CN102731405A - Photodynamic treatment medicament, medical composition and preparation method thereof - Google Patents
Photodynamic treatment medicament, medical composition and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a photodynamic treatment medical composition which consists of a photosensitizer and a chemical activator, wherein the photosensitizer is expressed by the formula I; the chemical activator comprises luminol, p-iodophenol, horse radish peroxidase and hydrogen peroxide; and the proportion of the photosensitizer expressed by the formula I, to the luminol to the p-iodophenol to the horse radish peroxidase to the hydrogen peroxide in the composition is 8-12muM:0.4-0.7mM:1-1.5mM:0.01-0.02mg/mL:2-3mM. In the composition of the invention, active oxygen generated by bioluminescence energy transfer between the photosensitizer expressed by the formula I and the luminol is utilized to kill cells and fungi. Compared with the traditional photodynamic treatment method, the composition can be used for treating in deep tissues; and damages to normal tissues, which are caused by long-time irradiation by an external light source, can be avoided; and meanwhile, the composition has a profound influence on the aspects of the clinic treatment of tumors and pathogenic bacteria infection.
Description
Technical field
The present invention relates to a kind of medicine that is used for optical dynamic therapy, pharmaceutical composition and preparation method thereof.
Background technology
Since 20th century the eighties be applied to clinically for the first time, PDT becomes a kind of novel therapies after chemotherapy, surgical operation and radiation-therapy.PDT has been widely used in the relevant disease of clinical treatment kinds of tumors, ophthalmology and skin.Photosensitizer, light source and molecular oxygen are most important three elements that produce cytotoxic active oxygen in the PDT.The major advantage of PDT is its spatial selectivity when disease treatment, and promptly only excite at selected wavelength down just can be by sensitization for photosensitizer.But the requirement of light source has limited the result of treatment of PDT in deep tissues to external world, and its reason is that the absorption and the scattering effect of biological tissue makes external light source can not penetrate deep tissues.Though infrared light can reduce the absorption and the scattering effect of biological tissue, the development of the photosensitizers of efficient absorption infrared light (for example two-photon is photosensitive dose) remains a challenge.
Summary of the invention
One of the object of the invention provides a kind of optical dynamic therapy medicine (photosensitizers) and preparation method thereof.
Optical dynamic therapy medicine provided by the present invention is called for short OPV, and its structural formula is suc as formula shown in the I:
The preparation method of compound comprises the steps: shown in the above-mentioned formula I
1) in the presence of alkaline condition and phase-transfer catalyst hexaoxacyclooctadecane-6-6, make compound and 1 shown in the formula 1,6-two
2) in the presence of tri-n-butylamine, compound shown in the formula 2 and 4-vinyl benzene methyl alcohol are reacted under palladium-phosphine composition or palladium catalyst and phosphine ligand catalysis, obtain compound shown in the formula 3;
3) in inert atmosphere, compound shown in the formula 3 and three normal-butyl vinyl tins are reacted under palladium-phosphine composition or palladium catalyst and phosphine ligand catalysis, obtain compound shown in the formula 4;
4) in inert atmosphere, compound shown in compound shown in the formula 4 and the formula 5 is reacted in the presence of tri-n-butylamine and under the catalysis of palladium-phosphine composition or palladium catalyst and phosphine part, obtain compound shown in the formula 6;
5) compound shown in the formula 6 and N-Methylimidazole are reacted, obtain compound shown in the formula I.
Above-mentioned steps 1) in, said alkaline condition is provided by salt of wormwood; The reaction solvent of said reaction is an acetone; The temperature of reaction of said reaction is 70-80 ℃, and the reaction times is 2-4 days.
Compound and 1 shown in the step 1) Chinese style 1, the mol ratio of 6-dibromo-hexane are 5-6mmol: 80-90mmol.The add-on of said hexaoxacyclooctadecane-6-6 and 1, the proportioning of 6-dibromo-hexane are 120-150mg: 15-25g.
Reaction described in the step 1) is gone out through adding shrend.
After said reaction finishes, also comprise the steps: in reaction system, to add methylene dichloride and extract, organic phase is used anhydrous magnesium sulfate drying, steams to desolventize back silicagel column separation, obtains compound shown in the formula 2; Wherein, the used eluent of silicagel column separation is that volume ratio is 1: 5 the methylene dichloride and the mixed solvent of sherwood oil.
Above-mentioned steps 2) in, the reaction solvent of said reaction is a toluene; The temperature of reaction of said reaction is 70-90 ℃, and the reaction times is 24-36 hour.
Step 2) in, the mol ratio of compound shown in the formula 2 and 4-vinyl benzene methyl alcohol is 2-3mmol: 6-7mmol.
Step 2) in, said palladium catalyst specifically can be palladium, and said phosphine part specifically can be the tri-o-tolyl phosphine, and the mass ratio of palladium and tri-o-tolyl phosphine can be (5-15mg): (20-30mg).
Step 2) reaction described in is gone out through adding shrend.
After said reaction finishes, also comprise the steps: in reaction system, to add methylene dichloride and extract, organic phase is used anhydrous magnesium sulfate drying, steams to desolventize back silicagel column separation, obtains compound shown in the formula 3; Wherein, the used eluent of silicagel column separation is that volume ratio is 1: 3 the methylene dichloride and the mixed solvent of sherwood oil.
Above-mentioned steps 3) in, the reaction solvent of said reaction is a toluene; The temperature of reaction of said reaction is 90-110 ℃, and the reaction times is 12-24 hour.
In the step 3), the mol ratio of compound shown in the formula 3 and three normal-butyl vinyl tins is 1-1.5mmol: 5-7mmol.Said palladium-phosphine composition specifically can be tetra-triphenylphosphine palladium, and its add-on can be 15-25mg.
Reaction described in the step 3) is through adding the cancellation of 2M potassium fluoride aqueous solution.
After said reaction finishes, also comprise the steps: in reaction system, to add methylene dichloride and extract, organic phase is used anhydrous magnesium sulfate drying, steams to desolventize back silicagel column separation, obtains compound shown in the formula 4; Wherein, the used eluent of silicagel column separation is that volume ratio is 1: 5 the methylene dichloride and the mixed solvent of sherwood oil.
Above-mentioned steps 4) in, the reaction solvent of said reaction is a toluene; The temperature of reaction of said reaction is 90-110 ℃, and the reaction times is 2-3 days.
In the step 4), the mol ratio of compound is 0.3-0.4mmol: 0.1-0.2mmol shown in compound shown in the formula 4 and the formula 5.
In the step 4), said phosphine part specifically can be the tri-o-tolyl phosphine, and the mass ratio of palladium and tri-o-tolyl phosphine can be (5-15mg): (15-25mg).
Reaction described in the step 4) is gone out through adding shrend.
After said reaction finishes, also comprise the steps: in reaction system, to add methylene dichloride and extract, methylene dichloride is used anhydrous magnesium sulfate drying mutually, steams to desolventize back silicagel column separation, obtains the crude product of compound shown in the formula 6; Crude product is dissolved in the acetone, adds the Soiodin stirring and refluxing and spend the night; Steaming desolventizes, and adds washing and removes unreacted Soiodin, adds the chloroform extraction product, uses the anhydrous magnesium sulfate drying organic phase, concentrates organic phase, obtains the pure article of compound shown in the formula 6; Wherein, the used eluent of silicagel column separation is that volume ratio is 500: 1 the methylene dichloride and the mixed solvent of methyl alcohol.
Above-mentioned steps 5) in, the reaction solvent of the reaction of said reaction is an acetonitrile, and said being reflected under the reflux state carried out, and the reaction times of said reaction is 24-36 hour.
In the step 5), the mol ratio of compound shown in the formula 6 and N-Methylimidazole is 0.07-0.09mmol: 1.5-1.7mmol.
After reaction finishes described in the step 5), also comprise the steps: to remove reaction system under reduced pressure solvent and N-Methylimidazole, the gained red oil is washed with ETHYLE ACETATE, obtains compound shown in the formula I.
Two of the object of the invention provides and a kind ofly utilizes chemical small molecules activated to be used for the pharmaceutical composition of optical dynamic therapy.
Pharmaceutical composition provided by the present invention is made up of photosensitizers and chemical activator; Wherein, Said photosensitizers is a compound shown in the formula I, and said chemical activator is by o-aminophthalylhydrazide (shown in the formula II), to iodophenol (formula III is said), horseradish peroxidase HRP and hydrogen peroxide H
2O
2Form, be called for short E+S; Compound shown in the formula I described in the said pharmaceutical composition, o-aminophthalylhydrazide, be (8-12 μ M): (0.4-0.7mM): (1-1.5mM): (0.01-0.02mg/mL): (2-3mM) to the proportioning of iodophenol, horseradish peroxidase and hydrogen peroxide; Hydrogen peroxide needs to separate packing with other component in the said pharmaceutical composition, during use its all components mixing is got final product.
The present invention also provides the application of aforementioned pharmaceutical compositions.
Application provided by the present invention is the application of said pharmaceutical composition in the medicine of medicine for preparing optical dynamic treatment of tumor and optical dynamic therapy fungi.
The present invention also protects a kind of medicine that is used for optical dynamic therapy.
Said medicine, it contains pharmaceutical composition provided by the invention, and pharmaceutically acceptable carrier.
Said medicine specifically can be antitumor drug or antifungal drug.Said tumour such as cervical cancer, kidney, mammary cancer, lung cancer, colorectal carcinoma etc.; Said fungi such as pathomycetes such as Candida albicans, black mold.
Antitumor and the antifungal medicine composition that is used for PDT provided by the invention; Its principle is: the horseradish peroxidase in the pharmaceutical composition (HRP) catalyzing hydrogen peroxide (H2O2) decomposes generation oxygen; Oxygen generates electronegative active intermediate with the o-aminophthalylhydrazide oxidation again; This active intermediate can combine with the OPV static of positively charged in the compsn; And this electronegative active intermediate can send blue fluorescence (emission maximum 425nm); The light of this wavelength region can quilt and its static bonded OPV to absorb that both resonance energy transfer take place and send emission maximum be that the fluorescence of 550nm produces active oxygen simultaneously, active oxygen can kill with pharmaceutical composition in electronegative cell or the fungi of positively charged OPV bonded.
Antitumor and the antifungal medicine composition that is used for PDT provided by the invention has overcome all deficiencies of existing optical dynamic therapy method.Compare with traditional optical dynamic therapy method; The present invention can treat at deep tissues; And can avoid the damage of the long-time irradiation of external light source, also can exert far reaching influence aspect the clinical treatment of tumour and pathogenic infection in this present invention simultaneously to healthy tissues.
Description of drawings
Fig. 1 is the chemical synthesis route figure of compound OPV shown in the formula I of the present invention.
Fig. 2 is that o-aminophthalylhydrazide shifts with the noclilucence energy of OPV under enzyme-catalyzed reaction condition.
Fig. 3 is used for the influence of the pharmaceutical composition of PDT to the HeLa cell survival rate.
Fig. 4 is used for the tumor suppression of the pharmaceutical composition of PDT to nude mice.
Fig. 5 is used for the inhibition lithograph of the pharmaceutical composition of PDT to the pathomycete Candida albicans.
Embodiment
The present invention will be described through specific embodiment below, but the present invention is not limited thereto.
Experimental technique described in the following embodiment like no specified otherwise, is ordinary method; Said reagent and biomaterial like no specified otherwise, all can obtain from commercial sources.
Compound OPV's shown in embodiment 1, the formula I is synthetic
Synthetic route chart is seen Fig. 1.
1, compound 2 (formula 2) is synthetic
Add 1.7g compound 1 (formula 1) in the 250mL single port bottle, 70mL removes the acetone of oxygen, 5.6g salt of wormwood, and 0.14g18-crown ether-6 and 20g 1, the 6-dibromo-hexane is warming up to 75 ℃ of reactions 3 days.Add the 100mL shrend reaction of going out, add 100mL dichloromethane extraction product again, organic phase use anhydrous magnesium sulfate drying, steams to desolventize back silicagel column separation (eluent: methylene dichloride: sherwood oil=1: 5 gets the 2.5g white solid after v/v).The sign of product: 1H NMR (400MHz, CDCl3) δ 7.27 (s, 1H), 6.98 (s, 1H), 3.95 (m, 4H); 3.43 (m, 4H), 1.91 (m, 4H), 1.82 (m, 4H), 1.54 (m; 8H) .13C NMR (100MHz, CDCl3) δ 152.62,150.50,124.37,117.19,112.66,33.91; 32.78,29.82,29.07,27.94,25.41,25.32.MS (MALDI-TOF): 640.0 (M+).Characterization data shows that product is a compound 2.
The compound method of compound is following shown in the formula 1:
9.5g the 4-bromobenzaldehyde is dissolved in the mixed solvent of 150mL chloroform and 75mL Virahol, to wherein adding 2.5g Peng Qinghuana and 5g 200-300 order silica gel, reaction mixture was at stirring at room 12-16 hour.Remove by filter silica gel, in reaction mixture, add the 100mL shrend reaction of going out, again to wherein adding 100mL chloroform extraction product.The gained organic phase is behind anhydrous magnesium sulfate drying, and removal of solvent under reduced pressure gets white solid product 8.2g 4-bromobenzene methyl alcohol.2.8g4-the bromobenzene dissolve with methanol in the 50mL dry toluene, feeds nitrogen 30min to remove the middle oxygen that desolvates, and under nitrogen protection, in solution, adds 6g three normal-butyl vinyl tins and 20mg tetra-triphenylphosphine palladium, is warming up to 110-120 ℃ of reaction 12-18 hour.With 20mL 2M potassium fluoride aqueous solution cancellation reaction and remove unreacted three normal-butyl vinyl tins.Separatory, organic phase is used anhydrous magnesium sulfate drying, and steaming desolventizes back silicagel column separation, and (eluent: sherwood oil: ETHYLE ACETATE=8: 1, v/v), getting the 1.1g colourless oil liquid is compound shown in the formula 1.
2, compound 3 (formula 3) is synthetic
300mg compound 2 and 4.2g4-vinyl benzene dissolve with methanol add 10mg palladium, 25mg tri-o-tolyl phosphine oxide and 600 μ L tri-n-butylamines in removing the toluene of oxygen, be warming up to 80 ℃ of reaction 24h.Add the 10mL shrend reaction of going out, add 100mL dichloromethane extraction product, organic phase use anhydrous magnesium sulfate drying, steams to desolventize back silicagel column separation (eluent: methylene dichloride: sherwood oil=1: 3 gets the 800mg yellow solid after v/v).The sign of product: 1H NMR (400MHz, d6-acetone) δ 7.53 (s, 1H), 7.51 (s, 1H), 7.45 (d, 1H); 7.40 (s, 1H), 7.38 (s, 1H), 7.36 (s, 2H), 7.22 (s; 1H), 4.64 (s, 2H), 4.10 (m, 4H), 3.52 (tm; 4H), and 1.96-1.79 (m, 8H), 1.58 (m, 8H) .MS (EI+): 646.0 (M+) .Anal.Calcd for C27H35Br3O3:C, 50.10; H, 5.45; Found:C, 49.64; H, 5.70.Characterization data shows that product is a compound 3.
3, compound 4 (formula 4) is synthetic
800mg compound 3 is dissolved in 50mL and removes in the toluene of oxygen, under nitrogen atmosphere, adds 1g three normal-butyl vinyl tins and 20mg tetra-triphenylphosphine palladium and is warming up to 100 ℃ of reaction 12h.Adding 50mL 2M potassium fluoride aqueous solution cancellation reaction, organic phase is used anhydrous magnesium sulfate drying, and steaming desolventizes back silicagel column separation, and (eluent: methylene dichloride: sherwood oil=1: 5 v/v), gets faint yellow solid 540mg.The sign of product: 1H NMR (400MHz, Acetone) δ 7.55-7.48 (m, 3H), 7.38 (s, 1H), 7.36 (s, 1H), 7.31 (m, 2H), 7.19 (s; 1H), 7.07 (dd, 1H), 5.84 (d, 1H), 5.23 (d, 1H), 4.63 (s, 2H), 4.09 (m; 4H), 3.52 (m, 4H), 1.88 (m, 8H), 1.70-1.48 (m, 8H) .13C NMR (100MHz, CDCl3) δ 151.21,149.98; 140.48,137.25,129.26,128.73,127.57,126.87,126.78,123.19,118.07; 112.08,111.89,110.66,70.20,69.54,65.32,33.97,33.84,33.56; 32.85,30.38,29.46,29.28,28.05,25.58,25.44,25.35,25.20.MS (MALDI-TOF): 594 (M+).Characterization data shows that product is a compound 4.
4, compound 6 (formula 6) is synthetic
The compound method of compound is following shown in the above-mentioned formula 5:
7.75g Potassium Iodate and 19.3g iodine are dissolved in the mixed solvent of acetate/sulfuric acid/water (v/v/v, 100/5/1.5), add 10g 1 again, the 4-dimethoxy benzene slowly is heated to backflow, reacts 6-8 hour.Reaction cooled has the grey black deposition to generate with the cooling of frozen water mixed solution to room temperature, filters collecting precipitation, and uses sodium hydrogen carbonate solution and distilled water wash, drying respectively.Crude product is dissolved in the 100mL chloroform, adds gac backflow 2-3 hour, uses ethyl alcohol recrystallization after the filtration washing drying, gets pale solid 17.7g, is compound shown in the formula 5.
5, OPV's is synthetic
Compound 6 is dissolved in the 10mL acetonitrile, adds 136mg, N-Methylimidazole, temperature rising reflux 24h.Remove solvent and N-Methylimidazole under reduced pressure, red oil with 20mL ETHYLE ACETATE wash orange solids 130mg.Product characterizes: 1HNMR (300MHz, CDCl3) δ 7.52 (m, 24H), 7.36 (s, 4H), 7.23 (m, 8H), 4.61 (s, 4H); 4.19 (m, 6H), 4.13 (m, 8H), 3.91 (m, 20H), 1.92 (m, 16H), 1.66 (m; 8H), 1.48 (m, 8H) .13C NMR (150MHz, MeOD) δ 151.65,151.21,151.05,140.80,137.06,128.51; 127.08,126.75,126.07,124.07,123.62,123.54,122.72,122.18,111.02; 110.53,109.12,69.04,68.85,63.51,55.70,49.36,35.14,35.09; 29.73,29.69,29.32,28.89,28.81,25.61,25.52,25.50,25.35.MS (MALDI-TOF): 1327.2 (M+-4I).Characterization data shows that product is compound OPV.
The pharmaceutical composition that embodiment 2, o-aminophthalylhydrazide luminescence system and OPV form is used for cancer cells and kills and wounds
(1), the noclilucence energy Transfer Spectroscopy of o-aminophthalylhydrazide and OPV is measured
In 967 μ L pH9.0 sodium carbonate buffers, add 3 μ L 1mg/mL HRP (horseradish peroxidase) pH7.0 sodium dihydrogen phosphates, 10 μ L 20mM o-aminophthalylhydrazides, 10 μ L 50mM OPV (making final concentration be respectively 10 μ M, 20 μ M, 30 μ M, 40 μ M and 50 μ M) to the iodophenol aqueous solution and different concns; Add 10 μ L 50mM aqueous hydrogen peroxide solution vortex 2s behind the vortex 5s and survey luminescent spectrum immediately, spectral range is 370nm～700nm.See Fig. 2.
(2), the cultivation of HeLa cell
The HeLa cell is put into 37 ℃ of constant incubators that contain 5% carbonic acid gas at the DMEM substratum that contains 10% Ox blood serum and is cultivated.
(3), the HeLa cell survival is analyzed
The HeLa cell inoculation is in 96 orifice plates, and density is 8 * 10
3Individual/hole; Put into 37 ℃ of incubators spend the night adherent after; Add different concns OPV and cell at 37 ℃ of effect 30min, (final concentration is respectively 0.01mg/mLHRP, and 1.25mM is to iodophenol to add enzyme and substrate again; 0.5mM o-aminophthalylhydrazide and 2mM hydrogen peroxide) room temperature dark place and cytosis 5min, the control operations that does not have enzyme-added and substrate or OPV is with above-mentioned.Cell sops up the PBS solution that the every hole of supernatant substratum adds 100 μ L 1mg/mL MTT after putting into 37 ℃ of incubator 24h, puts into to sop up the every hole of supernatant behind 37 ℃ of incubator 4h and add 100 μ L DMSO, 96 orifice plates is put into ELIASA measure the absorption of 520nm place.Blank (promptly not having group enzyme-added and substrate and OPV) is designated as A
0, adding the A that is designated as that enzyme and substrate or OPV or both add, cell survival rate (VR) is according to following Equation for Calculating, and the drafting cell survival curve, sees Fig. 3.
Can be known that by Fig. 3 when OPV concentration was identical, the cell survival rate that adds enzyme and substrate significantly descended, promptly combination drug has the antitumor cell effect.
The combination drug that embodiment 3, o-aminophthalylhydrazide luminescence system and OPV form is used for mouse interior tumor and suppresses
(1), the formation of nude mice HeLa cell tumour model
To contain 2 * 10
6200 μ L PBS damping fluid subcutaneous injections of individual HeLa cell are inoculated 40 in the female nude mice left fore of 14～15g oxter.
(2), grouping administration
Successively be divided into 4 groups according to the injection cell, 10 every group, promptly every group all has the back that also has of injection earlier to inject.First group is the blank group, only injects 100 μ L saline water; Second group of positive control group; Injection enzyme and substrate; Earlier injection 50 μ L contain HRP (0.01mg/mL), o-aminophthalylhydrazide luminescence enhancer and (to iodophenol, 1.25mM) and the physiological salt soln of o-aminophthalylhydrazide (0.5mM), inject 50 μ L hydrogen peroxide physiological salt solns (2mM) again; The 3rd group is experimental group, and earlier injection 50 μ L contain HRP (0.01mg/mL), o-aminophthalylhydrazide luminescence enhancer and (to iodophenol, 1.25mM), the physiological salt soln of o-aminophthalylhydrazide (0.5mM) and OPV (10 μ M), inject 50 μ L hydrogen peroxide physiological salt solns (2mM) again; The 4th group for only injecting the OPV positive controls, and the physiological salt soln (10 μ M) of injection 50 μ LOPV is injected 50 μ L saline water more earlier.Begin administration at the injection cell after 3 days.Be administered once every day, successive administration 17 days.
Three, tumour data characterization
During the administration, on every Mondays with claim the mouse body weight Thursday and with vernier callipers amount tumor size, successive administration was dissected tumor after 17 days, and claim that knurl is heavy.Blank group knurl heavily is designated as C, and experimental group and positive controls are designated as T, and tumor control rate (IR) is according to following Equation for Calculating, and drafting tumor suppression figure, sees Fig. 4.
Can know that by Fig. 4 the combination drug that o-aminophthalylhydrazide luminescence system and OPV form can suppress the growth of mouse tumor to a certain extent.
The combination drug that embodiment 4, o-aminophthalylhydrazide luminescence system and OPV form is used for the inhibition of pathomycete
(1), the cultivation of pathomycete Candida albicans
The extracting waste candidiasis adds in the 5mL YTD substratum (yeast extract 20g/L, peptone 20g/L, glucose 10g/L), 30 ℃ of overnight cultures.Get certain volume bacterium liquid, the centrifugal 2min of 3500g washes 3 times with PBS to remove nutrient solution, and in PBS, transferring bacterial concentration at last is OD600=1.0.
(2), o-aminophthalylhydrazide luminescence system and OPV and fungi effect
The bacterium liquid 100 μ L that get OD600=1.0 add 400 μ LPBS dilution again; Add OPV make its final concentration be 1 μ M at 30 ℃ of lucifuge effect 30min, add enzyme, o-aminophthalylhydrazide luminescence enhancer (to iodophenol), o-aminophthalylhydrazide and hydrogen peroxide (final concentration is respectively 0.004mg/mL, 0.5mM, 0.2mM and 0.5mM) again and in the dark act on 5min.Blank, the group that has only added enzyme and substrate or only added OPV are operated equally.Then bacterium liquid is diluted 10,000 times, get 100 μ L diluents and be layered on the YTD agar plate, the colony count on number flat board behind 30 ℃ of cultivation 24h, the blank group is designated as C
0, experimental group is designated as C, and fungi inhibiting rate (IR) is according to following Equation for Calculating, and the plate photo of clapping, and sees Fig. 5.
Can know that by Fig. 5 the combination drug that o-aminophthalylhydrazide luminescence system and OPV form has remarkable antifungic action.
Claims (10)
1. the compound shown in the formula I:
2. prepare the method for compound shown in the claim 1 Chinese style I, comprise the steps:
1) in the presence of alkaline condition and hexaoxacyclooctadecane-6-6, make compound and 1 shown in the formula 1, the reaction of 6-dibromo-hexane obtains compound shown in the formula 2;
2) in the presence of tri-n-butylamine, compound shown in the formula 2 and 4-vinyl benzene methyl alcohol are reacted under palladium-phosphine composition or palladium catalyst and phosphine ligand catalysis, obtain compound shown in the formula 3;
3) in inert atmosphere, compound shown in the formula 3 and three normal-butyl vinyl tins are reacted under palladium-phosphine composition or palladium catalyst and phosphine ligand catalysis, obtain compound shown in the formula 4;
4) in inert atmosphere, compound shown in compound shown in the formula 4 and the formula 5 is reacted in the presence of tri-n-butylamine and under the catalysis of palladium-phosphine composition or palladium catalyst and phosphine part, obtain compound shown in the formula 6;
5) compound shown in the formula 6 and N-Methylimidazole are reacted, obtain compound shown in the formula I.
3. method according to claim 2 is characterized in that: in the said step 1), said alkaline condition is provided by salt of wormwood; The reaction solvent of said reaction is an acetone; The temperature of reaction of said reaction is 70-80 ℃, and the reaction times is 2-4 days;
In the said step 1), compound and 1 shown in the said formula 1, the mol ratio of 6-dibromo-hexane is (5-6mmol): (80-90mmol); The add-on of said hexaoxacyclooctadecane-6-6 and 1, the proportioning of 6-dibromo-hexane are (120-150mg): (15-25g).
4. according to claim 2 or 3 described methods, it is characterized in that: said step 2), the reaction solvent of said reaction is a toluene; The temperature of reaction of said reaction is 7090 ℃, and the reaction times is 2436 hours;
Said step 2) in, the mol ratio of compound shown in the said formula 2 and 4-vinyl benzene methyl alcohol is (2-3mmol): (6-7mmol);
Said step 2) in, said palladium catalyst is a palladium, and said phosphine part is the tri-o-tolyl phosphine; The mass ratio of said palladium and tri-o-tolyl phosphine is (5-15mg): (20-30mg).
5. according to each described method among the claim 2-4, it is characterized in that: in the said step 3), the reaction solvent of said reaction is a toluene; The temperature of reaction of said reaction is 90-110 ℃, and the reaction times is 12-24 hour;
In the said step 3), the mol ratio of compound and three normal-butyl vinyl tins is (1-1.5mmol) shown in the said formula 3: (5-7mmol); Said palladium-phosphine composition is a tetra-triphenylphosphine palladium.
6. according to each described method among the claim 2-5, it is characterized in that: in the said step 4), the reaction solvent of said reaction is a toluene; The temperature of reaction of said reaction is 90-110 ℃, and the reaction times is 2-3 days;
In the said step 4), the mol ratio of compound shown in compound and the formula 5 is (0.3-0.4mmol) shown in the said formula 4: (0.1-0.2mmol); Said palladium catalyst is a palladium, and said phosphine part is the tri-o-tolyl phosphine; The mass ratio of said palladium and tri-o-tolyl phosphine is (5-15mg): (15-25mg).
In the said step 5), the reaction solvent of said reaction is an acetonitrile, and said being reflected under the reflux state carried out, and the reaction times of said reaction is 24-36 hour;
In the said step 5), the mol ratio of compound and N-Methylimidazole is (0.07-0.09mmol) shown in the said formula 6: (1.5-1.7mmol).
7. pharmaceutical composition that is used for optical dynamic therapy; Form by photosensitizers and chemical activator; Wherein, Said photosensitizers is a compound shown in the claim 1 Chinese style I, and said chemical activator is by forming iodophenol, horseradish peroxidase and hydrogen peroxide shown in the o-aminophthalylhydrazide shown in the formula II, the formula III; Compound shown in the formula I described in the said pharmaceutical composition, o-aminophthalylhydrazide, be (8-12 μ M): (0.4-0.7mM): (1-1.5mM): (0.01-0.02mg/mL): (2-3mM) to the proportioning of iodophenol, horseradish peroxidase and hydrogen peroxide; Hydrogen peroxide needs to separate packing with other component in the said pharmaceutical composition;
The described pharmaceutical composition of claim 7 the preparation following 1) and/or 2) in application: the 1) medicine of optical dynamic treatment of tumor; 2) medicine of optical dynamic therapy fungi.
9. medicine that is used for optical dynamic therapy, its activeconstituents is the described pharmaceutical composition of claim 7.
10. medicine according to claim 9 is characterized in that: said medicine is the antifungal drug that is used for the antitumor drug of optical dynamic therapy or is used for optical dynamic therapy.
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