CN100455575C - Isoselenothiazolidone compound and its complex and use thereof - Google Patents
Isoselenothiazolidone compound and its complex and use thereof Download PDFInfo
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- CN100455575C CN100455575C CNB2004100426180A CN200410042618A CN100455575C CN 100455575 C CN100455575 C CN 100455575C CN B2004100426180 A CNB2004100426180 A CN B2004100426180A CN 200410042618 A CN200410042618 A CN 200410042618A CN 100455575 C CN100455575 C CN 100455575C
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- 229910052714 tellurium Inorganic materials 0.000 claims description 11
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 claims description 11
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses new compounds, coordination compound derivatives and applications in anti-tumor medicines thereof and a method for synthesizing the compounds, and the compounds takes isoselenothiazolidone as core structures. Proved by in-vivo and in-vitro tests of animals, the compounds have anti-tumor pharmacological action, which forebodes the applications of the compounds in the preparation of the anti-tumor medicines.
Description
Technical field
The present invention relates to sulfinpyrazone compound and synthetic method thereof, relate in particular to Benzisoelenazolone compounds and its title complex and the application in the preparation antitumor drug thereof, and the method for preparing this compounds.
Background technology
Nearly two during the last ten years, and the biological function of selenium extensively is familiar with by people, and along with deepening continuously that selenium is familiar with, medicinal absorption, distribution and the drug effect of the selenium compound of different structure form and toxicity characteristicness are revealed comparatively clear.Many active selenium compound researchs have obtained a series of important breakthrough and progress, and wherein feature and the widely pharmacological action thereof of organic selenium compounds aspect life science comes into one's own day by day.Studies show that organic selenium compounds has tangible effect in anti-inflammatory, anti-oxidant, antitumor and treatment aspect the cardiovascular and cerebrovascular diseases, and can regulate immunity system.Representational medicine has ebselen (Ebselen), and this medicine has entered the clinical study stage at present as medicine.
Ebselen, it is 2-phenyl-1,2-benzisoxa selenazoles-3 (2H)-ketone (INN:Ebselen), it is the anti-inflammatory new drug in the external exploitation, be characterized in low toxicity and have pharmacologically active widely, for the treatment of active oxygen relative disease provides up-and-coming means, and showed wide prospect for the development of organoselenium medicine.Along with further investigation, be that the multiple compound of core texture is synthesized out successively with the Benzisoelenazolone, and its pharmacologically active also obtain broad research at the Ebselen medicine.But up to now, the application that is used for preparing antitumor drug of relevant Benzisoelenazolone still rarely has and sets foot in.
Summary of the invention
The object of the invention one provides the Benzisoelenazolone compounds that a class has anti-tumor activity.Described Benzisoelenazolone compounds has the structure of following general formula (I) or general formula (II):
Wherein, M=Se or Te, R=H, Na or C
1-6Alkyl.
Wherein Y=Pt or Pd, X=Se or Te.
Another object of the present invention is to provide the method for compound shown in preparation above-mentioned general formula (I) and the general formula (II).
Prepare the method for compound shown in the general formula (I), mainly may further comprise the steps:
1) after anthranilic acid and hydrochloric acid mix under cryosel is bathed, after wherein add sodium nitrite solution, reaction is finished that products therefrom is standby;
2) selenium powder and sodium hydroxide water-soluble after, add V-Brite B to it, after reaction is finished that products therefrom is standby;
3) product with the step 1) gained is added drop-wise to step 2) in the product of gained, the mixture stirring has been arranged until the nitrogen that produces,, filtered again with the reaction mixture hcl acidifying, and the precipitation that will filter gained washes in the rearmounted moisture eliminator dryly, and the product of gained is standby;
4) product with the step 3) gained is suspended in sulfur oxychloride, tetrahydrofuran (THF) or the ethanol, the dimethyl formamide that adds catalytic amount, stirring and refluxing, rotary evaporation is removed unnecessary thionyl chloride, residue normal hexane, sherwood oil or ether recrystallization, the crystal of gained is standby;
5) crystal with the step 4) gained is dissolved in the acetonitrile, and ice bath is cooled to below 5 ℃, drips 25% ammoniacal liquor, is warming up to 10-25 ℃ after regulating pH value, and continues reaction, filter, and water washing and precipitating, standby after placing baking oven dry the water-fast part;
6) product and the water of step 5) gained are pressed 3g: the mixed of 50ml, the mol ratio that stirs down by 1: 1 drips 0.1mol/L NaOH solution, after product is dissolved gradually, after insoluble part filtered out, at 45 ℃ of following evaporate to dryness water, obtains product.
Prepare the another kind of method of above-mentioned general formula (I) compound, mainly may further comprise the steps:
1) under nitrogen protection and condition of ice bath, be dissolved in benzamide in the anhydrous tetrahydro furan after, splash into n-butyllithium solution;
2) in the reaction solution of step 1) gained, add the tellurium powder, continue to stir 0.5-1 hour, be cooled to reaction solution below 0 ℃ and add CuBr
2, after stirring for some time under-40 ℃ of cold condition, at room temperature continue to stir, at last reaction solution is poured in the acetum, filter, the gained filter cake is preserved standby;
3) with step 2) filter cake and the water of gained presses 3g: the mixed of 50ml, the mol ratio that stirs down by 1: 1 drips 0.1mol/L NaOH solution, and product dissolves gradually, after insoluble part is filtered out, at 45 ℃ of following evaporate to dryness water, obtains product.
Prepare the method for above-mentioned general formula (II) compound, mainly may further comprise the steps:
1) with 1,2-Benzisoelenazolone sodium or 1,2-benzisoxa tellurium oxazolone sodium and (DACH) PtCl
2Or (DACH) PdCl
2Be suspended in the methyl alcohol backflow 1-3 hour;
2) in the described reaction solution of step 1), add entry, after waiting to precipitate generation, filter, water, each washing leaching cake several of ether, dry cake is promptly.
Another object of the present invention is to provide a kind of pharmaceutical composition with anti-tumor activity.This pharmaceutical composition is formed by the compound and the cooperation of pharmaceutically acceptable carrier of structure shown in general formula (I) or the general formula (II), the compound that is about to structure shown in the general formula (I) of pharmaceutically acceptable consumption and the general formula (II) is with after pharmaceutically acceptable carrier cooperates, and by the formulation method of this area routine it is prepared into any one appropriate drug composition.
Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication, for example percutaneous dosing.
Said composition can be liquid preparation forms such as tablet, capsule, pulvis, particle, lozenge, suppository, or oral liquid or aseptic parenteral suspension.
Said composition can be big or dosage forms such as small-volume injection, freeze-dried powder, aseptic powder packing.
In order to reach the consistence of administration, the present composition is preferably single agent form.
The single agent form that is used for oral administration can be tablet and capsule, and can contain conventional excipients such as tackiness agent, for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth or polyvinylpyrrolidone; Weighting agent, for example lactose, sugar, W-Gum, calcium phosphate, sorbyl alcohol or glycine; Compressing tablet lubricant, for example Magnesium Stearate; Disintegrating agent, for example starch, polyvinylpyrrolidone, Explotab or Microcrystalline Cellulose; Or pharmaceutically acceptable wetting agent, such as sodium lauryl sulphate.
Solid oral composition can prepare with conventional mixing, filling or pressed disc method.Repeating married operation can be used for promoting agent fully is distributed to the composition that uses a large amount of filling doses.Conventional in such operation yes this area.Tablet can make coating tablet or plain sheet according to conventional preparation method.
Oral liquid can be the form of example emulsion, syrup or elixir, perhaps can be used as drying products and exists, and water or other suitable carriers reconstitute again before the use.This liquid preparation can contain conventional additives, such as suspension agent, and for example sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat; Emulsifying agent, for example Yelkin TTS, anhydro sorbitol-oleic acid ester or gum arabic; Anhydrous carrier (can comprise edible oil), for example Prunus amygdalus oil, heating up in a steamer Oleum Cocois or oily ester, described oily ester comprises glyceryl ester, propylene glycol or ethanol; Sanitas, for example methyl p-hydroxybenzoate or propyl ester or Sorbic Acid; If desired, also can add conventional seasonings or tinting material.
For parenteral admin, particularly injection can utilize two kinds of active ingredients to prepare the unit liquid dosage form with sterile carrier respectively, and according to used concentration it is suspended in the carrier.Auxiliary such as local anesthetic, sanitas and buffer reagent can be dissolved in this carrier.For enhanced stability, recharge in the bottle after can be with said composition freezing, and under vacuum, remove moisture.The parenteral suspension is to prepare and get with identical in fact mode, and active ingredient can be by with after oxyethane contacts, and resuspending is in sterile carrier and sterilize.Advantageously, in said composition, comprise tensio-active agent or wetting agent to promote this compound uniform distribution.
In addition, also can pharmaceutical composition be made sustained-release preparation, as sustained release pellet or controlled release micro pill according to ordinary method.
According to different medications, composition can contain 0.1%-99% weight, the active substance of preferred 10-60% weight.
The series compound that the present invention prepares gained has significant antitumor efficacy through the pharmacology test proof, indicates that this compounds is having a wide range of applications aspect the medicine of preparation prevention, all kinds of tumours of treatment.
Embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
[embodiment 1] 1, the preparation of 2-benzisoxa selenazoles-3 (2H)-ketone (hereinafter to be referred as Eb-N)
1, the preparation of chlorination 2-phenylformic acid diazonium salt
Precision takes by weighing the 14.0g anthranilic acid, with itself and 40ml concentration is that 1: 1 hydrochloric acid mixes under condition of ice bath, then, slowly splashes into the solution that the 9.0g Sodium Nitrite is dissolved in 20ml water therein, drip off the back and continue reaction 2 hours, it is standby to obtain chlorination 2-phenylformic acid diazonium salt.
2, the preparation of two sodium selenides
In the deionized water of 60ml, add 8.8g selenium powder and 4.4g sodium hydroxide, under agitation condition, slowly add the 8.8g V-Brite B, continue reaction 2-4 hour, obtain two sodium selenide solution for standby.
3,2, the two benzoic preparations of 2 '-two selenizings
Under agitation condition, the chlorination 2-phenylformic acid diazonium salt solution of step 1 gained is added drop-wise in the two sodium selenide solution of step 2 gained, continued stirring reaction 2 hours, arrange up to the nitrogen that produces, and proved that through litmus paper solution is alkaline.With the reaction mixture hcl acidifying of gained, filter again, the precipitation of gained is washed in the rearmounted moisture eliminator be drying to obtain.Its productive rate is 90%.The fusing point (m.p.) of the recrystallization body of products therefrom is 294 ℃.
1H-NMR (300MHz, DMSO-d
6) δ: 7.33-8.04 (m, 4H, ph-H) 13.6 (br, COOH) IR (KBr) cm
-1: M (O-H) 3005, M (CO
2) 1672, M (C-N) 1264, MC=C (phenyl ring) 1560,1460,1417; MS-FAB (m/z): 201[1/2M
+] (Se-Se bond rupture).
4, the preparation of 2-selenium chloro-benzoyl chloride
With 2 of 40.0g, the two phenylformic acid of 2 '-two selenizings and 200ml sulfur oxychloride, 0.15ml concentration are after the DMF of 1.8mmol mixes, stirring and refluxing 3 hours, and rotary evaporation is removed unnecessary thionyl chloride, residue normal hexane recrystallization promptly gets the pure product of 2-selenium chloro-benzoyl chloride.Its productive rate is 90%.Fusing point (m.p.) is 66 ℃.
1H-NMR (300MHz, DMSO-d
6) δ: 7.33-8.16 (m, 4H, ph-H) IR (KBr) cm
-1M (COCl): 1641, MC=C (phenyl ring): 1581,1545,1432
MS-FAB(m/z)：253。
5,1, the preparation of 2-benzisoxa selenazoles-3 (2H)-ketone
The 2-selenium chloro-benzoyl chloride of 0.84g is dissolved in the 20ml acetonitrile, reacts under condition of ice bath, and drip 25% ammoniacal liquor under agitation condition, visible a large amount of precipitations generate, and are about 8 until the pH of reaction soln value.Reaction soln is risen to room temperature, continue reaction 2 hours, filter, be dried after the water washing and precipitating, promptly get product.Its productive rate is 44%, m.p.200-201 ℃.
1H-NMR:(300MHz, DMSO-d
6) δ 7.32-8.09 (m, Ph-H), 3.99 (s, 2H, CH
2); IR (KBr) cm
-1M (N-H): 3054, MC=C (phenyl ring): 1595,1558,1441; Ultimate analysis: C
7H
5NOSe calculated value (%): C42.44, H2.54N7.07, measured value (%): C42.57H2.74N7.20; MS-FAB (m/z): 200[M+1].
[embodiment 2] 1, the preparation of 2-Benzisoelenazolone sodium
With 1 of embodiment 1 preparation gained, 2-benzisoxa selenazoles-3 (2H)-ketone recrystallization, in the recrystallization thing of gained, add 50ml water again, and under agitation condition, drip the NaOH solution of 0.1mol/L, product is dissolved gradually, remove by filter insoluble part, gained filtrate 45 ℃ of following evaporating water promptly.
[embodiment 3] 1, the preparation of 2-Benzisoelenazolone platinum complex
With (DACH) PtCl
2With excessive 1,2-benzisoxa selenazoles-3 (2H)-ketone is suspended in the methyl alcohol, after backflow 1-3 hour, to wherein adding entry, treat that the adularescent precipitation generates after, filter, water, each washing leaching cake of ether for several times, after the drying promptly.
[embodiment 4] 1, the preparation of 2-Benzisoelenazolone palladium complex
With (DACH) PdCl
2With excessive 1,2-benzisoxa selenazoles-3 (2H)-ketone is suspended in the methyl alcohol, after backflow 1-3 hour, again to wherein adding entry, wait the adularescent precipitation to generate after, filter, water, each washing leaching cake of ether for several times, after the drying promptly.
[embodiment 5] 1, the preparation of 2-benzisoxa tellurium oxazolone (hereinafter to be referred as ET-N)
Under nitrogen protection and condition of ice bath, benzamide is dissolved in the anhydrous tetrahydro furan, and under agitation condition, splashes into n-butyllithium solution in mixing solutions; continue reaction after 0.5 hour, add the tellurium powder again, solution is brownish black; continue to stir 0.5-1 hour, be cooled to about-40 ℃, add CuBr
2, after stirring 0.5 hour under this temperature, at room temperature continue again to stir 2 hours.Reaction solution poured in 2% the acetum, crosses the leaching precipitation, after the drying product.
[embodiment 6] 1, the preparation of 2-benzisoxa tellurium oxazolone sodium
With embodiment 5 preparations 1,2-benzisoxa tellurium oxazolone recrystallization adds 50ml water again in the recrystallization thing of gained, and under agitation condition, drip 0.1mol/L NaOH solution, product is dissolved gradually, remove by filter insoluble part, gained filtrate is promptly got required compound 45 ℃ of following evaporating water.
[embodiment 7] 1, the preparation of 2-benzisoxa tellurium oxazolone platinum complex
With (DACH) PtCl
2With excessive 1, being suspended in the methyl alcohol of 2-benzisoxa tellurium oxazolone refluxed 1 hour, added entry more therein, wait the adularescent precipitation to generate after, filter, water, each washing leaching cake of ether is drying to obtain for several times.
[embodiment 8] 1, the preparation of 2-benzisoxa tellurium oxazolone palladium complex
(DACH) PdCl
2With excessive 1, being suspended in the methyl alcohol of 2-benzisoxa tellurium oxazolone refluxed 1 hour, added entry more therein, wait the adularescent precipitation to generate after, filter, water, each washing leaching cake of ether is drying to obtain for several times.
The anti-tumor activity of [test example 1] in vitro study The compounds of this invention
One, test materials
1, for the reagent thing: the Eb-N and the ET-N that prepare gained because of embodiment 1,5 are pale yellow powder, be insoluble in water, with the RPMI-1640 nutrient solution that contains 15% calf serum is the medicine to be measured (Eb-N or ET-N) of 100 μ mol/L with initial concentration, and then the soup to be measured of above-mentioned concentration is diluted to desired concn, promptly obtain the soup to be measured that final concentration is respectively 50,20,10,5,1 μ mol/L.
2, positive control drug: cis-platinum (DDP) obtains from the purchase of common pharmacy.Use physiological saline solution, and be the contrast soup that concentration is respectively 5,2.5,1.25 and 0.625 μ g/ml with its dilution with physiological saline.
3, experiment in vitro knurl strain Bel-7742 is provided by Department Of Medicine, Peking University National Key Laboratory, cultivates with the RPMI-1640 nutrient solution that contains 10% calf serum.
Two, test method
Tumor line Bel-7742 adds soup to be measured or contrast soup after using the RPMI-1640 nutrient solution cultivation 24h that contains 10% calf serum adherent then in each cell hole, medicine dosing 6 holes of every kind of concentration, and other establishes 6 holes, blank hole.
Cultivated respectively after the cell dosing 24,48 and 72 hours, and in each hole, added tetrazolium bromide (MTT) liquid, after 1 hour, add dimethyl sulfoxide (DMSO) (DMSO) colour developing, on BIO-RED 550 type microplate reader, survey its OD490 value, calculate the kill rate of each concentration medicine, and ask its IC with the Bliss method
50Value.
Three, experimental result is referring to table 1 and table 2.
Table 1Eb-N is to the growth-inhibiting effect of liver cancer cell (Bel-7742)
Table 2ET-N is to the growth-inhibiting effect of liver cancer cell (Bel-7742) cell
Conclusion: in vitro tests is the result show, Eb-N and ET-N can significantly suppress the growth of tumour cell Bel-7742, and its growth-inhibiting effect exists tangible dose-effect and time-effect relationship, shows that The compounds of this invention has notable antitumor activity.
The anti-tumor activity of research The compounds of this invention in [test example 2] body
One, test materials
1, for the reagent thing: be mixed with the solution to be measured of desired concn because of the Eb-N of embodiment 1,5 preparation gained and ET-N suspend with 1% Xylo-Mucine (CMC-Na) solution, place 4 ℃ of refrigerators preservations standby then.
2, positive control drug: endoxan (CTX) powder injection, Hualian Pharmaceutical Co., Ltd., Shanghai produces, and faces with before making normal saline solution.
3, laboratory animal: ICR kind mouse, C57BL/6 mouse (SPF level), body weight 18-22g, female, hero has concurrently, all available from Beijing dimension tonneau China laboratory animal company limited, animal production licence numbering: SCXK (capital) 2002-0003.Raise in the experimentation on animals of the SPF of The People's Hospital of Peking University level indoor, credit number: SYXK 11-00-0001.10/cage of mouse, ad lib drinking-water.
4, knurl strain: rat liver cancer (H
22) for this laboratory in the ascitic type knurl strain that Kunming mouse goes down to posterity and protects kind, extract the 7th day cancer ascites during experiment, be diluted to tumor cell suspension through physiological saline by 1: 3, for inoculating the mouse use.
Two, experimental technique
50 of ICR mouse are chosen in experiment, and male and female half and half, body weight are 18-22g.In right armpit subcutaneous vaccination H
22Tumor cell suspension 0.2ml/ only.After the inoculation mouse is divided into 5 groups at random, 10 every group.Next day, according to trial test administration as a result, the middle dosage group of setting for reagent thing Eb-N, ET-N is: the 120mg/kg body weight, and every day, gastric infusion was 1 time, and continuous 7 days, each administration capacity was the 0.2ml/10g body weight.Negative control group waits capacity physiological saline.1 subcutaneous injection of positive controls gives endoxan 60mg/kg body weight.Next day after the last administration, disconnected neck is put to death animal, weighs, and cuts solid tumor, claims knurl heavy, asks tumour inhibiting rate by following formula.
More than test equal triplicate, each is organized experimental result and carries out statistical procedures (t check).
Three, test-results is referring to table 3.
Table 3Eb-N and ET-N in the mouse body to H
22The growth of tumor restraining effect
Conclusion: in vivo test is the result show, Eb-N and ET-N are to H in the mouse body
22Growth of tumor has remarkable restraining effect, shows that The compounds of this invention has significant anti-tumor in vivo activity.
Claims (6)
1, the compound of following general formula (II) structure:
2, a kind of method for preparing the described general formula of claim 1 (II) compound mainly may further comprise the steps:
1) with 1,2-Benzisoelenazolone sodium or 1,2-benzisoxa tellurium oxazolone sodium and (DACH) PtCl2 or (DACH) PdCl2 be suspended in the pure reagent backflow 1-3 hour;
2) in the described reaction solution of step 1), add entry, after waiting to precipitate generation, filter, water, each washing leaching cake several of ether, dry cake is promptly.
3, a kind of pharmaceutical composition with anti-tumor activity is formed by the described general formula of claim 1 (II) compound and the cooperation of pharmaceutically acceptable carrier.
4, pharmaceutical composition according to claim 3, the dosage form of described composition are selected from tablet, capsule, pulvis, particle, lozenge, suppository, oral liquid, aseptic parenteral suspension liquid preparation, big or small-volume injection, lyophilized injectable powder or aseptic subpackaged dose.
5, the purposes of the described general formula of claim 1 (II) compound in the preparation antitumor drug.
6, application according to claim 5, described tumour are solid tumor.
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| CN100554255C (en) * | 2004-05-31 | 2009-10-28 | 北京大学 | Benzisoelenazolone derivative and preparation method thereof and application |
| CN102399214A (en) * | 2011-12-12 | 2012-04-04 | 天津理工大学 | Preparation method for 2-(2-substituted-1,3,4-oxadiazole-5-group)-benzisoselenazolone derivative |
| CN105277699B (en) * | 2014-07-21 | 2017-05-03 | 武汉尚宜康健科技有限公司 | Application of detection reagent in preparation of drugs for evaluation of clinical tumor patient clinical treatment monitoring |
| CN112724104B (en) * | 2020-12-24 | 2022-06-07 | 石家庄学院 | Selenium-containing melphalan derivative and preparation method and application thereof |
| CN115260260B (en) * | 2021-04-29 | 2024-08-09 | 杭州健昵福生物科技有限公司 | Selenium-containing ribose compound with KGA inhibition activity and application of synthesis method thereof |
| CN114891044B (en) * | 2022-06-13 | 2024-04-19 | 南京迈金生物科技有限公司 | Tetravalent platinum complex with anti-tumor activity and preparation method and application thereof |
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|---|---|---|---|---|
| DE3027074A1 (en) * | 1980-07-17 | 1982-02-18 | A. Nattermann & Cie GmbH, 5000 Köln | Benz-iso selenazolone derivs. as antiinflammatories - esp. for treating rheumatic illnesses, causing no ulcer formation or gastrointestinal irritation |
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2004
- 2004-05-27 CN CNB2004100426180A patent/CN100455575C/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3027074A1 (en) * | 1980-07-17 | 1982-02-18 | A. Nattermann & Cie GmbH, 5000 Köln | Benz-iso selenazolone derivs. as antiinflammatories - esp. for treating rheumatic illnesses, causing no ulcer formation or gastrointestinal irritation |
Non-Patent Citations (2)
| Title |
|---|
| Reactivity of Ebtellur Derivatives with the Peroxynitrite Anion:Comparison with their Ebselen Analogues. Y.Sakimoto et al.J.Phys.Chem.A,Vol.107 . 2003 |
| Reactivity of Ebtellur Derivatives with the Peroxynitrite Anion:Comparison with their Ebselen Analogues. Y.Sakimoto et al.J.Phys.Chem.A,Vol.107 . 2003 * |
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