CN103554134B - Containing chromone structure isoxazole norcantharidin derivative and preparation method thereof and application - Google Patents
Containing chromone structure isoxazole norcantharidin derivative and preparation method thereof and application Download PDFInfo
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- CN103554134B CN103554134B CN201310574470.4A CN201310574470A CN103554134B CN 103554134 B CN103554134 B CN 103554134B CN 201310574470 A CN201310574470 A CN 201310574470A CN 103554134 B CN103554134 B CN 103554134B
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- isoxazole
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Abstract
The invention discloses a kind of novel containing chromone structure isoxazole norcantharidin derivative and preparation method thereof and application, the preparation of this derivative is with 1,3-dipole-diople interaction method C in Norcantharidin structure
5and C
6isoxazole ring is introduced in position, react import chromone structure with chromone derivative, thus synthesize a series of totally 6 novel contain chromone structure isoxazole norcantharidin derivative.Above-mentioned isoxazole norcantharidin derivative is applied to the synthesis of antitumor drug, has broad application prospects.
Description
Technical field
The invention belongs to medical art, particularly relate to a kind of novel containing chromone structure isoxazole norcantharidin derivative and preparation method thereof and application.
Background technology
Norcantharidin, chemical name: 7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic anhydride, CAS:[5442-12-6; 29745-04-8], chemical structural formula is as follows:
Cantharidin is the effective ingredient of research malignant tumor medicine.Modern study proves, it has certain curative effect to primary hepatocarcinoma, and has leukocyte increasing, not the advantage such as Immunosuppression system, therefore, has very high with researching value, causes the extensive concern of people.But the toxicity of Cantharidin is larger, synthesize very complicated, recent research shows, 2 have been lacked in Norcantharidin, two methyl of 3, Norcantharidin not only maintains stronger anti-tumor activity and unique function of increasing leukocyte, and toxicity reduces greatly, substantially eliminates Cantharidin and swashs side effect to urinary system telson.
Therefore, relevant with a Cantharidin backbone modification synthetic work be significant removes prosposition methyl substituted.This structural modification can not affect Cantharidin antitumour activity and toxicity decreases, and synthesis step simplifies.
Summary of the invention
The object of this invention is to provide a kind of chromone that utilizes to transform in the structure of isoxazole, structure of modification is carried out to Norcantharidin, improve the novel containing chromone structure isoxazole norcantharidin derivative of the activity of Norcantharidin, and provide its preparation method and application.
In order to solve the problems of the technologies described above, the present invention is solved by following technical proposals:
Containing chromone structure isoxazole norcantharidin derivative, its general structure is as follows:
Wherein, R
1hydrogen, hydroxyl, methyl, nitro, chlorine or bromine.
The described preparation method containing chromone structure isoxazole norcantharidin derivative, comprises the following steps:
Step 1): the synthesis of dehydronorcantharidiimide element: by MALEIC ANHYDRIDE porphyrize, add ether, is stirred to dissolving under room temperature condition, instillation furans, stirring at room temperature 24-48 hour, there is Diels-Alder and react in furans and MALEIC ANHYDRIDE, obtained dehydronorcantharidiimide element after filtration under diminished pressure;
Step 2): the synthesis of N-substituted dehydronorcantharidiimide imide: be dissolved in acetone solvent by dehydronorcantharidiimide element, under agitation drips the acetone soln of aniline, reacts and adds manganese acetate, triethylamine and aceticanhydride after 1 hour, at room temperature reacts 8 hours; The precipitation be obtained by reacting is dissolved in DMF after vacuum-drying, with dicyclohexylcarbodiimide stirring reaction 10 hours in ice-water bath, filtrate is placed in frozen water and obtains crystallization, then recrystallization obtains N-substituted dehydronorcantharidiimide imide;
Step 3): import chromone structure: be mixed in alcohol by N-substituted dehydronorcantharidiimide imide and chromone oxime, add a small amount of chloramine-T, reflux 12 hours, carry out addition reaction, use methyl alcohol recrystallize, vacuum-drying obtains product.
As preferably, described step 3) in the preparation method of chromone oxime as follows: in Erlenmeyer flask, add oxammonium hydrochloride and water, magnetic agitation is clearly molten to oxammonium hydrochloride, under agitation, takes chromone and ethanol is poured in Erlenmeyer flask, vigorous stirring, after question response is complete, regulates the pH value of reaction solution to be neutral with sodium carbonate solution, placement is cooled to room temperature, produce a large amount of yellow mercury oxide, after putting into refrigerator overnight, filtration under diminished pressure, drying at room temperature, obtains the yellow crystals of needle-like.
As preferably, described step 2) in the temperature of ice-water bath be down to 0 DEG C.
As preferably, described recrystallization adopts methyl alcohol.
The above-mentioned chromone structure isoxazole norcantharidin derivative that contains is for the synthesis of antitumor drug.
The reaction that the present invention relates to is as follows:
R
1hydrogen, hydroxyl, methyl, nitro, chlorine or bromine
4aR
1hydrogen; 4bR
1it is hydroxyl; 4cR
1it is methyl; 4dR
1it is nitro; 4eR
1chlorine; 4fR
1it is bromine
Find after deliberation, the oxygen in Norcantharidin five-ring can replace with nitrogen or sulfo-, and some substituting groups can be substituted on nitrogen and sulphur.Meanwhile, at C
5and C
6that upper replacement can also change structure activity.Contriver draws following experimental data through research work for this reason:
The present invention, owing to have employed above technical scheme, has significant technique effect:
The inventive method uses the structure of chromone oxime Dui isoxazole to transform, and carries out structure of modification, improve the anti-tumor activity of Norcantharidin to Norcantharidin.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail:
The general structure of the raw material of the inventive method synthesis norcantharidin derivative is as shown below:
Compound 5 is chromone derivative, is that chromone and oxammonium hydrochloride react the chromone oxime generated.
The preparation method of above-mentioned chromone oxime is as follows: in Erlenmeyer flask, and add oxammonium hydrochloride and water, magnetic agitation is clearly molten to oxammonium hydrochloride.Under agitation, chromone is taken and ethanol is poured in Erlenmeyer flask, vigorous stirring.After question response is complete, regulate the pH value of reaction solution to be neutral with sodium carbonate solution, place and be cooled to room temperature, produce a large amount of yellow mercury oxide, after putting into refrigerator overnight, filtration under diminished pressure, drying at room temperature, obtains the yellow crystals of needle-like.
Embodiment 1
(1) synthesis of dehydronorcantharidiimide element: add 15mL ethyl ester successively in 100mL Erlenmeyer flask, 4.00g (40mmol) Powdered MALEIC ANHYDRIDE.After MALEIC ANHYDRIDE dissolving, under stirring, add 2.76g (40.5mmol) furans.And then ambient temperatare puts 24-48 hour, the product obtained after reacting completely is carried out filtration under diminished pressure and obtains Norcantharidin.
(2) synthesis of N-substituted dehydronorcantharidiimide imide: get 3.32g (20mmol) Norcantharidin and be dissolved in 30mL acetone, joins acetone soln and compound 2 in reaction Erlenmeyer flask, has a large amount of precipitations to generate as seen.React at normal temperatures after 8 hours, by sedimentation and filtration, out final vacuum is dry, is dissolved in 20mL dimethyl formamide, is cooled to 0 DEG C.Be placed in ice-water bath, add 3.09g (15mmol) dicyclohexylcarbodiimide, stirring reaction 10 hours.Then cool, filter, filtrate is poured in 50mL frozen water, separate out solid.Filtered, washing, finally obtains product 3a-3f by recrystallizing methanol.
(3) chromone structure is imported: by 1mmolN-substituted dehydronorcantharidiimide imide and 1.1mmol chromone derivative in 20mL ethanol, then add 1.2mmol chloramine-T, reflux 12 hours.By sedimentation and filtration, by recrystallizing methanol, after vacuum-drying, obtain these 6 products of 4a, 4b, 4c, 4d, 4e, 4f.
Specific experiment data are as follows:
4,8-epoxy-5,7-(1H, 6H)-diketone-6-(4-phenyl-3a, 4,4a, 7a, 8,8a-six hydrogen-3-(4H-chromone-4-ketone)-[3,4-f]-1,2-Ben Bing isoxazole (4a)
This compound is yellow crystals, yield 53.4%, m.p.98.7-100.5 DEG C
1HNMR(CDCl3)δ:6.864-7.825(m,9H,Ar-H),7.425(s,1H,C
7-H),3.127(s,1H,C
1-H),2.572(s,1H,C
2-H),2.679(s,1H,C
3-H),3.471(s,1H,C
4-H),2.714(s,1H,C
5-H),2.627-2.638(d,J＝4.4Hz,1H,C
6-H).
IR3064(ArH),1773(C＝O),1603(C＝N),1186(C-O)cm
-1
m/e:428.10(100.0％),429.10(26.7％),430.11(4.6％).
Anal.calcd.forC
24H
15N
2O
6.C,67.29；H,3.76；N,6.54；O,22.41.
4,8-epoxy-5,7-(1H, 6H)-diketone-6-(4-hydroxyphenyl)-3a, 4,4a, 7a, 8,8a-six hydrogen-3-(4H-chromone-4-ketone)-[3,4-f]-1,2-Ben Bing isoxazole (4b)
This compound is red powder, yield 15.2%m.p.131.8-133.2 DEG C
1HNMR(CDCl3)δ:7.263-7.823(m,8H,Ar-H),7.542-7.561(d,J＝7.6Hz,1H,C
7-H),2.325(s,1H,C
1-H),2.174(s,1H,C
2-H),2.246(s,1H,C
3-H),2.417(s,1H,C
4-H),2.401(s,1H,C
5-H),2.409(s,1H,C
6-H),6.860(s,1H,C
8-H).
IR3076(ArH),1755(C＝O),1644(C＝N),1230(C-O)cm
-1
m/e:444.10(100.0％),445.10(26.4％),446.10(4.9％).
Anal.calcd.forC
24H
15N
2O
7.C,64.87；H,3.63；N,6.30；O,25.20.
4,8-epoxy-5,7-(1H, 6H)-diketone-6-(4-p-tolyl)-3a, 4,4a, 7a, 8,8a-six hydrogen-3-(4H-chromone-4-ketone)-[3,4-f]-1,2-Ben Bing isoxazole (4c)
This compound is red powder, yield 2.5%m.p.104.2-106.1 DEG C
1HNMR(DMSO)δ:6.608-7.301(m,8H,Ar-H),7.144(s,1H,C
7-H),3.068(s,1H,C
1-H),2.509-2.512(d,J＝1.2Hz,1H,C2-H),2.527-2.518(d,J＝3.6Hz,1H,C
3-H),3.492(s,1H,C4-H),2.854(s,1H,C
5-H),2.743-2.749(d,J＝2.4Hz,1H,C
6-H),2.343(s,3H,C
8-H).
IR3091(ArH),1777(C＝O),1600(C＝N),1189(C-O)cm
-1
m/e:442.12(100.0％),443.12(27.5％),444.12(5.0％).
Anal.calcd.forC
25H
17N
2O
6.C,67.87；H,4.10；N,6.33；O,21.70.
4,8-epoxy-5,7-(1H, 6H)-diketone-6-(4-nitrophenyl)-3a, 4,4a, 7a, 8,8a-six hydrogen-3-(4H-chromone-4-ketone)-[3,4-f]-1,2-Ben Bing isoxazole (4d)
This compound is yellow powder, yield 57.8%m.p.114.7-115.6 DEG C
1HNMR(CDCl3)δ:7.307-8.410(m,8H,Ar-H),7.203(s,1H,C
7-H),3.418(s,1H,C
1-H),2.712-2.719(d,J＝2.8Hz,1H,C
2-H),2.651(s,1H,C
3-H),3.448(s,1H,C
4-H),2.720(s,1H,C
5-H),2.609(s,1H,C
6-H).
IR3083(ArH),1718(C＝O),1603(C＝N),1196(C-O)cm
-1
m/e:473.09(100.0％),474.09(26.4％),475.09(5.2％),474.08(1.1％).
Anal.calcd.forC
24H
14N
3O
8.C,60.89；H,3.19；N,8.88；O,27.04.
4,8-epoxy-5,7-(1H, 6H)-diketone-6-(4-chloro-phenyl-)-3a, 4,4a, 7a, 8,8a-six hydrogen-3-(4H-chromone-4-ketone)-[3,4-f]-1,2-Ben Bing isoxazole (4e)
This compound is yellow powder, yield 57.8%m.p.143.7-145.0 DEG C
1HNMR(CDCl3)δ:7.307-8.410(m,8H,Ar-H),7.203(s,1H,C
7-H),3.418(s,1H,C
1-H),2.706(s,1H,C
2-H),2.658(s,1H,C
3-H),3.457(s,1H,C
4-H),2.711(s,1H,C
5-H),2.617(s,1H,C
6-H).
IR3045(ArH),1791(C＝O),1616(C＝N),1232(C-O)cm
-1
m/e:462.06(100.0％),464.06(32.2％),463.07(26.4％),465.06(8.6％),464.07(4.6％),466.07(1.1％).Anal.calcd.forC
24H
14ClN
2O
6.C,62.28；H,3.27；Cl,7.66；N,6.05；O,20.74.
4,8-epoxy-5,7-(1H, 6H)-diketone-6-(4-bromophenyl-hydrazine)-3a, 4,4a, 7a, 8,8a-six hydrogen-3-(4H-chromone-4-ketone)-[3,4-f]-1,2-Ben Bing isoxazole (4f)
This compound is red crystals, yield 37.3%, m.p.140.2-141.7 DEG C
1HNMR(CDCl3)δ:6.892-7.947(m,8H,Ar-H),7.219(s,1H,C
7-H),3.421(s,1H,C
1-H),2.717(s,1H,C
2-H),2.667(s,1H,C
3-H),3.462(s,1H,C
4-H),2.701(s,1H,C
5-H),2.628(s,1H,C
6-H).
IR3089(ArH),1716(C＝O),1558(C＝N),1186(C-O-C),1170(C-N)cm
-1
m/e:506.01(100.0％),508.01(97.5％),507.01(26.7％),509.01(26.2％),508.02(4.6％),510.02(3.3％),510.01(1.4％).
Anal.calcd.forC
24H
14BrN
2O
6.C,56.82；H,2.98；Br,15.75；N,5.52；O,18.92.
The antitumor cytolytic activity result of norcantharidin derivative
Mtt assay measures the In-vitro Inhibitory Effect of three series compounds to different knurl strain:
Compound DMSO is dissolved, dilution, tumour cell Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukemia cell), ECA109 (colon-cancer cell), plant into 4000/200 μ L/ holes on 96 orifice plates, every hole adds compound 2 μ L, final concentration is 12.0 μMs, 6.0 μM, 3.0 μM, 1.5 μMs, jointly in 37 DEG C, 5%CO
272 hours are hatched, with DMSO (1%) for blank in cell culture incubator.After 72 hours, add the MTT that final concentration is 0.25mg/mL, be placed in 37 DEG C, 5%CO
2in cell culture incubator 4 hours, blot solvent afterwards, every hole added 100 μ lDMSO, and measure absorbancy (OD value) with enzyme linked immunological instrument in 570nm place, the data obtained is for calculating IC
50value.Select the compound that inhibit activities is high, the compound effects time under different concns of the measuring different impact on human tumor cells cycle and apoptosis.
The test-compound of different concns carries out scalping with 96 orifice plates, according to the inhibiting rate of gained, calculates IC
50value, the results are shown in following table.
Norcantharidin derivative is to the IC of six kinds of tumor cell lines
50value
In a word, the foregoing is only preferred embodiment of the present invention, all equalizations done according to the present patent application the scope of the claims change and modify, and all should belong to the covering scope of patent of the present invention.
Claims (6)
1., containing chromone structure isoxazole norcantharidin derivative, its general structure is as follows:
；
Wherein, R
1hydrogen, hydroxyl, methyl, nitro, chlorine or bromine.
2. the preparation method containing chromone structure isoxazole norcantharidin derivative according to claim 1, is characterized in that, comprise the following steps:
Step 1): the synthesis of dehydronorcantharidiimide element: by MALEIC ANHYDRIDE porphyrize, add ether, is stirred to dissolving under room temperature condition, instillation furans, stirring at room temperature 24-48 hour, there is Diels-Alder and react in furans and MALEIC ANHYDRIDE, obtained dehydronorcantharidiimide element after filtration under diminished pressure;
Step 2): the synthesis of N-substituted dehydronorcantharidiimide imide: be dissolved in acetone solvent by dehydronorcantharidiimide element, under agitation drips the acetone soln of aniline, reacts and adds manganese acetate, triethylamine and aceticanhydride after 1 hour, at room temperature reacts 8 hours; The precipitation be obtained by reacting is dissolved in DMF after vacuum-drying, with dicyclohexylcarbodiimide stirring reaction 10 hours in ice-water bath, filtrate is placed in frozen water and obtains crystallization, then recrystallization obtains N-substituted dehydronorcantharidiimide imide;
Step 3): import chromone structure: be mixed in alcohol by N-substituted dehydronorcantharidiimide imide and chromone oxime, add a small amount of chloramine-T, reflux 12 hours, carry out addition reaction, use methyl alcohol recrystallize, vacuum-drying obtains product.
3. the preparation method containing chromone structure isoxazole norcantharidin derivative according to claim 2, it is characterized in that: in described step 3), the preparation method of chromone oxime is as follows: in Erlenmeyer flask, add oxammonium hydrochloride and water, magnetic agitation is clearly molten to oxammonium hydrochloride, under agitation, take chromone and ethanol is poured in Erlenmeyer flask, vigorous stirring, after question response is complete, the pH value of reaction solution is regulated to be neutral with sodium carbonate solution, placement is cooled to room temperature, produce a large amount of yellow mercury oxide, after putting into refrigerator overnight, filtration under diminished pressure, drying at room temperature, obtain the yellow crystals of needle-like.
4. the preparation method containing chromone structure isoxazole norcantharidin derivative according to claim 2, is characterized in that: described step 2) in the temperature of ice-water bath be down to 0 DEG C.
5. the preparation method containing chromone structure isoxazole norcantharidin derivative according to claim 2, is characterized in that: described recrystallization adopts methyl alcohol.
6. arbitrary described containing the application of chromone structure isoxazole norcantharidin derivative on synthesizing antineoplastic medicament according to claim 1-5.
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| Title |
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| 1,3-Dipolar Cycloaddition Reaction: Synthesis of Novel 5,6-Dehydronorcantharidin Derivatives of Substituted Aromatic Amines with potential antitumor activities;Li-Ping Deng，等;《J. Heterocyclic Chem.》;20050228;第42卷(第1期);标题，第14页合成路线1及其中化合物7a，第16页右栏合成方法内容 * |
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