CN106749218A - A kind of cumarin phenyl-isoxazole Zole derivatives and application thereof - Google Patents
A kind of cumarin phenyl-isoxazole Zole derivatives and application thereof Download PDFInfo
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Abstract
The present invention relates to a kind of cumarin phenyl-isoxazole Zole derivatives and application thereof, such compound is raw material with 4 ' hydroxylated chalcones, under the catalysis of potassium carbonate, 15 cumarin phenyl-isoxazole Zole derivatives is obtained with the bromomethyl isoxazole reaction containing different substituents.And investigated influence of this 15 cumarin phenyl-isoxazole Zole derivatives to melanogenesis in mouse B16 cells and to Candida albicans, Escherichia coli, three kinds of inhibitory action of bacterium of staphylococcus aureus.Anti- leucoderma result shows：Compared with negative control, 15 compound 6a 6o can promote the generation of melanocyte in B16 cells, and compared with positive control, compound 6b 6f and 6j 6o is superior to positive control to the facilitation of melanogenesis.The anti-bacterial result shows：Compound 6d 6f, 6i and 6l 6n have inhibitory action to Candida albicans, and cumarin phenyl-isoxazole Zole derivatives 6d 6f, 6i and 6l 6n can be used to clinically prepare the purposes in the medicine for the treatment of leucoderma or candida albicans infection.
Description
Technical field
The present invention relates to a kind of cumarin phenyl-isoxazole Zole derivatives and application thereof, such compound by anti-leucoderma and
Antimicrobial Screening, compound 6a-6o is used to clinically prepare the medicine for the treatment of leucoderma.Compound 6d-6f, 6i, 6l-6n use
In the medicine for clinically preparing treatment Candida albicans (Candida albicans) infection.
Background technology
Leucoderma is a kind of common spontaneous or idiopathic depigmentation dermatoses, is referred to as world's skin disease three big
One of chronic disease, perplexs the patient in the whole world more than 50,000,000.In the world, different geographical, not agnate intercurrent disease rate are from 0.1%-
8%, China population illness rate is 0.56% or so, and only about half of patient fell ill before 20 one full year of life, male and female
The illness rate of property is equal.Leucoderma is mainly shown as skin, the hickie of mucous membrane and ash/white hair etc..Doctor trained in Western medicine thinks leucoderma
It is the hypofunction of tyrosinase system in the melanocyte due to skin and hair follicle, loses and cause.
Psoralea corylifolia for pulse family annual herb plant Psoralea corylifolia (Psoralea corylifolia L.) drying and ripening really
It is real, record in《Chinese Pharmacopoeia》、《Uygur medicine will》、《Chinese book on Chinese herbal medicine-Uygur's bundling》Deng, be the successive dynasties tradition Uygur cure
Treat the main classical medicine of leucoderma.Uygur's medical science thinks that leucoderma is mainly caused by abnormal phlegm, advocates clear during treatment
Except abnormal humour, abnormal makings is corrected, so as to recover body natural force.Psoralea corylifolia have raw dry heat, remove abnormal lymphatic temperament,
The effects such as net blood detoxifies, increases pigment, kills anthelmintic.Additionally, Psoralea corylifolia also has antibacterial, estrogen-like action, antitumor, anti-
The multiple biological activities such as oxidation, immunological regulation and antidepression.
The medicine and preparation with plant Psoralea corylifolia as main component, are clinically mainly used in treating leucoderma at present：As again
Square Psoralea corylifolia particle, malaytea scurfpea injection, compound psorolea tincture, the white Ba Busi pieces of drive, compound kaliziranding (dimension medicine name Wei A
Dew) etc..Although dimension medicine treatment leucoderma effect is significant, with the obvious advantage, its material base studies weakness, mechanism of action and body
Inside and outside metabolic process is not also apparent, and serious constrains its secondary development.
By studying for many years, domestic and international researcher divides from Psoralea corylifolia (Psoralea corylifolia L.)
Separate out coumarin kind compound, flavonoids, terpene and a small amount of lipid and volatile oil.Wherein coumarin kind compound is used as it
In main chemical compositions, research range is most wide.
Numerous studies and case confirmation, after oral or external application coumarin kind compound, then coordinate daylight or long wave ultraviolet
(UVA) irradiate, leucoderma can be treated.This kind of therapy can activate tyrosinase activity, be catalyzed melanin genesis, promote melanocyte thin
The division and movement of born of the same parents, finally increase B16 cell, and hickie color is gradually recovered, so as to reach the mesh for the treatment of leucoderma
's.
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derivatives from Psoralea corylifolia and their structure-activity
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activities of Chinese medicinal plants traditionally used for the management
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medicinal herb-Psoralea corylifolia[J].Food Chem.,2005,91,287-292.
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K.K.Immunomodulatory and antitumour properties of Psoralea corylifolia seeds
[J].Fitoterapia,2000,71,223-231.
Chen Y.,Wang H.D.,Xia X.,Kung H.F.,Pan Y.,Kong L.D.Behavioral and
biochemical studies of total furocoumarins from seeds of Psoralea corylifolia
in the chronic mild stress model of depression in mice[J].Phytomedicine.2007,
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The present invention at home and abroad about patent, the comprehensive analysis of document and this seminar previous research work on the basis of,
Anti- leucoderma reactive compound-cumarin in the plant, has carried out further transformation and modification, by alkylation reaction
Phenyl substitution isoxazoles etc. are incorporated into cumarin molecule, its druggability are improved, and be have studied these phenyl-isoxazole azoles and spread out
The biological influence to melanogenesis in mouse B16 cells, to find evident in efficacy, target spot clearly, the mechanism of action clearly resists
Leucoderma new drug；In addition, these derivatives are investigated to Candida albicans (Candida albicans), Escherichia coli
(Escherichia coli), the inhibitory action of staphylococcus aureus (Staphylococcus aureus), to find tool
There is the drug candidate of antibacterial activity.
The content of the invention
It is an object of the present invention to provide a kind of cumarin phenyl-isoxazole Zole derivatives and application thereof.Such compound with
4 '-hydroxylated chalcone is raw material, under the catalysis of potassium carbonate, 15 is obtained with the bromomethyl isoxazole reaction containing different substituents
Individual cumarin phenyl-isoxazole Zole derivatives.And this 15 cumarin phenyl-isoxazole Zole derivatives have been investigated in mouse B16 cells
The influence of melanogenesis and to Candida albicans (Candida albicans), Escherichia coli (Escherichia coli), gold
Three kinds of inhibitory action of bacterium of staphylococcus aureus (Staphylococcus aureus).Anti- leucoderma result shows：With feminine gender
Control is compared, and 15 for obtaining compound (6a-6o) can promote the generation of melanocyte in B16 cells, and facilitation is from 115%
To 390%；Compared with positive control, compound 6b-6f, 6j-6o are superior to positive right to the facilitation of melanogenesis
According to wherein compound 6f is 2.6 times of positive control to the facilitation of melanogenesis.) be used equally to clinically prepare treatment
The medicine of leucoderma.The anti-bacterial result shows：Compound (6d-6f, 6i, 6l-6n) is to Candida albicans (Candida
Albicans) have an inhibitory action, and 6e-6f, 6l-6m activity close to positive control amphotericin B；Cumarin phenyl-isoxazole azoles
Derivative 6d-6f, 6i, 6l-6n can be used to clinically prepare the medicine for the treatment of Candida albicans (Candida albicans) infection
Thing.
A kind of structural formula of cumarin phenyl-isoxazole Zole derivatives of the present invention is：
Wherein：
Compound 6a is 7- ((3- (4- fluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6b is 7- ((3- phenyl-isoxazole azoles -5- bases) methoxyl group) -4- methyl -2H- chromen-2-ones；
Compound 6c is 7- ((3- (4- chlorphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6d is 7- ((3- (3- chlorphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6e be 7- ((3- (3,4- dichlorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -
2- ketone；
Compound 6f be 7- ((3- (3,5- dichlorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -
2- ketone；
Compound 6g be 7- ((3- (4- methoxyphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -
2- ketone；
Compound 6h be 7- ((3- (2- methoxyphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -
2- ketone；
Compound 6i is 7- ((3- (3- fluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6j is 7- ((3- (3- Trifluoromethoxyphen-l) isoxazole -5-bases) methoxyl group) -4- methyl -2H- benzos
Pyran-2-one；
Compound 6k is 7- ((3- (1,4- benzdioxan -6- base) isoxazole -5-bases) methoxyl group) -4- methyl -2H- benzene
And pyran-2-one；
Compound 6l be 7- ((3- (3,4- difluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -
2- ketone；
Compound 6m be 7- ((3- (3,5- difluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -
2- ketone；
Compound 6n is 7- ((3- (the fluoro- 4- chlorphenyls) isoxazole -5-bases of 3-) methoxyl group) -4- methyl -2H- benzo pyrroles
Mutter -2- ketone；
Compound 6o is 7- ((3- (the fluoro- 5- iodophenyls) isoxazole -5-bases of 2-) methoxyl group) -4- methyl -2H- benzo pyrroles
Mutter -2- ketone.
A kind of cumarin chalcone Isoxazole derivative of the present invention, its structure is as shown in logical formula (I)：
Wherein R is respectively 4- fluorine, hydrogen, 4- chlorine, 3- chlorine, 3,4- dichloros, 3,5- dichloros, 4- methoxyl groups, 2- methoxyl groups, 3-
Fluorine, 2- trifluoros methoxy, 3,4- [1,4] e dioxanes base, 3,4- difluoros, 3,5- difluoros, the fluoro- 4- chlorine of 3-, the fluoro- 5- iodine of 2-.
Cumarin phenyl-isoxazole Zole derivatives of the present invention and application thereof, wherein mend cumarin phenyl-isoxazole azoles deriving
The preparation method of thing, follow these steps to carry out：
A, at ambient temperature, by 4-methyl umbelliferone, the bromomethyl isoxazole containing R substituent and to dry potassium carbonate molten
Solution is heated to 56 DEG C in the dry acetone of 20ml, makes its back flow reaction 4h；
B, TLC detection reaction completely after, stopping react and filter, filter vacuum desolventizing, by residue use eluant, eluent for
The petroleum ether of volume ratio 8: 1-4: 1: ethyl acetate column chromatography gradient elution, cumarin phenyl-isoxazole Zole derivatives 6a-6o is obtained final product,
Chemical equation is：
(i) hydroxylamine hydrochloride, sodium carbonate, 30% methanol aqueous solution, room temperature；(ii) N- chlorosuccinimides, propilolic alcohol, three
Ethamine, dichloromethane, backflow；(iii) phosphorus tribromide, dichloromethane, 0 DEG C of temperature；(iv) ethyl acetoacetate, the concentrated sulfuric acid, temperature
60 DEG C of degree；(v) potassium carbonate, acetone, backflow；
Wherein R is respectively 4- fluorine, hydrogen, 4- chlorine, 3- chlorine, 3,4- dichloros, 3,5- dichloros, 4- methoxyl groups, 2- methoxyl groups, 3-
Fluorine, 2- trifluoros methoxy, 3,4- [1,4] e dioxanes base, 3,4- difluoros, 3,5- difluoros, the fluoro- 4- chlorine of 3-, the fluoro- 5- iodine of 2-.
Specific embodiment
According to embodiment, the present invention is further described, but the present invention is not limited only to these embodiments；
Reagent：It is pure that all reagents are commercially available analysis；
Embodiment 1
The preparation (4a-4o) of 3- substituted-phenyl -5- bromomethyl isoxazoles：
The synthesis of 1.1 Substituted benzaldoximes (2a-2o)：
By dissolution of benzaldehyde of the 10.0mmol containing different R substitutions in the methanol aqueous solutions of 30mL 30%, stirring is lower to be added
695mg(10.0mmol)NH2OHHCl, is slowly added to 530mg (5.0mmol) Na after dissolving2CO3, room temperature reaction 2h, Ran Houjia
Enter 30mL distilled water and 30mL dichloromethane is extracted 3 times, merge organic phase, use anhydrous Na2SO4Dry, filtering is removed under reduced pressure molten
Agent obtains corresponding Substituted benzaldoxime 2a-2o, and the next step is directly carried out without isolating and purifying；
The synthesis of 1.2 3- substituted-phenyls -5- Qiang methyl-isoxazoles (3a-3o)：
Benzaldoximes (2a-2o) of the 10.0mmol containing different R substitutions is dissolved in 30mL dichloromethane, is added in batches under stirring
Enter 1.60g (12.0mmol) N- chlorosuccinimides (NCS), after the whole dissolving of N- chlorosuccinimides is heated to slightly,
0.56g (10.0mmol) 2- propine -1- alcohol is added dropwise, 1.01g (10.0mmol) triethylamine is then added dropwise, be heated to reflux, TLC is indicated
Reaction end, after the completion of reaction, is cooled to room temperature, mother liquor washing, anhydrous Na2SO4Dry, filtering removes solvent under reduced pressure, will be residual
It is the petroleum ether of volume ratio 5: 1-2: 1 that slag uses eluant, eluent: ethyl acetate column chromatography gradient elution, obtains final product corresponding 3- substituted benzenes
Base -5- Qiang methyl-isoxazoles 3a-3o；
The synthesis of 1.3 3- substituted-phenyls -5- bromomethyls isoxazole (4a-4o)：
3-s substituted-phenyl -5- Qiang methyl-isoxazole (3a-3o) of the 10.0mmol containing different R substitutions is placed in 20ml dry
In dichloromethane, stirring dissolves it under ice bath, is slowly added dropwise 0.95mL (10.0mmol) phosphorus tribromide, continues after completion of dropping
Reacted under ice bath, after TLC Indicator Reactions terminate, to addition 20mL distilled water in reaction system, and pH is adjusted with 10%NaOH
To neutral, 30mL dichloromethane extraction 2 times, merge organic phase, anhydrous Na2SO4Dry, remove solvent under reduced pressure, residue is used and is washed
De- agent is the petroleum ether of volume ratio 8: 1-5: 1: ethyl acetate column chromatography gradient elution, obtains final product corresponding 3- substituted-phenyls -5- bromines
Methyl-isoxazole 4a-4o.
Embodiment 2
The preparation of 4-methyl umbelliferone (compound 5)：
Under condition of ice bath, 2.0g (18.2mmol) resorcinol is dissolved in dioxane solution, be slowly added dropwise
The 0.5ml concentrated sulfuric acids, and reacting liquid temperature is no more than 20 DEG C.After after completion of dropping, continuing to adding 2.8g in reaction solution
(21.8mmol) ethyl acetoacetate, and it is heated to 60 DEG C, after TLC detection raw materials all disappear, reaction solution is poured into frozen water, analysis
Go out a large amount of solids, filter, dry crude product obtains 2.87g 4-methyl umbelliferones (compound 5) after recrystallizing methanol.
Embodiment 3
7- ((3- (4- fluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6a)
Preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.307g (1.2mmol) 3- (4- fluorine) phenyl-
5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to temperature 56
DEG C, make its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, and filter vacuum desolventizing adopts residue
With the petroleum ether that eluant, eluent is volume ratio 6: 1: ethyl acetate column chromatography gradient elution, obtain final product 0.284g compounds 6a.
7- ((3- (4- fluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6a)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.83-7.76 (m, 2H), 7.55 (d, J=8.6Hz, 1H), 7.15 (t, J=
8.6Hz,2H),6.98-6.91(m,2H),6.66(s,1H),6.18(s,1H),5.27(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ167.37,165.19,162.70,160.46,155.12,152.31,
130.91,128.82,125.92,116.15,112.60,102.07,101.95,61.46,18.69。
Embodiment 4
The system of 7- ((3- phenyl-isoxazole azoles -5- bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6b)
It is standby：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.286g (1.2mmol) 3- phenyl -5- bromine first
Isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56 DEG C, it is flowed back
Reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, filter vacuum desolventizing, and it is body that residue is used into eluant, eluent
Product compares 8: 1 petroleum ether: ethyl acetate column chromatography gradient elution, obtains final product 0.286g compounds 6b.
The nuclear-magnetism of 7- ((3- phenyl-isoxazole azoles -5- bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6b)
Data：
1H NMR(400MHz,CDCl3) δ 7.84-7.77 (m, 2H), 7.54 (d, J=8.7Hz, 1H), 7.50-7.43 (m,
3H),6.98-6.91(m,2H),6.69(s,1H),6.17(s,1H),5.27(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ167.29,162.76,161.07,160.65,159.02,155.26,
152.41,130.40,129.12,127.00,126.04,114.72,112.82,112.52,102.17,61.62,18.82。
Embodiment 5
7- ((3- (4- chlorphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6c)
Preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.328g (1.2mmol) 3- (4- chlorine) phenyl-
5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56 DEG C, make
Its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, filter vacuum desolventizing, residue is used and is eluted
Agent is the petroleum ether of volume ratio 6: 1: ethyl acetate column chromatography gradient elution, obtains final product 0.301g compounds 6c.
7- ((3- (4- chlorphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6c)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.75 (d, J=8.5Hz, 2H), 7.55 (d, J=8.7Hz, 1H), 7.44 (d, J
=8.5Hz, 2H), 6.97-6.90 (m, 2H), 6.67 (s, 1H), 6.18 (s, 1H), 5.27 (s, 2H), 2.41 (s, 3H)
13C NMR(101MHz,CDCl3)δ167.66,161.80,161.05,160.58,155.27,152.40,
136.50,129.43,128.27,127.18,126.07,114.77,112.88,112.52,102.22,101.93,61.59,
18.83。
Embodiment 6
7- ((3- (3- chlorphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6d)
Preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.328g (1.2mmol) 3- (3- chlorine) phenyl-
5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56 DEG C, make
Its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, filter vacuum desolventizing, residue is used and is eluted
Agent is the petroleum ether of volume ratio 5: 1: ethyl acetate column chromatography gradient elution, obtains final product 0.297g compounds 6d.
7- ((3- (3- chlorphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6d)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.61-7.50 (m, 3H), 7.48-7.40 (m, 1H), 7.16 (td, J=8.3,
2.5,1H),6.98-6.91(m,2H),6.68(s,1H),6.18(s,1H),5.28(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ167.73,164.38,161.05,160.57,155.28,152.39,
130.80,126.07,122.75,117.47,117.26,114.78,114.14,113.92,112.89,112.51,102.14,
61.59,18.83。
Embodiment 7
7- ((3- (3,4- dichlorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6e) preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.368g (1.2mmol) 3- (3,4- dichloro)
Phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56
DEG C, make its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, and filter vacuum desolventizing adopts residue
With the petroleum ether that eluant, eluent is volume ratio 8: 1: ethyl acetate column chromatography gradient elution, obtain final product 0.322g compounds 6e.
7- ((3- (3,4- dichlorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6e) nuclear magnetic spectrogram：
1H NMR(400MHz,CDCl3)δ7.68-7.62(m,1H),7.57-7.52(m,3H),6.98-6.91(m,2H),
6.67(s,1H),6.18(s,1H),5.28(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ167.93,164.86,160.74,159.36,155.13,152.24,
131.07,130.23,128.67,127.31,125.93,114.67,112.78,112.35,102.05,101.68,61.42,
18.68。
Embodiment 8
7- ((3- (3,5- dichlorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6f) preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.368g (1.2mmol) 3- (3,5- dichloro)
Phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56
DEG C, after making its back flow reaction 4h, TLC detection reaction completely, stopping is reacted and is filtered, and filter vacuum desolventizing uses residue
Eluant, eluent is the petroleum ether of volume ratio 8: 1: ethyl acetate column chromatography gradient elution, obtains final product 0.310g compounds 6f.
7- ((3- (3,5- dichlorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6f) nuclear magnetic spectrogram：
1H NMR(400MHz,CDCl3) δ 7.70 (d, J=1.5Hz, 2H), 7.55 (d, J=8.7Hz, 1H), 7.45 (s,
1H),6.97-6.90(m,3H),6.67(s,1H),6.18(s,1H),5.28(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ168.24,161.02,160.47,159.56,155.28,152.37,
135.92,131.51,130.30,126.90,126.11,125.43,114.85,112.95,112.48,102.21,101.87,
61.57,18.84。
Embodiment 9
7- ((3- (4- methoxyphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6g) preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.322g (1.2mmol) 3- (4- methoxyl groups)
Phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56
DEG C, make its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, and filter vacuum desolventizing adopts residue
With the petroleum ether that eluant, eluent is volume ratio 6: 1: ethyl acetate column chromatography gradient elution, obtain final product 0.291g compounds 6g.
7- ((3- (4- methoxyphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6g) nuclear magnetic spectrogram：
1H NMR(400MHz,CDCl3) δ 7.74 (d, J=8.8Hz, 2H), 7.54 (d, J=8.6Hz, 1H), 7.01-6.90
(m, 4H), 6.63 (s, 1H), 6.17 (d, J=0.6Hz, 1H), 5.26 (s, 2H), 3.86 (s, 3H), 2.41 (s, 3H)
13C NMR(101MHz,CDCl3)δ167.00,162.35,161.34,161.09,160.68,155.27,
152.42,128.42,126.02,121.18,114.61,112.81,112.52,102.26,101.87,61.65,55.52,
18.82。
Embodiment 10
For 7-, ((3- (2- methoxyphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (are changed
Compound 6h) preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.322g (1.2mmol) 3- (2- methoxyl groups)
Phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56
DEG C, after making its back flow reaction 4h, TLC detection reaction completely, stopping is reacted and is filtered, and filter vacuum desolventizing uses residue
Eluant, eluent is the petroleum ether of volume ratio 5: 1: ethyl acetate column chromatography gradient elution, obtains final product 0.286g compounds 6h.
7- ((3- (2- methoxyphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6h) nuclear magnetic spectrogram：
1H NMR(400MHz,CDCl3) δ 7.89 (dd, J=7.7,1.5Hz, 1H), 7.54 (d, J=8.6Hz, 1H), 7.43
(td, J=8.5,1.6Hz, 1H), 7.07-6.93 (m, 4H), 6.90 (s, 1H), 6.17 (s, 1H), 5.26 (s, 2H), 3.91 (s,
3H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ165.78,161.15,160.84,160.40,157.36,155.27,
152.46,131.60,129.66,125.96,121.14,117.63,114.60,112.71,111.59,105.82,102.24,
61.59,55.74,18.83。
Embodiment 11
7- ((3- (3- fluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6i)
Preparation method：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.307g (1.2mmol) 3- (3- fluorine) phenyl-
5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56 DEG C, make
Its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, filter vacuum desolventizing, residue is used and is eluted
Agent is the petroleum ether of volume ratio 6: 1: ethyl acetate column chromatography gradient elution, obtains final product 0.275g compounds 6i.
7- ((3- (3- fluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones (compound 6i)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.61-7.50 (m, 3H), 7.48-7.40 (m, 1H), 7.16 (td, J=8.3,
2.5,1H),6.98-6.91(m,2H),6.68(s,1H),6.18(s,1H),5.28(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ167.73,164.38,161.05,160.57,155.28,152.39,
130.80,126.07,122.75,117.47,117.26,114.78,114.14,113.92,112.89,112.51,102.14,
61.59(s),18.83(s)。
Embodiment 12
7- ((3- (3- Trifluoromethoxyphen-l) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones
The preparation of (compound 6j)：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.386g (1.2mmol) 3- (3- trifluoro methoxies
Base) phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and be dissolved in the dry acetone of 50ml, heat
To 56 DEG C, make its back flow reaction 4h.After TLC detection reactions completely, stopping is reacted and is filtered, filter vacuum desolventizing, by residue
It is the petroleum ether of volume ratio 5: 1 to use eluant, eluent: ethyl acetate column chromatography gradient elution, obtains final product 0.321g compounds 6j.
7- ((3- (3- Trifluoromethoxyphen-l) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones
The nuclear magnetic data of (compound 6j)：
1H NMR(400MHz,CDCl3) δ 7.74 (d, J=7.8Hz, 1H), 7.67 (s, 1H), 7.58-7.47 (m, 2H),
7.35-7.29(m,1H),6.98-6.91(m,2H),6.70(s,1H),6.18(s,1H),5.28(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ167.93,161.59,161.05,160.55,159.49,155.28,
152.39,149.83,130.66,126.09,125.36,122.73,119.60,114.80,112.90,112.50,102.23,
101.99,61.58,18.83。
Embodiment 13
7- ((3- (1,4- benzdioxan -6- base) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
The preparation of ketone (compound 6k)：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.355g (1.2mmol) 3- (Isosorbide-5-Nitrae benzos two
Oxane -6- bases) phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and be dissolved in the dry acetone of 50ml
In, 56 DEG C are heated to, make its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, filter vacuum precipitation
Agent, it is the petroleum ether of volume ratio 5: 1 that residue is used into eluant, eluent: ethyl acetate column chromatography gradient elution, obtains final product 0.348g chemical combination
Thing 6k.
7- ((3- (1,4- benzdioxan -6- base) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
The nuclear magnetic data of ketone (compound 6k)：
1H NMR(400MHz,CDCl3) δ 7.73-7.67 (m, 1H), 7.53 (d, J=8.8,2H), 7.35-7.26 (m,
2H),6.97-6.90(m,2H),6.59(s,1H),6.17(s,1H),5.24(s,2H),4.29(s,4H),2.40(s,3H).
13C NMR(101MHz,CDCl3)δ167.89,167.02,162.23,161.10,160.67,155.26,
152.43,145.53,143.99,132.59,131.01,128.94,126.02,122.00,120.38,117.96,116.04,
114.69,112.80,112.51,102.26,101.96,64.65,64.43,61.62,18.82。
Embodiment 14
7- ((3- (3,4- difluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6l) preparation method：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.329g (1.2mmol) 3- (3,4- difluoro)
Phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56
DEG C, make its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, and filter vacuum desolventizing adopts residue
With the petroleum ether that eluant, eluent is volume ratio 8: 1: ethyl acetate column chromatography gradient elution, obtain final product 0.317g compounds 6l.
7- ((3- (3,4- difluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6l) nuclear magnetic data：
1H NMR(400MHz,CDCl3)δ7.70-7.62(m,1H),7.58-7.51(m,2H),7.30-7.22(m,1H),
6.98-6.90(m,2H),6.64(s,1H),6.18(s,1H),5.27(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ167.97,161.03,160.53,155.27,152.39,126.09,
123.45,118.26,118.08,116.31,116.12,114.80,112.90,112.50,102.20,101.84,61.56,
18.82。
Embodiment 15
7- ((3- (3,5- difluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6m) preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.329g (1.2mmol) 3- (3,5- difluoro)
Phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56
DEG C, make its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, and filter vacuum desolventizing adopts residue
With the petroleum ether that eluant, eluent is volume ratio 8: 1: ethyl acetate column chromatography gradient elution, obtain final product 0.308g compounds 6m.
7- ((3- (3,5- difluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6m) nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.55 (d, J=8.7Hz, 1H), 7.34 (d, J=6.2Hz, 2H), 6.99-6.87
(m,3H),6.66(s,1H),6.18(s,1H),5.28(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ168.20,161.02,160.49,155.28,152.38,126.10,
114.84,112.94,112.50,110.26,110.00,106.01,105.76,105.51,102.21,101.93,77.48,
77.16,76.84,61.55,18.83。
Embodiment 16
7- ((3- (the fluoro- 4- chlorphenyls) isoxazole -5-bases of 3-) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6n) preparation method：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.348g (1.2mmol) 3- (the fluoro- 4- chlorine of 3-)
Phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56
DEG C, make its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, and filter vacuum desolventizing adopts residue
With the petroleum ether that eluant, eluent is volume ratio 8: 1: ethyl acetate column chromatography gradient elution, obtain final product 0.293g compounds 6n.
7- ((3- (the fluoro- 4- chlorphenyls) isoxazole -5-bases of 3-) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6n) nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.62 (d, J=9.7Hz, 1H), 7.58-7.46 (m, 3H), 6.98-6.90 (m,
2H),6.66(s,1H),6.18(s,1H),5.28(s,2H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ168.07,161.03,160.51,155.28,152.38,131.46,
126.10,123.39,115.27,115.04,114.82,112.93,112.50,102.21,101.87,61.56,18.83。
Embodiment 17
7- ((3- (the fluoro- 5- iodophenyls) isoxazole -5-bases of 2-) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6o) preparation：
At ambient temperature, by 0.176g (1mmol) 4-methyl umbelliferone, 0.457g (1.2mmol) 3- (the fluoro- 5- iodine of 2-)
Phenyl -5- bromomethyls isoxazole and 0.414g (3.0mmol) dry potassium carbonate and are dissolved in the dry acetone of 50ml, are heated to 56
DEG C, make its back flow reaction 4h, after detecting reaction completely with TLC, stopping is reacted and is filtered, and filter vacuum desolventizing adopts residue
With the petroleum ether that eluant, eluent is volume ratio 8: 1: ethyl acetate column chromatography gradient elution, obtain final product 0.333g compounds 6o.
7- ((3- (the fluoro- 5- iodophenyls) isoxazole -5-bases of 2-) methoxyl group) -4- methyl -2H- chromen-2-one (chemical combination
Thing 6o) nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.32 (dd, J=6.7,2.0Hz, 1H), 7.76-7.69 (m, 1H), 7.55 (d, J
=8.7Hz, 1H), 7.01-6.90 (m, 3H), 6.82 (d, J=3.3Hz, 1H), 6.18 (s, 1H), 5.28 (s, 2H), 2.41 (s,
3H).
13C NMR(101MHz,CDCl3)δ167.51,161.12,160.58,156.88,155.24,152.48,
140.73,137.75,136.42,126.05,118.80,117.65,114.74,112.59,104.52,102.18,61.47,
18.82。
Embodiment 18
Purposes of the described cumarin phenyl-isoxazole Zole derivatives in treatment leucoderma medicament is prepared, by embodiment 2-17
Effect of the compound 5 and compound 6a-6o of acquisition to the melanin genesis of B16 melanoma cells is determined：
(1) screening model：Murine melanoma cells B16；
(2) cell derived：Chinese Academy of Sciences's cell bank is provided；
(3) condition of culture：10% hyclone, 1% dual anti-DMEM in high glucose culture medium are added not after carrying out cultured cells 24h
With the medicine and positive control of concentration, tyrosine activity and melanin content are determined in 48h and 72h respectively；
(4) assay method：
Protein quantification is determined with Bradford methods：
Protein standard substance (5mg/mlBSA) is completely dissolved, 10 μ l is taken and is diluted to 100 μ l, make final concentration of 0.5mg/ml.Egg
In what solution, standard items also preferably use that what solution dilutes to white sample.But for simplicity, it is also possible to use 0.9%
NaCl or PBS dilution standard product；Standard items (0.5mg/mlBSA) are added separately to by 0,1,2,4,8,12,16,20 μ l after diluting
In 96 orifice plates, plus standard dilutions supply to 20 μ l all standard items；Plus proper volume sample is to the sample well of 96 orifice plates
In, plus standard dilutions are supplied to 20 μ l；Each hole adds 200 μ l Bradford dyeing liquors, and mixing is gently blown and beaten with sample loading gun
(being careful not to make aeration reading) room temperature is placed 3-5 minutes；A595 is determined with ELIASA；Calculated according to standard curve
Protein concentration in sample；
The content of melanocyte is measured with alkali digestion：
Be in the B16 melanoma cells of exponential phase be inoculated in 6cm culture dishes in, concentration be 2 × 105Individual/ml, respectively
Hole adds 5ml cell suspending liquids；After inoculation 12h, the medication after cell is completely adherent, Drug level is respectively 5,10,20 and 40 μ g/
ml；Cell is collected after 72h；The 1MNaOH/10%DMSO solution of 200 μ l is added in the case of not smudge cells, 80 DEG C are put
Determine absorption value A in water-bath after 2h at 470nm.Non- medication group (negative control group) is contrasted with medication group as a control group
It is shown in Table 1：
The cumarin phenyl-isoxazole Zole derivatives 6a-6o of table 1 is to melanin genesis in cell and the antibacterial activity knot of three kinds of bacteriums
Really
Embodiment 19
Purposes of the described cumarin phenyl-isoxazole Zole derivatives in antibacterials are prepared, embodiment 2-17 is obtained
Compound 5 and compound 6a-6o are to Candida albicans (Candida albicans), Escherichia coli (Escherichia
Coli), the inhibitory action of staphylococcus aureus (Staphylococcus aureus) is determined：
(1) melt agar medium, treat that its temperature is down to 46 ± 0.5 DEG C, add cultured bacterium solution, hang test organisms
Liquid concentration is 5 × 105Cfu/ml~5 × 106Cfu/ml, is down flat ware, and 15-20ml/ wares, placement 20mine solidifies it.
(2) punched with Gelose punch, a diameter of 5-6mm, 4-5 hole/ware are uniformly distributed, between each print center apart
More than 25mm, with the periphery of flat board at a distance of more than 15mm.
(3) sample concentration is 100mg/ml (100mM)；Add the μ l of sample solution 20 per hole, cover plate, be placed in 37 DEG C of temperature
Incubator 30-60min, makes solution be absorbed completely, is inverted culture 16h-18h, with the diameter of vernier caliper measurement antibacterial ring size simultaneously
Record.Compound and positive controls are shown in Table 1 to the inhibitory action of three kinds of bacterial strains.
(4) evaluate
The judgement of bacteriostasis:
Inhibition zone diameter is more than 7mm person, has been judged to bacteriostasis.
Inhibition zone diameter is less than or equal to 7mm person, is judged to without bacteriostasis.
Claims (3)
1. a kind of cumarin phenyl-isoxazole Zole derivatives, it is characterised in that the structure of such compound is：
Wherein：
Compound 6a is 7- ((3- (4- fluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones；
Compound 6b is 7- ((3- phenyl-isoxazole azoles -5- bases) methoxyl group) -4- methyl -2H- chromen-2-ones；
Compound 6c is 7- ((3- (4- chlorphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones；
Compound 6d is 7- ((3- (3- chlorphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones；
Compound 6e is 7- ((3- (3,4- dichlorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6f is 7- ((3- (3,5- dichlorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6g is 7- ((3- (4- methoxyphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6h is 7- ((3- (2- methoxyphenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6i is 7- ((3- (3- fluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromen-2-ones；
Compound 6j be 7- ((3- (3- Trifluoromethoxyphen-l) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -
2- ketone；
Compound 6k is 7- ((3- (1,4- benzdioxan -6- base) isoxazole -5-bases) methoxyl group) -4- methyl -2H- benzo pyrroles
Mutter -2- ketone；
Compound 6l is 7- ((3- (3,4- difluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6m is 7- ((3- (3,5- difluorophenyl) isoxazole -5-bases) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6n is 7- ((3- (the fluoro- 4- chlorphenyls) isoxazole -5-bases of 3-) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone；
Compound 6o is 7- ((3- (the fluoro- 5- iodophenyls) isoxazole -5-bases of 2-) methoxyl group) -4- methyl -2H- chromenes -2-
Ketone.
2. compound 6a-6o is preparing treatment leucoderma in a kind of cumarin phenyl-isoxazole Zole derivatives as claimed in claim 1
Purposes in the medicine of wind.
3. compound 6d-6f, 6i and 6l-6n are making in a kind of cumarin phenyl-isoxazole Zole derivatives as claimed in claim 1
Purposes in the medicine of standby treatment Candida albicans Candida albicans infection.
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|---|---|---|---|---|
| CN109293616A (en) * | 2018-09-29 | 2019-02-01 | 贵州大学 | One kind chalcones containing cumarin derivative, preparation method and application |
| CN115677607A (en) * | 2022-11-16 | 2023-02-03 | 遵义医科大学 | Isoxazole amide derivative and preparation method and application thereof |
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| US2073563A (en) * | 1936-05-28 | 1937-03-09 | Lonnie H Phillips | Log loading device |
| CN105801509A (en) * | 2016-05-03 | 2016-07-27 | 中国科学院新疆理化技术研究所 | Preparation method and application of phenylisoxazole-containing chalcone derivatives |
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| US2073563A (en) * | 1936-05-28 | 1937-03-09 | Lonnie H Phillips | Log loading device |
| CN105801509A (en) * | 2016-05-03 | 2016-07-27 | 中国科学院新疆理化技术研究所 | Preparation method and application of phenylisoxazole-containing chalcone derivatives |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293616A (en) * | 2018-09-29 | 2019-02-01 | 贵州大学 | One kind chalcones containing cumarin derivative, preparation method and application |
| CN109293616B (en) * | 2018-09-29 | 2022-06-21 | 贵州大学 | Coumarin-containing chalcone derivatives, and preparation method and application thereof |
| CN115677607A (en) * | 2022-11-16 | 2023-02-03 | 遵义医科大学 | Isoxazole amide derivative and preparation method and application thereof |
| CN115677607B (en) * | 2022-11-16 | 2023-10-31 | 遵义医科大学 | Isoxazole amide derivative and preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN106749218B (en) | 2019-06-04 |
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