CN102702210B - Application of phthalocyanine metal complex containing piperazine ethyoxyl modified groups - Google Patents
Application of phthalocyanine metal complex containing piperazine ethyoxyl modified groups Download PDFInfo
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- CN102702210B CN102702210B CN201210176671.4A CN201210176671A CN102702210B CN 102702210 B CN102702210 B CN 102702210B CN 201210176671 A CN201210176671 A CN 201210176671A CN 102702210 B CN102702210 B CN 102702210B
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Abstract
The invention belongs to the field of the preparation of photodynamic medicines or photosensitizers, and discloses application of a phthalocyanine metal complex containing piperazine ethyoxyl modified groups. The phthalocyanine metal complex can be used for preparing the photodynamic medicines or the photosensitizers, and has the characteristics that the phthalocyanine metal complex is amphipathic, absorption spectrum red is transferred to wavelengths which facilitate the penetration of tissues of human bodies, and the capacity of generating active oxygen by photosensitization is high.
Description
Technical field
The invention belongs to photo-dynamical medicine or photosensitizers preparation field, be specifically related to the application containing the phthalocyanine metal complex of piperazine oxyethyl group modification group.
Background technology
Phthalocyanine complex is the important functional materials of a class, in fields such as dyestuff, optical recording medium, nonlinear optical material, catalyzer, there is important application, wherein, phthalocyanine complex as photosensitizers the prospect in optical dynamic therapy (Photodynamic Therapy) noticeable.
So-called optical dynamic therapy (or claiming photodynamic therapy) in fact, is that the Photosensitive reaction of photosensitizers (or claiming photosensitive drug) is in the application of medical field.Its mechanism is, first photosensitizers is injected to body, (this period of waiting time be allow medicine enrichment relatively in target body) after a period of time, rayed target body (can import light source by interventional techniques such as optical fiber to endoceliac target) with specific wavelength, be enriched in photosensitizers in target body under optical excitation, inspire a series of optical physics photochemical reactions, produced active oxygen, and then destroyed target body (for example cancer cells and cancerous tissue).
In some developed countries, optical dynamic therapy has become the 4th kind of ordinary method for the treatment of cancer.With traditional therapy, as surgical operation, chemotherapy, radiotherapy are compared, the advantage of photodynamic therapy maximum is can cancerous tissue be carried out selective destruction and needn't be performed surgical operation, and side effect is little, thereby gets most of the attention.
Meanwhile, research in recent years also shows, photodynamic therapy also can be treated the non-Cancerous diseases such as bacterium infection, oral disease, macular degeneration illness in eye, arteriosclerosis, wound infection and tetter effectively.Photosensitizers can also be for light power sterilization, most importantly for the sterilization of water body, blood and blood derivatives.Meanwhile, utilizing the photoluminescent property of photosensitizers to carry out light power diagnosis, is also an important use of photosensitive drug.
The key of optical dynamic therapy is photosensitizers, and light power curative effect depends on the quality of photosensitizers.Based on optical dynamic therapy in the potentiality aspect treatment tumour and Other diseases, scientific circles generally believe, optical dynamic therapy will become the important therapy of 21 century, so, as the photosensitizers of optical dynamic therapy core, will become an important and tempting new high-tech industry.
So far, get permission the formal photosensitizers using clinically and be mainly hematoporphyrin derivative.In states such as the U.S., Canada, Germany, Japan, use be Photofrin(U.S. FDA in nineteen ninety-five official approval Photofrin for clinical anticancer), it is the mixture of the haematoporphyrin oligopolymer that extracts from cow blood and carry out chemical modification.Hematoporphyrin derivative has shown certain curative effect, but also exposed critical defect: maximum absorption wavelength (380-420nm) is not to tissue transmitance preferably red light district (650-800nm), skin phototoxicity is large, mixture, form unstable etc., thereby clinical application is restricted, so Development of New Generation photo-dynamical medicine (photosensitizers) is international study hotspot.
Owing to having maximum absorption wavelength, be positioned at the features such as the ruddiness region that easily sees through tissue, dark toxicity be low, phthalocyanine metal complex is paid much attention to as the application of novel photosensitive agent.But, current reported the still Shortcomings part of bioactive phthalocyanine complex that has, or lack amphipathic, or poor stability, or complex synthetic route, or biological selectivity is good etc., need to further improve.On the other hand, due to photosensitizers with the potential huge economic society of optical dynamic therapy is worth, the refinement of range of application and treatment focus greatly, preparing the phthalocyanine complex more with comparative advantages is very necessary as drug candidate.
Summary of the invention
The object of the present invention is to provide the application containing the phthalocyanine metal complex of piperazine oxyethyl group modification group, there is following characteristics: amphipathic, absorption spectrum Einstein shift is to being more conducive to penetrate the wavelength place of tissue, and the ability of photo-generating active oxygen is high.
For achieving the above object, the present invention adopts following technical scheme:
The quaternary phthalocyanine metal complex of non-periphery containing piperazine oxyethyl group modification group shown in structural formula (1) has the purposes of preparing photo-dynamical medicine or photosensitive medicament.
Formula (1)
In formula (1), M is metal ion, and R represents substituted radical, and four substituted radicals are the non-peripheral position in phthalocyanine ring all, claims a position, i.e. 1 (4), 8 (11), 15 (18), 22 (25) positions, and wherein substituent group R is:
.
Phthalocyanine metal complex shown in structural formula (1) can called after 1,8 (11), 15 (18), 22 (25)-tetra-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex, or claim four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex; 1,8 (11), 15 (18), 22 (25)-tetra-(2-piperazinyl oxyethyl group) phthalocyanine metal complex, or claim four-a-(2-piperazinyl oxyethyl group) phthalocyanine metal complex.
The mono-substituted phthalocyanine metal complex of non-periphery containing piperazine oxyethyl group modification group shown in structural formula (2) has the purposes of preparing photo-dynamical medicine or photosensitive medicament.
Formula (2)
In above formula, M is metal ion, and R represents substituted radical, and wherein substituent R is:
.
Phthalocyanine metal complex shown in structural formula (2) can called after 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex; 1-(2-piperazinyl oxyethyl group) phthalocyanine metal complex.
Utilize the phthalocyanine metal complex of the non-peripheric substitution containing piperazine oxyethyl group modification group shown in structural formula of the present invention (1) and structural formula (2) for the preparation of photo-dynamical medicine or photosensitive medicament, preferably corresponding ZnPcS2P2.
Phthalocyanine metal complex containing piperazine oxyethyl group modification group provided by the invention can be used for preparing photo-dynamical medicine or photosensitive medicament.Described photosensitive medicament, or be called for short photosensitizers, or claim photosensitive drug preparation, be called again light power medicament.Prepared photo-dynamical medicine or photosensitive medicament can be used for optical dynamic therapy, light power diagnosis or the sterilization of light power.Described optical dynamic therapy can be the optical dynamic therapy of malignant tumour, or carcinoid optical dynamic therapy, or the external smooth power purification treatment of leukemic marrow, or the optical dynamic therapy of non-Cancerous disease.Described non-Cancerous disease, can be that bacterium infects, or oral disease, or macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.Described light power sterilization can be the light power sterilization purification of blood or blood derivatives, or the light power sterilization of water, or light power sterilization medical or life use device.
The method of utilizing phthalocyanine metal complex of the present invention to prepare photosensitive medicament is: water, or the mixed solution of water and other material, wherein the massfraction of other material is not higher than 10%, as solvent, dissolve phthalocyanine metal complex of the present invention, be mixed with containing certain density photosensitive medicament, the concentration of phthalocyanine metal complex is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive to keep chemical stability and the biocompatibility of photosensitive medicament;
Other described material is one or more the miscellany in castor oil polyoxyethylene 35 ethers, methyl-sulphoxide, ethanol, glycerine, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
Beneficial effect of the present invention and outstanding advantage are:
(1) title complex provided by the present invention has been introduced 2-piperazinyl oxyethyl group or 2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group at the non-peripheral position of phthalocyanine ring, has wetting ability, is easy to be prepared into photosensitive medicament.The phthalocyanine complex that 2-piperazinyl oxyethyl group replaces has shown good amphipathic, and valuable especially in field of photodynamic.
(2) title complex provided by the present invention is the non-peripheral position at phthalocyanine ring, on so-called a position, introduces substituting group.In a position, introduce hydrophilic radical, than in b position, can effectively stop phthalocyanine ring to be assembled in Aquo System, thereby improve photodynamic activity significantly.
(3) maximum absorption wavelength of phthalocyanine complex provided by the present invention is greater than 670nm, and molar absorption coefficient (reaches 10 greatly
5the order of magnitude), its spectral quality is better than first-generation photosensitizers greatly.A provided by the invention position substituted phthalocyanine, with respect to corresponding b position substituted phthalocyanine, maximum absorption spectrum red shift, this is favourable to optical dynamic therapy, because spectral red shift can improve the transmitance of excitation light used to tissue.
(4) title complex provided by the present invention has been introduced 2-piperazinyl oxyethyl group at the non-peripheral position of phthalocyanine ring, and the introducing of this group has improved fungal cell and the cancer cells uptake ratio of phthalocyanine complex, thereby has improved the photodynamic activity of phthalocyanine complex.Select this group to determine after by a large amount of comparative tests as non-peripheric substitution base; introduce some other similar group; for example; piperazinyl, oxyethyl group, ethanoyl piperazine oxyethyl group, ethanoyl piperazine phenoxy group, kharophen phenoxy group, 4-formic acid phenoxy group, 3-formic acid phenoxy group etc., improve the cellular uptake rate of phthalocyanine complex and the effect of photodynamic activity all not as introducing 2-piperazinyl oxyethyl group.
(5) non-periphery monosubstituted phthalocyanine metal complexes provided by the present invention, except possessing above-mentioned advantage, also asymmetric because of having, and valuable especially in field of photodynamic.1-provided by the invention (2-piperazinyl oxyethyl group) Phthalocyanine Zinc had both shown the high light power inhibition of cancer cells active, has shown again the high light power of fungi is suppressed to active.Because cancer cells and fungal cell there are differences forming in structure, the general high reactivity that possesses two aspects when different of phthalocyanines photosensitizers, 1-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc has unique advantage in this respect.
(6) the syntheti c route reasonable of phthalocyanine complex provided by the present invention, synthesis material is easy to get, easily industrialization.In the present invention 1,8 (11), 15 (18), 22 (25)-tetra-(2-piperazinyl oxyethyl group) phthalocyanine metal complex and 1-(2-piperazinyl oxyethyl groups) synthetic route of phthalocyanine metal complex and the selection of technique just obtain through a large amount of creative experiments.Conventional method is by preparation 3-[2-(piperazinyl) oxyethyl group] phthalic nitrile is as intermediate; and then synthesize target phthalocyanine complex by template; but in practice; find 3-[2-(piperazinyl) oxyethyl group] synthetic yield very low (being mainly because the amino in piperazine has also participated in nucleophilic substitution reaction) of phthalic nitrile; and after the amino in piperazine is protected by tertbutyloxycarbonyl; can address this problem preferably; and the reduction of protection after product polarity, be easier to separation and purification.Obtained the phthalocyanine complex after amido protecting; deprotection how; also be a key in synthesis technique; conventional deprotection method, is included in trifluoroacetic acid, phosphoric acid and HCl etc. in differing temps and solvent, all can not be when not destroying phthalocyanine ring; deprotection effectively; by a large amount of contrast experiments, the present invention has adopted tetra-tert Neutral ammonium fluoride as deprotecting regent, obtains good effect.
Embodiment
Phthalocyanine metal complex provided by the invention can be used for preparing photo-dynamical medicine or photosensitive medicament, be applied in optical dynamic therapy or light power diagnosis, optical dynamic therapy of the present invention can be the optical dynamic therapy of malignant tumour, or carcinoid optical dynamic therapy, or the external smooth power purification treatment of leukemic marrow, or the optical dynamic therapy of non-Cancerous disease.Non-Cancerous disease of the present invention, can be that bacterium infects, or oral disease, or macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.
Phthalocyanine metal complex provided by the invention can be used for preparing photosensitive medicament, for the sterilization of light power, described light power sterilization can be the light power sterilization purification of blood or blood derivatives, or the light power sterilization of water, or light power sterilization medical or life use device.
The application of phthalocyanine metal complex of the present invention in optical dynamic therapy, light power diagnosis and the sterilization of light power, need supporting suitable light source, described suitable light source can be connected that suitable spectral filter provides or be provided by the laser of specific wavelength by ordinary light source, and the wavelength region of light source is 680～700nm.
The basic skills of utilizing phthalocyanine metal complex of the present invention to prepare photo-dynamical medicine (being photosensitive medicament) is: make water, or the mixed solution (content of other material is not higher than 10%(wt%) of water and other material) as solvent, dissolve phthalocyanine metal complex of the present invention, be mixed with containing certain density photosensitive medicament, the concentration of phthalocyanine metal complex is not higher than its saturation concentration.Other described material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N, dinethylformamide, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.Also can be first with hydrochloric acid or sulfuric acid or etc. acidic substance two [4-(2-amino-ethyl) phenoxy group] of the present invention silicon phthalocyanine is converted into the form of salt, then use above-mentioned dissolution with solvents.In the solution of making, can add antioxidant, buffer reagent and isotonic agent as additive to keep chemical stability and the biocompatibility of photosensitive medicament.
The preparation of using for topical, can be dissolved in phthalocyanine metal complex of the present invention in perviousness solvent, maybe will be injected in ointment, washing lotion or gel.The preferred 5-35%(wt% of described perviousness solvent) aqueous solution of methyl-sulphoxide.
The invention will be further described below to adopt non-limiting example.
Embodiment 1
Synthetic and the physico-chemical property of 1,8 (11), 15 (18), 22 (25)-tetra-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc
Formula (1)
This compound also can claim four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc, its structure as the formula (1), wherein:
.
(1) N-hydroxyethyl piperazine middle-end is amino by BOC(tertbutyloxycarbonyl) protection: at preferred 30 ml of 20 ~ 60ml() CH
2cl
2in, add preferably 30 mmol of 20mmolN-hydroxyethyl piperazine and 20 ~ 40mmol() triethylamine, then slowly drip preferably 40 mmol of 20 ~ 50mmol() tert-Butyl dicarbonate, 0 ℃ of stirring reaction 0.5 ~ 2 hour (preferably 1 hour), then 30 ℃ of stirring reactions, by thin-layer chromatography, monitor termination reaction when N-hydroxyethyl piperazine is exhausted substantially.Revolve and boil off except CH
2cl
2and triethylamine, the pale yellow oily liquid body CH obtaining
2cl
2dissolve, wash three times, collect organic phase, anhydrous MgSO
4dry, revolve to boil off and desolventize, obtain holding the N-hydroxyethyl piperazine of amino BOC protection.
(2) prepare 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile: with the N-hydroxyethyl piperazine (10 ~ 15mmol of the amino BOC protection of the end of 3-nitro phthalic nitrile (10mmol) and above-mentioned acquisition, preferred 10mmol) be reactant, with N, N dimethyl formamide (DMF) is solvent (20 ~ 50ml, preferred 25ml), at salt of wormwood (15 ~ 30mmol, preferred 22 mmol, add in three batches) exist and nitrogen protection under, room temperature ~ 45 ° C(is 45 ° of C preferably) descend stirring reaction 48 ~ 96 hours, by thin-layer chromatography, monitor, termination reaction when 3-nitro phthalic nitrile is exhausted substantially.Reaction mixture micropore organic membrane filter, collects filtrate, then this filtrate is joined in 500ml mixture of ice and water, stir, separate out a large amount of lightpink precipitations, standing, centrifugal, washing, collects solid, lyophilize, obtain lightpink solid, and further by diluted hydrochloric acid dissolution, sodium hydroxide solution, separate out and carry out purifying, after washing and drying, obtain white powder product, productive rate 80%.
The characterization data of product is as follows:
mS(ESI): m/z 391.9[M+Cl]
-.
1 HNMR（DMSO-d
6，ppm）：δ：7.85（t，1H），7.66-7.69（t，?2H），4.35（t，2H），3.29（t，2H），2.76（t，2H），2.48（t，2H），1.38（s，9H）。
ultimate analysis(C
19h
24n
4o
3calculated value: C (64.03 %), H (6.79%), N (15.72 %); Measured value: C (63.81 %), H (6.71%), N (16.63%).
(3) prepare the quaternary phthalocyanine metal complex of non-periphery: under the protection of nitrogen; 3-[2-(the N-tert-butoxycarbonyl-piperazine base) oxyethyl group that said process (1) is obtained] phthalic nitrile 1mmol joins 20-30ml Pentyl alcohol (or N; dinethylformamide; or dimethylethanolamine) (preferred Pentyl alcohol in; 25ml), stirring intensification makes it to dissolve completely.Add the preferred 0.5mmol of 0.25 ~ 2 mmol() zinc acetate and the preferred 0.6ml of 0.4 ~ 0.8ml() 1,8-diazabicylo [5.4.0]+-carbene-7(DBU), continue logical nitrogen, and return stirring reaction response 6 ~ 12 hours (monitoring reaction end by thin-layer chromatography).Rotary evaporation in vacuo is removed after solvent, with a small amount of DMF solubilizing reaction product, join in 500ml frozen water, filter and collect blue precipitation, by diluted hydrochloric acid dissolution, sodium hydroxide solution, separate out and carry out preliminary purification, after centrifugal drying, using ethyl acetate/DMF (volume ratio 10:1) mixed solvent is eluent, separated by silica gel column chromatography, collects deep green elution fraction, after concentrated, by gel chromatography (S-X3 type), be further purified, after vacuum-drying, obtain obtaining 60mg deep green product.The maximum absorption band of product in DMF is positioned at 701 nm places, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution is positioned at 704nm place.
The characterization data of product is as follows:
1 hNMR(DMSO-d
6, ppm): δ: 8.92-9.05(m, 4H, H
α) 8.09-8.15(m, 4H, H
β) 7.74-7.85(m, 4H, H
β) 4.86-5.09(m, 8H) 3.26-3.28(m, 16H) 2.86-2.88(m, 8H) 2.65-2.69(m, 16H) 1.23-1.35(m, 36H).
ultimate analysis(C
76h
96n
16o
12zn): calculated value: C (61.22%), H (6.94%), N (15.03%); Measured value: C (61.37%), H (6.89%), N (15.21%).
Embodiment 2
Synthetic and the physico-chemical property of 1,8 (11), 15 (18), 22 (25)-tetra-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc
This compound also can claim four-a-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc, its structure as the formula (1), wherein:
.
Under nitrogen protection condition; 0.25mmol tetra--a-that embodiment 1 is obtained [2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc joins the tetrahydrofuran solution of 5 ml tetrabutyl ammonium fluorides (TBAF); the concentration of tetrabutyl ammonium fluoride is the preferred 1M of 0.5 ~ 2M(); stirring and refluxing reaction 5 ~ 10 hours, monitors reaction end by thin-layer chromatography.Revolve to boil off and desolventize, washing, freezing drying under reduced pressure.Then the THF of take crosses gel column purifying as moving phase, collects deep green component, dry, obtains 122mg product, and productive rate is 45%.The maximum absorption band of product in DMF is positioned at 699 nm places, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution is positioned at 703nm place.
The characterization data of product is as follows:
mS(ESI): m/z 1090.2[M]
+.
1 HNMR（DMSO-d
6，ppm）：δ：8.91-9.00（m，4H，Pc-H
α）7.71-7.78（m，8H，Pc-H
β）4.90-4.94（m，8H）4.65-4.70（m，12H）3.78-3.82（m，16H）。
ultimate analysis(C
56h
64n
16o
4zn): calculated value: C (61.67%), H (5.91%), N (20.55%); Measured value: C (60.98%), H (5.90%), N (20.35%).
Embodiment 3
1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] the synthetic and physico-chemical property of Phthalocyanine Zinc
Formula (2)
The structure of this compound as the formula (2), wherein:
.
(1) N-hydroxyethyl piperazine middle-end is amino by BOC(tertbutyloxycarbonyl) protection: at preferred 30 ml of 20 ~ 60ml() CH
2cl
2in, add preferably 30 mmol of 20mmolN-hydroxyethyl piperazine and 20 ~ 40mmol() triethylamine, then slowly drip preferably 40 mmol of 20 ~ 50mmol() tert-Butyl dicarbonate, 0 ℃ of stirring reaction 0.5 ~ 2 hour (preferably 1 hour), then 30 ℃ of stirring reactions, by thin-layer chromatography, monitor termination reaction when N-hydroxyethyl piperazine is exhausted substantially.Revolve and boil off except CH
2cl
2and triethylamine, the pale yellow oily liquid body CH obtaining
2cl
2dissolve, wash three times, collect organic phase, anhydrous MgSO
4dry, revolve to boil off and desolventize, obtain holding the N-hydroxyethyl piperazine of amino BOC protection.
(2) prepare 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile: with the N-hydroxyethyl piperazine (10 ~ 15mmol of the amino BOC protection of the end of 3-nitro phthalic nitrile (10mmol) and above-mentioned acquisition, preferred 10mmol) be reactant, with N, N dimethyl formamide (DMF) is solvent (20 ~ 50ml, preferred 25ml), at salt of wormwood (15 ~ 30mmol, preferred 22 mmol, add in three batches) exist and nitrogen protection under, room temperature ~ 45 ° C(is 45 ° of C preferably) descend stirring reaction 48 ~ 96 hours, by thin-layer chromatography, monitor, termination reaction when 3-nitro phthalic nitrile is exhausted substantially.Reaction mixture micropore organic membrane filter, collects filtrate, then this filtrate is joined in 500ml mixture of ice and water, stir, separate out a large amount of lightpink precipitations, standing, centrifugal, washing, collects solid, lyophilize, obtain lightpink solid, and further by diluted hydrochloric acid dissolution, sodium hydroxide solution, separate out and carry out purifying, after washing and drying, obtain white powder product, productive rate 80%.
The characterization data of product is as follows:
mS(ESI): m/z 391.9[M+Cl]
-.
1 HNMR（DMSO-d
6，ppm）：δ：7.85（t，1H），7.66-7.69（t，?2H），4.35（t，2H），3.29（t，2H），2.76（t，2H），2.48（t，2H），1.38（s，9H）。
ultimate analysis(C
19h
24n
4o
3calculated value: C (64.03 %), H (6.79%), N (15.72 %); Measured value: C (63.81 %), H (6.71%), N (16.63%).
(3) prepare the mono-substituted phthalocyanine metal complex of non-periphery: by the 3-[2-of 1.0 mmol (N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile and the preferred 5mmol of 3 ~ 6mmol() phthalic nitrile joins in 20 ~ 35ml (preferably 25ml) Pentyl alcohol, logical nitrogen, stir and be warmed up to completely and dissolve, add again the preferred 2mmol of 0.25 ~ 2() Glacial acetic acid zinc and 0.3 ~ 0.7ml (preferably 0.6ml) DBU, stirring and refluxing reaction (monitoring reaction end by thin-layer chromatography).Rotary evaporation in vacuo is removed after solvent, with a small amount of DMF solubilizing reaction product, join in frozen water, filter and collect blue precipitation, by diluted hydrochloric acid dissolution, sodium hydroxide solution, separate out and carry out preliminary purification, after centrifugal drying, using ethyl acetate/DMF (volume ratio 10:1) mixed solvent is eluent, separated by silica gel column chromatography, collects second blue elution fraction, after concentrated, by gel chromatography (S-X3 type), be further purified, after vacuum-drying, obtain obtaining 40mg blue product.The maximum absorption band of product in DMF is positioned at 677nm place, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution is positioned at 681nm place.
The characterization data of product is as follows:
mS(ESI): m/z 805.0[M+H]
+.
1 HNMR（DMSO-d
6，ppm）δ：9.27-9.38（m，6H，Pc-H
α），8.96（s，1H，Pc-H
α），8.10-8.27（m，8H，Pc-H
β），5.29-5.33（t，2H），4.85（t，2H），3.35-3.44（m，8H），1.32（s，9H）。
ultimate analysis(C
43h
36n
10o
3zn): calculated value: C (64.06%), H (4.50%), N (17.37%); Measured value: C (64.36%), H (4.41%), N (17.35%).
Embodiment 4
Synthetic and the physico-chemical property of 1-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc
The structure of this compound as the formula (2), wherein:
.
Under nitrogen protection condition; the 0.25mmol1-that embodiment 3 is obtained [2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc 0.25mmol joins the tetrahydrofuran solution of 5 ml tetrabutyl ammonium fluorides (TBAF); the concentration of tetrabutyl ammonium fluoride is the preferred 1M of 0.5 ~ 2M(); stirring and refluxing reaction 5 ~ 10 hours, monitors reaction end by thin-layer chromatography.Revolve to boil off and desolventize, washing, freezing drying under reduced pressure.Then the THF of take crosses gel column purifying as moving phase, collects deep green component, dry, obtains 70mg product, and productive rate is 40%.The maximum absorption band of product in DMF is positioned at 677 nm places, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution is positioned at 680nm place.
The characterization data of product is as follows:
mS(ESI): m/z 703.1 [M-H]
-.
1 HNMR（DMSO-d
6，ppm）δ：9.39-9.42（m，6H，Pc-H
α），?9.02（s，1H，Pc-H
α），?8.23-8.25（m，8H，Pc-H
β），?6.68（s，1H），5.32（t，2H），4.68（t，2H），3.32-3.43（m，8H）。
ultimate analysis(C
43h
36n
10o
3zn): calculated value: C (64.64%), H (4.00%), N (19.84%); Measured value: C (64.68%), H (4.08%), N (19.35%).
Embodiment 5
Central ion is Co
2+phthalocyanine complex synthetic
With the zinc acetate in equimolar cobalt chloride alternate embodiment 1 and embodiment 3, can obtain the corresponding substituted phthalocyanine cobalt of each embodiment (II), i.e. four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Cobalt Phthalocyanine and 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Cobalt Phthalocyanine.With equimolar four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group in Cobalt Phthalocyanine alternate embodiment 2] Phthalocyanine Zinc, can obtain four-a-(2-piperazinyl oxyethyl group) Cobalt Phthalocyanine.With equimolar 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group in Cobalt Phthalocyanine alternate embodiment 4] Phthalocyanine Zinc, can obtain 1-(2-piperazinyl oxyethyl group) Cobalt Phthalocyanine.The structure of products therefrom is except the Zn at phthalocyanine center replaces with Co, the same with the phthalocyanine product described in embodiment 1-4.
Embodiment 6
Central ion is Cu
2+phthalocyanine complex synthetic
With the zinc acetate in equimolar anhydrous cupric chloride alternate embodiment 1 and embodiment 3, can obtain the corresponding substituted phthalocyanine copper of each embodiment (II), i.e. four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] CuPc and 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] CuPc.With equimolar four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group in CuPc alternate embodiment 2] Phthalocyanine Zinc, can obtain four-a-(2-piperazinyl oxyethyl group) CuPc.With equimolar 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group in CuPc alternate embodiment 4] Phthalocyanine Zinc, can obtain 1-(2-piperazinyl oxyethyl group) CuPc.The structure of products therefrom is except the Zn at phthalocyanine center replaces with Cu, the same with the phthalocyanine product described in embodiment 1-4.
Embodiment 7
Central ion is Fe
2+phthalocyanine complex synthetic
With the zinc acetate in equimolar iron protochloride alternate embodiment 1 and embodiment 3, can obtain the corresponding substituted phthalocyanine iron of each embodiment (II), i.e. four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] FePC and 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] FePC.With equimolar four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group in FePC alternate embodiment 2] Phthalocyanine Zinc, can obtain four-a-(2-piperazinyl oxyethyl group) FePC.With equimolar 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group in FePC alternate embodiment 4] Phthalocyanine Zinc, can obtain 1-(2-piperazinyl oxyethyl group) FePC.The structure of products therefrom is except the Zn at phthalocyanine center replaces with Fe, the same with the phthalocyanine product described in embodiment 1-4.
Embodiment 8
Central ion is Ni
2+phthalocyanine complex synthetic
With the zinc acetate in equimolar nickelous chloride alternate embodiment 1 and embodiment 3, can obtain the corresponding substituted phthalocyanine nickel of each embodiment (II), i.e. four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Nickel Phthalocyanine and 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Nickel Phthalocyanine.With equimolar four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group in Nickel Phthalocyanine alternate embodiment 2] Phthalocyanine Zinc, can obtain four-a-(2-piperazinyl oxyethyl group) Nickel Phthalocyanine.With equimolar 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group in Nickel Phthalocyanine alternate embodiment 4] Phthalocyanine Zinc, can obtain 1-(2-piperazinyl oxyethyl group) Nickel Phthalocyanine.The structure of products therefrom is except the Zn at phthalocyanine center replaces with Ni, the same with the phthalocyanine product described in embodiment 1-4.
Embodiment 9
The method of utilizing phthalocyanine metal complex of the present invention to prepare photo-dynamical medicine (being photosensitive medicament) is: make water, or the mixed solution (content of other material is not higher than 10%(wt%) of water and other material) as solvent, dissolve phthalocyanine metal complex of the present invention, be mixed with blue solution (being photosensitive medicament) uniformly, in photosensitive medicament, the concentration of phthalocyanine metal complex is 0.08mM.Other described material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N, dinethylformamide, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.Also can be first with hydrochloric acid or sulfuric acid or etc. acidic substance two [4-(2-amino-ethyl) phenoxy group] of the present invention silicon phthalocyanine is converted into the form of salt, then use above-mentioned dissolution with solvents.In the solution of making, can add antioxidant, buffer reagent and isotonic agent as additive to keep chemical stability and the biocompatibility of photosensitive medicament.
Phthalocyanine metal complex of the present invention is dissolved in to 5-35%(wt%) aqueous solution of methyl-sulphoxide, can be used as the preparation that topical is used.
Embodiment 10
Photo-dynamical medicine, photosensitive medicament or photosensitizers that the present invention is prepared, at optical dynamic therapy, or light power diagnosis, or the using method in the sterilization of light power is identical with the using method of the photosensitive medicament that uses non-phthalocyanine of the present invention or porphyrin compound to prepare in prior art or photosensitizers, but need supporting suitable light source, described suitable light source can be connected that suitable spectral filter provides or be provided by the laser of specific wavelength by ordinary light source, the wavelength region of light source is 300-800nm, preferably 680-704nm.
Embodiment 11
Phthalocyanine metal complex described in the claims in the present invention 1 is dissolved in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution, makes the photosensitive medicament of 0.08mM.Test their dark toxicity and photodynamic activities to people's cancer of the stomach BGC823.
The photosensitive medicament of 0.08mM is diluted in cell culture fluid, makes the cell culture fluid containing phthalocyanine complex of different concns.Cancer cells is cultivated 2 hours respectively in the nutrient solution of the phthalocyanine complex that contains different concns, abandoned thereafter nutrient solution, with PBS, clean after cell, add new nutrient solution (not containing phthalocyanine metal complex).Illumination experiment group, cell is carried out to red light irradiation, and (exciting light sources used is the ruddiness that wavelength is greater than 610nm, irradiates 30 minutes, and the power that irradiates light is 15mw * cm
-2); Irradiation group, is not placed in dark place 20 minutes by cell.After illumination or not illumination, the survival rate of cell adopts mtt assay to investigate.Specific experiment step is referring to < <
bioorganic & Medicinal Chemistry Letters > >, 2006,16,2450-2453.
The ruddiness that above-mentioned wavelength is greater than 610nm is that the halogen lamp by 500W connects heat insulation tank and strengthens in the spectral filter of 610nm and provide.
Result shows, if do not carry out illumination, the phthalocyanine complex described in embodiment 1-8 does not does not kill and wound and growth-inhibiting effect people's cancer of the stomach BGC823, shows that they do not have dark toxicity; If but carry out red light irradiation, and the phthalocyanine complex described in embodiment 1-8 has shown different photodynamic activities, wherein, four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] toxic limit medium dose (IC of Phthalocyanine Zinc
50, kill the required drug level of 50% cancer cells) and be 0.91 * 10
-6mol/L, the IC of four-a-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc
50value is 1.11 * 10
-6mol/L, 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] IC of Phthalocyanine Zinc
50value is 0.82 * 10
-6mol/L, the IC of 1-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc
50value is 0.70 * 10
-6mol/L, the IC of other phthalocyanine complexes described in embodiment 1-8
50value is all greater than 20 * 10
-6mol/L.
Embodiment 12
Phthalocyanine complex described in the claims in the present invention 1-4 is dissolved in 1% castor oil derivative (Cremophor EL, wt%) PBS damping fluid, makes the photosensitive medicament of 0.1mM, test them the light power of fungi is suppressed to active.
Fungi is Candida albicans CMCC (F) C1a(Candida albicans, C. albicans), first prepare the physiological saline bacteria suspension of Candida albicans, concentration is controlled at 1-10 * 10
6cFU/ml.The photosensitive medicament of 0.1mM is diluted in bacteria suspension, makes the nutrient solution containing different concns phthalocyanine complex.Cultivate after 3 hours, illumination experiment group, bacteria suspension is carried out to red light irradiation, and (exciting light sources used is the ruddiness that wavelength is greater than 610nm, irradiates 30 minutes, and the power that irradiates light is 15mw * cm
-2); Irradiation group, is not placed in dark place 20 minutes by bacteria suspension.After illumination or not illumination, get 20 μ L bacteria suspensions, dilute 100 times, then with liquid-transfering gun, quantitatively pipette 20 μ L and be uniformly coated on SDA plate media surface, 37 ℃ of lucifuges of constant temperature are inverted and are cultivated, and interval 48h observes the colony number of Candida albicans.Bacteriostasis rate clicks formula counting: bacteriostasis rate=100% * (1-experimental group colony number mean value/control group colony number mean value).
Result shows, the phthalocyanine complex described in the claims in the present invention 1-4 has significant light restraining effect to Candida albicans, and solvent control group, irradiation group, not administration of an irradiation group all do not affect the growth of Candida albicans in an administration.Wherein, four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] toxic limit medium dose (IC of Phthalocyanine Zinc
50, kill the required drug level of 50% fungal cell) and be 8.5 * 10
-5mol/L, the IC of four-a-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc
50value is 5.5 * 10
-5mol/L, the IC of 1-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc
50value is 3.0 * 10
-6mol/L.When 1-(2-piperazinyl oxyethyl group) phthalocyanine zinc concentration arrives 5.0 * 10
-5during mol/L, under red light irradiation, can suppress the growth of Candida albicans completely.
The ruddiness that above-mentioned wavelength is greater than 610nm is that the halogen lamp by 500W connects heat insulation tank and strengthens in the spectral filter of 610nm and provide.
The foregoing is only preferred embodiment of the present invention, all equalizations of doing according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.
Claims (3)
1. contain an application for the quaternary phthalocyanine metal complex of non-periphery of piperazine oxyethyl group modification group, it is characterized in that: for the preparation of photo-dynamical medicine or photosensitive medicament;
The described quaternary phthalocyanine metal complex of non-periphery containing piperazine oxyethyl group modification group is: 1,8 (11), 15 (18), 22 (25)-tetra-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex, or claim four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex; Or 1,8 (11), 15 (18), 22 (25)-tetra-(2-piperazinyl oxyethyl group) phthalocyanine metal complex, or claim four-a-(2-piperazinyl oxyethyl group) phthalocyanine metal complex;
The described quaternary phthalocyanine metal complex of non-periphery containing piperazine oxyethyl group modification group is corresponding ZnPcS2P2.
2. contain an application for the mono-substituted phthalocyanine metal complex of non-periphery of piperazine oxyethyl group modification group, it is characterized in that: for the preparation of photo-dynamical medicine or photosensitive medicament;
The described mono-substituted phthalocyanine metal complex of non-periphery containing piperazine oxyethyl group modification group is: 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex; Or 1-(2-piperazinyl oxyethyl group) phthalocyanine metal complex;
The described mono-substituted phthalocyanine metal complex of non-periphery containing piperazine oxyethyl group modification group is corresponding ZnPcS2P2.
3. the application of phthalocyanine metal complex according to claim 1 and 2, it is characterized in that: the method for preparing photosensitive medicament is: water, or the mixed solution of water and other material, wherein the massfraction of other material is not higher than 10%, as solvent, dissolve phthalocyanine metal complex, be mixed with containing certain density photosensitive medicament, the concentration of phthalocyanine metal complex is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive to keep chemical stability and the biocompatibility of photosensitive medicament;
Other described material is one or more the miscellany in castor oil polyoxyethylene 35 ethers, methyl-sulphoxide, ethanol, glycerine, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
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