CN1280279C - Dibenzo-isozaolone compounds and their synthesis process and application - Google Patents
Dibenzo-isozaolone compounds and their synthesis process and application Download PDFInfo
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- CN1280279C CN1280279C CN 03156590 CN03156590A CN1280279C CN 1280279 C CN1280279 C CN 1280279C CN 03156590 CN03156590 CN 03156590 CN 03156590 A CN03156590 A CN 03156590A CN 1280279 C CN1280279 C CN 1280279C
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Abstract
The present invention relates to the synthesis of dibenzo-isozaolone compounds and preparing process for the compositions of dibenzo-isozaolone compounds, and the pharmaceutical use of the dibenzo-isozaolone compounds, in particular to the application in the preparation of the antineoplastic, antiviral and antibacterial medicine.
Description
Invention field
The present invention relates to two benzisoxa sulfinpyrazone compounds, synthetic method and the pharmaceutical composition that contains it, and the pharmaceutical use of two benzisoxa sulfinpyrazone compounds, the especially application in preparing antitumor, antiviral and antibacterials.
Background technology
Recent two decades comes, and the biochemical research of selenium obtains a series of important breakthrough and progress, and 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 organoselenium medicine ebselen (Ebselen) has entered III phase clinical study.
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.Theory thinks that this compound is the most successful small molecules organic selenium compounds of simulation Selenoperoxidase (GSH-PX), but the various organic hydroperoxides of catalysis GSH reduction decomposition.
Its analogue benzisothia oxazolone is stronger antioxidant, also is a kind of good sterilization agent simultaneously, and bacterium, fungi are all had restraining effect, has biological function characteristics comparatively widely.But it is the formation of the anti-hemostasis suppository of the simultaneously all right anticoagulant of sterilization not only, and atherosclerosis prevents cardiopathic outbreak.The effect that contains selenium analogue Ebselen at anti-inflammatory activity and its is similar.Isothiazolones also has the good restraining effect to retrovirus.But two benzisoxa sulfinpyrazone compounds are synthetic and use as: the symmetrical structure of bis-isothiazolones; The symmetrical structure of two different tellurium oxazolones; The unsymmetrical structure of isothiazolones and different selenazoles ketone; The unsymmetrical structure of isothiazolones and different tellurium oxazolone; The unsymmetrical structure of different selenazoles ketone and different tellurium oxazolone, the someone reports as yet.Aspect bioactivity research, do not appear in the newspapers as yet as the sulfur-bearing of above a series of pairs of benzisoxa sulfinpyrazone compounds, antitumor, the antibacterial research of tellurium organic compound.
We select Benzisoelenazolone as basic parent nucleus, and selenium is replaced to its congeners sulphur, and tellurium has synthesized corresponding two benzisoxa sulfinpyrazone compound, and has studied its antitumor, anti-microbial activity.
Summary of the invention
The present invention relates to acceptable salt on two benzisoxa sulfinpyrazone compounds of following general formula and the pharmacology thereof:
R wherein
1And R
2Be identical or different, be selected from S independently of one another, Se or Te;
Wherein R is C1-C20 linearity or branching, saturated or undersaturated bivalent hydrocarbon radical, the C6-C30 arylidene, the C5-C20 cycloalkylidene, the inferior heterocyclic radical of C5-C20, contain carbocyclic ring, the C4-C30 bivalent hydrocarbon radical of heterocycle or aromatic ring, carbocyclic ring wherein, heterocycle or aromatic ring can be arranged in the chain or the end of the chain, the organic radical alkylsulfonyl, or carbonyl organic radical carbonyl (organic radical comprises alkylidene group, alkenylene, arylidene, inferior heterocyclic radical etc.), all these groups are replacements or unsubstituted, for example by acidic group, ester group, hydroxyl, amino, halogen, replacements such as amide group, its carbochain can be inserted arbitrarily and be selected from O, one or more heteroatomss among N and the S;
R (CH preferably wherein
2)
n-, wherein n is 1-8; Or-(C
6H
4)
n-, wherein n is 1-3; Or-(CH
2)
n-SS-(CH
2)
n-, wherein n is 1-3; Or-(CH
2)
n-NH-(CH
2)
n-, wherein n is 1-3; Or-C (=O)-R '-C (=O)-, wherein R ' is a bivalent hydrocarbon radical, as alkylidene group, and alkenylene, arylidene, cycloalkylidene or inferior heterocyclic radical; Or-(CH
2)
n-O-(CH
2)
n-, wherein n is 1-4.
Especially preferred is the compound of following structural formula:
n＝2-8；
R
1=R
2Or R
1≠ R
2R wherein
1, R
2=S or Se or Te
n＝1-3；
R
1=R
2Or R
1≠ R
2R wherein
1, R
2=S or Se or Te
n＝1-3；
R
1=R
2Or R
1≠ R
2R wherein
1, R
2=S or Se or Te
Another object of the present invention provides the preparation method of above-mentioned general formula compound, may further comprise the steps: allow the compound of following structural formula II I and IV:
With structural formula H
2N-R-NH
2Compound under-20 ℃ to 5 ℃ temperature, in inert solvent, under alkaline condition, reaction makes required compound under protection of inert gas.
R wherein
1And R
2Be identical or different, be selected from S independently of one another, Se or Te;
Wherein R is C1-C20 linearity or branching, saturated or undersaturated bivalent hydrocarbon radical, the C6-C30 arylidene, the C5-C20 cycloalkylidene, the inferior heterocyclic radical of C5-C20, contain the C4-C30 bivalent hydrocarbon radical of carbocyclic ring, heterocycle or aromatic ring, wherein carbocyclic ring, heterocycle or aromatic ring can be arranged in the chain or the end of the chain, the organic radical alkylsulfonyl, or carbonyl organic radical carbonyl, the carbochain of all these groups can be inserted the one or more heteroatomss that are selected among O, N and the S arbitrarily;
R (CH preferably wherein
2)
n-, wherein n is 1-8;-(C
6H
4)
n-, wherein n is 1-3;-(CH
2)
n-SS-(CH
2)
n-, wherein n is 1-3;-(CH
2)
n-NH-(CH
2)
n-, wherein n is 1-3; Or-(CH
2)
n-O-(CH
2)
n-, wherein n is 1-4.
Suitable inert solvent comprises for example tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE, methylene dichloride, ether etc.
The alkaline condition that is fit to for example is pH8-11.
According to the method described above, obtained two kinds of isomer of structural formula I of the present invention and II, these two kinds of isomer generally exist jointly with 1: 1 mol ratio.
Another purpose of the present invention provides the application of above-mentioned general formula compound in preparing antitumor, antiviral and antibacterials.
Another object of the present invention provides the above-mentioned general formula (I) that contains pharmacy effective dose or pharmaceutical composition that (II) acceptable vehicle or carrier or optional additive such as flavouring agent, sweeting agent etc. are formed on compound and the pharmacology.Its formula of (I) or the content of compound (II) in pharmaceutical composition for example can be 1-95%.
Pharmaceutical composition of the present invention also routinely technology make capsule, tablet, oral liquid, injection or transfusion formulation, and make controlled release or slow-released system administration as required.
General formula of the present invention (I) or compound (II) can use alone or use with the form of composition.
The dosage of general formula of the present invention (I) or compound (II) decides according to the factors such as weight of patient age, body weight, the course of disease, disease.For example, as a reference, under the situation of oral dosage form, the consumption of compound of the present invention can be 0.1-10mg/kg/d, and under the situation of injection type, compound amount of the present invention can be 0.1-5mg/kg/d.
Specific embodiment
In following examples, synthesized following compound according to following synthetic route, should be noted that these embodiment only are used for the purpose of illustration, do not limit the scope of the invention.Though only provided a kind of isomeric forms of The compounds of this invention, also comprised its isomeric forms in this article.
Compound: 1,4-two [2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-benzene synthetic
Compd E IS:1,2-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-ethane synthetic
Compd E IIS:1,3-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-propane synthetic
Compd E IIIS:1,4-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-butane synthetic
Compd E ITe:1,2-two [2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)]-ethane synthetic
Compd E bs-1:1-[2-(1,2-benzisothiazole-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)] ethane synthetic
Compd E sTe:1-[2-(1,2-benzisothiazole-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)] ethane synthetic
Compd E bTe:1-[2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)] ethane synthetic
1,2-two [2-(1,2-benzisoxa selenazoles-3 (2H)-ketone) methyl]-disulfide
1,4-two [2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-benzene sulfonyl compound
1,2-two [(1,2-benzisoxa selenazoles-3 (2H)-ketone-2-yl) carbonyl] ethane
Synthesizing of embodiment 1 intermediate product
Intermediate product 1: diazonium salt synthetic
To contain the 18g anthranilic acid and 1: 1 hydrochloric acid 51.4mL solution is chilled to less than 5 ℃ with ice bath, stir that slowly being added dropwise to sodium nitrite solution makes diazonium salt down.
Synthesizing of intermediate product 2:2-selenium chloro-benzoyl chloride
(1) 2, the two benzoic preparations of 2 '-two selenizings:
Under the room temperature nitrogen protection, in 6g selenium powder and 50mL water blended suspension, slowly drip the POTASSIUM BOROHYDRIDE aqueous solution.Selenium powder all dissolves, and adds equivalent 6g selenium powder again, obtains dark red solution.Stirring at room 0.5 hour adds aqueous sodium hydroxide solution again, is added dropwise to diazonium salt solution then.Dropwise, be warming up to 60 ℃ of reactions 2 hours, continue reaction 3 hours.Add 1: 1 hcl acidifying, after the filtration washing gained sorrel solid is joined in the 100mL sodium carbonate solution, remove insolubles.The hydrochloric acid that adds 1mol/L after the cooling again to pH value less than 1, filtration under diminished pressure, the washing after drying gets the 49.6g faint yellow solid.Be the two phenylformic acid of 2,2 '-two selenizings.
(2) preparation of 2-selenium chloro-benzoyl chloride:
With 6g2, the two phenylformic acid of 2-two selenizings add the 30ml thionyl chloride and mix, and reflux is revolved after 3 hours and steamed unnecessary thionyl chloride under stirring.Remaining material normal hexane recrystallization gets yellow solid 3.4g, is 2-selenium chloro-benzoyl chloride.
Synthesizing of intermediate product 3:2-sulphur chloro-benzoyl chloride
(1) 2, the two benzoic preparations of 2 '-curing:
Under the room temperature nitrogen protection, in 2.4g sulphur powder and 50mL water blended suspension, slowly drip the POTASSIUM BOROHYDRIDE aqueous solution.Sulphur powder small part dissolving adds equivalent 2.4g sulphur powder again, stirring at room 1 hour 45 minutes, and solution becomes yellow again and becomes red-brown at last, the most of dissolving of sulphur powder from the colourless yellow-green colour that becomes.Add aqueous sodium hydroxide solution (20g sodium hydroxide+50mL water) again, be added dropwise to diazonium salt solution then, produce orange red bubble, the sulphur powder dissolves substantially.Dropwise, be warming up to 60 ℃ of reactions 2 hours, continue reaction 3 hours.Add 1: 1 hcl acidifying, after the filtration washing gained light yellow solid is joined in the 100mL sodium carbonate solution, remove insolubles.The hydrochloric acid that adds 1mol/L after the cooling again to pH value less than 1, filtration under diminished pressure, the washing after drying gets the 47.6g white solid.Be 2, the two phenylformic acid of 2 '-curing.
(2) preparation of 2-sulphur chloro-benzoyl chloride
With 9.1g2, the two phenylformic acid of 2-curing add the 59.34ml thionyl chloride and mix, and reflux is revolved after 3 hours and steamed unnecessary thionyl chloride under stirring.Remaining material normal hexane recrystallization gets golden yellow solid 3.7g, is 2-sulphur chloro-benzoyl chloride.
Synthesizing of intermediate product 4:2-tellurium chloro-benzoyl chloride
(1) 2, the two benzoic preparations of 2 '-two telluriumizations:
Under the room temperature nitrogen protection, in 4.85g tellurium powder and 25mL water blended suspension, slowly drip the POTASSIUM BOROHYDRIDE aqueous solution.The tellurium powder is partly dissolved, and the solution blackening becomes clarification again and becomes purple at last.Add equivalent 4.85g tellurium powder again, liquid level produces a large amount of bubbles, last bubble collapse, and solution becomes dark red.Add aqueous sodium hydroxide solution again, be added dropwise to diazonium salt solution then, generate white mist, the black bubble, solution becomes dark red.Dropwise, be warming up to 60 ℃ of reactions 2 hours, continue reaction 3 hours, obtain amaranth solution.Add 1: 1 hcl acidifying, after the filtration washing the green sticky solid of gained is joined in the 50mL sodium carbonate solution, remove insolubles.The hydrochloric acid that adds 1mol/L after the cooling again to pH value less than 1, filtration under diminished pressure, the washing after drying gets the 12.7g yellow solid.Be the two phenylformic acid of 2,2 '-two telluriumizations.
(2) preparation of 2-tellurium chloro-benzoyl chloride
With 6.0g2, the two phenylformic acid of 2-two telluriumizations add the 24.13ml thionyl chloride and mix, and reflux is revolved after 3 hours and steamed unnecessary thionyl chloride under stirring.Remaining material benzene recrystallization gets golden yellow solid 5.2g, is 2-tellurium chloro-benzoyl chloride.
Embodiment 2
Compd E IS:1,2-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-ethane synthetic
Add 12ml tetrahydrofuran (THF), 0.37ml quadrol, 3.44ml triethylamine in the 250ml there-necked flask, ice bath stirs and feeds nitrogen down.Take by weighing 2.2g sulphur chlorine solid and put into small beaker and add the 53.5ml tetrahydrofuran (THF), the dissolving of sulphur chlorine obtains yellow transparent solution.This solution is splashed into there-necked flask with dropping funnel, and rate of addition is very fast.Have light yellow solid to generate, solution colour becomes yellow.There is little white floss floating in the bottle.The sulphur chlorine solution dropwised reaction after three hours, filtration under diminished pressure.Obtain yellow solid, washing filtrate is yellow.Recrystallization obtains colourless acicular crystal 0.4g.Productive rate 23.0%, m.p.206 ℃.EI-MS：(M
+)328。
Embodiment 3
Compd E IIS:1,3-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-propane synthetic
Add 2.25ml tetrahydrofuran (THF), 0.41ml propylene diamine, 3.23ml triethylamine in the 250ml there-necked flask, ice bath stirs and feeds nitrogen down.Take by weighing 2.0g sulphur chlorine solid and put into small beaker and add the 30ml tetrahydrofuran (THF), the dissolving of sulphur chlorine obtains yellow transparent solution.This solution is splashed into there-necked flask with dropping funnel, and rate of addition is very fast.Have light yellow sticky solid to generate, solution colour becomes yellow.There is little white floss floating in the bottle.The sulphur chlorine solution dropwised reaction after three hours, filtration under diminished pressure.Washing obtains white solid, and it is yellow that filtrate is.Recrystallization obtains colourless acicular crystal 1g.Productive rate 60.6%, m.p.163 ℃.FAB-MS：(M
+)342。
Embodiment 4
Compd E IIIS:1,4-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-butane synthetic
Add 2.5ml tetrahydrofuran (THF), 0.43ml butanediamine, 2.87ml triethylamine in the 250ml there-necked flask, ice bath stirs and feeds nitrogen down.Take by weighing 1.78g sulphur chlorine solid and put into small beaker and add the 30ml tetrahydrofuran (THF), the dissolving of sulphur chlorine obtains yellow transparent solution.This solution is splashed into there-necked flask with dropping funnel, and rate of addition is very fast.Have light yellow sticky solid to generate, solution colour becomes yellow.There is little white floss floating in the bottle.The sulphur chlorine solution dropwised reaction after three hours, filtration under diminished pressure.Washing obtains white solid, and it is yellow that filtrate is.Recrystallization obtains colourless acicular crystal 1.1g.Productive rate 64.3%, m.p.207 ℃.FAB-MS：(M+1)357。
Embodiment 5
Compd E ITe:1,2-two [2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)]-ethane synthetic
Add 5.9ml tetrahydrofuran (THF), 0.18ml quadrol, 1.68ml triethylamine in the 250ml there-necked flask, ice bath stirs and feeds nitrogen down.Take by weighing 1.6g tellurium chlorine solid and put into small beaker and add the 26.5ml tetrahydrofuran (THF), the dissolving of tellurium chlorine obtains brown-red solution.This solution is splashed into there-necked flask with dropping funnel, and rate of addition is very fast.Have yellow solid to generate, solution colour becomes yellow.There is little white floss floating in the bottle.The tellurium chlorine solution dropwised reaction after three hours, filtration under diminished pressure.Obtain yellow solid, it is yellow that filtrate is.Use the distilled water wash solid several times, the solid color shoals, and the filtrate color is yellow.Wash this solid phase prod on a small quantity with anhydrous diethyl ether again, the filtrate color is a yellow-green colour.This solid phase prod of water washing, filtrate color are yellow-green colour.Product drying obtains 1.2g, productive rate 86.5%, m.p.203 ℃.FAB-MS：(M
+)523；1HNMR：δ8～7.6(m，8H，ArH)，δ2.7(s，4H，-CH
2-)。
Embodiment 6
Compd E bs-1:1-[2-(1,2-benzisothiazole-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)] ethane synthetic
Add 12ml tetrahydrofuran (THF), 0.37ml quadrol, 3.44ml triethylamine in the 250ml there-necked flask, ice bath stirs and feeds nitrogen down.Take by weighing 1.1g sulphur chlorine solid and put into small beaker and add the 26.5ml tetrahydrofuran (THF), the dissolving of sulphur chlorine obtains yellow transparent solution.Take by weighing 1.35g selenium chlorine solid again and put into small beaker and add the 26.5ml tetrahydrofuran (THF), the dissolving of selenium chlorine obtains brown clear solution.Above two kinds of solution are splashed into there-necked flask with dropping funnel, drip simultaneously, and speed is identical, rate of addition is very fast.Have light yellow solid to generate, solution colour becomes yellow.There is little white floss floating in the bottle.Solution dropwises the back and continues reaction three hours, with the reaction solution filtration under diminished pressure.Obtain faint yellow solid, it is yellow that filtrate is.Use the distilled water wash solid several times, the solid color shoals, and the filtrate color is yellow.Wash this solid phase prod on a small quantity with anhydrous diethyl ether again, the filtrate color is a yellow-green colour.Wash this solid phase prod on a small quantity with anhydrous diethyl ether at last, the filtrate color is a yellow-green colour.Product drying obtains 1.8g, productive rate 90.5%, m.p.268 ℃.EI-MS：(M
+)375，
1HNMR：δ8～7.3(m，8H，ArH)，δ4.3～3.3(s，4H，-CH
2-)。
Embodiment 7
Compd E sTe:1-[2-(1,2-benzisothiazole-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)] ethane synthetic
Add 5.9ml tetrahydrofuran (THF), 0.18ml quadrol, 1.68ml triethylamine in the 250ml there-necked flask, ice bath stirs and feeds nitrogen down.Take by weighing 0.6g sulphur chlorine solid and put into small beaker and add the 13.25ml tetrahydrofuran (THF), the dissolving of sulphur chlorine obtains yellow transparent solution.Take by weighing 0.8g tellurium chlorine solid again and put into small beaker and add the 13.25ml tetrahydrofuran (THF), the dissolving of tellurium chlorine obtains brown solution.Above two kinds of solution are splashed into there-necked flask with dropping funnel, drip simultaneously, and speed is identical, rate of addition is very fast.Have yellow solid to generate, solution colour becomes yellow.There is little white floss floating in the bottle.Solution dropwises the back and continues reaction three hours, with the reaction solution filtration under diminished pressure.Obtain yellow solid, it is yellow that filtrate is.Use the distilled water wash solid several times, the solid color shoals, and the filtrate color is yellow.Wash this solid phase prod on a small quantity with anhydrous diethyl ether again, the filtrate color is yellow.Last water washs this solid phase prod on a small quantity, and the filtrate color is yellow.Product drying obtains 1.1g, productive rate 89.4%, m.p.287 ℃.FAB-MS：(M+K)463。
Embodiment 8
Compd E bTe:1-[2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)] ethane synthetic
Add 5.9ml tetrahydrofuran (THF), 0.18ml quadrol, 1.68ml triethylamine in the 250ml there-necked flask, ice bath stirs and feeds nitrogen down.Take by weighing 0.68g selenium chlorine solid and put into small beaker and add the 13.25ml tetrahydrofuran (THF), the dissolving of selenium chlorine obtains orange red clear solution.Take by weighing 0.8g tellurium chlorine solid again and put into small beaker and add the 13.25ml tetrahydrofuran (THF), the dissolving of tellurium chlorine obtains brown solution.Above two kinds of solution are splashed into there-necked flask with dropping funnel, drip simultaneously, and speed is identical, rate of addition is very fast.Have yellow solid to generate, solution colour becomes yellow.There is little white floss floating in the bottle.Solution dropwises the back and continues reaction three hours, with the reaction solution filtration under diminished pressure.Obtain yellow solid, it is yellow that filtrate is.Use the distilled water wash solid several times, the solid color shoals, and the filtrate color is yellow.Product drying obtains 1.2g, productive rate 95.23%, m.p.247 ℃.FAB-MS：(M
+)471；1HNMR：δ8～7.3(m，8H，ArH)，δ4.0～2.9(s，4H，-CH
2-)。
Embodiment 9
1,4-two [2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-benzene synthetic
0.38g aniline, the 1.3ml triethylamine is dissolved among the 10mlTHF, and the logical N2 of ice bath stirs, 1g selenium chlorine is dissolved among the 20mlTHF, slowly splashes in the aniline solution, drips off in the 1h. continue to stir more than three hours. get yellow mercury oxide, filtering, with THF and washing with alcohol precipitation, oven dry. mother liquor leaves standstill crystallization after concentrating.Productive rate 5%, mp＞300 ℃; EI-MS:(M
+) 474.
Embodiment 10
1,2-two [2 (1,2-benzisoxa selenazoles-3 (2H)-ketone)]-disulfide synthetic
Add 6.9ml tetrahydrofuran (THF), 1.18ml disulfide diamines, 1.68ml triethylamine in the 250ml there-necked flask, ice bath stirs and feeds nitrogen down.Take by weighing 1.6g selenium chlorine solid and put into small beaker and add the 26.5ml tetrahydrofuran (THF), the dissolving of selenium chlorine splashes into there-necked flask, has yellow solid to generate, and solution colour becomes yellow.Dropwise reaction after three hours, filtration under diminished pressure.Obtain yellow solid, it is yellow that filtrate is.Use the distilled water wash solid several times, the solid color shoals.Product drying obtains 1.2g, productive rate 76.5%, m.p.183 ℃.
Embodiment 11
1,4-two [2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-benzene sulfonyl synthetic
Take by weighing 1.6g selenium chlorine solid and put into small beaker and add the 26.5ml tetrahydrofuran (THF), the dissolving of selenium chlorine.In the 250ml there-necked flask, add the 6.9ml tetrahydrofuran (THF), with 4-aminobenzene sulfonamide, the 1.68ml triethylamine of selenium chlorine equimolar amount, ice bath stirs and feeds nitrogen down.Selenium chlorine is splashed into there-necked flask, have yellow solid to generate, solution colour becomes yellow.Dropwise reaction after three hours, filtration under diminished pressure.Obtain yellow solid, it is yellow that filtrate is.Use the distilled water wash solid several times, the solid color shoals.Fusing point: 260 ℃-315 ℃
Embodiment 12
1,2-two [(1,2-benzisoxa selenazoles-3 (2H)-ketone-2-yl) carbonyl] ethane synthetic
Take by weighing 1.6g selenium chlorine solid and put into small beaker and add the 26.5ml tetrahydrofuran (THF), the dissolving of selenium chlorine.In the 250ml there-necked flask, add the 6.9ml tetrahydrofuran (THF), with succinic diamide, the 1.68ml triethylamine of selenium chlorine equimolar amount, ice bath stirs and feeds nitrogen down.Selenium chlorine is splashed into there-necked flask, have yellow solid to generate, solution colour becomes yellow.Dropwise reaction after three hours, filtration under diminished pressure.Obtain yellow solid, it is yellow that filtrate is.Use the distilled water wash solid several times, the solid color shoals.Fusing point: 280 ℃-320 ℃
Embodiment 13
With above-claimed cpd 20mg of the present invention, add after soil temperature 80 stirs hydrotropies, add injection physiological saline 2ml, and to make the ultimate density of soil temperature 80 be 0.1%, sterilization filling is made injection after filtration.
Embodiment 14
With above-claimed cpd 50mg of the present invention and lactose 180mg, after starch 260mg and Magnesium Stearate 10mg mixed evenly, technology was made tablet routinely.
Compound of the present invention also can with other pharmaceutically acceptable vehicle or carrier routinely technology make formulations such as oral liquid, capsule or transfusion, and can make controlled release or slow-released system administration as required.
Embodiment 15 compound pharmacology activity researchs
One, the anti tumor activity in vitro of above-mentioned synthetic compound research
(1) the cell in vitro counting process is observed inhibition rate of tumor cell:
1. with compound of the present invention preparating liquid as follows, employed in the method compound is:
EbS-1
EIS
EITe
Above-mentioned three kinds of compounds with after the DMSO dissolving, are added 1640 substratum that do not contain foetal calf serum, and it is diluted to final concentration is 50 μ M.L
-1, 500 μ M L
-1Soup, wherein the final content of DMSO is less than 0.1% (v/v), and the administration volume of each cell hole is 1/10 of cell suspension and medicine liquid volume summation, promptly the final administration concentration of above-claimed cpd is 5 μ M.L
-1With 50 μ ML
-1
2. cell counting: with cleaning behind the 96% alcohol flushing tally, other cleans one of cover plate; Cover plate is overlayed on above the tally, makes it to shift to a side slightly, expose the tally table top a little, tally is lain on the stage of microscope, add the cell suspension that 1-2 drips lightly from the tally edge immediately, make it to be full of between tally and cover plate in the space.Mirror is observed down visible cell and is disperseed everywhere, and the healthy cell cell space is complete, and is transparent not painted, and all cytochromes are unhealthy person.Calculate the cell count in four jiaos of big grids, press the center line person only to calculate the left line and the person of reaching the standard grade, right line does not count with rolling off the production line.Gate time is 24h, 48h after the administration, 72h.And according to formula 1)-3) calculate the inhibiting rate of cell count and compound pair cell.
1) the big lattice total cellular score in cell count/milliliter stock suspension=4/4 * 10000 extension rates
2) cell survival rate %=(dosing group cell count/cellular control unit number) * 100
3) cell proliferation inhibition rate %=[1-(dosing group cell count/cellular control unit number)] * 100
3. experimental result sees Table 1 and table 2
Table 1: final administration concentration is 5 μ M.L
-1
| 5μM.L -1Group | 0h | 24h | 48h | 72h |
| EIS | 0 | 43.36％ | 36.90％ | 81.78％ |
| EbS-1 | 0 | -62.29％ | -34.05％ | -11.56％ |
| EITe | 0 | 37.94％ | 65.06％ | 38.19％ |
Table 2: final administration concentration is 50 μ M.L
-1
| 50μM.L -1Group | 0h | 24h | 48h | 72h |
| EIS | 0 | 59.79％ | 90.22％ | 77.55％ |
| EbS-1 | 0 | 75.06％ | 74.23％ | 91.81％ |
| EITe | 0 | 75.36％ | 94.66％ | 95.43％ |
(2) srb assay and mtt assay research compound is to the growth-inhibiting effect of tumour cell
1. wherein attached cell is adopted srb assay, and suspension cell adopts mtt assay to study the growth-inhibiting effect of compound to tumour cell, and the compound soup that uses is prepared in a manner described.
2.SRB method: the cell in the vegetative period of taking the logarithm (3-5 * 10
4Cells/ml), be inoculated in respectively in (180ul/ hole) in 96 well culture plates, place 37 ℃, 5%CO
2, behind the cultivation 24h, add the test-compound of 20ul different concns in the incubator of saturated humidity, place 37 ℃, 5%CO
2, continue to cultivate required time in the incubator of saturated humidity more respectively.Cell discards nutrient solution after end is cultivated in dosing, add 10% Tricholroacetic Acid (TCA) 100ul and place 4 ℃ of refrigerators, fixed cell 1 hour.After discarding cell fixation liquid, use deionized water rinsing culture plate aperture 5 times.After drying water, 96 orifice plates are placed air drying.Every hole adds 0.4% SRB solution (with the preparation of 1%HAC solution) 50 μ l, and room temperature was placed 10 minutes.After discarding unnecessary SRB, the acetum with 1% washes 96 orifice plates 5 times, removes not and protein bound SRB.After the drying of 96 orifice plates, place dry air.Every hole adds 10mmol/L non-buffering Tris alkali lye (PH10.5) 150 μ l, fully dissolved cell bonded SRB.After dull and stereotyped shaking table shakes up,, measure the OD value of each aperture at the 540nm place of TECAN SUNRISE Magellan 96 Well microplate reader (USA).
3.MTT method: the cell in the vegetative period of taking the logarithm (3-5 * 10
4Cells/ml), be inoculated in respectively in (180ul/ hole) in 96 well culture plates, place 37 ℃, 5%CO
2, behind the cultivation 4-6h, add the test-compound of 20ul different concns in the incubator of saturated humidity, place 37 ℃, 5%CO
2, continue to cultivate required time in the incubator of saturated humidity more respectively.Cell is after end is cultivated in dosing, and every hole adds MTT solution (with the preparation of sterilization 1 * PBS solution) the 20 μ l of 5mg/ml, places 37 ℃, 5%CO
2, continue to cultivate 4h in the incubator of saturated humidity.Then, culture plate is placed on the plate machine, carry out centrifugal, 3000r/min * 30min.After discarding supernatant, culture plate under the situation of lucifuge, is carried out dry air.Afterwards, every hole adds acidifying Virahol 150 μ l, dissolve the Formazan that viable cell generates fully after, at the 570nm place of TECAN SUNRISEMagellan 96 Well microplate reader (USA), measure the OD value of each aperture.
4. the analytical procedure of experimental result
Calculate used test hole OD value=test hole OD value-background OD value (being that perfect medium adds MTT, SRB, acellular).The OD value of repeating hole is mean value ± SD.
Cell survival rate %=(the OD value of the OD value/control cells of dosing cell) * 100
Cell proliferation inhibition rate %=[1-(the OD value of the OD value/control cells of dosing cell)] * 100
5. The compounds of this invention is to the growth-inhibiting exercising result brief summary of several tumour cells
Remarks:
(1) above-mentioned various tumour cell derives from College of Pharmacy, Beijing Univ screening center.
(2) wherein HL-60 is the human leukemia cell, also is suspended culture cell, and Bel-7402 is a human liver cancer cell, and Hela is a human cervical carcinoma cell, and BGC823 is a gastric carcinoma cells, and MDA-MB-435 is a human breast carcinoma, and PC-3MIE8 is a human prostata cancer.
Two, the extracorporeal antivirus effect activity research of The compounds of this invention
(1) extracorporeal antivirus effect of EITe, EIIIS and EIIISe test
Whole signs of the 2.2.15 cell strain energy effective expression hbv replication that HBV-DNA transfection human liver cancer cell strain Hep G2 is set up, this experiment is a target cell with the 2.2.15 cell strain, content by HBsAg and HBeAg in the detection culture supernatant, detect the antivirus action of EITe, EIIIS and EIIISe, and observe the antivirus action of other compounds.
After EITe, EIIIS and EIIISe added an amount of DMSO dissolving, add 10 times of distilled water dilutings after, make the compound water solution of desired concn, pair cell administration after carrying out the 0.2um filtration sterilization.
Get the 2.2.15 cell of well-grown state, be inoculated in 24 well culture plates, 37 ℃ cultivate 48 hours after, use the nutrient solution that contains different pharmaceutical concentration instead, changed once fresh pastille nutrient solution (concrete concentration sees the following form) every 3 days, twice totally, administration is collected supernatant liquor after 8 days altogether,-20 ℃ of preservations, HBeAg to be checked measures the cytotoxicity of medicine simultaneously.
The detection of HBsAg and HBeAg in the supernatant liquor, is drawn culture supernatant and is adopted ELISA to measure (test kit is created Science and Technology Ltd. available from Ying Kexin) in the time of 8 days in test, and method shown in the by specification detects.Inhibiting rate (%)=(control wells A
595-experimental port A
595)/(control wells A595-2.1) * 100%, ID
50It for the HBeAg inhibiting rate 50% o'clock drug level.
Measure cell survival rate to characterize the cytotoxicity of medicine by mtt assay.Cell survival rate (%)=experimental port (A
595-A
650)/control wells (A
595-A
650) * 100%, CD
50Be that the experimental group survivaling cell is 50% o'clock a drug level of control group.
Be subjected to anti--HBV activity, the wherein TI=CD of reagent thing with therapeutic index (Treaty Index:TI) evaluation
50/ ID
50When TI＜1, being subjected to the reagent thing is that poor efficiency is poisonous, is subjected to the reagent thing effectively poisonous when 1≤TI≤2, when TI 〉=2.1, is subjected to the reagent object height to imitate low toxicity, and TI is big more, shows that then this medicine is strong more to the restraining effect of HBV, and cytotoxicity is little.This experiment is as follows to the result of study of EITe, EIIIS and EIIISe:
| 30ug/ml | 15ug/ml | 7.5ug/ml | 3.75 ug/ml | 1.38 ug/ml | CD50 | ED50 | TI | |
| The EITe cell survival rate | 4.2 | 5.3 | 10.0 | 44.7 | 77.4 | 2.97 | ||
| The HbsAg inhibiting rate | 100 | 100 | 100 | 64.7 | 49.8 | 1.57 | 1.89 | |
| The HbeAg inhibiting rate | 73.4 | 64.1 | 64.1 | 48.4 | 31.3 | 4.57 | 0.65 | |
| The EIIIS cell survival rate | 51.5 | 60.1 | 65.3 | 90.2 | 95.9 | 22.52 | ||
| The HbsAg inhibiting rate | 100 | 80.4 | 58.8 | 56.8 | 49.8 | 2.94 | 7.65 | |
| The HbeAg inhibiting rate | 56.3 | 53.1 | 40.6 | 31.3 | 17.2 | 14.44 | 1.56 | |
| The EIIISe cell survival rate | 46.4 | 58.1 | 69.3 | 74.3 | 100 | 17.14 | ||
| The HbsAg inhibiting rate | 100 | 100 | 62.8 | 54.9 | 37.3 | 2.89 | 5.39 | |
| The HbeAg inhibiting rate | 62.5 | 51.6 | 40.6 | 31.3 | 28.1 | 12.40 | 1.58 |
TI＞2.1 of interpretation of result: EIIIS and EIIISe medicine HBsAg illustrate that the two medicine has the effect that suppresses cell HBsAg, and the TI of EITe＜2.1, then may be invalid.
Three, the in-vitro antibacterial of above-mentioned synthetic compound research
Send clinical pharmacology to carry out clinical common bacterial classification antibacterial activity test the synthetic a series of compounds of institute, the used test method is standard plate doubling dilution (with reference to microbial testing technology, Guo Jiyan edits calendar year 2001).Experimental result is as follows:
The MIC result of benzisothiazole, benzisoxa tellurium oxazole derivatives
Wherein EbS-1 is 8mg/L to the MIC value of 5 strain streptococcus aureuses, has bacteriostatic action.
Claims (10)
1, two benzisoxa sulfinpyrazone compounds of following general formula I or II:
R wherein
1And R
2Be identical or different, be selected from S independently of one another, Se or Te;
Wherein, work as R
1And R
2When being not Se simultaneously, R is C1-C20 linearity or branching, saturated or undersaturated bivalent hydrocarbon radical, the C6-C30 arylidene, the C5-C20 cycloalkylidene, the inferior heterocyclic radical of C5-C20 contains the C4-C30 bivalent hydrocarbon radical of carbocyclic ring, heterocycle or aromatic ring, and wherein carbocyclic ring, heterocycle or aromatic ring can be arranged in the chain or the end of the chain, organic radical alkylsulfonyl, or carbonyl organic radical carbonyl; Work as R
1And R
2When being Se simultaneously; R is the C5-C20 cycloalkylidene; the inferior heterocyclic radical of C5-C20; contain the C4-C30 bivalent hydrocarbon radical of carbocyclic ring, heterocycle or aromatic ring, wherein carbocyclic ring, heterocycle or aromatic ring can be arranged in the chain or the end of the chain, the organic radical alkylsulfonyl; or carbonyl organic radical carbonyl; all these groups are replacements or unsubstituted, and its carbochain can be inserted the one or more heteroatomss that are selected among O, N and the S arbitrarily, and described substituting group is selected from acidic group, ester group, hydroxyl, amino, halogen or amide group.
2, according to two benzisoxa sulfinpyrazone compounds of claim 1, wherein, work as R
1And R
2When being not Se simultaneously, R is (CH
2)
n-, wherein n is 1-8;-(C
6H
4)
n-, wherein n is 1-3;-(CH
2)
n-SS-(CH
2)
n-, wherein n is 1-3;-(CH
2)
n-NH-(CH
2)
n-, wherein n is 1-3; Or-(CH
2)
n-O-(CH
2)
n-, wherein n is 1-4; Work as R
1And R
2When being Se simultaneously, R is-(CH
2)
n-SS-(CH
2)
n-, wherein n is 1-3;-(CH
2)
n-NH-(CH
2)
n-, wherein n is 1-3; Or-(CH
2)
n-O-(CH
2)
n-, wherein n is 1-4.
3. described pair of benzisoxa sulfinpyrazone compound of claim 1 is selected from:
1) 1,2-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-ethane;
2) 1,3-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-propane;
3) 1,4-two [2-(1,2-benzisothiazole-3 (2H)-ketone)]-butane;
4) 1,2-two [2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)]-ethane;
5) 1-[2-(1,2-benzisothiazole-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)] ethane;
6) 1-[2-(1,2-benzisothiazole-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)] ethane;
7) 1-[2-(1,2-benzisothiazole-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)] ethane;
8) 1-[2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-2-[2-(1,2-benzisoxa tellurium azoles-3 (2H)-ketone)] ethane;
9) 1,2-two [2-(1,2-benzisoxa selenazoles-3 (2H)-ketone) methyl]-disulfide;
10) 1,4-two [2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-benzene;
11) 1,4-two [2-(1,2-benzisoxa selenazoles-3 (2H)-ketone)]-benzene sulfonyl; Or
12) 1,2-two [(1,2-benzisoxa selenazoles-3 (2H)-ketone-2-yl) carbonyl] ethane.
4, the preparation method of described pair of benzisoxa sulfinpyrazone compound of claim 1 may further comprise the steps:
With compound and the structural formula of following structural formula II I and IV is H
2N-R-NH
2Compound under-20 ℃ to 5 ℃ temperature, in inert solvent, under alkaline condition, under protection of inert gas, react,
R wherein
1And R
2Be identical or different, be selected from S independently of one another, Se or Te; Wherein, work as R
1And R
2When being not Se simultaneously, R is C1-C20 linearity or branching, saturated or undersaturated bivalent hydrocarbon radical, the C6-C30 arylidene, the C5-C20 cycloalkylidene, the inferior heterocyclic radical of C5-C20 contains the C4-C30 bivalent hydrocarbon radical of carbocyclic ring, heterocycle or aromatic ring, and wherein carbocyclic ring, heterocycle or aromatic ring can be arranged in the chain or the end of the chain, organic radical alkylsulfonyl, or carbonyl organic radical carbonyl; Work as R
1And R
2When being Se simultaneously; R is the C5-C20 cycloalkylidene; the inferior heterocyclic radical of C5-C20; the C4-C30 bivalent hydrocarbon radical that contains carbocyclic ring, heterocycle or aromatic ring; wherein carbocyclic ring, heterocycle or aromatic ring can be arranged in the chain or the end of the chain, organic radical alkylsulfonyl, or carbonyl organic radical carbonyl; the carbochain of all these groups can be inserted the one or more heteroatomss that are selected among O, N and the S arbitrarily, and described substituting group is selected from acidic group, ester group, hydroxyl, amino, halogen or amide group.
5, according to the preparation method of claim 4, wherein, work as R
1And R
2When being not Se simultaneously, R is (CH
2)
n-, wherein n is 1-8;-(C
6H
4)
n-, wherein n is 1-3;-(CH
2)
n-SS-(CH
2)
n-, wherein n is 1-3;-(CH
2)
n-NH-(CH
2)
n-, wherein n is 1-3; Or-(CH
2)
n-O-(CH
2)
n-, wherein n is 1-3; Work as R
1And R
2When being Se simultaneously, R is-(CH
2)
n-SS-(CH
2)
n-, wherein n is 1-3;-(CH
2)
n-NH-(CH
2)
n-, wherein n is 1-3; Or-(CH
2)
n-O-(CH
2)
n-, wherein n is 1-4.
6, the application of each described pair of benzisoxa sulfinpyrazone compound of claim 1-3 in the preparation antitumor drug.
7, the application of each described pair of benzisoxa sulfinpyrazone compound of claim 1-3 in the preparation antiviral.
8, the application of each described pair of benzisoxa sulfinpyrazone compound of claim 1-3 in the preparation antibacterials.
9, a kind ofly be used for antitumor, antiviral or the antimicrobial pharmaceutical composition, by each the described compound of claim 1-3 and the pharmaceutically acceptable carrier of pharmacy effective dose.
10, pharmaceutical composition according to claim 9, its pharmaceutical dosage form can be selected from tablet, capsule, oral liquid, injection, infusion preparation or slowly-releasing or controlled-release administrating system.
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| WO2021223780A2 (en) | 2020-05-06 | 2021-11-11 | 上海元熙医药科技有限公司 | Use of benzisoselazole derivative for anti-coronavirus and control of interstitial lung disease (ild) related to coronavirus |
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| JP2013043881A (en) * | 2011-08-26 | 2013-03-04 | Sumitomo Seika Chem Co Ltd | Method for producing 1,2-benzisothiazolin-3-one compound |
| CN106146371B (en) * | 2015-04-23 | 2018-05-15 | 南京凯熙医学科技有限公司 | Benzisoelenazolone class compound metabolites, its synthetic method and its application |
| CN110801449A (en) * | 2018-08-06 | 2020-02-18 | 上海元熙医药科技有限公司 | Application of benzisoselenazole derivative in preparation of tumor treatment drug |
| CN110856717A (en) * | 2018-08-06 | 2020-03-03 | 上海元熙医药科技有限公司 | Tumor immunomodulator and application thereof |
| CN113372296B (en) * | 2020-03-10 | 2024-08-23 | 杭州汉菁生物科技有限公司 | Selen compound for inhibiting multi-drug-resistant staphylococcus aureus and application thereof |
| CN113527301B (en) * | 2020-04-13 | 2024-05-17 | 凯熙医药（武汉）股份有限公司 | Tetrazine substituent-containing arylisoxazole compound and synthetic method and application thereof |
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