CN101016319B - Benzoisoselenothiazolidone aminosugar derivative, preparing method and application therheof - Google Patents
Benzoisoselenothiazolidone aminosugar derivative, preparing method and application therheof Download PDFInfo
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- CN101016319B CN101016319B CN2007100133376A CN200710013337A CN101016319B CN 101016319 B CN101016319 B CN 101016319B CN 2007100133376 A CN2007100133376 A CN 2007100133376A CN 200710013337 A CN200710013337 A CN 200710013337A CN 101016319 B CN101016319 B CN 101016319B
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Abstract
The invention discloses a making method and application of benzo isoselenazole aminosugar derivant with tumour resistance, which comprises the following steps: reacting 2-aminosurgar protected by hydroxy and amino acid protected by benzyl oxylcarbonyl group catalyzed by DCC; reducing reactant through hydrogen catalyzed by palladium carbon to remove benzyl oxylcarbonyl group; or reacting 2-aminosurgar protected by hydroxy and 2-cholbenzoyl chloride selenide catalyzed by trimethylamine directly.
Description
Invention field
The present invention relates to a kind of Benzisoelenazolone aminosaccharide derivative and its production and application with antitumor action.
Background technology
In the last thirty years, the biochemical research of selenium obtains a series of important breakthrough and progress, studies show that, organic selenium compounds anti-inflammatory, anti-oxidant, antitumor and the treatment cardiovascular disorder tangible effect is arranged, make the research that contains the selenium medicine be subjected to paying attention to widely and attracting attention, developed a series of active organic selenium compounds of good biological that have in succession, it is clinical that representational organoselenium medicine ebselen woods (Ebselen) entered for three phases.This ebselen is a 2-phenyl-1,2-benzisoxa selenazoles-3 (2H)-ketone, it is the anti-inflammatory new drug of external exploitation, be characterized in low toxicity and have pharmacologically active widely, for the treatment with the active oxygen relative disease provides up-and-coming means, and opened up space widely for the development of organoselenium medicine.The ebselen analogue that with the Benzisoelenazolone is core in recent years is synthesized successively and studies, and showed good activity, but all do not obtaining tangible progress aspect the reduction toxicity, this has become a major issue that limits this compounds Application and Development, so by all means, comprise bio-transformation and change method such as chemical structure, obtain low toxicity, organic selenium compounds is the organic chemistry and pharmaceutical chemical key subjects of selenium efficiently.
Summary of the invention
The purpose of this invention is to provide a kind of Benzisoelenazolone amino sugar derivative and its production and application, to remedy the above-mentioned deficiency of prior art with antitumor action.
A kind of Benzisoelenazolone amino sugar derivative is characterized in that its structural formula is:
R in the formula
3Be respectively no linking group ,-CH
2CONH-,-(CH
2)
2CONH-,-(CH
2)
3(CH
2)
2CONH-,-(CHCH
3) CONH-or-C
6H
4During CONH-, R
4During=-OAc, R
5=-OAc, R
6=-H; R
4During=-OAc, R
5=-H, R
6=-OAc; R
4During=-OBn, R
5=-H, R
6=-OBn; R
4During=-OBn, R
5=-OBn, R
6=-H; R
4R during=-OBz
5=-H, R
6=-Obz; R
4During=-OBz, R
5=-OBz, R
6=-H.
The preparation method of above-mentioned Benzisoelenazolone amino sugar derivative, it is characterized in that making the 2-aminosugar of hydroxyl protection and the amino acid of carbobenzoxy-(Cbz) protection under DCC catalysis, to react, reaction product removes carbobenzoxy-(Cbz) with hydrogen reducing again under the catalysis of palladium carbon, generate the sugared amide derivatives of hydroxyl protection, this derivative reacts with 2-chlorine seleno Benzoyl chloride under triethylamine catalysis; Or the 2-aminosugar that makes hydroxyl protection is direct and 2-chlorine seleno Benzoyl chloride reacts under the catalysis of triethylamine.
The application of above-mentioned Benzisoelenazolone amino sugar derivative in the preparation antitumor drug.
Benzisoelenazolone amino sugar derivative of the present invention is simple in structure, and is synthetic convenient, has significant antitumor efficacy, so this compounds is having broad application prospect aspect the medicine of prevention or treatment tumour.
Embodiment
Aminosugar compound such as D-2-glucosamine and D-2-galn are an important monose of higher animal glycoprotein chains, almost be distributed in human body institute in a organized way, have multiple biological activity, particularly tumour cell is had lethal effect preferably, and very little to human normal cell's toxicity.The present invention modifies the Benzisoelenazolone compound with amino sugar derivative, is intended to obtain Benzisoelenazolone amino sugar derivative of the present invention.
Embodiment 1
Benzisoelenazolone amino sugar derivative 2-(1 ', 3 ', 4 ', 6 '-four-O-benzoyl-2 '-deoxidation-β-D-glucopyranosyl)-(1,2-d)-preparation of benzisoxa selenazoles-3 (2H)-ketone
1, the preparation of 2-chlorine seleno Benzoyl chloride
I) preparation of chlorination 2-phenylformic acid diazonium salt
Add anthranilic acid 28g (0.21mol), water 40ml, concentrated hydrochloric acid 40ml in 500mL eggplant type bottle, ice-water bath is cooled to 0 ℃, fully stirs slowly to drip sodium nitrite in aqueous solution down, and volume is 32ml, and concentration is 6.25mol/L.Temperature is controlled at 0～5 ℃, reacts 1 hour, and it is standby to get chlorination 2-phenylformic acid diazonium salt solution.
The ii) preparation of two sodium selenides
Under protection of nitrogen gas, take by weighing selenium powder 16g (0.21mol) and cetyl trimethylammonium bromide 400mg (1.1mmol) puts into the 500ml there-necked flask, and add the aqueous solution 100ml (concentration is 2mol/L) of NaOH with dropping funnel.Take by weighing NaOH solid 0.8g (20mmol), the ice bath cooling adds NaBH down
4Lg (26mmol) uses the 20ml water dissolution.Slowly drip the NaBH of above-mentioned preparation with dropping funnel
4-NaOH the aqueous solution and at room temperature stirred 1 hour in the Se-NaOH solution of above-mentioned preparation, be warmed up to 90 ℃ then and continue to stir half an hour, two sodium selenide solution for standby.
The iii) two benzoic preparations of 2,2 '-two selenizings
Under agitation condition, above-mentioned gained chlorination 2-phenylformic acid diazonium salt solution slowly is added drop-wise in the two sodium selenide solution, be heated to 40 ℃ of reactions 2 hours.Reaction finishes after-filtration.The hcl acidifying that filtrate adds 6mol/L occurs muddy.Filter, filter cake washes with water, and drying gets the khaki color solid, yield 80%, m.p.295-296 ℃.
IV) preparation of 2-chlorine seleno Benzoyl chloride
Get the two phenylformic acid 20g (50mmol) of above-mentioned 2,2 '-two selenizings and sulfur oxychloride 80mL reflux 3 hours in 200ml eggplant type bottle, underpressure distillation boils off unreacted sulfur oxychloride.Extract with anhydrous n-hexane, the gained solid is used the ether dissolution recrystallization again, gets faint yellow solid, is 2-chlorine seleno Benzoyl chloride, yield 80.5%, m.p.60-62 ℃.
2,1,3,4, the preparation of 6-four-O-benzoyl-2-deoxidation-β-D-pyran glucosamine
I) preparation of N-(to anisole methene base)-2-deoxidation-D-pyran glucosamine
2-amino-2-deoxy-D-glucose hydrochloride 78.1g (0.36mol) is put into reaction flask, add NaOH solution 364mL (concentration is 1mol/L), stirring and dissolving slowly splashes into anisyl aldehyde 48mL (0.40mol), stirs simultaneously, after waiting to occur a large amount of white precipitates, cooling, suction filtration gets white solid after the drying, yield: 84.2%, m.p.164-166 ℃.
Ii) N-(to anisole methene base)-1,3,4, the preparation of 6-four-O-benzoyl-2-deoxidation-β-D-pyran glucosamine
Add the dry pyridine 11.6ml that crosses in three-necked bottle, the dry methylene dichloride 14.0ml that crosses drips the solution that Benzoyl chloride 14.0ml and methylene dichloride 11.0ml form to three-necked bottle in ice-water bath.Temperature is controlled at below 10 ℃ in the dropping process.Add N-(right-methoxy benzene methene base)-D-glucosamine 8.37g (28mmol) in batches.Under condition of ice bath, reacted 1 hour again after adding.Reacted again at ambient temperature 24 hours then.Add methylene dichloride 60ml, slowly add saturated NaHCO again
3The aqueous solution.Branch vibration layer, dichloromethane layer water are given a baby a bath on the third day after its birth inferior, use anhydrous Na
2SO
4Boil off methylene chloride after the drying, get white solid, yield: 71.4%.m.p.165-168 ℃.
Iii) 1,3,4, the preparation of 6-four-O-benzoyl-2-deoxidation-D-Glucopyranose amine hydrochlorate
With N-(to anisole methene base)-1,3,4; 6-four-O-benzoyl-2-deoxidation-β-D-pyran glucosamine 15.7g (22mmol) puts into reaction flask, adds acetone 80mL, make its dissolving after; splash into hydrochloric acid 20ml (4mol/L); white gelatin solid appears, cooling, suction filtration; with washing with acetone repeatedly; 35 ℃ of oven dryings spend the night, and obtain white solid, yield: 85.2%.m.p.206-207 ℃.
Iv) 1,3,4, the preparation of 6-four-O-benzoyl-2-deoxidation-β-D-pyran glucosamine
Get 1,3,4,6-four-O-benzoyl-2-deoxidation-β-D-Glucopyranose amine hydrochlorate 18.5g (26mmol) adds acetone 130mL, triethylamine 4.4mL, and stirring reaction is 12 hours under the room temperature condition; Filter, filtrate is rotated evaporate to dryness, pour in the frozen water, stir, have solid to separate out gradually, cooled off three hours.Suction filtration, drying, white solid, promptly 1,3,4,6-four-O-benzoyl-2-deoxidation-β-D-pyran glucosamine, yield: 92.5%.
3,2-(1 ', 3 ', 4 ', 6 '-four-O-benzoyl-2 '-deoxidation-β-D-glucopyranosyl)-(1,2-d)-preparation of benzisoxa selenazoles-3 (2H)-ketone
Add 1,3,4 in three-necked bottle, 6-four-O-benzoyl-2-deoxidation-β-D-pyran glucosamine 1.19g (2mmol) adds chloroform 10ml and makes its dissolving; Other takes by weighing 2-chlorine seleno Benzoyl chloride 0.5g (2mmol) and is dissolved among the chloroform 10ml, pipettes triethylamine 0.6mL (4mmol) and 10mL chloroform wiring solution-forming again; Ice bath is added dropwise to back two kinds of solution in the reaction flask down simultaneously, drips off about half an hour, rises to room temperature reaction 4h; Filter, filtrate is separated with silicagel column, and concentrated solvent gets faint yellow solid, yield: 65.3%m.p.127-129 ℃.
1H NMR (CDCl
3) δ: 7.25-8.04 (m, 24H, Ar-H), 6.60 (d, 1H, J=6.9Hz C
1'-H), 5.29-6.21 (3H C
2'-H, C
3'-H, C
4'-H), 4.65 (dd, 1H, J=2.5,12.1Hz C
6'-H
1), 4.48-4.52 (m, 2H, C
6'-H
2, C
5'-H), 1.90-2.12 (4s, 12H, Ac-H) IR (KBr) υ: 2955.52 (C-H) 1734.97 (O-C=O) 1655.99 (O=C-N) 1600,1450.47 (Ar-H), 1267 (C-O-C) 937 (sugared skeleton)
Above-claimed cpd 2-(1 '; 3 '; 4 '; 6 '-four-O-benzoyl-2 '-deoxidation-β-D-glucopyranosyl)-(1; 2-d)-benzisoxa selenazoles-3 (2H)-ketone is a kind of of Benzisoelenazolone amino sugar derivative of the present invention; be hydroxyl protection aminosugar directly with one of reaction product of 2-chlorine seleno Benzoyl chloride, other compound can be by changing different aminosugars or changing the different protecting groups acquisitions of aminosugar.
Embodiment 2
Benzisoelenazolone amino sugar derivative 2-(N '-1 ", 3 ", 4 ", 6 " four-O-ethanoyl-2 '-deoxidation-β-D-Glucopyranose-2 '-acetamido)-(1,2-d)-preparation of benzisoxa selenazoles-3 (2H)-ketone
1, the preparation of N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl)-glycosides propylhomoserin acid amides
I) preparation of N-carbobenzoxy-(Cbz)-glycine
Add the aqueous solution of glycine 1.5g (20mmol) at the 50mL eggplant-shape bottle, and transfer to pH=9-10, pipette Carbobenzoxy Chloride 3ml (18mmol), slowly be added dropwise in the reaction flask with sodium hydroxide (2mol/L), temperature control 0-5 ℃, stirring 5h.Reaction solution extracted with diethyl ether three times keep water layer; Water layer transfers to pH＜1 with hydrochloric acid (2mol/L), and uses ethyl acetate extraction, tells organic layer; Organic layer is respectively given a baby a bath on the third day after its birth time with saturated nacl aqueous solution and water; Spend the night with anhydrous sodium sulfate drying, filter; The solvent evaporated ethyl acetate gets white solid 2.65g, yield 70.5%.
The ii) preparation of N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl)-N '-carbobenzoxy-(Cbz)-glycosides propylhomoserin acid amides
In the single port bottle of 20ml, add N-carbobenzoxy-(Cbz)-glycine 0.42g (2mmol), add anhydrous methylene chloride 10ml again and make its dissolving.Ice bath adds N down, N '-dicyclohexylcarbodiimide (DCC) 0.43g (2mmol), 1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-pyran glucosamine 0.69g (2mmol), reaction 12h.Filter, filtrate decompression is concentrated, column chromatography for separation gets white solid 0.86g, yield 79.6%.
The iii) preparation of N-(1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl)-glycosides propylhomoserin acid amides
Get N-1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl-N '-carbobenzoxy-(Cbz)-glycosides propylhomoserin acid amides 0.86g (1.6mmol) is dissolved in 30ml methyl alcohol, adds 5% (weight percentage) Pd/C, feeds hydrogen and stirs 5h.Filter, filtrate decompression is concentrated, column chromatography for separation, drying gets white solid 0.62g.Yield: 91.2%, m.p.148-150 ℃.
2,1,3,4, the preparation of 6-four-O-ethanoyl-2-deoxidation-β-D-pyran glucosamine
I) preparation of N-(to anisole methene base)-2-deoxidation-D-pyran glucosamine
2-amino-2-deoxy-D-glucose hydrochloride 78.1g (0.36mol) is put into reaction flask, add NaOH solution 364ml (1mol/L), stirring and dissolving, slowly splash into anisyl aldehyde 48ml (0.40mol), stir simultaneously, wait to occur a large amount of white precipitates after, cooling, suction filtration gets white solid after the drying.Yield: 85.3%, m.p.164-166 ℃.
Ii) N-(to anisole methene base)-1,3,4, the preparation of 6-four-O-ethanoyl-2-deoxidation-β-D-pyran glucosamine
Acetic anhydride 263ml (2.7mol), exsiccant pyridine 473.1ml are poured in the reaction flask, mix and be cooled to 0 ℃, add compound N-(to anisole methene base)-2-deoxidation-D-pyran glucosamine 90g (0.30mol) stirring at room to molten entirely, after placing 24h, pour among the frozen water 1500ml, white precipitate appears in vigorous stirring simultaneously.Suction filtration, drying is used ethyl alcohol recrystallization, gets white crystal 102g, productive rate: 74%, m.p.185-187 ℃.
Iii) 1,3,4, the preparation of 6-four-O-ethanoyl-2-deoxidation-D-Glucopyranose amine hydrochlorate
With N-(to anisole methene base)-1,3,4; 6-four-O-ethanoyl-2-deoxidation-β-D-pyran glucosamine 102g (0.22mol) puts into reaction flask, adds 800ml acetone, make its dissolving after; splash into hydrochloric acid 200ml (4mol/L), white gelatin solid occurs, cooling; suction filtration; with washing with acetone repeatedly, 35 ℃ of oven dryings spend the night, and obtain white solid 80g; productive rate 95%, m.p.220-221 ℃.
Iv) 1,3,4, the preparation of 6-four-O-ethanoyl-2-deoxidation-β-D-pyran glucosamine
Get 1,3,4,6-four-O-ethanoyl-2-deoxidation-D-Glucopyranose amine hydrochlorate 10g (26mmol) adds 130mL acetone, 4.4mL triethylamine, and room temperature condition stirs 12h down; Filter, filtrate is rotated evaporate to dryness, pour in the frozen water, under agitation have solid to separate out gradually, cooled off three hours.Suction filtration, with the gained filtration cakes torrefaction, getting white solid is 1,3,4,6-four-O-ethanoyl-2-deoxidation-β-D-pyran glucosamine 6.75g, yield 74.2%, m.p.135-137 ℃.
3,2-(N '-1 ", 3 ", 4 ", 6 " four-O-ethanoyl-2 '-deoxidation-β-D-Glucopyranose-2 '-acetamido)-(1,2-d)-preparation of benzisoxa selenazoles-3 (2H)-ketone
In there-necked flask, add N-1; 3; 4; 6-four-O-ethanoyl-2-deoxidation-β-D-glucopyranosyl-glycosides propylhomoserin acid amides 0.41g (1mmol); add chloroform 10ml and make its dissolving; take by weighing 2-chlorine seleno Benzoyl chloride 0.25g (1mmol) and be dissolved in chloroform 10ml, pipette triethylamine 0.30ml (2mmol) and 10ml chloroform wiring solution-forming.Under the ice bath two kinds of solution are added dropwise in the reaction flask simultaneously, drip off about half an hour, rise to stirring at room 4h.Filter, concentrated solvent, last silicagel column separates, and gets Off-white solid 0.32 gram, yield 55.1%, m.p.222-225 ℃.
1H?NMR(CDCl
3)δ：7.41-8.02(m，4H，ArH)，7.04(d，1H，J＝9.1Hz，N-H)5.84(d，1H，J＝8.7Hz，C
1′-H)，5.29(t，1H，J＝9.6Hz，C
4′-H)5.09(t，1H，J＝9.6Hz，C
3′-H，)，4.38(s，1H，N-CH
2)，4.26(dd，1H，J＝4.5，12.3Hz，C
6′-H
1)，4.18(dd，1HJ＝9.1Hz，C
2′-H)，4.08(dd，1H，J＝2.2，12.3Hz，C
6′-H
2)，3.99-4.01(m，1H，C
5′-H)，1.92-2.09(4s，12H，Ac-H)ESI-MS?m/z?608.8[M+Na]
+，584.9[M-H]
-IR(KBr)υ：3299.4(N-H)2933.97(C-H)1754.20(O--C＝O)1689.64(O＝C-N)1540.14，1443.43(Ar--H)1223.50(C-O-C)
The compound 2-of above-mentioned preparation (N '-1 "; 3 " 4 "; 6 "-four-O-ethanoyl-2 '-deoxidation-β-D-Glucopyranose-2 '-acetamido)-(1; 2-d)-benzisoxa selenazoles-3 (2H)-ketone; be a kind of of Benzisoelenazolone amino sugar derivative of the present invention; be after the amino acid of hydroxyl protection 2-aminosugar and carbobenzoxy-(Cbz) protection generates the sugared amide derivatives of hydroxyl protection; react one of product that generates again with 2-chlorine seleno Benzoyl chloride, other compound can be by changing the different protecting groups acquisitions of different aminosugars or change aminosugar.
Embodiment 3 Benzisoelenazolone amino sugar derivative anti tumor activity in vitro screenings of the present invention
The inventor proves that by pharmacological experiment Benzisoelenazolone amino sugar derivative of the present invention has significant antitumor efficacy, illustrates that this derivative is having broad application prospect aspect the medicine of prevention and treatment tumour.
Derivative of the present invention shows through the anti tumor activity in vitro screening, this analog derivative has preferably cytotoxic activity during for 100uM or has good cell growth inhibiting effect in concentration, and selected cell strain is human breast cancer cell (MCF7), nervus centralis cancer cells (SF-268) and human lung carcinoma cell (NCI-H460).Its result is as shown in table 1.
Table 1
The medicine made from derivative of the present invention can also be fit to other administering mode by oral administration and drug administration by injection, as percutaneous dosing etc.Medicine can be made liquid preparation forms such as tablet, capsule, pulvis, particle, lozenge, suppository or oral liquid or aseptic parenteral suspension.Also have big or injection forms such as small-volume injection, lyophilisate.The medicine of above-mentioned formulation all can be according to the ordinary method preparation of pharmaceutical field.
As needs, medicine of the present invention can also add one or more pharmaceutically acceptable carriers, and carrier comprises thinner, weighting agent, tackiness agent, wetting agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc.
Claims (3)
1. Benzisoelenazolone amino sugar derivative, it is as follows to it is characterized in that it has a structural formula:
In the formula: R
3Be respectively-CH
2CONH-,-(CH
2)
2CONH-,-(CH
2)
3(CH
2)
2CONH-,-(CHCH
3) CONH-or-C
6H
4During CONH-, R
4During=-OAc, R
5=-OAc, R
6=-H; R
4During=-OAc, R
5=-H, R
6=-OAc; R
4R during=-OBz
5=-H, R
6=-OBz; R
4During=-OBz, R
5=-OBz, R
6=-H.
2. the application of the described Benzisoelenazolone amino sugar derivative of claim 1 in the preparation antitumor drug.
3. the preparation method of the described Benzisoelenazolone amino sugar derivative of claim 1; it is characterized in that making the 2-aminosugar of hydroxyl protection and the amino acid of carbobenzoxy-(Cbz) protection under DCC catalysis, to react; reaction product removes carbobenzoxy-(Cbz) with hydrogen reducing again under the catalysis of palladium carbon; generate the sugared amide derivatives of hydroxyl protection, this derivative reacts with 2-chlorine seleno Benzoyl chloride under triethylamine catalysis.
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| CN109627198B (en) * | 2019-02-01 | 2020-11-10 | 河南科技大学 | 2-acetonyl selenium-based benzamide compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1390837A (en) * | 2001-06-08 | 2003-01-15 | 北京大学药学院 | Anti-inflammatory and antineoplastic R-bis or glycophenylpropane isoselenazole substituted compound |
| CN1463972A (en) * | 2002-06-19 | 2003-12-31 | 中国医学科学院药物研究所 | Novel N-substituted pyridine Benzisoxazolone compound, method for making same and its pharmaceutical composition and use thereof |
| CN1511835A (en) * | 2002-12-27 | 2004-07-14 | 北京大学药学院 | Benzo-isoselenazole derivatives having anti inflammation, anti-tumor and anti-thrumbosis function and its use |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1390837A (en) * | 2001-06-08 | 2003-01-15 | 北京大学药学院 | Anti-inflammatory and antineoplastic R-bis or glycophenylpropane isoselenazole substituted compound |
| CN1463972A (en) * | 2002-06-19 | 2003-12-31 | 中国医学科学院药物研究所 | Novel N-substituted pyridine Benzisoxazolone compound, method for making same and its pharmaceutical composition and use thereof |
| CN1511835A (en) * | 2002-12-27 | 2004-07-14 | 北京大学药学院 | Benzo-isoselenazole derivatives having anti inflammation, anti-tumor and anti-thrumbosis function and its use |
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