CN106543197B - A kind of psoralen Schiff bases derivative and purposes - Google Patents
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract
The present invention relates to a kind of psoralen Schiff bases derivative and purposes.Such compound is 4 methyl, 7 Hydroxycoumarin（Intermediate 1）；4 methyl, 7 hydroxy ethoxy cumarin（Intermediate 2）；4 methyl, 7 formyl methoxy coumarin（Intermediate 3）；5 methyl 7HFurans [3,2g] 7 ketone of chromene（Compound 4）；7 oxos 7HFurans [3,2g] 5 formaldehyde of chromene（Compound 5）；Compound 6a 6k.And the influence of melanogenesis and the inhibiting effect to Candida albicans, Escherichia coli, staphylococcus aureus in this 11 psoralen Schiff bases Derivatives In Mice B16 cells are investigated.Its result compound 6a 6b, compound 6d 6f and compound 6j 6k are used equally for clinically preparing the drug for the treatment of leucoderma.The psoralen Schiff bases derivative obtained is used equally for clinically preparing the drug for the treatment of candida albicans infection, and compound 6b 6c, 6e 6h and 6k can be additionally used in the drug for clinically preparing treatment infection of staphylococcus aureus.
Description
Technical field
The present invention relates to a kind of psoralen Schiff bases derivative and purposes, such compound is by anti-leucoderma and resists
Bacterium screening active ingredients, compound 6a-6b, 6d-6f, 6j-6k are used equally for purposes in the drug for clinically preparing treatment leucoderma.Institute
There is psoralen Schiff bases derivative to be used equally for clinically preparing treatment Candida albicans (Candida albicans) sense
Purposes in the drug of dye, and compound 6b-6c, 6e-6h, 6k can also be used to clinically prepare treatment staphylococcus aureus
Purposes in the drug of (Staphylococcus aureus) infection.
Background technology
Leucoderma is a kind of common spontaneous or idiopathic depigmentation dermatoses, and it is big to be referred to as world's skin disease three
One of chronic disease perplexs the patient in 50,000,000 or more the whole world.In the world, different geographical, not agnate intercurrent disease rate are from 0.1%-
8% differs, and China's population illness rate is 0.56% or so, and approximately 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 caused by the hypofunction, forfeiture of tyrosinase system in the melanocyte of skin and hair follicle.
Psoralea corylifolia is the drying and ripening fruit of pulse family annual herb plant psoralea corylifolia (Psoralea corylifolia L.)
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 drug of leucoderma.Uygur's medicine thinks that leucoderma is mainly caused by abnormal phlegm, advocates when treatment clear
Except abnormal humour, abnormal makings is corrected, to restore body natural force.Psoralea corylifolia have raw dry heat, remove abnormal lymphatic temperament,
Net blood removing toxic substances increases pigment, kills anthelmintic and other effects.In addition, psoralea corylifolia also has antibacterial, estrogen-like action, antitumor, anti-
The multiple biological activities such as oxidation, immunological regulation and antidepression.
At present with plant psoralea corylifolia drug as main component and preparation, clinically it is mainly used for treating leucoderma：As again
Square psoralea corylifolia particle, compound psorolea tincture, drives white Ba Busi pieces, compound kaliziranding (dimension medicine name Wei A at malaytea scurfpea injection
Dew) etc..Although tieing up medicine treats leucoderma significant effect, with the obvious advantage, the research of its material base is weak, mechanism of action and body
Inside and outside metabolic process is not also apparent, serious to constrain its secondary development.
By studying for many years, domestic and international researcher divides from psoralea corylifolia (Psoralea corylifolia L.)
Separate out Psoralens resistance compound (furocoumarin compound), flavonoids, terpene and a small amount of lipid and volatile oil.Its
Middle Psoralens resistance compound (furocoumarin compound) is used as main chemical compositions therein, research range most wide.
Psoralens resistance compound (Psoralen) is the current most common photosensitizer of clinical treatment leucoderma, but
It is that must coordinate daylight or long wave ultraviolet (UVA) irradiation treatment, so such therapy is known as PUVA (Psoralen+
UVA).It is later and artificial synthesized there are commonly 8-methoxypsoralen (8-MOP) and 5-bergapten (5-MOP)
Trimethyl psoralen (TMP), as shown in structure.In the treatment of leucoderma, PUVA can activate tyrosinase activity, catalysis
Melanin genesis promotes the division and movement of melanocyte, finally B16 cell is made to increase, and hickie color is gradually restored.
The structure of three kinds of common Psoralens resistance compounds
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The present invention at home and abroad in relation to patent, the comprehensive analysis of document and this seminar previous research work on the basis of,
Reactive compound-psoralen in the plant is further transformed and is modified, by condensation reaction by substituted-phenyl
Etc. being introduced into psoralen molecules, its druggability is improved, and have studied in these Schiff bases Derivatives In Mice B16 cells
The influence of melanogenesis, to find that significant in efficacy, target spot is clear, the mechanism of action clearly anti-leucoderma new drug；In addition to this,
Be investigated these derivatives to Candida albicans (Candida albicans), Escherichia coli (Escherichia coli),
The inhibiting effect of staphylococcus aureus (Staphylococcus aureus), to find the candidate medicine with antibacterial activity
Object.
Invention content
The object of the present invention is to provide a kind of psoralen Schiff bases derivative and purposes.Such compound with
Benzenediol is starting material, under the action of sulfuric acid, obtains 4-methyl-7-hydroxycoumarin (intermediate 1)；4- methyl -7- hydroxyls
Ethoxy coumarin (intermediate 2)；4- methyl -7- formyls methoxy coumarins (intermediate 3)；5- methyl -7H- furans [3,2-
G] chromene -7- ketone (compound 4)；7- oxo -7H- furans [3,2-g] chromene -5- formaldehyde (compound 5)；Compound
6a-6k.And the influence of melanogenesis and dialogue in this 11 psoralen Schiff bases Derivatives In Mice B16 cells are investigated
Color candida albicans (Candida albicans), Escherichia coli (Escherichia coli), staphylococcus aureus
The inhibiting effect of (Staphylococcus aureus) three kinds of bacteriums.Its result compound 6a-6b, compound 6d-6f and chemical combination
Object 6j-6k is used equally for clinically preparing the drug for the treatment of leucoderma.The psoralen Schiff bases derivative obtained
The drug infected for clinically preparing treatment Candida albicans (Candida albicans), and compound 6b-6c, 6e-6h,
6k can also be used to clinically prepare the drug that treatment staphylococcus aureus (Staphylococcus aureus) infects.
A kind of psoralen Schiff bases derivative of the present invention, such derivant structure are：
Wherein：
Compound 6a is (Z) -5- (2- aminomethyl phenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6b is (Z) -5- (4- aminomethyl phenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6c is (Z) -5- (4- chlorphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6d is (Z) -5- (phenyl imine) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6e is (Z) -5- (4- methoxyphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6f is (Z) -5- (3.4- 3,5-dimethylphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6g is (Z) -5- (4- fluorophenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6h is (Z) -5- (3,4- difluorophenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6i is (Z) -5- (3- chlorphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6j is (Z) -5- (2- methoxyphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6k is (Z) -5- (4- hydroxybenzeneiminos) methyl -7H- furans [3,2-g] chromene -7- ketone.
The purposes of the psoralen Schiff bases derivative, compound 6a-6b, compound 6d-6f and compound 6j-
Purposes of the 6k in the drug for preparing treatment leucoderma.
Purposes of the psoralen Schiff bases derivative in the drug for preparing treatment candida albicans infection.
The psoralen Schiff bases derivative purposes, compound 6b-6c, compound 6e-6h and compound 6k exist
Prepare the purposes in the drug for the treatment of infection of staphylococcus aureus.
A kind of psoralen Schiff bases derivative and purposes, the analog derivative of the present invention are with resorcinol
Beginning raw material is condensed to yield 4-methyl-7-hydroxycoumarin (intermediate 1) with ethyl acetoacetate first under the action of sulfuric acid；
4- methyl -7- hydroxy ethoxies cumarins (intermediate 2) are obtained by the reaction in intermediate 1 with chlorethanol again；Then intermediate 2 is aoxidized
To 4- methyl -7- formyls methoxy coumarins (intermediate 3)；Next, intermediate 3 is under the catalysis of sodium hydroxide (NaOH),
Cyclization forms furan nucleus, to obtain 5- methyl -7H- furans [3,2-g] chromene -7- ketone (compound 4)；
After having obtained parent nucleus compound 4, its 5- methyl further is aoxidized using selenium dioxide, obtains 7- oxo -7H- furans
It mutters [3,2-g] chromene -5- formaldehyde (compound 5)；Compound 5 is condensed to yield compound 6a- from different substituted anilines
6k；
And the influence of melanogenesis and right is investigated in this 11 psoralen Schiff bases Derivatives In Mice B16 cells
Candida albicans (Candida albicans), Escherichia coli (Escherichia coli), staphylococcus aureus
The inhibiting effect of (Staphylococcus aureus) three kinds of bacteriums, result：
Anti- leucoderma result is shown：Compared with negative control, totally 7 compounds are equal by compound 6a-6b, 6d-6f, 6j-6k
It can promote the generation of melanocyte in B16 cells, and facilitation is differed from 116% to 237%；Compared with positive control, compound
6a-6b, 6e-6f, 6j-6k are superior to positive control to the facilitation of melanogenesis, and wherein compound 6k is to melanogenesis
1.8 times close to positive control of facilitation.Psoralen Schiff bases derivative 6a-6b, 6d-6f, 6j-6k are used equally for facing
The drug for the treatment of leucoderma is prepared on bed；
The anti-bacterial result is shown：All psoralen Schiff bases derivatives are to Candida albicans (Candida albicans)
There is inhibiting effect, and 6g-6h's is active close to positive control amphotericin B；Compound 6b-6c, 6e-6h, 6k are to golden yellow
Staphylococcus (Staphylococcus aureus) also shows inhibiting effect, and the activity of compound 6h is right close to the positive
According to ampicillin.All psoralen Schiff bases derivatives are used equally for clinically preparing treatment Candida albicans (Candida
Albicans) the drug infected, and compound 6b-6c, 6e-6h, 6k can also be used to clinically prepare treatment Staphylococcus aureus
The drug of bacterium (Staphylococcus aureus) infection.
A kind of psoralen Schiff bases derivative of the present invention and purposes, structure is as shown in logical formula (I)：
Wherein R1Respectively 2- methyl, 4- methyl, 4- chlorine, hydrogen, 4- methoxyl groups, 3,4- dimethyl, 4- fluorine, 3,4- difluoros,
3- fluorine, 2- methoxyl groups, 4- hydroxyls.
Psoralen Schiff bases derivative of the present invention and purposes, wherein psoralen Schiff bases derivative
Preparation method follows these steps to carry out：
The preparation of intermediate 1：
A, under condition of ice bath, resorcinol is dissolved in suitable dry Isosorbide-5-Nitrae-dioxane, is stirred to all molten
Solution, is slowly added dropwise the concentrated sulfuric acid, so that its temperature is no more than 20 DEG C, after being added dropwise, adds ethyl acetoacetate, then heat to
60 DEG C, being sufficiently stirred makes it the reaction was complete, and reaction solution pours into ice water, adopts and is extracted with ethyl acetate after standing, organic to be harmonious
And it is dry, intermediate Isosorbide-5-Nitrae-Methyl-7-hydroxy-coumarin is obtained after concentration；
The preparation of intermediate 2：
B, appropriate potassium carbonate and 4-methyl-7-hydroxycoumarin are dissolved in the acetone of 20mL, and ethylene chlorhydrin are added,
Back flow reaction all disappears to raw material, reaction solution filtering, and residue is used column chromatography gradient elution by concentration, and eluant, eluent is volume
Petroleum ether than 1: 1: ethyl acetate is to get intermediate 2,4- methyl -7- hydroxy ethoxy cumarins；
The preparation of intermediate 3：
C, by oxalyl chloride as dimethyl sulfoxide (DMSO) (DMSO) in -78 DEG C of low-temp reaction device, is slowly added dropwise, stirring half is small
When, then the obtained 4- methyl -7- ethoxys oxygroup cumarins of step b are dissolved in dry dichloromethane, it is slowly added dropwise
It into reaction system, stirs half an hour, then it is complex dissociation formed in reaction system that triethylamine, which is added dropwise, drips after being added dropwise
Room temperature is slowly extended to after adding, reaction solution is washed three times, and organic phase is dried overnight, and is concentrated to give intermediate 3,4- methyl 7- formyls
Methoxy coumarin；
The preparation of compound 4：
D, the NaOH aqueous solutions of 1mol/L are prepared, heating makes its reflux, by obtained 4- methyl -7- formyls in step c
Methoxy coumarin is dissolved in 1-, in 4 dioxane, is slowly added dropwise into the NaOH aqueous solutions of reflux, is sufficiently stirred and keeps
Back flow reaction all disappears to raw material, is cooled to room temperature, and 1mol/L hydrochloric acid solutions are added and adjust pH to neutrality, ethyl acetate extraction
It takes, merges organic phase, concentration, it is the petroleum ether of volume ratio 7: 1: acetic acid second that residue, which is used column chromatography gradient elution, eluant, eluent,
Ester is to get compound 4,5- methyl -7H- furans [3,2-g] chromene -7- ketone；
The preparation of compound 5：
E, the obtained compounds 4 of step d and selenium dioxide are dissolved in dry dimethylbenzene, are heated to back flow reaction,
It after raw material all disappears, is cooled to room temperature, mother liquor filtering, residue is used column chromatography gradient elution by concentration, and eluant, eluent is body
Product ratio 10:1 petroleum ether: ethyl acetate is to get compound 5,7- oxo -7H- furans [3,2-g] chromene -5- formaldehyde；
The preparation of compound 6a-6k：
F, obtained compound 5 in step e and corresponding substituted aniline are dissolved in absolute ethyl alcohol, back flow reaction is straight
It all disappears to raw material, is cooled to room temperature, concentrates, it is volume ratio 15: 1-that residue, which is used column chromatography gradient elution, eluant, eluent,
10:1 petroleum ether: ethyl acetate is to get compound 6a-6k.
Psoralen Schiff bases derivative of the present invention and purposes, wherein psoralen Schiff bases derivative,
Be using resorcinol as starting material, obtained with ethyl acetoacetate under the action of sulfuric acid 4- methylumbelliferones (in
Mesosome 1)；4- methyl -7- hydroxy ethoxies cumarins (intermediate 2) are obtained by the reaction in intermediate 1 with chlorethanol again；Oxidation intermediates 2
Ethoxy obtain 4- methyl -7- formyls methoxy coumarins (intermediate 3)；Cyclization obtains intermediate 3 in the presence of alkali again
5- methyl -7H- furans [3,2-g] chromene -7- ketone (compound 4)；Further oxidation 4 obtains 7- oxo -7H- furans
[3,2-g] chromene -5- formaldehyde (compound 5)；Finally, compound 5 is condensed to yield compound from different substituted anilines
6a-6k.Chemical equation is：
(i) ethyl acetoacetate, the concentrated sulfuric acid, 60 DEG C；(ii) chlorethanol, potassium carbonate, acetone, reflux；(iii) temperature -78
DEG C, oxalyl chloride, dimethyl sulfoxide (DMSO), triethylamine, dichloromethane；(iv) 1M sodium hydrate aqueous solutions, Isosorbide-5-Nitrae-dioxane；(v) two
Selenium oxide, dimethylbenzene, reflux；(vi) absolute ethyl alcohol, reflux；Wherein R1Respectively 2- methyl, 4- methyl, 4- chlorine, hydrogen, 4- methoxies
Base, 3,4- dimethyl, 4- fluorine, 3,4- difluoros, 3- fluorine, 2- methoxyl groups, 4- hydroxyls.
Specific implementation mode
According to embodiment, the present invention is further described, but the present invention is not limited only to these embodiments；
Reagent：All reagents are that commercially available analysis is pure；
Embodiment 1
The preparation of intermediate 2：
At ambient temperature, 1.76g (10mmol) intermediate 1 and 2.76g (20mmol) potassium carbonate are dissolved in 50mL third
In ketone, 1.20g (15mmol) ethylene chlorhydrin is added, back flow reaction is heated to, after raw material all disappears, stops reaction, it is cold
But to room temperature, filtering, filtrate concentration, it is the petroleum ether of volume ratio 1: 1: second that residue, which is used column chromatography gradient elution, eluant, eluent,
Acetoacetic ester is to get 2.10g intermediates 2,4- methyl -7- hydroxy ethoxy cumarins；
The nuclear magnetic data of 4- methyl -7- hydroxy ethoxies cumarins (intermediate 2)：
1H NMR(400MHz,CDCl3) d 7.51 (d, J=9.0Hz, 1H), 6.91-6.83 (m, 2H), 6.15 (d, J=
1.1Hz, 1H), 4.15 (t, J=8.7Hz, 2H), 4.01 (m, 2H), 2.40 (d, J=1.1Hz, 3H)；
The preparation of intermediate 3：
Under the conditions of -78 DEG C of low-temp reaction, 50.25g (2mmol) oxalyl chloride is dissolved in a small amount of dry methylene chloride
In, the dichloromethane solution containing 0.16g (2mmol) dimethyl sulfoxide (DMSO) (DMSO) is slowly added dropwise, stirs half an hour, then will
0.22g (1mmol) intermediate 2 is dissolved in dry dichloromethane, is slowly added dropwise into reaction system, is stirred after being added dropwise
0.51g (5mmol) triethylamine is finally added dropwise to reaction system, makes complex dissociation formed in reaction system by half an hour, drop
Room temperature is slowly extended to after adding, reaction solution is washed three times, and organic phase is dried overnight, and is concentrated to give 0.21g intermediates 3,4- first
Base 7- formyl methoxy coumarins；
The nuclear magnetic data of 4- methyl 7- formyls methoxy coumarins (intermediate 3)：
1H NMR(400MHz,CDCl3) δ 9.85 (s, 1H), 7.53 (d, J=8.8Hz, 1H), 6.89 (dd, J=8.8,
2.6Hz, 1H), 6.78 (d, J=2.5Hz, 1H), 6.15 (d, J=1.0Hz, 1H), 4.68 (s, 2H), 2.39 (d, J=0.9Hz,
3H).
The preparation of compound 4：
The sodium hydrate aqueous solution of 1M is configured, heating makes its reflux, by 1.09g (5mmol) 4- methyl -7- formyl methoxyl groups
Cumarin is dissolved in 50mL 1-, in 4 dioxane, is slowly added dropwise into the NaOH aqueous solutions of the 1mol/L of reflux, is sufficiently stirred
It all disappears, is cooled to room temperature to raw material, 1mol/L hydrochloric acid solutions are added and adjust pH to neutrality, ethyl acetate extraction is associated with
Machine phase, concentration, uses eluant, eluent for the petroleum ether of volume ratio 7: 1 residue:Ethyl acetate column chromatography gradient elution to get
0.60g compounds 4,5- methyl -7H- furans [3,2-g] chromene -7- ketone；
The nuclear magnetic data of 5- methyl -7H- furans [3,2-g] chromene -7- ketone (compound 4)：
1H NMR(400MHz,CDCl3) δ 7.81 (s, 1H), 7.69 (d, J=2.2Hz, 1H), 7.47 (s, 1H), 6.85 (d,
J=2.1Hz, 1H), 6.27 (s, 1H), 2.50 (s, 3H)
The preparation of compound 5：
0.20g (1mmol) compound 4 and 0.17g (1.5mmol) selenium dioxide are dissolved in dry dimethylbenzene, heated
It is cooled to room temperature after raw material all disappears to back flow reaction, mother liquor filtering, concentration washes residue using column chromatography gradient
De-, eluant, eluent is volume ratio 10:1 petroleum ether: ethyl acetate is to get 0.16g compounds 5,7- oxo -7H- furans [3,2-g]
Chromene -5- formaldehyde；
The nuclear magnetic data of 7- oxo -7H- furans [3,2-g] chromene -5- formaldehyde (compound 5)：
1H NMR(400MHz,CDCl3) δ 10.14 (s, 1H), 8.90 (s, 1H), 7.72 (d, J=2.1Hz, 1H), 7.54
(s, 1H), 6.89 (d, J=2.0Hz, 1H), 6.86 (s, 1H)
The preparation of compound 6a：
0.21g (1mmol) compound 5 and 0.16g (1.5mmol) 2-aminotoluene are dissolved in absolute ethyl alcohol, flowed back
Reaction all disappears to raw material, is cooled to room temperature, mother liquor concentrations, residue is used column chromatography gradient elution, eluant, eluent is volume
Petroleum ether than 15: 1: ethyl acetate is to get 0.10g compound 6a, (Z) -5- (2- aminomethyl phenyls imines) methyl -7H- furans
[3,2-g] chromene -7- ketone；
(Z) core of -5- (2- aminomethyl phenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6a)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 9.23 (s, 1H), 8.59 (s, 1H), 7.71 (d, J=2.1Hz, 1H), 7.55 (s,
1H), 7.34-7.26 (m, 3H), 7.03 (d, J=7.2Hz, 1H), 6.87 (d, J=1.9Hz, 1H), 6.79 (s, 1H), 2.46
(s,3H).
13C NMR(101MHz,CDCl3)δ161.19,156.77,156.38,152.62,149.92,147.06,
146.14,133.02,130.91,127.79,127.19,125.17,119.59,118.71,117.10,113.41,107.12,
100.20,18.35。
Embodiment 2
The preparation of compound 6b：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.16g (1.5mmol) 4- methylanilines are dissolved in absolute ethyl alcohol, flowed back
Reaction all disappears to raw material, is cooled to room temperature, mother liquor concentrations, residue is used column chromatography gradient elution, eluant, eluent is volume
Petroleum ether than 15: 1: ethyl acetate is to get 0.11g compound 6b, (Z) -5- (4- aminomethyl phenyls imines) methyl -7H- furans
[3,2-g] chromene -7- ketone；
(Z) core of -5- (4- aminomethyl phenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6b)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 9.18 (s, 1H), 8.67 (s, 1H), 7.70 (d, J=2.2Hz, 1H), 7.54 (s,
1H), 7.05 (d, J=8.1Hz, 2H), 6.90-6.85 (m, 3H), 6.77 (s, 1H), 2.42 (s, 3H)
13C NMR(151MHz,CDCl3)δ161.19,156.35,152.60,148.19,147.01,146.27,
138.29,130.24,125.14,121.21,119.60,118.35,116.04,113.42,107.14,100.17,21.31。
Embodiment 3
The preparation of compound 6c：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.19g (1.5mmol) 4- chloroanilines are dissolved in absolute ethyl alcohol, reflux is anti-
It should all disappear, be cooled to room temperature, mother liquor concentrations to raw material, residue is used into column chromatography gradient elution, eluant, eluent is volume ratio
15: 1 petroleum ether: ethyl acetate is (Z) -5- (4- chlorphenyls imines) methyl-to get 0.09g compound 6c, compound 6c
7H- furans [3,2-g] chromene -7- ketone；
(Z) nuclear-magnetism of -5- (4- chlorphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6c)
Data：
1H NMR(600MHz,CDCl3) δ 9.13 (s, 1H), 8.64 (s, 1H), 7.71 (d, J=2.0Hz, 1H), 7.55 (s,
1H), 7.45 (d, J=7.4Hz, 2H), 7.28 (d, J=8.2Hz, 2H), 6.89 (d, J=1.9Hz, 1H), 6.78 (s, 1H)
13C NMR(151MHz,CDCl3)δ160.84,157.72,147.23,146.99,145.68,138.10,
133.61,129.65,125.06,124.42,122.36,113.02,119.28,118.88,106.96,100.14。
Embodiment 4
The preparation of compound 6d：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.15g (1.5mmol) aniline are dissolved in absolute ethyl alcohol, back flow reaction is extremely
Raw material all disappears, and is cooled to room temperature, mother liquor concentrations, and it is volume ratio 12: 1 that residue, which is used column chromatography gradient elution, eluant, eluent,
Petroleum ether: ethyl acetate to get 0.07g compound 6d, compound 6d be (Z) -5- (phenyl imine) methyl -7H- furans [3,
2-g] chromene -7- ketone；
(Z) nuclear magnetic data of -5- (phenyl imine) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6d)：
1H NMR(600MHz,CDCl3) δ 9.16 (s, 1H), 8.66 (s, 1H), 7.71 (d, J=2.1Hz, 1H), 7.55 (s,
1H), 7.48 (dd, J=8.0,7.6Hz, 2H), 7.36 (t, J=7.4Hz, 1H), 7.33 (d, J=7.4Hz, 2H), 6.89 (d, J
=2.1Hz, 1H), 6.78 (s, 1H)
13C NMR(151MHz,CDCl3)δ161.12,157.54,156.42,152.59,150.82,147.06,
146.10,129.63,127.94,124.55,121.12,119.56,118.72,113.31,107.13,100.21。
Embodiment 5
The preparation of compound 6e：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.18g (1.5mmol) 4- aminoanisoles are dissolved in absolute ethyl alcohol, returned
Stream reaction all disappears to raw material, is cooled to room temperature, mother liquor concentrations, residue is used column chromatography gradient elution, eluant, eluent is body
Petroleum ether of the product than 12: 1: ethyl acetate is (Z) -5- (phenyl imine) methyl-to get 0.09g compound 6e, compound 6e
7H- furans [3,2-g] chromene -7- ketone；
(Z) -5- (4- methoxyphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6e)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 9.18 (s, 1H), 8.69 (s, 1H), 7.70 (d, J=2.2Hz, 1H), 7.53 (s,
1H), 7.39 (d, J=8.9Hz, 2H), 7.01 (d, J=8.9Hz, 2H), 6.89 (d, J=2.0Hz, 1H), 6.76 (s, 1H),
3.88(s,3H).
13C NMR(151MHz,CDCl3)δ161.12,159.91,156.21,154.37,152.43,146.84,
143.32,124.94,122.84,119.41,117.71,116.66,114.70,113.35,106.98,99.99,55.60。
Embodiment 6
The preparation of compound 6f：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.18g (1.5mmol) 3.4- dimethoxyanilines are dissolved in absolute ethyl alcohol
In, back flow reaction to raw material all disappears, and is cooled to room temperature, mother liquor concentrations, and residue is used column chromatography gradient elution, eluant, eluent
For the petroleum ether of volume ratio 15: 1: ethyl acetate is to get 0.08g compound 6f, (Z) -5- (3.4- 3,5-dimethylphenyls imines) first
Base -7H- furans [3,2-g] chromene -7- ketone；
(Z) -5- (3.4- 3,5-dimethylphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6f)
Nuclear magnetic data：
Embodiment 7
The preparation of compound 6g：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.17g (1.5mmol) 4- fluoroanilines are dissolved in absolute ethyl alcohol, reflux is anti-
It should all disappear, be cooled to room temperature, mother liquor concentrations to raw material, residue is used into column chromatography gradient elution, eluant, eluent is volume ratio
15: 1 petroleum ether: ethyl acetate is to get 0.07g compound 6g, (Z) -5- (4- fluorophenyls imines) methyl -7H- furans [3,2-
G] chromene -7- ketone；
(Z) nuclear-magnetism of -5- (4- fluorophenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6g)
Data：
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.65 (s, 1H), 7.71 (d, J=2.2Hz, 1H), 7.54 (s,
1H), 7.39-7.31 (m, 2H), 7.22-7.12 (m, 2H), 6.89 (d, J=1.9Hz, 1H), 6.77 (s, 1H)
13C NMR(101MHz,CDCl3)δ161.23,157.07,152.77,151.77,147.39,146.97,
145.23,125.17,122.97,119.44,118.71,116.69,116.40,113.64,107.10,106.68,100.03。
Embodiment 8
The preparation of compound 6h：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.20g (1.5mmol) 3,4- difluoroanilines are dissolved in absolute ethyl alcohol, returned
Stream reaction all disappears to raw material, is cooled to room temperature, mother liquor concentrations, residue is used column chromatography gradient elution, eluant, eluent is body
Petroleum ether of the product than 15: 1: ethyl acetate is to get 0.08g compound 6g, (Z) -5- (3,4- difluorophenyl imines) methyl -7H-
Furans [3,2-g] chromene -7- ketone；
(Z) -5- (3,4- difluorophenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6h)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 9.09 (s, 1H), 8.62 (s, 1H), 7.69 (d, J=2.2Hz, 1H), 7.49 (s,
2H),6.91-6.89(m,2H),6.87-6.84(m,2H),6.79(s,1H).
13C NMR(101MHz,CDCl3)δ161.26,156.75,154.30,152.79,146.98,146.16,
132.69,128.76,127.82,124.57,119.15,116.70,113.66,110.18,106.68,100.32。
Embodiment 9
The preparation of compound 6i：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.19g (1.5mmol) 3- chloroanilines are dissolved in absolute ethyl alcohol, reflux is anti-
It should all disappear, be cooled to room temperature, mother liquor concentrations to raw material, residue is used into column chromatography gradient elution, eluant, eluent is volume ratio
15: 1 petroleum ether: ethyl acetate is to get 0.09g compound 6i, (Z) -5- (3- chlorphenyls imines) methyl -7H- furans [3,2-
G] chromene -7- ketone；
(Z) nuclear-magnetism of -5- (3- chlorphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6i)
Data：
1H NMR(600MHz,CDCl3) δ 9.12 (s, 1H), 8.63 (s, 1H), 7.72 (d, J=2.1Hz, 1H), 7.56 (s,
1H), 7.45-7.38 (m, 1H), 7.36-7.31 (m, 2H), 7.21 (d, J=8.3,1H), 6.90 (d, J=2.0Hz, 1H),
6.79(s,1H).
13C NMR(101MHz,CDCl3)δ161.31,157.36,154.20,152.54,150.13,148.06,
147.41,133.72,131.18,128.40,126.88,125.37,120.91,118.63,117.80,114.74,108.62,
101.10。
Embodiment 10
The preparation of compound 6j：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.18g (1.5mmol) 2- aminoanisoles are dissolved in absolute ethyl alcohol, returned
Stream reaction all disappears to raw material, is cooled to room temperature, mother liquor concentrations, residue is used column chromatography gradient elution, eluant, eluent is body
Petroleum ether of the product than 12: 1: ethyl acetate is to get 0.07g compound 6j, (Z) -5- (2- methoxyphenyls imines) methyl -7H-
Furans [3,2-g] chromene -7- ketone；
Compound is (Z) -5- (2- methoxyphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone (chemical combination
Object 6j) nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 9.13 (s, 1H), 8.76 (s, 1H), 7.69 (d, J=2.2Hz, 1H), 7.53 (s,
1H), 7.33-7.28 (m, 1H), 7.15 (dd, J=7.9,1.4Hz, 1H), 7.08-7.01 (m, 2H), 6.87 (d, J=2.1,
1H),6.76(s,1H),3.94(s,3H).
13C NMR(101MHz,CDCl3)δ191.81,161.08,156.26,152.61,151.59,147.19,
146.79,124.60,124.38,121.06,118.96,116.52,113.46,106.93,106.50,100.12,99.86,
56.10。
Embodiment 11
The preparation of compound 6k：
Prepared by compound 2- compounds 5 carries out according to embodiment 1：
0.21g (1mmol) compound 5 and 0.16g (1.5mmol) 4- hydroxyanilines are dissolved in absolute ethyl alcohol, flowed back
Reaction all disappears to raw material, is cooled to room temperature, mother liquor concentrations, residue is used column chromatography gradient elution, eluant, eluent is volume
Petroleum ether than 10: 1: ethyl acetate is to get 0.06g compound 6k, (Z) -5- (4- hydroxybenzeneiminos) methyl -7H- furans
[3,2-g] chromene -7- ketone；
(Z) core of -5- (4- hydroxybenzeneiminos) methyl -7H- furans [3,2-g] chromene -7- ketone (compound 6k)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 9.18 (s, 1H), 8.68 (s, 1H), 7.71 (d, J=2.2Hz, 1H), 7.54 (s,
1H), 7.35 (d, J=8.6Hz, 2H), 6.95 (d, J=8.8Hz, 2H), 6.91-6.88 (d, J=2.0Hz, 1H), 6.76 (s,
1H).
13C NMR(101MHz,CDCl3)δ162.00,156.31,154.48,153.12,147.44,139.88,
136.63,130.60,123.10,121.42,119.12,115.48,114.37,110.11,106.51,99.54。
Embodiment 12
Psoralen Schiff bases derivative of the present invention is preparing the purposes in treating leucoderma medicament, will implement
The compound 6a-6k that example 1-11 is obtained measures the melanin content of B16 melanoma cells：
(1) screening model：Murine melanoma cells B16；
(2) cell origin：Chinese Academy of Sciences's cell bank provides；
(3) condition of culture：10% fetal calf serum, 1% dual anti-DMEM in high glucose culture medium are added not afterwards for 24 hours to cultivate cell
With the drug and positive control of concentration, tyrosine activity and melanin content are measured in 48h and 72h respectively；
(4) assay method：
Protein quantification is measured with Bradford methods：
It is completely dissolved protein standard substance (5mg/mlBSA), takes 10 μ l to be diluted to 100 μ l, makes final concentration of 0.5mg/ml.Egg
For white sample in what solution, standard items also preferably use any solution dilution.But for simplicity 0.9% can also be used
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, standard dilutions is added to supply all standard items to 20 μ l；Add proper volume sample to the sample well of 96 orifice plates
In, add standard dilutions to supply to 20 μ l；200 μ l Bradford dyeing liquors are added in each hole, and mixing is gently blown and beaten with sample loading gun
(being careful not to make aeration reading) is placed at room temperature for 3-5 minutes；A595 is measured with microplate reader；It is calculated according to standard curve
Albumen concentration in sample；
The content of melanocyte is measured with alkali digestion：
The B16 melanoma cells for being in exponential phase are inoculated in 6cm culture dishes, a concentration of 2 × 105A/ml, respectively
Hole adds 5ml cell suspending liquids；Be inoculated with 12h after, after cell completely it is adherent after medication, 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, sets 80 DEG C
Measure absorption value A in water-bath after 2h at 470nm.Non- medication group (negative control group) is compared with medication group as a control group
It is shown in Table 1；
Antibacterial activity result of 1 derivative of table to melanin genesis in cell and three kinds of bacteriums
As can be seen from the table：Compound 6a-6b, compound 6d-6f and compound 6j-6k are used equally for clinically preparing
Treat the drug of leucoderma.The psoralen Schiff bases derivative obtained is used equally for clinically preparing treatment Candida albicans
The drug of bacterium infection, and compound 6b-6c, 6e-6h and 6k can also be used to clinically prepare treatment infection of staphylococcus aureus
Drug.
Claims (4)
1. a kind of psoralen Schiff bases derivative, it is characterised in that such derivant structure is：
Wherein：Compound 6a is (Z) -5- (2- aminomethyl phenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6b is (Z) -5- (4- aminomethyl phenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6c is (Z) -5- (4- chlorphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6d is (Z) -5- (phenyl imine) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6e is (Z) -5- (4- methoxyphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6f is (Z) -5- (3.4- 3,5-dimethylphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6g is (Z) -5- (4- fluorophenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6h is (Z) -5- (3,4- difluorophenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6i is (Z) -5- (3- chlorphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6j is (Z) -5- (2- methoxyphenyls imines) methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 6k is (Z) -5- (4- hydroxybenzeneiminos) methyl -7H- furans [3,2-g] chromene -7- ketone.
2. a kind of purposes of psoralen Schiff bases derivative as described in claim 1, it is characterised in that compound 6a-
The purposes of 6b, compound 6d-6f and compound 6j-6k in the drug for preparing treatment leucoderma.
3. a kind of psoralen Schiff bases derivative as described in claim 1 is in the medicine for preparing treatment candida albicans infection
Purposes in object.
4. a kind of purposes of psoralen Schiff bases derivative as described in claim 1, it is characterised in that compound 6b-
The purposes of 6c, compound 6e-6h and compound 6k in the drug for preparing treatment infection of staphylococcus aureus.
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