CN106565734A - Psoralen ester derivatives and applications thereof - Google Patents
Psoralen ester derivatives and applications thereof Download PDFInfo
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- CN106565734A CN106565734A CN201610983128.3A CN201610983128A CN106565734A CN 106565734 A CN106565734 A CN 106565734A CN 201610983128 A CN201610983128 A CN 201610983128A CN 106565734 A CN106565734 A CN 106565734A
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- 0 *C(c(cc(cc[o]1)c1c1)c1O1)=CC1=O Chemical compound *C(c(cc(cc[o]1)c1c1)c1O1)=CC1=O 0.000 description 5
- HBSHRKLYVCAGLZ-UHFFFAOYSA-N CC1c(cc(C(COC(C)=O)=CC(O2)=O)c2c2)c2OC1 Chemical compound CC1c(cc(C(COC(C)=O)=CC(O2)=O)c2c2)c2OC1 HBSHRKLYVCAGLZ-UHFFFAOYSA-N 0.000 description 1
- VMUHIKNDCMVXED-UHFFFAOYSA-N COC(C=C1)=CCC1C(OCC(c(c(O1)c2)cc3c2[o]cc3)=CC1=O)=O Chemical compound COC(C=C1)=CCC1C(OCC(c(c(O1)c2)cc3c2[o]cc3)=CC1=O)=O VMUHIKNDCMVXED-UHFFFAOYSA-N 0.000 description 1
- YTHPNVGTVVOODN-UHFFFAOYSA-N COc(cccc1)c1C(OCC(c(c([O-]1)c2)cc3c2[o]cc3)=CC1=O)=[O-] Chemical compound COc(cccc1)c1C(OCC(c(c([O-]1)c2)cc3c2[o]cc3)=CC1=O)=[O-] YTHPNVGTVVOODN-UHFFFAOYSA-N 0.000 description 1
- VYFPABMBHJZTLT-UHFFFAOYSA-N Cc(cc1)ccc1C(OCC(C(C(C1)O2)=Cc3c1[o]cc3)=CC2=O)=O Chemical compound Cc(cc1)ccc1C(OCC(C(C(C1)O2)=Cc3c1[o]cc3)=CC2=O)=O VYFPABMBHJZTLT-UHFFFAOYSA-N 0.000 description 1
- WRNPIMIPDWZHJT-UHFFFAOYSA-N N=C(c1ccc(C(F)(F)F)cc1)OCC(c(c(O1)c2)cc3c2[o]cc3)=CC1=O Chemical compound N=C(c1ccc(C(F)(F)F)cc1)OCC(c(c(O1)c2)cc3c2[o]cc3)=CC1=O WRNPIMIPDWZHJT-UHFFFAOYSA-N 0.000 description 1
- CXSCQFHCONQPOK-UHFFFAOYSA-N N=C1Oc(cc2[o]ccc2c2)c2C(COC(c2cccc([N+]([O-])=O)c2)=O)=C1 Chemical compound N=C1Oc(cc2[o]ccc2c2)c2C(COC(c2cccc([N+]([O-])=O)c2)=O)=C1 CXSCQFHCONQPOK-UHFFFAOYSA-N 0.000 description 1
- ZVRDJKWIDJQSCW-DUSLRRAJSA-N N=C1Oc2cc([o]cc3)c3cc2C(COC(C2)[C@H]2c2cc(Cl)cc(Cl)c2)=C1 Chemical compound N=C1Oc2cc([o]cc3)c3cc2C(COC(C2)[C@H]2c2cc(Cl)cc(Cl)c2)=C1 ZVRDJKWIDJQSCW-DUSLRRAJSA-N 0.000 description 1
- CJWQLCIZRFODKS-UHFFFAOYSA-N O=C(/C=[O]/CC(C(C1)C(O2)=Cc3c1cc[o]3)=CC2=O)c1ccccc1 Chemical compound O=C(/C=[O]/CC(C(C1)C(O2)=Cc3c1cc[o]3)=CC2=O)c1ccccc1 CJWQLCIZRFODKS-UHFFFAOYSA-N 0.000 description 1
- PPELPVDCKZWBAV-UHFFFAOYSA-N O=C(c(c(F)c1)ccc1F)[U]CC(c(c(O1)c2)cc3c2[o]cc3)=CC1=O Chemical compound O=C(c(c(F)c1)ccc1F)[U]CC(c(c(O1)c2)cc3c2[o]cc3)=CC1=O PPELPVDCKZWBAV-UHFFFAOYSA-N 0.000 description 1
- WNQVQZJLNHTCJB-UHFFFAOYSA-N O=C(c(cc1)ccc1F)OCC(c(cc(cc[o]1)c1c1)c1O1)=CC1=O Chemical compound O=C(c(cc1)ccc1F)OCC(c(cc(cc[o]1)c1c1)c1O1)=CC1=O WNQVQZJLNHTCJB-UHFFFAOYSA-N 0.000 description 1
- XAGHUQOLLXEHHR-UHFFFAOYSA-N O=C(c(cccc1)c1Cl)OCC(c(c([O-]1)c2)cc3c2[o]cc3)=CC1=O Chemical compound O=C(c(cccc1)c1Cl)OCC(c(c([O-]1)c2)cc3c2[o]cc3)=CC1=O XAGHUQOLLXEHHR-UHFFFAOYSA-N 0.000 description 1
- NZGZWRPXPMIHRW-UHFFFAOYSA-N OCC(c(cc(cc[o]1)c1c1)c1O1)=CC1=O Chemical compound OCC(c(cc(cc[o]1)c1c1)c1O1)=CC1=O NZGZWRPXPMIHRW-UHFFFAOYSA-N 0.000 description 1
- LJZZQGWQGPHMBT-UHFFFAOYSA-N [O-][N+](c1cc(C(OCC(c(c(O2)c3)cc4c3[o]cc4)=CC2=O)=O)cc(N=O)c1)=O Chemical compound [O-][N+](c1cc(C(OCC(c(c(O2)c3)cc4c3[o]cc4)=CC2=O)=O)cc(N=O)c1)=O LJZZQGWQGPHMBT-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to psoralen ester derivatives and applications thereof; the compounds comprise 4-methyl-7-hydroxy coumarin (an intermediate 1), 4-methyl-7-hydroxyethoxy coumarin (an intermediate 2), 4-methyl-7-formyl methoxy coumarin (an intermediate 3), 5-methyl-7H-furan[3,2-g]benzopyran-7-one (a compound 4), 7-oxo-7H-furan[3,2-g] benzopyran-5-formaldehyde (a compound 5), 5-hydroxymethyl-7H-furan[3,2-g]benzopyran-7-one (a compound 6), (7-oxo-7H-furan[3,2-g]benzopyran-5-yl)methyl acetate (a compound 7) and compounds 8a-8p. The 20 psoralen ester derivatives have influence on generation of melanin in mouse B16 cells and have the inhibitory effect on candida albicans, escherichia coli and staphylococcus aureus. The compounds 4-7, the compounds 8a-8d and the compounds 8k-8o are used for preparation of drugs for treating leucoderma. The obtained psoralen Schiff base derivatives are used for preparation of drugs for treatment of candida albicans infection, and the compound 5 and the compound 7 are also used for preparation of drugs for treatment of staphylococcus aureus infection.
Description
Technical field
The present invention relates to a kind of psoralen esters derivative and purposes, more particularly to such compound is through anti-vitiligo
And Antimicrobial Screening, all psoralen esters derivative are used equally to clinically prepare treats Candida albicans (Candida
Albicans the medicine for) infecting；13 compounds of remaining in addition to 8e-8j, 8p are used equally to clinically prepare treatment leucoderma
The medicine of wind；And compound 5 and 7 can be additionally used in clinically preparing treatment staphylococcus aureuses (Staphylococcus
Aureus the medicine for) infecting.
Background technology
Vitiligo is a kind of common spontaneous or idiopathic depigmentation dermatoses, is referred to as world's dermatosiss three big
One of pertinacious 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 prevalence is 0.56% or so, and only about half of patient fell ill before 20 one full year of life, male and female
The prevalence of property is equal.Vitiligo is mainly shown as skin, the white macula of mucosa and ash/white hair etc..Doctor trained in Western medicine thinks vitiligo
It is the hypofunction of tryrosinase system in the melanocyte due to skin and hair follicle, loses and cause.
Drying and ripening fruit of the Fructus Psoraleae for pulse family annual herb plant Fructus Psoraleae (Psoralea corylifolia L.)
It is real, record in《Chinese Pharmacopoeia》、《Uigurs medicine will》、《Chinese book on Chinese herbal medicine-Uygur's bundling》Deng, be the successive dynasties tradition Uygur cure
Treat leukodermic main classical medicine.Uygur's medical science thinks that vitiligo is mainly caused by abnormal phlegm, advocates clear during treatment
Except abnormal humour, abnormal makings is corrected, so as to recover body natural agent.Fructus Psoraleae have raw dry heat, remove abnormal lymphatic temperament,
The effects such as net blood detoxifies, increases pigment, kills anthelmintic.Additionally, Fructus Psoraleae also has antibacterial, estrogen -like effectss, antitumor, anti-
The multiple biological activities such as oxidation, immunomodulating and antidepressant.
Medicine and preparation with plant Fructus Psoraleae as main component, is clinically mainly used in treating vitiligo at present：As again
Square Fructus Psoraleae granule, Fructus Psoraleae injection, compound psorolea tincture, the white Ba Busi pieces of drive, compound kaliziranding (dimension medicine name Wei A
Dew) etc..Although dimension medicine treatment vitiligo 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.
Study through for many years, domestic and international research worker is divided from Fructus Psoraleae (Psoralea corylifolia L.)
Separate out Psoralens resistance compound (furocoumarin compound), flavonoid, terpenoid and a small amount of lipid and volatile oil.Its
, used as main chemical compositions therein, research range is most wide for middle Psoralens resistance compound (furocoumarin compound).
Psoralens resistance compound (Psoralen) is the most frequently used photosensitizer of current clinical treatment vitiligo, but
It is to coordinate daylight or long wave ultraviolet (UVA) irradiation treatment, so this kind of Therapeutic Method is referred to as PUVA (Psoralen+
UVA).Conventional has 8-methoxypsoralen (8-MOP) and 5-bergapten (5-MOP), later again synthetic
Trimethylpsoralen (TMP), as shown in structure.In leukodermic treatment, PUVA can activity of tyrosinase, catalysis
Melanin genesis, promote melanocytic division and movement, finally increase B16 cell, and white macula color is gradually recovered.
Jing is retrieved, and relevant document is：
[1]Kruger C.,Schallreuter K.U.A review of the worldwide prevalence of
vitiligo in children/adolescents and adults[J].Int.J.Dermatol.,2012,51,1206-
1212.
[2] Wang Xiaoyan. Chinese six provinces and cities vitiligo Epidemiological study [M]. Chinese journal of dermatology, 2010,463-
466.
[3]Alikhan A.,Felsten L.M.,Daly M.,Petronic-Rosic V.Vitiligo:A
comprehensive overview Part I.Introduction,epidemiology,quality of life,
diagnosis,differential diagnosis,associations,histopathology,etiology,and
work-up[J].J.Am.Acad.Dermatol.,2011,65,473-491.
[4]Arcos-Burgos M.,Parodi E.,Salgar M.,Bedoya E.,Builes J.,Jaramillo
D.,Ceballos G.,Uribe A.,Rivera N.,Rivera D.,Fonseca I.,Camargo M.,Palacio
G.Vitiligo:complex segregation and linkage disequilibrium analyses with
respect to microsatellite loci spanning the HLA[J].Hum.Genet.,2002,110,334-
342.
[5]AlainVitiligo as an inflammatory skin disorder:a therapeutic
perspective[J].Pigm.Cell Melanoma Res.,2012,25,9-13.
[6]Hirschhorn J.N.,Lohmueller K.,Byrne E.,Hirschhorn K.A
comprehensive review of genetic association studies[J].Genet.Med.,2002,4,45-
61.
[7]Schallreuter K.U.,Krüger C.,Rokos H.,Hasse S.,Zothner C.,Panske
A.Basic research confirms coexistence of acquired blaschkolinear Vitiligo and
acrofacial vitiligo[J].Arch.Dermatol.Res.,2007,299,225-230.
[8]Ezzedine K.,Eleftheriadou V.,Whitton M.,van Geel N.Vitiligo.Lancet
[J].2015,in press,Doi:10.1016/S0140-6736(14)60763-7.
[9] Er Xunwufuer, Si Lafuaibai are told, Re Fuhatisai buys and carries, a Ju Laitia not all watt clothing is carried,
Yi Li karrs visit a gram Dalmatia. and dimension medicine maturing agent and scavenger treat 166 progressive stage Vitiligos [J]. Chinese medicines
Reason and clinical, 2012,28,161-162.
[10] the western nguktrum Xiao Gai of summer wood is carried, and Si Lafuaibai, Re Nakasi are wooden. leukodermic Current medicine treatment
[J]. National medicine magazine, 2011,8,62-64.
[11] Huang is built, Zhao Luhua, Zou Qiaogen. Constituents in Fruits of Psoralea corylifolia L and pharmacological research progress [J]. pharmacy is in progress, and 2000,
24,212-214.
[12]Yin S.,Fan C.Q.,Wang Y.,Dong L.,Yue J.M.Antibacterial
prenylflavone derivatives from Psoralea corylifolia and their structure-
activity relationship study[J].Bioorg.Med.Chem.,2004,12,4387-4392.
[13]Zhang C.Z.,Wang S.X.,Zhang Y.,Chen J.P.,Liang X.M.In vitro
estrogenic activities of Chinese medicinal plants traditionally used for the
management of menopausal symptoms[J].J.Ethnopharmacol.,2005,98,295-300.
[14]Bapat K.,Chintalwar G.J.,Pandey U.,Thakur V.S.,Sarma H.D.,Samuel
G.,Pillai M.R,Chattopadhyay S.,Venkatesh M.Preparation and in vitro
evaluation of radio iodinated bakuchiol as an anti tumor agent[J]
.Appl.Radiat.Isot.,2005,62,389-393.
[15]Guo J.N.,Wen X.C.,Wu H.,Li Q.H.,Bi K.Antioxidants from a Chinese
medicinal herb-Psoralea corylifolia[J].Food Chem.,2005,91,287-292.
[16]Latha P.G.,Evans D.A.,Panikkar K.R.,Jayavardhanan
K.K.Immunomodulatory and antitumour properties of Psoralea corylifolia seeds
[J].Fitoterapia,2000,71,223-231.
[17]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,
14,523-529.
[18]Yue F.W.,Ya N.L.,Wen X.,Dong M.Y.,Yan Z.,Xiu M.G.,Yan T.X.,Ai
D.Q.A UPLC–MS/MS method for in vivo and in vitro pharmacokinetic studies of
psoralenoside,isopsoralenoside,psoralen and isopsoralen from Psoralea
corylifolia extract[J].J.Ethnopharmacol.,2014,151,609-617.
[19]Ruan B.,Kong L.Y.,Takaya Y.,Niwa M.Studies on the chemical
constituents of Psoralea corylifolia L[J].J.Asian Nat.Prod.Res.,2007,9,41-44.
[20]Hsu Y.T.,Wu C.J.,Chen J.M.,Yang Y.C.,Wang S.Y.The presence of
three isoflavonoid compounds in Psoralea corylifolia[J].J.Chromatogr.Sci.,
2001,39,441-444.
[21]Amit N.S.,Nutan M.,Devanand P.,Fulzele.Determination of
isoflavone content and antioxidant activity in Psoralea corylifolia L.callus
cultures[J].Food Chem.,2010,118,128-132.
[22]Cheng Z.W.,Cai X.F.,Dat N.T.,Hong S.S.,Han A.R.,Seo E.K.,Hwang
B.Y.,Nan J.X.,Lee D.H.,Lee J.J.Bisbakuchiols A and B,novel dimeric
meroterpenoids from Psoralea corylifolia[J].Tetrahedron Lett.,2007,48,8861-
8864.
[23]Njoo M.D.,Westerhof W.Vitiligo.Pathogenesis and treament[J]
.Am.J.Clin.Dermatol.,2001,2,167-181。
The present invention at home and abroad about 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 modified, by esterification by substituted-phenyl
Etc. being incorporated in psoralen molecules, its druggability is improved, and these esters derivative are have studied to melanocyte in mice B16 cells
The impact of generation, to find evident in efficacy, target spot clearly, the mechanism of action clearly anti-vitiligo new drug；In addition, also grind
These derivants have been studied carefully to Candida albicans (Candida albicans), escherichia coli (Escherichia coli), golden yellow
The inhibitory action of color staphylococcuses (Staphylococcus aureus), to finding the drug candidate with antibacterial activity.
The content of the invention
It is an object of the present invention to provide a kind of psoralen esters derivative and purposes, such compound be 4- methyl-
Umbelliferone (intermediate 1)；4- methyl -7- hydroxy ethoxy coumarins (intermediate 2)；4- methyl -7- formyl methoxy basic notes
Legumin (intermediate 3)；5- methyl -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone (compound 4)；7- oxo -7H- furan [3,2-
G] .alpha.-5:6-benzopyran -5- formaldehyde (compound 5)；5- methylols -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone (compound 6)；(7-
Oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- bases) methyl acetic acid ester (compound 7) and compound 8a-8p.And investigate this 20
Individual psoralen esters derivative is on melanogenic impact in mice B16 cells and to Candida albicans, escherichia coli, golden yellow
The staphylococcic inhibitory action of color, anti-vitiligo result：13 compounds of remaining in addition to 8e-8j, 8p are preparing treatment in vain
The medicinal usage of purplish or white patches on the skin wind.The anti-bacterial result：The 20 psoralen esters derivative for being obtained are preparing treatment Candida albicans sense
The medicinal usage of dye, and compound 5 and 7 can be additionally used in the medicinal usage in preparation treatment infection of staphylococcus aureus.
A kind of psoralen esters derivative of the present invention, such derivant structure formula is：
Wherein：Compound 4 is 5- methyl -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone；
Compound 5 is 7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- formaldehyde；
Compound 6 is 5- methylol -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone；
Compound 7 is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- bases) methyl acetic acid ester；
Compound 8a is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- methyl) benzoate；
Compound 8b is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- methyl) benzoate；
Compound 8c is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- methoxyl groups) benzoate；
Compound 8d is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- methoxyl groups) benzoate；
Compound 8e is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- chlorine) benzoate；
Compound 8f is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- chlorine) benzoate；
Compound 8g is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,4- dichloros) benzoate；
Compound 8h is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,5- dichloros) benzoate；
Compound 8i is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- fluorine) benzoate；
Compound 8j is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2,4- difluoros) benzoate；
Compound 8k is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl benzoic acid ester；
Compound 8l is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- nitros) benzoate；
Compound 8m is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- trifluoromethyls) benzoic acid
Ester；
Compound 8n is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3- nitros) benzoate；
Compound 8o is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,5- dinitros) benzoic acid
Ester；
Compound 8p is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- iodine) benzoate.
Purposes of the described psoralen esters derivative in the medicine for preparing treatment candida albicans infection.
In described psoralen esters derivative, compound 4-7, compound 8a-8d and compound 8k-8o are controlled in preparation
Treat the purposes in leukodermic medicine.
In described psoralen esters derivative, compound 5 and 7 is preparing the medicine for the treatment of infection of staphylococcus aureus
Purposes in thing.
A kind of psoralen esters derivative of the present invention and purposes, such compound is with resorcinol as initial former
Material, in the presence of sulphuric acid, is condensed to yield AP20am16 (intermediate 1) first with ethyl acetoacetate；It is middle
Body 1 obtains 4- methyl -7- hydroxy ethoxy coumarins (intermediate 2) with 2-chloroethyl alcohol reaction again；Then the oxidation of intermediate 2 is obtained into 4-
Methyl -7- formyl methoxy coumarins (intermediate 3)；By intermediate 3 under the catalysis of sodium hydroxide, cyclization forms furan nucleuss,
So as to obtain 5- methyl -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone (compound 4)；After by the parent nucleus compound 4 for obtaining, enter
One step aoxidizes its 5- positions methyl using selenium dioxide, obtains 7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- formaldehyde (chemical combination
Thing is 5)；Again at ambient temperature, the aldehyde radical of compound 5 is reduced into into methylol, obtains 5- methylol -7H- furan [3,2-g] benzene
And pyrans -7- ketone (compound 6)；Finally, adopt acetic anhydride and different substituted benzoic acids for esterifying reagent, prepare (7-
Oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- bases) methyl acetic acid ester (compound 7) and compound 8a-8p.Again by acquisition
This 20 psoralen esters derivative in mice B16 cells it is melanogenic impact and to Candida albicans, escherichia coli,
The inhibitory action of staphylococcus aureuses is investigated, its result：
Anti- vitiligo result shows：Compared with negative control, 13 compounds of remaining in addition to 8e-8j, 8p can promote
The generation of melanocyte in B16 cells, and facilitation is from 112% to 200%；Compared with positive control, compound 6,8a-
8d, 8l, 8n-8o are superior to positive control to melanogenic facilitation, and wherein compound 8n and 8o is to melanogenic rush
Enter and act on 1.5 times that are close to positive control.
The anti-bacterial result shows：The 20 psoralen esters derivative for being obtained are to Candida albicans (Candida
Albicans) there is inhibitory action, wherein compound 5 is to escherichia coli (Escherichia coli) and staphylococcus aureuses
(Staphylococcus aureus) also shows inhibitory action, and to Candida albicans (Candida albicans)
Activity is better than positive control Amphotericin B (Amphotericin B)；Compound 7 is to staphylococcus aureuses
(Staphylococcus aureus) also shows inhibitory action, and to Candida albicans (Candida albicans)
Activity is better than positive control Amphotericin B (Amphotericin B).All compounds are used equally to clinically prepare treatment in vain
The medicine that color candidiasises (Candida albicans) infect, and compound 5 and compound 7 can be additionally used in clinically preparing treatment
The medicine that staphylococcus aureuses (Staphylococcus aureus) infect.
A kind of psoralen esters derivative of the present invention, its structure is as shown in logical formula (I)：
The preparation method of psoralen esters derivative of the present invention, follow these steps to carry out：
The preparation of intermediate 1：
A, under condition of ice bath, by resorcinol be dissolved in it is appropriate be dried in Isosorbide-5-Nitrae-dioxane, stir to all molten
Solution, is slowly added dropwise concentrated sulphuric acid so as to which temperature is less than 20 DEG C, after completion of dropping, adds ethyl acetoacetate, then heats to
60 DEG C, it is sufficiently stirred for making which react complete, reactant liquor is poured in frozen water, adopts and be extracted with ethyl acetate after standing, organic to be harmonious
And be dried, intermediate Isosorbide-5-Nitrae-Methyl-7-hydroxy-coumarin is obtained after concentration；
The preparation of intermediate 2：
B, appropriate potassium carbonate and AP20am16 are dissolved in the acetone of 20mL, and add ethylene chlorhydrin,
Back flow reaction all disappears to raw material, reacting liquid filtering, concentration, and residue is adopted column chromatography gradient elution, and eluant is volume
Petroleum ether than 1: 1: ethyl acetate, obtain final product intermediate 2,4- methyl -7- hydroxy ethoxy coumarins；
The preparation of intermediate 3：
In c, the low-temp reaction device by oxalyl chloride as -78 DEG C, dimethyl sulfoxide (DMSO) is slowly added dropwise, stirring half is little
When, then the 4- methyl -7- ethoxy epoxide coumarins obtained by step b are dissolved in dry dichloromethane, it is slowly added dropwise
Into reaction system, stir half an hour after completion of dropping, then Deca triethylamine is complex dissociation formed in reaction system, drip
Add and after finishing, slowly extend room temperature, reactant liquor is washed three times, and organic faciess are dried overnight, and are concentrated to give intermediate 3,4- methyl 7- formyls
Methoxy coumarin；
The preparation of compound 4：
D, the NaOH aqueous solutions for preparing 1mol/L, heating make which flow back, by 4- methyl -7- formyls resulting in step c
Methoxy coumarin is dissolved in 1-, in 4 dioxane, is slowly added dropwise into the NaOH aqueous solutions of backflow, is sufficiently stirred for and keeps
Back flow reaction all disappears to raw material, is cooled to room temperature, adds 1mol/L hydrochloric acid solutions to adjust pH to neutrality, ethyl acetate extraction
Take, merge organic faciess, residue is adopted column chromatography gradient elution, petroleum ether of the eluant for volume ratio 7: 1: acetic acid second by concentration
Ester, obtains final product compound 4,5- methyl -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone；
The preparation of compound 5：
E, the compound 4 and selenium dioxide obtained by step d is dissolved in it is dried in dimethylbenzene, is heated to back flow reaction,
After raw material all disappears, room temperature is cooled to, mother solution is filtered, residue is adopted column chromatography gradient elution by concentration, and eluant is body
Product compares 10:1 petroleum ether: ethyl acetate, obtain final product compound 5,7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- formaldehyde；
The preparation of compound 6：
F, the compound 5 obtained by step e is dissolved in dehydrated alcohol, is sufficiently stirred for dissolving which, adds by several times
Sodium borohydride, continuation react at room temperature and all disappear until raw material, add dilute hydrochloric acid that reaction is quenched, acetic acid is used after dilute
Ethyl ester is extracted, and organic faciess are dried, concentration, residue is adopted column chromatography gradient elution, petroleum ether of the eluant for volume ratio 5: 1:
Ethyl acetate, obtains final product compound 6,5- methylol -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone；
The preparation of compound 7：
G, compound 6 obtained by step f, 4- dimethylamino pyridines and a drop acetic anhydride are dissolved in into a small amount of pyrrole being dried
In pyridine, it is stirred overnight at room temperature, adds appropriate frozen water, ethyl acetate extraction, organic faciess to be dried, residue is adopted column chromatography by concentration
Gradient elution, petroleum ether of the eluant for volume ratio 10: 1: ethyl acetate, compound 7 is obtained final product, (7- oxo -7H- furan [3,2-
G] .alpha.-5:6-benzopyran -5- bases) methyl acetic acid ester；
The preparation of compound 8a-8p：
Under h, condition of ice bath, by compound 7 resulting in step g, dicyclohexylcarbodiimide (DCC), 4- dimethylamine
Yl pyridines (DMAP) and corresponding benzoic acid are dissolved in appropriate dichloromethane, are sufficiently stirred for making which complete molten, are moved to room temperature condition
It is lower to continue reaction, after raw material all disappears, filter, mother solution is washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution successively,
It is dried, concentration, residue is adopted into column chromatography gradient elution, eluant is volume ratio 15: 1-10:1 petroleum ether: ethyl acetate,
Obtain final product compound 8a-8p；
Psoralen esters derivative of the present invention and purposes, wherein psoralen esters derivative, are with isophthalic
Diphenol is initiation material, obtains 4- methylumbelliferones (intermediate 1) in the presence of sulphuric acid with ethyl acetoacetate；In
Mesosome 1 obtains 4- methyl -7- hydroxy ethoxy coumarins (intermediate 2) with 2-chloroethyl alcohol reaction again；The ethoxy of oxidation intermediates 2 is obtained
To 4- methyl -7- formyl methoxy coumarins (intermediate 3)；The cyclization in the presence of alkali obtains 5- methyl -7H- to intermediate 3 again
Furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone (compound 4).Next, further oxidation 4 obtains 7- oxos -7H- furan [3,2-g]
.alpha.-5:6-benzopyran -5- formaldehyde (compound 5)；5 aldehyde radical is reduced into into methylol again, 5- methylols -7H- furan [3,2-g] is obtained
.alpha.-5:6-benzopyran -7- ketone (compound 6)；Finally, 6 esterifications are prepared by (7- oxygen using acetic anhydride and different substituted benzoic acids
Generation -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- bases) methyl acetic acid ester (compound 7) and compound 8a-8p.Chemical equation is：
(i) ethyl acetoacetate, concentrated sulphuric acid, temperature 60 C；(ii) 2-chloroethyl alcohol, potassium carbonate, acetone, backflow；(iii) temperature
- 78 DEG C of degree, oxalyl chloride, dimethyl sulfoxide, triethylamine, dichloromethane；(iv) 1M sodium hydrate aqueous solutions, Isosorbide-5-Nitrae-dioxane；
(v) selenium dioxide, dimethylbenzene, backflow；(vi) dehydrated alcohol, sodium borohydride, room temperature；(vii) 4- dimethylamino pyridines, acetic acid
Acid anhydride, pyridine, room temperature；(viii) dicyclohexylcarbodiimide, 4- dimethylamino pyridines, dichloromethane, 0 DEG C-room temperature of temperature；Wherein
R1Respectively 4- methyl, 2- methyl, 4- methoxyl groups, 2- methoxyl groups, 4- chlorine, 2- chlorine, 3,4- dichloros, 3,5- dichloros, 4- fluorine, 2,4-
Difluoro, hydrogen, 4- nitros, 4- trifluoromethyls, 3- nitro bases, 3,4- dinitros, 2- iodine.
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 of intermediate 2：
At ambient temperature, 1.76g (10mmol) intermediate 1 and 2.76g (20mmol) potassium carbonate are dissolved in into 50mL third
In ketone, 1.20g (15mmol) ethylene chlorhydrin is added, back flow reaction is heated to, after raw material all disappears, stopped reaction is cold
But to room temperature, filter, filtrate concentration, residue is adopted into column chromatography gradient elution, petroleum ether of the eluant for volume ratio 1: 1: second
Acetoacetic ester, obtains final product 2.10g intermediate 2,4- methyl -7- hydroxy ethoxy coumarins；
The nuclear magnetic data of 4- methyl -7- hydroxy ethoxy coumarins (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 the low-temp reaction of -78 DEG C of temperature, 50.25g (2mmol) oxalyl chloride is dissolved in and a small amount of is dried dichloromethane
In alkane, the dichloromethane solution containing 0.16g (2mmol) dimethyl sulfoxide (DMSO) is slowly added dropwise, is stirred 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 completion of dropping
Half an hour, 0.51g (5mmol) triethylamine is dropped to into reaction system finally, make complex dissociation formed in reaction system, dripped
Add and after finishing, slowly extend room temperature, reactant liquor is washed three times, and organic faciess are dried overnight, and are concentrated to give 0.21g intermediate 3,4- first
Base 7- formyl methoxy coumarins；
The nuclear magnetic data of 4- methyl 7- formyl 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 configuration 1M, heating makes which flow back, by 1.09g (5mmol) 4- methyl -7- formyl methoxyl groups
Coumarin is dissolved in 50mL 1-, in 4 dioxane, is slowly added dropwise into the NaOH aqueous solutions of the 1mol/L of backflow, is sufficiently stirred for
All disappear to raw material, be cooled to room temperature, add 1mol/L hydrochloric acid solutions pH to be adjusted to neutrality, ethyl acetate extraction, be associated with
Machine phase, concentration, by residue adopt eluant for volume ratio 7: 1 petroleum ether:Ethyl acetate column chromatography gradient elution, obtains final product
0.60g compounds 4,5- methyl -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone；
The nuclear magnetic data of 5- methyl -7H- furan [3,2-g] .alpha.-5:6-benzopyran -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 and are dried in dimethylbenzene, is heated
To back flow reaction, after raw material all disappears, room temperature is cooled to, mother solution is filtered, residue is washed by concentration using column chromatography gradient
De-, eluant is volume ratio 10:1 petroleum ether: ethyl acetate, obtain final product 0.16g compounds 5,7- oxos -7H- furan [3,2-g]
.alpha.-5:6-benzopyran -5- formaldehyde；
The nuclear magnetic data of 7- oxos -7H- furan [3,2-g] .alpha.-5:6-benzopyran -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 6：
0.21g (1mmol) compound 5 is dissolved in dehydrated alcohol, is sufficiently stirred for dissolving which, add 0.019g by several times
(0.5mmol) sodium borohydride, continuation react at room temperature and all disappear until raw material, add dilute hydrochloric acid that reaction is quenched, add water dilute
It is extracted with ethyl acetate after releasing, organic faciess are dried, concentration, residue is adopted into column chromatography gradient elution, eluant is volume ratio 5: 1
Petroleum ether: ethyl acetate, obtain final product 0.17g compounds 6,5- methylol -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone；
The nuclear magnetic data of 5- methylols -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone (compound 6)：
1H NMR(400MHz,Acetone-d6) δ 7.98 (s, 1H), 7.89 (d, J=2.3Hz, 1H), 7.57 (s, 1H),
6.99 (d, J=2.1,1H), 6.58 (s, 1H), 4.97 (s, 2H).
The preparation of compound 7：
By 0.216g (1mmol) compound 6,1mg 4- dimethylamino pyridines and a drop acetic anhydride are dissolved in a small amount of drying
In pyridine, it is stirred overnight at room temperature, adds appropriate frozen water, ethyl acetate extraction, organic faciess to be dried, residue is adopted post layer by concentration
Analysis gradient elution, petroleum ether of the eluant for volume ratio 10: 1: ethyl acetate, 0.20g compounds 7 are obtained final product, (7- oxo -7H- furans
Mutter [3,2-g] .alpha.-5:6-benzopyran -5- bases) methyl acetic acid ester；
The nuclear magnetic data of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- bases) methyl acetic acid ester (compound 7)：
1H NMR(400MHz,CDCl3) δ 7.82 (s, 1H), 7.71 (d, J=2.1,1H), 7.47 (s, 1H), 6.86 (d, J
=2.0,1H), 6.49 (s, 1H), 5.37 (s, 2H), 2.23 (s, 3H).
The preparation of compound 8a：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.16g (1.2mmol) 4- ar-Toluic acids are dissolved in appropriate dichloromethane
In alkane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is used successively
1M hydrochloric acid solutions and saturated sodium bicarbonate solution washing, are dried, concentration, and by residue using column chromatography gradient elution, eluant is
The petroleum ether of volume ratio 15: 1: ethyl acetate, 0.30g compound 8a are obtained final product, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyrans -
5-) methyl-(4- methyl) benzoate；
The core of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- methyl) benzoate (compound 8a)
Magnetic data：
1H NMR(600MHz,CDCl3) δ 8.02 (d, J=8.1Hz, 2H), 7.81 (s, 1H), 7.71 (d, J=2.1Hz,
1H), 7.53 (s, 1H), 7.29 (d, J=8.0Hz, 2H), 6.86 (d, J=2.1Hz, 1H), 6.60 (s, 1H), 5.60 (s, 2H),
2.44(s,3H).
13C NMR(101MHz,CDCl3)δ165.77,160.75,156.37,151.71,149.62,147.14,
144.67,129.89,129.40,126.23,124.94,115.46,113.68,111.57,106.57,100.37,61.65,
21.76。
Embodiment 2
The preparation of compound 8b：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.16g (1.2mmol) 2- ar-Toluic acids are dissolved in appropriate dichloromethane
In alkane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is used successively
1M hydrochloric acid solutions and saturated sodium bicarbonate solution washing, are dried, concentration, and by residue using column chromatography gradient elution, eluant is
The petroleum ether of volume ratio 15: 1: ethyl acetate, 0.31g compound 8b are obtained final product, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyrans -
5-) methyl-(2- methyl) benzoate；
The core of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- methyl) benzoate (compound 8b)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 8.04 (8.04 (dd, J=7.8,0.8Hz, 1H), 7.83 (s, 1H), 7.72 (d, J
=2.1Hz, 1H), 7.54 (s, 1H), 7.50-7.44 (m, 1H), 7.33-7.28 (m, 2H), 6.87 (d, J=2.2Hz, 1H),
6.59(s,1H),5.60(s,2H),2.65(s,3H)；
13C NMR(101MHz,CDCl3)δ166.28,160.68,156.35,151.71,149.55,147.11,
141.04,132.82,132.00,130.76,125.99,124.91,115.45,113.69,111.74,106.53,100.36,
61.61,21.88。
Embodiment 3
The preparation of compound 8c：
The preparation of compound 2- compounds 7 is according to embodiment 1.
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.18g (1.2mmol) 4- methoxybenzoic acids are dissolved in appropriate dichloro
In methane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is successively
Washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, be dried, residue is adopted column chromatography gradient elution, eluant by concentration
For the petroleum ether of volume ratio 15: 1: ethyl acetate, 0.32g compound 8c are obtained final product, (7- oxo -7H- furan [3,2-g] benzo pyrroles
Mutter -5-) methyl-(4- methoxyl groups) benzoate；
(7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- methoxyl groups) benzoate (compound 8c)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.09 (d, J=8.8Hz, 2H), 7.82 (s, 1H), 7.71 (d, J=2.1Hz,
1H), 7.54 (s, 1H), 6.97 (d, J=8.9Hz, 2H), 6.86 (d, J=2.0Hz, 1H), 6.59 (s, 1H), 5.60 (s, 2H),
3.89(s,3H).
13C NMR(101MHz,CDCl3)δ165.56,160.91,156.52,151.87,149.90,147.28,
132.12,129.20,125.08,121.44,115.62,114.11,113.91,111.67,106.72,100.51,61.68,
55.69。
Embodiment 4
The preparation of compound 8d：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.18g (1.2mmol) 2-methoxybenzoic acid are dissolved in appropriate dichloro
In methane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is successively
Washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, be dried, residue is adopted column chromatography gradient elution, eluant by concentration
For the petroleum ether of volume ratio 15: 1: ethyl acetate, 0.31g compound 8d are obtained final product, (7- oxo -7H- furan [3,2-g] benzo pyrroles
Mutter -5-) methyl-(2- methoxyl groups) benzoate；
(7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- methoxyl groups) benzoate (compound 8d)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.92 (dd, J=7.9,1.8Hz, 1H), 7.82 (s, 1H), 7.71 (d, J=
2.2Hz, 1H), 7.57-7.50 (m, 1H), 7.06-7.00 (m, 2H), 6.86 (d, J=2.2Hz, 1H), 6.73 (s, 1H), 5.60
(s,2H),3.95(s,3H).
13C NMR(101MHz,CDCl3)δ165.56,160.86,159.54,156.33,151.72,149.65,
147.10,134.49,132.20,124.87,120.35,118.61,115.50,113.73,112.11,111.79,106.57,
100.30,61.78,55.94。
Embodiment 5
The preparation of compound 8e：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.19g (1.2mmol) 4- chlorobenzoic acids are dissolved in appropriate dichloromethane
In, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution uses 1M successively
Hydrochloric acid solution and saturated sodium bicarbonate solution washing, are dried, and residue is adopted column chromatography gradient elution by concentration, and eluant is body
Product compares 12: 1 petroleum ether: ethyl acetate, obtains final product 0.33g compound 8e, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyrans -
5-) methyl-(4- chlorine) benzoate；
The nuclear-magnetism of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- chlorine) benzoate (compound 8e)
Data：
1H NMR(400MHz,CDCl3) δ 8.07 (d, J=8.6Hz, 2H), 7.80 (s, 1H), 7.72 (d, J=2.3Hz,
1H), 7.55 (s, 1H), 7.48 (d, J=8.6Hz, 2H), 6.87 (d, J=2.1Hz, 1H), 6.57 (s, 1H), 5.62 (s, 2H).
13C NMR(101MHz,CDCl3)δ164.89,160.63,156.42,151.72,149.20,147.22,
140.40,131.23,129.10,127.41,125.00,115.41,113.58,111.72,106.56,100.46,62.03。
Embodiment 6
The preparation of compound 8f：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.19g (1.2mmol) 2- chlorobenzoic acids are dissolved in appropriate dichloromethane
In, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution uses 1M successively
Hydrochloric acid solution and saturated sodium bicarbonate solution washing, are dried, and residue is adopted column chromatography gradient elution by concentration, and eluant is body
Product compares 12: 1 petroleum ether: ethyl acetate, obtains final product 0.33g compound 8f, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyrans -
5-) methyl-(2- chlorine) benzoate；
The nuclear-magnetism of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- chlorine) benzoate (compound 8f)
Data：
1H NMR(400MHz,CDCl3) δ 7.95 (dd, J=7.6,1.3Hz, 1H), 7.82 (s, 1H), 7.72 (d, J=
2.3Hz, 1H), 7.54 (s, 1H), 7.53-7.48 (m, 2H), 7.41-7.35 (m, 1H), 6.87 (d, J=2.2Hz, 1H), 6.64
(s,1H),5.63(s,2H).
13C NMR(101MHz,CDCl3)δ164.92,160.79,156.55,151.89,149.04,147.33,
134.37,133.55,131.94,131.60,128.88,127.01,125.11,115.68,113.74,112.24,106.71,
100.56,62.57。
Embodiment 7
The preparation of compound 8g：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.23g (1.2mmol) 3,4- dichlorobenzoic acids are dissolved in appropriate dichloro
In methane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is successively
Washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, be dried, residue is adopted column chromatography gradient elution, eluant by concentration
For the petroleum ether of volume ratio 12: 1: ethyl acetate, 0.35g compound 8g are obtained final product, (7- oxo -7H- furan [3,2-g] benzo pyrroles
Mutter -5-) methyl-(3,4- dichloros) benzoate；
(7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,4- dichloros) benzoate (compound 8g)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.20 (d, J=2.0Hz, 1H), 7.95 (dd, J=8.4,1.9Hz, 1H), 7.80
(s, 1H), 7.73 (d, J=2.3Hz, 1H), 7.59 (d, J=8.4Hz, 1H), 7.55 (s, 1H), 6.87 (d, J=2.1Hz,
1H),6.55(s,1H),5.63(s,2H).
13C NMR(101MHz,CDCl3)δ163.97,160.54,158.21,153.31,147.28,143.32,
138.63,136.04,131.73,130.90,128.83,127.59,122.64,120.23,115.41,111.86,106.56,
100.50,62.34。
Embodiment 8
The preparation of compound 8h：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.23g (1.2mmol) 3,5- dichlorobenzoic acids are dissolved in appropriate dichloro
In methane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is successively
Washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, be dried, residue is adopted column chromatography gradient elution, eluant by concentration
For the petroleum ether of volume ratio 12: 1: ethyl acetate, 0.35g compound 8h are obtained final product, (7- oxo -7H- furan [3,2-g] benzo pyrroles
Mutter -5-) methyl-(3,5- dichloros) benzoate；
(7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,5- dichloros) benzoate (compound 8h)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.98 (d, J=1.9Hz, 2H), 7.79 (s, 1H), 7.73 (d, J=2.2Hz,
1H), 7.62 (t, J=1.9Hz, 1H), 7.55 (s, 1H), 6.87 (d, J=2.1Hz, 1H), 6.54 (s, 1H), 5.63 (s, 2H).
13C NMR(101MHz,CDCl3)δ163.67,160.63,156.59,151.86,148.84,147.41,
135.83,133.77,131.88,128.96,128.32,125.18,115.52,112.04,106.68,100.63,62.64。
Embodiment 9
The preparation of compound 8i：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.17g (1.2mmol) 4- fluobenzoic acids are dissolved in appropriate dichloromethane
In, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution uses 1M successively
Hydrochloric acid solution and saturated sodium bicarbonate solution washing, are dried, and residue is adopted column chromatography gradient elution by concentration, and eluant is body
Product compares 12: 1 petroleum ether: ethyl acetate, obtains final product 0.30g compound 8i, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyrans -
5-) methyl-(4- fluorine) benzoate；
The core of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- fluorine) benzoate (compound 8i is)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 8.19-8.12 (m, 2H), 7.81 (s, 1H), 7.72 (d, J=2.2Hz, 1H),
7.54 (s, 1H), 7.18 (t, J=8.6Hz, 2H), 6.87 (d, J=2.1Hz, 1H), 6.57 (s, 1H), 5.62 (s, 2H).
13C NMR(101MHz,CDCl3)δ164.87,160.78,156.54,151.85,149.47,147.35,
146.81,132.62,125.13,116.20,115.98,115.56,111.78,106.69,100.56,62.04。
Embodiment 10
The preparation of compound 8j：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.19g (1.2mmol) 2,4 difluorobenzene formic acid are dissolved in appropriate dichloro
In methane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is successively
Washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, be dried, residue is adopted column chromatography gradient elution, eluant by concentration
For the petroleum ether of volume ratio 12: 1: ethyl acetate, 0.32g compound 8i are obtained final product, (7- oxo -7H- furan [3,2-g] benzo pyrroles
Mutter -5-) methyl-(2,4- difluoros) benzoate；
(7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2,4- difluoros) benzoate (compound 8j)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.08 (td, J=8.5,6.5Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=
2.2Hz, 1H), 7.54 (s, 1H), 7.04-6.90 (m, 2H), 6.87 (d, J=2.0Hz, 1H), 6.63 (s, 1H), 5.63 (s
2H).
13C NMR(101MHz,CDCl3)δ165.18,164.55,162.94,160.79,156.54,151.85,
149.00,147.33,134.41,125.10,115.56,113.67,112.34,112.12,111.97,106.70,105.76,
100.56,62.40。
Embodiment 11
The preparation of compound 8k
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.15g (1.2mmol) benzoic acid are dissolved in appropriate dichloromethane, are filled
Divide stirring to make which complete molten, move to, after raw material all disappearance, filter, mother solution uses 1M hydrochloric acid successively
Solution and saturated sodium bicarbonate solution washing, are dried, and residue is adopted column chromatography gradient elution by concentration, and eluant is volume ratio
12: 1 petroleum ether: ethyl acetate, 0.29g compound 8i are obtained final product, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) first
Yl benzoic acid ester；
The nuclear magnetic data of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl benzoic acid ester (compound 8k)：
1H NMR(400MHz,CDCl3) δ 8.16-8.11 (m, 2H), 7.82 (s, 1H), 7.72 (d, J=2.2Hz, 1H),
7.64 (t, J=7.4Hz, 1H), 7.56-7.47 (m, 3H), 6.87 (d, J=2.2Hz, 1H), 6.61 (s, 1H), 5.63 (s,
2H).
13C NMR(101MHz,CDCl)δ165.87 160.85,156.54,151.88,149.61,147.32,133.94,
131.04,130.01,128.85,125.11,115.60,113.81,111.79,106.72,100.55,61.96。
Embodiment 12
The preparation of compound 8l
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.20g (1.2mmol) 4- nitrobenzoic acids are dissolved in appropriate dichloromethane
In alkane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is used successively
1M hydrochloric acid solutions and saturated sodium bicarbonate solution washing, are dried, concentration, and by residue using column chromatography gradient elution, eluant is
The petroleum ether of volume ratio 12: 1: ethyl acetate, 0.30g compound 8l are obtained final product, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyrans -
5-) methyl-(4- nitros) benzoate；
The core of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- nitros) benzoate (compound 8l)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 8.38-8.26 (m, 5H), 7.81 (s, 1H), 7.73 (d, J=2.3Hz, 1H),
7.56 (s, 1H), 6.87 (d, J=2.1Hz, 1H), 6.57 (s, 1H), 5.68 (s, 2H).
13C NMR(101MHz,CDCl3)δ165.87,160.85,156.54,151.88,149.61,147.32,
133.94,131.04,130.01,128.85,125.11,115.60,113.81,111.79,106.72,100.55,61.96。
Embodiment 13
The preparation of compound 8m
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.23g (1.2mmol) 4- (Trifluoromethyl)benzoic acid .s are dissolved in appropriate two
In chloromethanes, be sufficiently stirred for making which complete molten, move to, after raw material all disappears, filter, mother solution according to
Secondary 1M hydrochloric acid solutions and saturated sodium bicarbonate solution are washed, and are dried, and residue is adopted column chromatography gradient elution, eluting by concentration
Petroleum ether of the agent for volume ratio 12: 1: ethyl acetate, 0.34g compound 8m are obtained final product, (7- oxo -7H- furan [3,2-g] benzos
Pyrans -5-) methyl-(4- trifluoromethyls) benzoate；
(7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- trifluoromethyls) benzoate (compound 8m)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.25 (d, J=8.0Hz, 2H), 7.81 (s, 1H), 7.77 (d, J=8.3Hz,
2H), 7.73 (d, J=2.3Hz, 1H), 7.56 (s, 1H), 6.87 (d, J=2.2Hz, 1H), 6.58 (s, 1H), 5.66 (s, 2H).
13C NMR(101MHz,CDCl3)δ166.84,160.71,156.60,151.87,149.06,147.42,
137.47,130.44,127.12,125.94,125.18,115.53,112.03,110.18,106.70,100.67,62.48。
Embodiment 14
The preparation of compound 8n
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.23g (1.2mmol) 3- nitrobenzoic acids are dissolved in appropriate dichloromethane
In alkane, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution is used successively
1M hydrochloric acid solutions and saturated sodium bicarbonate solution washing, are dried, concentration, and by residue using column chromatography gradient elution, eluant is
The petroleum ether of volume ratio 12: 1: ethyl acetate, 0.31g compound 8n are obtained final product, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyrans -
5-) methyl-(3- nitros) benzoate；
The core of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3- nitros) benzoate (compound 8n)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 8.52-8.37 (m, 4H), 7.83 (s, 1H), 7.73 (d, J=2.2Hz, 1H),
7.56 (s, 1H), 6.87 (d, J=2.1Hz, 1H), 6.56 (s, 1H), 5.69 (s, 2H).
13C NMR(101MHz,CDCl3)δ164.82,162.22,156.99,156.59,147.46,142.58,
135.51,133.05,130.20,129.53,128.34,125.05,115.55,112.20,109.31,106.70,100.71,
62.77。
Embodiment 15
The preparation of compound 8o
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.25g (1.2mmol) 3,5- dinitrobenzoic acids are dissolved in appropriate two
In chloromethanes, be sufficiently stirred for making which complete molten, move to, after raw material all disappears, filter, mother solution according to
Secondary 1M hydrochloric acid solutions and saturated sodium bicarbonate solution are washed, and are dried, and residue is adopted column chromatography gradient elution, eluting by concentration
Petroleum ether of the agent for volume ratio 12: 1: ethyl acetate, 0.35g compound 8o are obtained final product, (7- oxo -7H- furan [3,2-g] benzos
Pyrans -5-) methyl-(3,5- dinitros) benzoate；
(7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,5- dinitros) benzoate (compound 8o)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 9.30 (s, 1H), 9.24-9.21 (m, 2H), 7.83 (s, 1H), 7.74 (d, J=
2.2Hz, 1H), 7.57 (s, 1H), 6.89 (d, J=2.1Hz, 1H), 6.53 (s, 1H), 5.75 (s, 2H).
13C NMR(101MHz,CDCl3)δ165.43,161.05,156.71,152.14,148.89,146.65,
144.81,135.20,132.03,129.76,128.83,124.97,116.08,112.12,107.33,100.36,62.43。
Embodiment 16
The preparation of compound 8p
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.30g (1.2mmol) 2- iodo-benzoic acids are dissolved in appropriate dichloromethane
In, it is sufficiently stirred for making which complete molten, moves to, after raw material all disappears, filter, mother solution uses 1M successively
Hydrochloric acid solution and saturated sodium bicarbonate solution washing, are dried, and residue is adopted column chromatography gradient elution by concentration, and eluant is body
Product compares 12: 1 petroleum ether: ethyl acetate, obtains final product 0.38g compound 8p, (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyrans -
5-) methyl-(2- iodine) benzoate；
The nuclear-magnetism of (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- iodine) benzoate (compound 8p)
Data：
1H NMR(400MHz,CDCl3) δ 8.06 (d, J=8.0Hz, 1H), 7.92 (d, J=7.6Hz, 1H), 7.82 (s,
1H), 7.72 (d, J=1.9Hz, 1H), 7.54 (s, 1H), 7.50-7.42 (m, 2H), 6.87 (d, J=2.0Hz, 1H), 6.62
(s,1H),5.63(s,2H).
13C NMR(101MHz,CDCl3)δ160.79,156.46,149.03,147.35,141.89,133.56,
131.41,128.33,125.13,123.26,116.70,115.69,113.65,112.28,110.17,106.72,100.58,
62.59。
Embodiment 17
Purposes of the Psoralens resistance compound of the present invention in treatment leucoderma medicament is prepared, by embodiment 1-16
The compound 4,5,6,7,8a-8p of acquisition is determined to the melanin content of B16 melanoma cells：
(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 substance 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；After diluting, by 0,1,2,4,8,12,16,20 μ l are added separately to standard substance (0.5mg/mlBSA)
In 96 orifice plates, plus all standard substance are supplied 20 μ l by standard dilutions；Plus proper volume sample is to the sample well of 96 orifice plates
In, plus standard dilutions supply 20 μ l；Each hole adds 200 μ l Bradford dyeing liquors, gently blows and beats mixing with sample loading gun
(being careful not to make aeration reading) room temperature places 3-5 minutes；A595 is determined with microplate reader；Calculated according to standard curve
Protein 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 dishs, concentration is 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 cellses, 80 DEG C are put
Absorption value A is determined at 470nm after 2h in water-bath.Non- medication group (negative control group) is contrasted with medication group as a control group
It is shown in Table 1；
Antibacterial activity result of 1 derivant of table to melanin genesis in cell and three kinds of antibacterials
As can be seen from the table：Compound 4-7, compound 8a-8d and compound 8k-8o are used equally to clinically prepare and control
Treat leukodermic medicine.The psoralen Schiff basess derivant for being obtained is used equally to clinically prepare treatment Candida albicans
The medicine of infection, and compound 5 and compound 7 can be additionally used in clinically preparing the medicine for the treatment of infection of staphylococcus aureus.
Claims (4)
1. a kind of psoralen esters derivative, it is characterised in that such derivant structure formula is：
Wherein：Compound 4 is 5- methyl -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone；
Compound 5 is 7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- formaldehyde；
Compound 6 is 5- methylol -7H- furan [3,2-g] .alpha.-5:6-benzopyran -7- ketone；
Compound 7 is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5- bases) methyl acetic acid ester；
Compound 8a is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- methyl) benzoate；
Compound 8b is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- methyl) benzoate；
Compound 8c is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- methoxyl groups) benzoate；
Compound 8d is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- methoxyl groups) benzoate；
Compound 8e is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- chlorine) benzoate；
Compound 8f is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- chlorine) benzoate；
Compound 8g is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,4- dichloros) benzoate；
Compound 8h is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,5- dichloros) benzoate；
Compound 8i is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- fluorine) benzoate；
Compound 8j is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2,4- difluoros) benzoate；
Compound 8k is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl benzoic acid ester；
Compound 8l is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- nitros) benzoate；
Compound 8m is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(4- trifluoromethyls) benzoate；
Compound 8n is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3- nitros) benzoate；
Compound 8o is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(3,5- dinitros) benzoate；
Compound 8p is (7- oxo -7H- furan [3,2-g] .alpha.-5:6-benzopyran -5-) methyl-(2- iodine) benzoate.
2. a kind of psoralen esters derivative as claimed in claim 1 is in the medicine for preparing treatment candida albicans infection
Purposes.
3. a kind of psoralen esters derivative as claimed in claim 1, it is characterised in that compound 4-7, compound 8a-8d
With purposes of the compound 8k-8o in the leukodermic medicine for the treatment of is prepared.
4. a kind of psoralen esters derivative as claimed in claim 1, it is characterised in that compound 5 and compound 7 are in system
Purposes in the medicine of standby treatment infection of staphylococcus aureus.
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