CN107814809A - The psoralen derivative and purposes of a kind of triazole containing phenyl - Google Patents
The psoralen derivative and purposes of a kind of triazole containing phenyl Download PDFInfo
- Publication number
- CN107814809A CN107814809A CN201710995086.XA CN201710995086A CN107814809A CN 107814809 A CN107814809 A CN 107814809A CN 201710995086 A CN201710995086 A CN 201710995086A CN 107814809 A CN107814809 A CN 107814809A
- Authority
- CN
- China
- Prior art keywords
- methyl
- phenyl
- furans
- chromene
- ketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the psoralen derivative and purposes of a kind of triazole containing phenyl, the analog derivative is the Hydroxycoumarin of 4 methyl 7（Intermediate 1）；4 methyl 7 (2 oxo) benzene ethoxy coumarins（Intermediate 2）；The phenyl psoralen of 5 methyl 3（Intermediate 3）；The phenyl of 7 oxo 37HThe formaldehyde of furans [3,2 g] chromene 5（Intermediate 4）；The phenyl of 5 methylol 37HThe ketone of furans [3,2 g] chromene 7（Intermediate 5）；The phenyl of 5 bromomethyl 37HThe ketone of furans [3,2 g] chromene 7（Intermediate 6）；The phenyl of 5 azido-methyl 37HThe ketone of furans [3,2 g] chromene 7（Intermediate 7）With the psoralen derivative 8a 8o of the triazole containing phenyl.And by the psoralen derivative of obtain 15 triazoles containing phenyl（8a‑8o）The Experiment on Function of melanogenesis and tyrosinase activity in mouse B16 cells is carried out, its result is shown, the psoralen derivative of totally 5 triazoles containing phenyl is used equally for clinically preparing the medicine for treating leucoderma by compound 8a, 8j, 8m 8o.
Description
Technical field
The present invention relates to the psoralen derivative and purposes of a kind of triazole containing phenyl, such compound passes through anti-leucoderma
Wind screening active ingredients, compound 8a, 8j, 8m-8o totally 5 triazoles containing phenyl psoralen derivative prepare treat leucoderma
Medicine in purposes.
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, perplex 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's population illness rate is 0.56% or so, and only about half of patient fell ill before 20 one full year of life, male and female
The illness rate of property is equal.Leucoderma is mainly shown as skin, the hickie of mucous membrane and ash/white hair etc..Doctor trained in Western medicine thinks leucoderma
Be due to tyrosinase system in the melanocyte of skin and hair follicle hypofunction, lose caused by.
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 medicine of leucoderma.Uygur's medical science thinks that leucoderma is mainly caused by abnormal phlegm, advocates during treatment clear
Except abnormal humour, abnormal makings is corrected, so as to recover body natural force.Psoralea corylifolia have raw dry heat, remove abnormal lymphatic temperament,
Net blood removing toxic substances, increase pigment, kill 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.
Medicine and preparation using plant psoralea corylifolia as main component at present, clinically it is mainly used in treating leucoderma：As again
Square psoralea corylifolia particle, malaytea scurfpea injection, compound psorolea tincture, the white Ba Busi pieces of drive, compound kaliziranding (dimension medicine name Wei A
Dew) etc..Although tieing up medicine treatment 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, and serious constrains 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 most wide as main chemical compositions therein, research range.
Psoralens resistance compound (Psoralen) is the most frequently used photosensitizer of current clinical treatment leucoderma, but
It is that must coordinate daylight or long wave ultraviolet (UVA) irradiation treatment, so such a treatment method is referred to as PUVA (Psoralen+
UVA).Conventional have a 8-methoxypsoralen (8-MOP) and 5-bergapten (5-MOP), later and artificial synthesized
Trimethyl psoralen (TMP), as shown in structure.In the treatment of leucoderma, PUVA can activate tyrosinase activity, catalysis
Melanin genesis, promote the division and movement of melanocyte, finally increase B16 cell, hickie color is gradually recovered.
Through retrieval, 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] Chinese six provinces and cities leucoderma epidemiology survey [M] Chinese journal of dermatology of the gorgeous of Wang Xiao, 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, which is bought, to be carried, and a Ju Laitia not all watt clothing carries,
Yi Li karrs visit gram Dalmatia dimension medicine maturing agents and scavenger treats 166 progressive stage Vitiligo [J] Chinese medicines
Reason is with clinical, 2012,28,161-162.
[10] the western nguktrum Xiao Gai of summer wood is carried, Si Lafuaibai, the Current medicine treatment of Re Nakasi wood leucoderma
[J] National medicine magazines, 2011,8,62-64.
[11] Huang is built, Zhao Luhua, Zou Qiao root Constituents in Fruits of Psoralea corylifolia L and pharmacological research progress [J] pharmacy 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, is reacted by click chemistry by difference
Benzene oxy-acetylene be incorporated into psoralen molecules, improve its druggability, and have studied the psoralea corylifolia of these triazoles containing phenyl
The influence of melanogenesis and tyrosinase activity, its result indicate evident in efficacy, target spot in plain Derivatives In Mice B16 cells
Clearly, the mechanism of action clearly anti-leucoderma new drug.
The content of the invention
It is an object of the present invention to provide the psoralen derivative and purposes of a kind of triazole containing phenyl, such derivative
Thing is using resorcinol as initiation material, in the presence of sulfuric acid, is condensed to yield 4- methyl -7- hydroxyls with ethyl acetoacetate first
Cumarin (intermediate 1)；Intermediate 1 is reacted with alpha-brominated acetophenone again to obtain 4- methyl -7- (2- oxos) benzene ethoxy basic note
Legumin (intermediate 2)；By intermediate 2, cyclization forms 5- methyl -3- phenyl psoralen (centre in potassium hydroxide-ethanol solution
Body 3)；Intermediate 3 is aoxidized by selenium dioxide to obtain corresponding aldehyde, i.e. 7- oxos -3- phenyl -7H- furans [3,2-g] benzo pyrrole
Mutter -5- formaldehyde (intermediate 4)；Recycle sodium borohydride that intermediate 4 is reduced into 5- methylol -3- phenyl -7H- furans [3,2-
G] chromene -7- ketone (intermediate 5)；Intermediate 5 obtains 5- bromomethyl -3- phenyl -7H- furans [3,2- by further bromo
G] chromene -7- ketone (intermediate 6)；Intermediate 6 and sodium azide flowed back in acetonitrile obtain 5- azido-methyl -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone (intermediate 7)；Finally, intermediate 7 obtains from different substituted benzene oxygen acetylene reactions
The psoralen derivative 8a-8o of the triazole containing phenyl.And by the psoralen derivative of obtain 15 triazoles containing phenyl
(8a-8o) has carried out the Experiment on Function of melanogenesis and tyrosinase activity in mouse B16 cells, and its result is shown, compound
The psoralen derivative of totally 5 triazoles containing phenyl is used equally for clinically preparing the medicine for treating leucoderma by 8a, 8j, 8m-8o
Purposes in thing.
A kind of psoralen derivative of triazole containing phenyl of the present invention, such derivant structure are：
Wherein：
Compound 8a be 5- ((4- ((4- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8b be 5- ((4- ((2- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8c be 5- ((4- ((3- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8d is 5- ((4- ((2,4 dichloro benzene epoxide) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3-
Phenyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 8e is 5- ((4- ((3,5- dichlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3-
Phenyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 8f is 5- ((4- ((3,4- dichlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3-
Phenyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 8g be 5- ((4- ((4- fluorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8h be 5- ((4- ((2- fluorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8i is 5- ((4- ((3,5- difluoros phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3-
Phenyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 8j be 5- ((4- ((4- bromobenzenes epoxide) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8k is 5- ((4- (phenoxymethyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
Mutter [3,2-g] chromene -7- ketone；
Compound 8l is 5- ((4- ((2- methylphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- benzene
Base -7H- furans [3,2-g] chromene -7- ketone；
Compound 8m is 5- ((4- ((4- methylphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- benzene
Base -7H- furans [3,2-g] chromene -7- ketone；
Compound 8n is 5- ((4- ((2- methoxyphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3-
Phenyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 8o is 5- ((4- ((4- methoxyphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3-
Phenyl -7H- furans [3,2-g] chromene -7- ketone；
In the psoralen amine derivant, the psoralen of compound 8a, 8j, 8m-8o totally 5 triazoles containing phenyl
Derivative is used equally for clinically preparing the medicine for the treatment of leucoderma.
A kind of psoralen derivative of triazole containing phenyl of the present invention, its structure is as shown in logical formula (I)：
The psoralen derivative of a kind of triazole containing phenyl of the present invention, by obtain 15 triazoles containing phenyl
Psoralen derivative (8a-8o) carried out the Experiment on Function of melanogenesis and tyrosinase activity in mouse B16 cells, promote
The result for entering melanin genesis is shown：Compared with negative control, all 15 derivatives, it can promote in B16 cells in addition to 8i
The generation of melanocyte, and facilitation is from 102.13%-211.36%；Compared with positive control, compound 8a, 8j, 8m-8o
Totally 5 compounds are superior to positive control to the facilitation of melanogenesis, and promotions of the wherein compound 8o to melanogenesis is made
With being more than 1.6 times of positive control；
The result of activation tyrosinase activity is shown：It is all in addition to 8d, 8e, 8f, 8i and 8k compared with negative control
Compound can activate the activity of tyrosinase, and activation is from 100.72%-132.80%；With positive control phase
Than totally 2 compounds are superior to positive control to the activation of tyrosinase activity by compound 8a and 8o.
In summary, totally 5 psoralen amine derivants are used equally for clinically preparing and controlled compound 8a, 8j, 8m-8o
Treat the purposes in the medicine of leucoderma.
The psoralen derivative and purposes of a kind of triazole containing phenyl of the present invention, wherein the triazole containing phenyl
The preparation method of Psoralen derivatives, follow these steps to carry out：
The preparation of intermediate 1：
A, under condition of ice bath, resorcinol is dissolved in appropriate drying Isosorbide-5-Nitrae-dioxane, stirred to all molten
Solution, is slowly added dropwise the concentrated sulfuric acid, its temperature is no more than 0 DEG C, after being added dropwise, adds ethyl acetoacetate, then heat to
60 DEG C, being sufficiently stirred makes its reaction completely, and reaction solution is poured into frozen water, is adopted and is extracted with ethyl acetate after standing, organic to be harmonious
And dry, intermediate Isosorbide-5-Nitrae-Methyl-7-hydroxy-coumarin is obtained after concentration；
The preparation of intermediate 2：
B, appropriate potassium carbonate and intermediate 1 are dissolved in 20mL acetone, and add alpha-brominated acetophenone, back flow reaction
All disappeared to raw material, reacting liquid filtering, concentration, residue is used into column chromatography gradient elution, eluant, eluent is the stone of volume ratio 5: 1
Oily ether: ethyl acetate, intermediate 2,4- methyl -7- (2- oxos) benzene ethoxy coumarin are produced；
The preparation of intermediate 3：
C, the intermediate 2 that step b is obtained is dissolved in absolute ethyl alcohol, it is molten for the ethanol of 4% potassium hydroxide adds concentration
Liquid, back flow reaction is heated to, after raw material all disappears, is concentrated under reduced pressure, residue is used into column chromatography gradient elution, eluant, eluent is
Volume ratio 10:1 petroleum ether: ethyl acetate, intermediate 3,5- methyl -3- phenyl psoralens are produced；
The preparation of intermediate 4：
D, the intermediate 3 obtained by step c and selenium dioxide are dissolved in dry dimethylbenzene, are heated to back flow reaction,
After raw material all disappears, room temperature is cooled to, mother liquor filtering, concentration, residue is used into column chromatography gradient elution, eluant, eluent is body
Product ratio 10:1 petroleum ether: ethyl acetate, intermediate 4,7- oxos -3- phenyl -7H- furans [3,2-g] chromene -5- are produced
Formaldehyde；
The preparation of intermediate 5：
E, intermediate 4 resulting in step d is dissolved in absolute ethyl alcohol, being sufficiently stirred makes its dissolving, adds by several times
Sodium borohydride, continuation are reacted until raw material all disappears at room temperature, and reaction is quenched in addition watery hydrochloric acid, and acetic acid is used after being diluted with water
Ethyl ester is extracted, and organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is volume ratio 5:1 petroleum ether:
Ethyl acetate, produce intermediate 5,5- methylols -3- phenyl -7H- furans [3,2-g] chromene -7- ketone；
The preparation of intermediate 6：
F, the intermediate 5 obtained in step e is dissolved in anhydrous tetrahydro furan, being stirred under ice bath makes its dissolving, slowly
The tetrahydrofuran solution of phosphorus tribromide is added dropwise, room temperature reaction is moved to after being added dropwise, after TLC Indicator Reactions terminate, to reactant
Distilled water is added in system, and adjusts pH with sodium bicarbonate solution and is dried to neutrality, dichloromethane extraction, organic phase, concentration will be residual
Slag uses column chromatography gradient elution, and eluant, eluent is volume ratio 10:1 petroleum ether: ethyl acetate, intermediate 6,5- bromine first are produced
Base -3- phenyl -7H- furans [3,2-g] chromene -7- ketone；
The preparation of intermediate 7：
G, the intermediate 6 and sodium azide that are obtained in step f are dissolved in anhydrous acetonitrile, heat treats original to back flow reaction
After material all disappears, room temperature is cooled to, concentrates, residue is used into column chromatography gradient elution, eluant, eluent is volume ratio 10:1 stone
Oily ether: ethyl acetate, intermediate 7,5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone are produced；
Compound 8a-8o preparation：
H, the intermediate 7 obtained in step g and different substituted benzene oxygen acetylene are dissolved in volume VThe tert-butyl alcohol∶VWater=3:1
In the mixed solvent, cupric sulfate pentahydrate and copper powder are added, reacted overnight at 80 DEG C.After raw material all disappears, room is cooled to
Temperature, water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, is eluted
Agent is volume ratio 2:1 petroleum ether: ethyl acetate, corresponding derivative 8a-8o is produced.
Chemical equation is：
(I) ethyl acetoacetate, the concentrated sulfuric acid, 0-60 DEG C of temperature；(II) alpha-brominated acetophenone, potassium carbonate, acetone, backflow；
(III) 4% potassium hydroxide-ethanol solution, backflow；(IV) selenium dioxide, dimethylbenzene, backflow；(V) sodium borohydride, methanol, room temperature；
(VI) phosphorus tribromide, tetrahydrofuran, 0 DEG C of-rt；(VII) sodium azide, acetonitrile, backflow；(VIII) different benzene oxygen propine, five water sulphur
Sour copper, copper powder, volume ratio 1:3 tert-butyl alcohol:Water, 80 DEG C of temperature；
Wherein R1Respectively 4- chlorine, 2- chlorine, 3- chlorine, 2.4- dichloros, 3.5- dichloros, 3,4- dichloros, 4- fluorine, 2- fluorine, 3,5-
Difluoro, 4- bromines, hydrogen, 2- methyl, 4- methyl, 2- methoxyl groups, 4- methoxyl groups.
Brief description of the drawings
Fig. 1 is that the psoralen derivative 8a-8o of the triazole containing phenyl in the present invention is acted on melanin genesis in B16 cells
Figure；
Fig. 2 is the psoralen derivative 8a-8o of the triazole containing phenyl in the present invention to tyrosinase activity in B16 cells
Action diagram.
Embodiment
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 1：
Under condition of ice bath, 2.0g resorcinols are dissolved in 50mL drying Isosorbide-5-Nitrae-dioxane, stirred to whole
Dissolving, is slowly added dropwise the 0.5mL concentrated sulfuric acids, its temperature is maintained at 0 DEG C, after being added dropwise, add 2.8g ethyl acetoacetates,
60 DEG C are then heated to, being sufficiently stirred makes its reaction completely, and reaction solution is poured into frozen water, extracts after standing using ethyl acetate
Take, organic phase merges drying, and it is AP20am16 that 3.02g intermediates 1 are obtained after concentration；
The preparation of intermediate 2：
1.4g potassium carbonate and 0.88g intermediates 1 are dissolved in 50mL acetone, and add the alpha-brominated acetophenones of 1.49g,
Back flow reaction all disappears to raw material, reacting liquid filtering, concentration, residue is used into column chromatography gradient elution, eluant, eluent is volume
Petroleum ether than 5: 1: ethyl acetate, it is 4- methyl -7- (2- oxos) benzene ethoxy coumarin to produce 1.25g intermediates 2；
The preparation of intermediate 3：
2.94g intermediates 2 are dissolved in 100mL absolute ethyl alcohols, add the ethanol that 2 0mL concentration are 4% potassium hydroxide
Solution, back flow reaction is heated to, after raw material all disappears, is concentrated under reduced pressure, residue is used into column chromatography gradient elution, eluant, eluent
For the petroleum ether of volume ratio 10: 1: ethyl acetate, it is 5- methyl -3- phenyl psoralens to produce 1.34g intermediates 3；
The preparation of intermediate 4：
5.52g intermediates 3 and 3.33g selenium dioxide are dissolved in dry dimethylbenzene, are heated to back flow reaction, treats raw material
After all disappearing, room temperature is cooled to, mother liquor filtering, concentration, residue is used into column chromatography gradient elution, eluant, eluent is volume ratio 10
: 1 petroleum ether: ethyl acetate, it is 7- oxos -3- phenyl -7H- furans [3,2-g] chromene -5- to produce 3.83g intermediates 4
Formaldehyde；
The preparation of intermediate 5：
5.80g intermediates 4 are dissolved in absolute ethyl alcohol, being sufficiently stirred makes its dissolving, adds 0.38g hydroborations by several times
Sodium, continuation are reacted until raw material all disappears at room temperature, and reaction is quenched in addition watery hydrochloric acid, is extracted after being diluted with water with ethyl acetate
Take, organic phase is dried, concentration, residue is used into column chromatography gradient elution, eluant, eluent is the petroleum ether of volume ratio 5: 1: acetic acid second
Ester, it is 5- methylols -3- phenyl -7H- furans [3,2-g] chromene -7- ketone to produce 4.56g intermediates 5；
The preparation of intermediate 6：
2.92g intermediates 5 are dissolved in 25mL anhydrous tetrahydro furan, being stirred under ice bath makes its dissolving, is slowly added dropwise
The tetrahydrofuran solution of the phosphorus tribromide containing 0.95mL, room temperature reaction is moved to after being added dropwise, after TLC Indicator Reactions terminate, to anti-
To answer and distilled water is added in system, and adjust pH with sodium bicarbonate solution and extracted to neutrality, dichloromethane, organic phase is dried, concentration,
Residue is used into column chromatography gradient elution, eluant, eluent is the petroleum ether of volume ratio 10: 1: ethyl acetate, produces 3.12g intermediates 6
For 5- bromomethyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone；
The preparation of intermediate 7：
3.55g intermediates 6 and 0.96g sodium azide are dissolved in anhydrous acetonitrile, heat to back flow reaction, treat raw material whole
After disappearance, room temperature is cooled to, is concentrated, residue is used into column chromatography gradient elution, eluant, eluent is the petroleum ether of volume ratio 10: 1: second
Acetoacetic ester, it is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone to produce 2.57g intermediates 7.
Embodiment 2
Compound 8a preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 4- chlorobenzene oxy-acetylene 0.199g is dissolved in volume ratio 3:1 tert-butyl alcohol: water 20mL in the mixed solvents, add
0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room temperature,
Water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 2: 1: ethyl acetate, 0.451g compounds 8a, entitled 5- ((4- ((4- chlorophenoxies) first are finally given
Base) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((4- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,
2-g] chromene -7- ketone (compound 8a) nuclear magnetic data：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.70(s,1H),7.58–7.53(m,5H),
7.48-7.41 (m, 1H), 7.21 (d, J=9.0Hz, 2H), 6.88 (d, J=9.0Hz, 2H), 6.05 (s, 1H), 5.80 (s,
2H),5.21(s,2H)。
13C NMR(101MHz,CDCl3)δ160.06,157.52,156.70,152.07,148.18,143.47,
130.56,129.60,129.54,128.48,127.65,124.70,123.40,122.48,116.24,115.20,114.02,
113.62,101.06,62.33,50.95。
Embodiment 3
Compound 8b preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 2- chlorobenzene oxy-acetylene 0.199g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, add
0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room temperature,
Water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 2: 1: ethyl acetate, 0.440g compounds 8b, entitled 5- ((4- ((2- chlorophenoxies) first are finally given
Base) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((2- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,
2-g] chromene -7- ketone (compound 8b) nuclear magnetic data：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.77(s,1H),7.59–7.50(m,5H),
7.48-7.40 (m, 1H), 7.33 (d, J=8.0Hz, 1H), 7.22-7.15 (m, 1H), 7.06 (d, J=8.2Hz, 1H), 6.94-
6.87(m,1H),6.02(s,1H),5.81(s,2H),5.33(s,2H).
13C NMR(101MHz,CDCl3)δ160.05,157.51,153.66,152.08,148.24,145.51,
143.42,132.60,131.02,130.57,129.53,128.95,128.46,127.98,127.67,124.68,123.49,
122.51,115.16,114.57,113.92,101.05,63.52,50.90。
Embodiment 4
Compound 8c preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and-chlorobenzene oxy-acetylene 0.199g 3 are dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, add
0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room temperature,
Water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 2: 1: ethyl acetate, 0.434g compounds 8c, entitled 5- ((4- ((3- chlorophenoxies) first are finally given
Base) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((3- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,
2-g] chromene -7- ketone (compound 8c) nuclear magnetic data：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.71(s,1H),7.59–7.52(m,5H),
7.48-7.41 (m, 1H), 7.22-7.15 (m, 1H), 6.99-6.92 (m, 2H), 6.85 (d, J=8.6Hz, 1H), 6.06 (s,
1H),5.81(s,2H),5.22(s,2H).
13C NMR(101MHz,CDCl3)δ160.06,158.84,157.53,152.09,148.17,143.45,
135.14,131.06,130.56,130.50,129.54,128.48,127.67,123.36,121.83,115.56,115.21,
114.04,113.64,113.22,110.17,101.08,62.27,50.96。
Embodiment 5
Compound 8d preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 2,4 dichloro benzene oxy-acetylene 0.201g are dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, then add
Enter 0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room
Temperature, water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, is eluted
Agent is the petroleum ether of volume ratio 2: 1: ethyl acetate, finally gives 0.477g compounds 8d, entitled 5- ((4- ((2,4- dichloros
Phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((2,4 dichloro benzene epoxide) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
Mutter the nuclear magnetic data of [3,2-g] chromene -7- ketone (compound 8d)：
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.86(s,1H),7.75(s,1H),7.59–7.50(m,5H),
7.48-7.41 (m, 1H), 7.32 (d, J=2.4Hz, 1H), 7.14 (dd, J=8.8,2.5Hz, 1H), 7.00 (d, J=8.8Hz,
1H),6.03(s,1H),5.81(s,2H),5.30(s,2H).
13C NMR(101MHz,CDCl3)δ161.13,157.53,155.69,152.48,148.16,143.47,
142.31,131.06,130.29,129.53,128.99,128.47,127.87,127.65,125.78,124.70,123.58,
115.35,115.14,113.98,110.98,101.09,63.68,50.95。
Embodiment 6
Compound 8e preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 3,5- Dichlorophenoxy acetylene 0.201g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, then add
Enter 0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room
Temperature, water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, is eluted
Agent is the petroleum ether of volume ratio 2: 1: ethyl acetate, finally gives 0.450g compounds 8e, 5- ((4- ((3,5- dichlorophenoxy)
Methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((3,5- dichlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
Mutter the nuclear magnetic data of [3,2-g] chromene -7- ketone (compound 8e)：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.70(s,1H),7.57–7.51(m,5H),
7.48-7.41 (m, 1H), 6.97 (t, J=1.8Hz, 1H), 6.87 (d, J=1.7Hz, 2H), 6.07 (s, 1H), 5.82 (s,
2H),5.20(s,2H).
13C NMR(101MHz,CDCl3)δ160.04,157.32,156.52,152.79,148.11,143.48,
131.06,129.54,129.41,128.99,128.49,127.66,124.73,123.47,121.98,115.20,114.06,
113.77,109.69,101.10,62.44,50.98。
Embodiment 7
Compound 8f preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 3,4- Dichlorophenoxy acetylene 0.201g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, then add
Enter 0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room
Temperature, water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, is eluted
Agent is the petroleum ether of volume ratio 2: 1: ethyl acetate, finally gives 0.463g compounds 8f, entitled 5- ((4- ((3,4- dichloros
Phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((3,4- dichlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
Mutter the nuclear magnetic data of [3,2-g] chromene -7- ketone (compound 8f)：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.71(s,1H),7.59–7.52(m,5H),
7.49-7.41 (m, 1H), 7.30 (d, J=8.9Hz, 1H), 7.07 (d, J=2.9Hz, 1H), 6.82 (dd, J=9.0,2.9Hz,
1H),6.06(s,1H),5.81(s,2H),5.20(s,2H).
13C NMR(101MHz,CDCl3)δ160.05,157.54,157.10,156.31,152.08,148.13,
143.49,130.95,129.53,128.48,127.65,124.72,123.47,122.49,117.05,115.19,114.77,
114.05,113.60,110.15,101.09,62.46,50.98。
Embodiment 8
Compound 8g preparation：
0.317g intermediates 7 and 0.150g 4- fluorobenzene oxy-acetylene are dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL of water
In the mixed solvent, 0.44g cupric sulfate pentahydrates and 0.06g copper powders are added, reacted overnight at 80 DEG C.Treat that raw material all disappears
Afterwards, room temperature is cooled to, water distilled water is added, is extracted with dichloromethane, organic phase is dried, concentration, by residue using column chromatography ladder
Degree elution, eluant, eluent are the petroleum ether of volume ratio 2: 1: ethyl acetate, finally give 0.415g compounds 8g, 5- ((4- ((4- fluorine
Phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((4- fluorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,
2-g] chromene -7- ketone (compound) nuclear magnetic data：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.71(s,1H),7.59–7.50(m,6H),
7.48–7.41(m,1H),6.99–6.85(m,4H),6.04(s,1H),5.80(s,2H),5.19(s,2H).
13C NMR(101MHz,CDCl3)δ160.06,157.50,156.54,154.20,152.05,148.24,
143.45,131.02,129.53,128.93,128.46,127.65,124.67,123.40,122.48,116.21,115.98,
115.20,113.95,113.63,101.03,62.71,50.90.
Embodiment 9
Compound 8h preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 2- fluorobenzene oxy-acetylene 0.150g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, add
0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room temperature,
Water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 2: 1: ethyl acetate, 0.406g compounds 8h, entitled 5- ((4- ((2- fluorophenoxies) first are finally given
Base) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((2- fluorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,
2-g] chromene -7- ketone (compound 8h) nuclear magnetic data：
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.85(s,1H),7.71(s,1H),7.61–7.49(m,5H),
7.47–7.40(m,1H),7.12–6.96(m,3H),6.96–6.85(m,1H),6.01(s,1H),5.80(s,2H),5.30(s,
2H).
13C NMR(101MHz,CDCl3)δ160.03,157.50,154.29,152.06,148.21,146.00,
143.42,132.45,131.05,130.56,129.52,128.97,128.45,127.66,124.58,122.41,116.46,
115.19,113.94,113.66,101.03,63.65,50.94。
Embodiment 10
Compound 8i preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 3,5- difluorobenzene oxy-acetylene 0.168g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, then add
Enter 0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room
Temperature, water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, is eluted
Agent is the petroleum ether of volume ratio 2: 1: ethyl acetate, finally gives 0.438g compounds 8i, entitled 5- ((4- ((3,5- difluoros
Phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((3,5- difluoros phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
Mutter the nuclear magnetic data of [3,2-g] chromene -7- ketone (compound 8i)：
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.86(s,1H),7.72(s,1H),7.59–7.52(m,5H),
7.47-7.43 (m, 1H), 6.50 (d, J=8.8Hz, 2H), 6.43 (t, J=8.9Hz, 1H), 6.06 (s, 1H), 5.82 (s,
2H),5.19(s,2H).
13C NMR(101MHz,CDCl3)δ160.04,157.54,155.60,152.09,148.12,143.48,
131.06,129.54,128.99,128.49,127.66,124.74,123.02,122.53,115.20,114.05,113.58,
109.19,101.09,62.49,50.98。
Embodiment 11
Compound 8j preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 4- bromobenzene oxy-acetylene 0.211g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, add
0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room temperature,
Water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 2: 1: ethyl acetate, 0.479g compounds 8j, entitled 5- ((4- ((4- bromobenzenes epoxide) first are finally given
Base) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((4- bromobenzenes epoxide) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,
2-g] chromene -7- ketone (compound 8j) nuclear magnetic data：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.71(s,1H),7.59–7.51(m,5H),
7.48-7.41 (m, 1H), 7.35 (d, J=8.9Hz, 2H), 6.84 (d, J=8.9Hz, 2H), 6.05 (s, 1H), 5.80 (s,
2H),5.20(s,2H).
13C NMR(101MHz,CDCl3)δ160.06,157.52,157.21,153.19,152.07,148.17,
143.47,132.54,129.54,128.48,127.65,124.69,123.41,122.49,116.75,115.20,114.03,
113.85,113.62,101.07,62.25,50.95。
Embodiment 12
Compound 8k preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and benzene oxy-acetylene 0.132g are dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, 0.44g is added
Cupric sulfate pentahydrate and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room temperature, add water
Distilled water, extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is volume ratio
2: 1 petroleum ether: ethyl acetate, finally give 0.407g compounds 8k, entitled 5- ((4- (phenoxymethyl) -1H-1,2,
3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- (phenoxymethyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] benzene
And the nuclear magnetic data of pyrans -7- ketone (compound 8k)：
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.86(s,1H),7.72(s,1H),7.61–7.50(m,5H),
7.48-7.41 (m, 1H), 7.28 (d, J=8.0Hz, 2H), 6.96 (d, J=8.0Hz, 3H), 6.05 (s, 1H), 5.80 (s,
2H),5.24(s,2H).
13C NMR(101MHz,CDCl3)δ160.07,158.12,157.51,152.08,148.24,143.42,
130.57,129.72,129.53,128.46,127.67,124.68,123.32,122.52,121.59,115.23,114.91,
114.00,113.67,101.03,62.09,50.90。
Embodiment 13
Compound 8l preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 2- methylenedioxy phenoxy acetylene 0.146g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, add
0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room temperature,
Water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 2: 1: ethyl acetate, 0.420g compounds 8l, entitled 5- ((4- ((2- methylphenoxies) are finally given
Methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((2- methylphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
The nuclear magnetic data of [3,2-g] chromene -7- ketone (compound 8l)：
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.86(s,1H),7.68(s,1H),7.61–7.50(m,5H),
7.48–7.41(m,1H),7.08–7.17(m,2H),6.96–6.83(m,2H),6.04(s,1H),5.81(s,2H),5.25(s,
2H),2.19(s,3H).
13C NMR(101MHz,CDCl3)δ160.09,157.51,156.28,152.08,148.31,143.39,
131.02,130.57,129.53,128.46,127.67,127.01,124.68,122.52,121.31,115.19,113.89,
113.69,111.70,101.07,62.41,50.92,29.86。
Embodiment 14
Compound 8m preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 4- methylenedioxy phenoxy acetylene 0.146g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, add
0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room temperature,
Water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 2: 1: ethyl acetate, 0.411g compounds 8m, entitled 5- ((4- ((4- methylphenoxies) are finally given
Methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((4- methylphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
The nuclear magnetic data of [3,2-g] chromene -7- ketone (compound 8m)：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.72(s,1H),7.60–7.51(m,5H),
7.48-7.41 (m, 1H), 7.06 (d, J=8.1Hz, 2H), 6.85 (d, J=8.4Hz, 2H), 6.05 (s, 1H), 5.79 (s,
2H),5.20(s,2H),2.27(s,3H).
13C NMR(101MHz,CDCl3)δ160.07,157.50,156.00,152.08,148.23,143.45,
143.37,130.89,130.57,130.15,129.54,128.46,127.67,124.67,122.52,115.28,115.23,
114.81,114.06,113.99,113.68,101.05,62.26,50.98,29.85。
Embodiment 15
Compound 8n preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 2- methoxybenzene oxy-acetylene 0.162g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, then add
Enter 0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room
Temperature, water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, is eluted
Agent is the petroleum ether of volume ratio 2: 1: ethyl acetate, finally gives 0.429g compounds 8n, entitled 5- ((4- ((2- methoxyl groups
Phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((2- methoxyphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
Mutter the nuclear magnetic data of [3,2-g] chromene -7- ketone (compound 8n)：
1H NMR(600MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.71(s,1H),7.59–7.51(m,5H),
7.48-7.41 (m, 1H), 6.99 (d, J=8.0Hz, 1H), 6.95-6.90 (m, 1H), 6.89-6.81 (m, 2H), 6.05 (s,
1H),5.78(s,2H),5.32(s,2H).
13C NMR(101MHz,CDCl3)δ160.06,157.52,156.69,152.11,148.21,143.39,
145.97,130.57,130.18,129.54,128.45,127.68,124.67,123.44,122.39,121.02,115.30,
114.94,114.09,113.70,112.08,101.02,63.48,55.96,50.90。
Embodiment 16
Compound 8o preparation：
The intermediate 7 that embodiment 1 is obtained is 5- azido-methyls -3- phenyl -7H- furans [3,2-g] chromene -7- ketone
0.317g and 2- methoxybenzene oxy-acetylene 0.162g is dissolved in volume ratio 3:1 tert-butyl alcohol: the 20mL in the mixed solvents of water, then add
Enter 0.44g cupric sulfate pentahydrates and 0.06g copper powders, reacted at 80 DEG C of temperature overnight, after raw material all disappears, be cooled to room
Temperature, water distilled water is added, is extracted with dichloromethane, organic phase is dried, and concentration, residue is used into column chromatography gradient elution, is eluted
Agent is the petroleum ether of volume ratio 2: 1: ethyl acetate, finally gives 0.415g compounds 8o, entitled 5- ((4- ((4- methoxyl groups
Phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,2-g] chromene -7- ketone.
5- ((4- ((4- methoxyphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans
Mutter the nuclear magnetic data of [3,2-g] chromene -7- ketone (compound 8o)：
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.71(s,1H),7.60–7.50(m,5H),
7.48-7.41 (m, 1H), 6.93 (d, J=9.1Hz, 2H), 6.84 (d, J=9.1Hz, 2H), 6.03 (s, 1H), 5.79 (s,
2H),5.19(s,2H),3.77(s,3H).13C NMR(101MHz,CDCl3)δ160.07,157.50,154.47,152.19,
151.82,148.25,143.46,130.57,129.54,128.46,127.67,124.67,122.51,116.29,116.08,
115.20,114.84,114.00,113.67,101.06,62.88,55.79,50.98。
Embodiment 17
The psoralen derivative (8a-8o) of triazole of the present invention containing phenyl as shown in structural formula is thin to B16
The effect measure of melanin genesis and tyrosinase activity in born of the same parents：
Screening model：Murine melanoma cells B16
Cell derived：Chinese Academy of Sciences's cell bank provides；
(1) cell toxicity test (mtt assay)：
The melanocyte for being in exponential phase is inoculated in 96 orifice plates, is 5 × 103/ holes per hole cell number, each
Concentration sets 8 multiple holes, after 24h (after cell attachment), adds the samples of various concentrations, 48h post processings cell, per hole adds 10 μ L's
4h is cultivated after MTT (concentration 5mg/mL) in 37 DEG C of incubators of temperature, every hole adds 150 μ L DMSO simultaneously after taking out 96 orifice plates
10min is shaken, absorbance (A570), the hole conduct of non-dosing are determined at 570nm with ELIASA after crystallization all dissolving
Control group, cytoactive calculate by 100%, and dosing group experimental data at least repeats 3 times；
(2) protein quantification is determined with Bradford methods：
Protein standard substance (5mg/mL BSA) is completely dissolved, takes 10 μ L to be diluted to 100 μ L, makes final concentration of 0.5mg/mL.
For protein sample in what solution, standard items also preferably use the dilution of what solution, but for simplicity 0.9% can also be used
NaCl or PBS dilution standard product；Standard items (0.5mg/mLB SA) are added respectively by 0,1,2,4,8,12,16,20 μ L after diluting
Into 96 orifice plates, standard dilutions are added to supply all standard items to 20 μ L；Add proper volume sample to the sample of 96 orifice plates
Kong Zhong, standard dilutions are added to supply to 20 μ L；Each hole adds 200 μ L Bradford dyeing liquors, is gently blown and beaten with sample loading gun mixed
Even (being careful not to make aeration reading) room temperature places 3-5min；A595 is determined with ELIASA；Calculated according to standard curve
The protein concentration gone out in sample；
(3) melanin content is measured with alkali digestion：
Melanocyte in exponential phase is inoculated in 6cm culture dishes, concentration is 5 × 105/ml, each hole adds
5mL cell suspending liquids；Be inoculated with 12h after, after cell completely it is adherent after medication, Drug level is respectively 1,5,10,20,50 and 100 μ
g/mL；Cell is collected after 72h；200 μ L 1M NaOH solutions are added in the case of not smudge cells, put 80 DEG C of water of temperature
In bath after 2h, the absorbance (A470 values) at wavelength 470nm is determined, non-medication group is contrasted with medication group as a control group；
(4) tyrosinase activity is measured with L-Dopa decoration methods：
The melanocyte for being in exponential phase is inoculated in 12 orifice plates, concentration is 2 × 105/mL, and each hole adds 1mL
Cell suspending liquid；Be inoculated with 12h after, after cell completely it is adherent after medication, Drug level is respectively 1,5,10,20,50 and 100 μ g/
mL；Cell is collected after 48h；Handle after cell in each EP pipes plus the μ L of Tris-0.1%Triton-100 solution 200, put
Enter 30min-1h in -20 DEG C of refrigerators to be cracked；Determining the protein quantity is carried out with Bradford methods；Sample protein content is transferred to
Uniform concentration；Each reaction system is put into 37 DEG C of incubators of temperature after adding 100 μ L 0.1%L-DOPA, cultivate after 2h
Absorbance (A475) is determined at 475nm.The group of non-medication is contrasted with medication group as a control group.
As a result：Totally 5 psoralen amine derivants are used equally for clinically preparing treatment in vain by compound 8a, 8j, 8m-8o
The purposes of the medicine of purplish or white patches on the skin wind.
Claims (2)
1. the psoralen derivative of a kind of triazole containing phenyl, it is characterised in that such derivant structure is：
Wherein：
Compound 8a is 5- ((4- ((4- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H-
Furans [3,2-g] chromene -7- ketone；
Compound 8b is 5- ((4- ((2- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H-
Furans [3,2-g] chromene -7- ketone；
Compound 8c is 5- ((4- ((3- chlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H-
Furans [3,2-g] chromene -7- ketone；
Compound 8d be 5- ((4- ((2,4 dichloro benzene epoxide) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8e be 5- ((4- ((3,5- dichlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8f be 5- ((4- ((3,4- dichlorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8g is 5- ((4- ((4- fluorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H-
Furans [3,2-g] chromene -7- ketone；
Compound 8h is 5- ((4- ((2- fluorophenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H-
Furans [3,2-g] chromene -7- ketone；
Compound 8i be 5- ((4- ((3,5- difluoros phenoxy group) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8j is 5- ((4- ((4- bromobenzenes epoxide) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H-
Furans [3,2-g] chromene -7- ketone；
Compound 8k be 5- ((4- (phenoxymethyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -7H- furans [3,
2-g] chromene -7- ketone；
Compound 8l be 5- ((4- ((2- methylphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8m be 5- ((4- ((4- methylphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8n be 5- ((4- ((2- methoxyphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone；
Compound 8o be 5- ((4- ((4- methoxyphenoxies) methyl) -1H-1,2,3- triazole -1- bases) methyl) -3- phenyl -
7H- furans [3,2-g] chromene -7- ketone.
2. in a kind of psoralen derivative of the triazole containing phenyl as claimed in claim 1, compound 8a, 8j, 8m-8o contain
Purposes of the psoralen derivative of phenyl triazole in the medicine for preparing treatment leucoderma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710995086.XA CN107814809B (en) | 2017-10-23 | 2017-10-23 | A kind of psoralen derivative and purposes of the triazole containing phenyl |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710995086.XA CN107814809B (en) | 2017-10-23 | 2017-10-23 | A kind of psoralen derivative and purposes of the triazole containing phenyl |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107814809A true CN107814809A (en) | 2018-03-20 |
| CN107814809B CN107814809B (en) | 2019-07-19 |
Family
ID=61607500
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710995086.XA Active CN107814809B (en) | 2017-10-23 | 2017-10-23 | A kind of psoralen derivative and purposes of the triazole containing phenyl |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107814809B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552309A (en) * | 2020-12-17 | 2021-03-26 | 中国科学院新疆理化技术研究所 | Psoralen benzene sulfonate derivative and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832720A (en) * | 2016-05-03 | 2016-08-10 | 中国科学院新疆理化技术研究所 | Application of psoralen compounds |
| CN106543197A (en) * | 2016-11-09 | 2017-03-29 | 中国科学院新疆理化技术研究所 | A kind of psoralen Schiff basess derivant and purposes |
| CN106565734A (en) * | 2016-11-09 | 2017-04-19 | 中国科学院新疆理化技术研究所 | Psoralen ester derivatives and applications thereof |
-
2017
- 2017-10-23 CN CN201710995086.XA patent/CN107814809B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832720A (en) * | 2016-05-03 | 2016-08-10 | 中国科学院新疆理化技术研究所 | Application of psoralen compounds |
| CN106543197A (en) * | 2016-11-09 | 2017-03-29 | 中国科学院新疆理化技术研究所 | A kind of psoralen Schiff basess derivant and purposes |
| CN106565734A (en) * | 2016-11-09 | 2017-04-19 | 中国科学院新疆理化技术研究所 | Psoralen ester derivatives and applications thereof |
Non-Patent Citations (3)
| Title |
|---|
| A. V. LIPEEVA ET AL.: "Plant Coumarins: XV.* Oreoselone in the Synthesis of 3-[(Z)-Alkenyl]- and 3-(1H-1,2,3-Triazol-4-yl)psoralens", 《RUSSIAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| QING-KUN SHEN ET AL.: "Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| YOSHIYUKI URUMA ET AL.: "Design, synthesis, and biological evaluation of a highly water-soluble psoralen-based photosensitizer", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112552309A (en) * | 2020-12-17 | 2021-03-26 | 中国科学院新疆理化技术研究所 | Psoralen benzene sulfonate derivative and application thereof |
| CN112552309B (en) * | 2020-12-17 | 2023-03-14 | 中国科学院新疆理化技术研究所 | Psoralen benzene sulfonate derivative and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107814809B (en) | 2019-07-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105832720B (en) | A kind of purposes of Psoralens resistance compound | |
| Nie et al. | Discovery and anti-diabetic effects of novel isoxazole based flavonoid derivatives | |
| Yang et al. | Development of a novel nitric oxide (NO) production inhibitor with potential therapeutic effect on chronic inflammation | |
| Rullah et al. | Inhibition of prostaglandin E2 production by synthetic minor prenylated chalcones and flavonoids: Synthesis, biological activity, crystal structure, and in silico evaluation | |
| CN113730391B (en) | Application of myrtle ketone compound in preparation of medicine for resisting novel coronavirus SARS-CoV-2 | |
| AU2008201553A1 (en) | Composition for treating cancer cells and synthetic method for the same | |
| Lin et al. | Phenolic compounds from Tournefortia sarmentosa | |
| CN106543197B (en) | A kind of psoralen Schiff bases derivative and purposes | |
| CN113045399A (en) | Chalcone derivatives and uses thereof | |
| Gu et al. | Synthesis, crystal structure, spectroscopic characterization and anti-fungal activity of Ethyl 2-Oxo-2H-chromene-3-carboxylateDerivatives | |
| Lang'at-Thoruwa et al. | A simple synthesis of 7, 4 ‘-dihydroxy-6-methoxyisoflavone, glycitein, the third soybean isoflavone | |
| CN107814809B (en) | A kind of psoralen derivative and purposes of the triazole containing phenyl | |
| CN106565734B (en) | A kind of psoralen ester derivative and purposes | |
| CN113735814B (en) | Myrtle ketone compound and application thereof in preparation of anti-influenza virus drugs | |
| CN106749218B (en) | A kind of cumarin phenyl Isoxazole derivative and application thereof | |
| CN103102331B (en) | Pharmaceutical application of chalcone compound containing piperazine ring | |
| CN101508693A (en) | Xylogen like flavonoid compounds, method of preparing the same and pharmaceutical use | |
| CN108948038B (en) | Neopteridine flavonoid compound and application thereof | |
| Lin et al. | Structure–activity relationship study of growth inhibitory 2-styrylchromones against carcinoma cells | |
| CN107298686B (en) | A kind of psoralen amine derivant and purposes | |
| CN107602520B (en) | A kind of quasi-isoflavone compound and its preparation method and application containing piperazine ring | |
| CN107641109B (en) | A kind of flavonoids and its preparation method and application | |
| CN101548969B (en) | Use of ethyl malonyl silybin derivant in preparing antioxidant medicine | |
| CN101830961B (en) | Ursolic acid ester derivatives, preparation method thereof and application thereof | |
| CN107586284A (en) | A kind of purposes of 2 arylbenzofuran analog derivative in gout medicine is prepared |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |