentration is set to: 40 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml and 2.5 μ g/ml, five concentration).In addition, each concentration establishes negative control (isoconcentration DMSO) and blank background (not adding cell), all establishes 6 multiple holes for each group.Cultured continuously 24h again, then every hole adds the MTT solution 10 μ L of 5mg/ml, after continuing to cultivate 4h, carefully sucks supernatant liquor (suspension cell needs first centrifugal, then sucks supernatant).Every hole adds 100 μ LDMSO, and put micro oscillator concussion 5min and dissolve completely to make crystallization, microplate reader 492nm Single wavelength colorimetric, measures OD value.Inhibitory rate of cell growth is calculated as evaluation index using following method.
Inhibiting rate (%)=[1-(experimental group OD average-blank group OD average)/(control group OD average-blank group OD average)] × 100%.According to inhibitory rate of cell growth, calculate IC with straight-line regression method
50value.
(4) experimental result:
To the IC of the tumour cell of vitro culture
50(μ g/ml)
(5) conclusion:
According to above-mentioned in vitro tests result, we can find out that the compound with structure shown in formula I has stronger restraining effect to above-mentioned human tumor cell.
Accompanying drawing explanation
Accompanying drawing is the general structure figure of the compound with structure shown in formula I.
Embodiment
Below in conjunction with embodiment, the present invention is described further, and embodiment is only indicative, never means that it limits the scope of the invention by any way.
The preparation of embodiment 1: I-1
In the reaction flask that stirring, condenser, thermometer are housed, add 21.59g (0.10mol) compound a and 350ml acetonitrile, stir, 0 ~ 15 DEG C, drip the mixing solutions of 23.9g4-methoxycarbonyl-5-methyl-2-furans SULPHURYL CHLORIDE (b), 61.5g (0.25mol) diisopropylethylamine and 150ml acetonitrile, after dropwising, back flow reaction 2h, TLC display reacts completely, solvent evaporated, residue silicagel column is separated (petroleum ether-ethyl acetate=7:3), obtains faint yellow solid, yield 44.8%, m/z:421.08.
Get chemical compounds I-1 solid 3.0g, be dissolved in 10mlDMSO.Ice-water bath is cooled to 0 DEG C, and dripping ethereal HCI solution is 2 to pH, continues at stir about 1h under ice-water bath.Filter, vacuum-drying, obtains white solid powder, i.e. the hydrochloride of I-1.
With reference to the method for embodiment 1, can synthetic compound I-2 ~ I-6.
The preparation of embodiment 2: I-2
By the method preparation that embodiment 1 is similar, change 4-methoxycarbonyl-5-methyl-2-furans SULPHURYL CHLORIDE into 5-methoxycarbonyl-2-furans SULPHURYL CHLORIDE.
Faint yellow solid, yield 49.6%, m/z:407.06.
The preparation of embodiment 3: I-3
By the method preparation that embodiment 1 is similar, change 4-methoxycarbonyl-5-methyl-2-furans SULPHURYL CHLORIDE into 2,5-methyl-3-furans SULPHURYL CHLORIDE.
Faint yellow solid, yield 51.9%, m/z:377.09.
The preparation of embodiment 4: I-4
By the method preparation that embodiment 1 is similar, change 4-methoxycarbonyl-5-methyl-2-furans SULPHURYL CHLORIDE into 2-trifluoromethyl-5-methyl-3-furans SULPHURYL CHLORIDE.
Faint yellow solid, yield 55.4%, m/z:435.09.
Get I-4 solid 3.8g, be dissolved in 30mLDMF.To add etc. mole p-methyl benzenesulfonic acid after being heated to backflow, continue at stirred at reflux and react about 1h.React complete, in left at room temperature 2h.Separate out white crystals, filter, vacuum-drying, obtains the toluenesulfonate of I-4.
The preparation of embodiment 5: I-5
By the method preparation that embodiment 1 is similar, change 4-methoxycarbonyl-5-methyl-2-furans SULPHURYL CHLORIDE into the chloro-4-nitro of 2,5-bis--3-thiophenesulfonyl chloride.
Yellow solid, yield 50.9%, m/z:477.94.
The preparation of embodiment 6: I-6
By the method preparation that embodiment 1 is similar, change 4-methoxycarbonyl-5-methyl-2-furans SULPHURYL CHLORIDE into 5-chloro-2-thiophenesulfonyl chloride.
Yellow solid, yield 49.1%, m/z:398.99.
In order to the pharmaceutical composition of the compound containing benzazepine of the present invention is described more fully, provide following example of formulations below, described embodiment only for illustration of, instead of for limiting the scope of the invention.Described preparation can use any active compound in the compounds of this invention and salt thereof.
embodiment 7:
Hard gelatin capsule is prepared by following compositions:
Preparation technology: supplementary material is dry in advance, crosses 100 mesh sieves for subsequent use.After mentioned component being mixed by recipe quantity, be packed in hard gelatin capsule.
embodiment 8:
Tablet is prepared by following compositions:
Preparation technology: supplementary material is dry in advance, crosses 100 mesh sieves for subsequent use.First the auxiliary material of recipe quantity is fully mixed.Be added in auxiliary material by bulk drug to increase progressively dilution method, each added-time fully mixes 2-3 time, ensures that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 DEG C of ventilated drying ovens, dry particle crosses the whole grain of 16 mesh sieve, measure intermediates content, mix, compressing tablet on tabletting machine.
embodiment 9:
The preparation of injection lyophilized powder:
The hydrochloride 50mg of chemical compounds I-1
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, makes it dissolve by medicinal basic adjust ph to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving, add gac by the requirement of injection, adopt filtering with microporous membrane, filtrate carries out packing, adopts freeze-drying, and obtained loose block, sealing, to obtain final product.
Claims (7)
1. there is compound or its pharmacy acceptable salt of structure shown in formula I:
Wherein:
X, Y are O, S, N;
R1, R2 are at the same time or separately: hydrogen, C
1-C
4alkyl;
R3 is: at the same time or separately by C
1-C
4alkyl, the C of halogen substiuted
1-C
4alkyl, C
1-C
4carbalkoxy, nitro, phenyl, trifluoromethyl, C
1-C
4alkoxyl group list or two or trisubstituted furans-2-base, furans-3-base, thiophene-2-base, thiene-3-yl-.
2. have compound or its pharmacy acceptable salt of structure shown in formula I, described compound is:
3. type I compound as claimed in claim 1 or its pharmacy acceptable salt, its pharmacy acceptable salt is: formula I and mineral acid, organic acid salify.
4. formula I as claimed in claim 3 or its pharmacy acceptable salt, its pharmacy acceptable salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, butyrates, lactic acid salt, mesylate, tosilate.
5. the preparation method of type I compound in claim 1, is characterized in that: compound (2), and in aprotic solvent, with compound (3) under the catalysis of alkaline acid binding agent ,-10 ~ 30 DEG C of reactions are obtained,
X, Y, R1, R2, R3 definition as previously mentioned.
6. an antitumor medicine composition, it comprises the compound of any one of claim 1 ~ 2 for the treatment of significant quantity or its pharmacy acceptable salt and one or more pharmaceutical carriers.
7. the compound of any one of claim 1 ~ 2 or its pharmacy acceptable salt are for the preparation of the application in antitumor drug.
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|---|---|---|---|
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| Publication Number | Publication Date |
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| CN105037345B CN105037345B (en) | 2019-01-25 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357842A (en) * | 2019-08-27 | 2019-10-22 | 南京工业大学 | A kind of fluoroalkyl substituted furan class compound and preparation method thereof |
Citations (4)
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|---|---|---|---|---|
| WO2008061109A2 (en) * | 2006-11-15 | 2008-05-22 | Forest Laboratories Holdings Limited | Indazole derivatives useful as melanin concentrating receptor ligands |
| WO2011130628A1 (en) * | 2010-04-16 | 2011-10-20 | Curis, Inc. | Treatment of cancers having k-ras mutations |
| CN102341108A (en) * | 2009-01-08 | 2012-02-01 | 柯瑞斯公司 | Phosphoinositide 3-kinase inhibitors with zinc binding moiety |
| WO2013090227A1 (en) * | 2011-12-12 | 2013-06-20 | Allergan, Inc. | Benzisothiazol-3(1h)-one-5-sulfonyl derivatives as chemokine receptor modulators |
-
2015
- 2015-06-09 CN CN201510311971.2A patent/CN105037345B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008061109A2 (en) * | 2006-11-15 | 2008-05-22 | Forest Laboratories Holdings Limited | Indazole derivatives useful as melanin concentrating receptor ligands |
| CN102341108A (en) * | 2009-01-08 | 2012-02-01 | 柯瑞斯公司 | Phosphoinositide 3-kinase inhibitors with zinc binding moiety |
| WO2011130628A1 (en) * | 2010-04-16 | 2011-10-20 | Curis, Inc. | Treatment of cancers having k-ras mutations |
| WO2013090227A1 (en) * | 2011-12-12 | 2013-06-20 | Allergan, Inc. | Benzisothiazol-3(1h)-one-5-sulfonyl derivatives as chemokine receptor modulators |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357842A (en) * | 2019-08-27 | 2019-10-22 | 南京工业大学 | A kind of fluoroalkyl substituted furan class compound and preparation method thereof |
| CN110357842B (en) * | 2019-08-27 | 2022-12-16 | 南京工业大学 | Fluoroalkyl substituted furan compound and preparation method thereof |
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Granted publication date: 20190125 Termination date: 20190609 |