CN102675325A - Phthalocyanine metal complex containing piperazine ethyoxyl modification group and preparing method thereof - Google Patents
Phthalocyanine metal complex containing piperazine ethyoxyl modification group and preparing method thereof Download PDFInfo
- Publication number
- CN102675325A CN102675325A CN2012101766729A CN201210176672A CN102675325A CN 102675325 A CN102675325 A CN 102675325A CN 2012101766729 A CN2012101766729 A CN 2012101766729A CN 201210176672 A CN201210176672 A CN 201210176672A CN 102675325 A CN102675325 A CN 102675325A
- Authority
- CN
- China
- Prior art keywords
- phthalocyanine
- metal complex
- tert
- solvent
- oxyethyl group
- 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
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a phthalocyanine metal complex containing piperazine ethyoxyl modification group and a preparing method thereof and belongs to the field of photodynamic drug preparing or photosensitizer preparing. The phthalocyanine metal complex containing piperazine ethyoxyl modification group is characterized in that the phthalocyanine metal complex has amphipathy and absorbs and sends spectrums to the wavelength position where the spectrums can pierce through human tissues in red shift mode, and photosensitizer is high in reactive oxygen production capacity. The preparing method is simple and has remarkable economic effect and social effect.
Description
Technical field
The invention belongs to photo-dynamical medicine or photosensitizers preparation field, be specifically related to phthalocyanine metal complex that contains piperazine oxyethyl group modification group and preparation method thereof.
Background technology
Phthalocyanine complex is one type of important functional material; In fields such as dyestuff, optical recording medium, nonlinear optical material, catalyzer important application is arranged; Wherein, phthalocyanine complex is noticeable as the prospect of photosensitizers in optical dynamic therapy (Photodynamic Therapy).
So-called optical dynamic therapy (or claim PDT) in fact, is the application that the photosensitization of photosensitizers (or claiming photosensitive drug) is reflected at medical field.Its mechanism is; Earlier photosensitizers is injected body, (this section waiting time be let medicine enrichment relatively in target body) after a period of time is with the rayed target body of specific wavelength (can be by interventional techniques such as optical fiber importing light source to endoceliac target); Be enriched in photosensitizers in the 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 of treatment cancer.With traditional therapy, to compare like surgical operation, chemotherapy, radiotherapy, the photodynamic therapy biggest advantage is to carry out selective destruction and needn't perform surgical operation cancerous tissue, and spinoff is little, thereby gets most of the attention.
Simultaneously, research in recent years shows that also PDT also can be treated non-Cancerous diseases such as infectation of bacteria, oral disease, degeneration of macula illness in eye, arteriosclerosis, wound infection and tetter effectively.Photosensitizers can also be used for the sterilization of light power, most importantly is used for the sterilization of water body, blood and blood derivatives.Simultaneously, utilizing the photoluminescent property of photosensitizers to carry out light power diagnosis, also is 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 disease; Scientific circles generally believe; Optical dynamic therapy will become the important therapy of 21 century, so, will become an important and tempting new high-tech industry as the photosensitizers of optical dynamic therapy core.
So far, get permission the formal clinically photosensitizers that uses and be mainly hematoporphyrin derivative.In states such as the U.S., Canada, Germany, Japan; What use is Photofrin (U.S. FDA is used for clinical anticancer in nineteen ninety-five official approval Photofrin), and it is the mixture of the porporino oligopolymer that from cow blood, extracts and carry out chemical modification.Hematoporphyrin derivative has shown certain curative effect; But also exposed critical defect: maximum absorption wavelength (380-420nm) is not at the red light district preferable to the tissue transmitance (650-800nm); The skin phototoxicity is big; Be mixture, form instability etc., thereby clinical application is restricted, so Development of New Generation photo-dynamical medicine (photosensitizers) is international research focus.
Be positioned at characteristics such as regional, the dark toxicity of easy ruddiness through tissue is low owing to have maximum absorption wavelength, phthalocyanine metal complex is paid much attention to as the application of novel photosensitive agent.But still there is weak point in the phthalocyanine complex of the present biologically active of reporting, or lack amphipathic, or poor stability, or complex synthetic route, or biological selectivity is good or the like, needs further to improve.On the other hand, because the huge economic society of photosensitizers and optical dynamic therapy potential is worth, the refinement of range of application and treatment focus greatly, preparing the phthalocyanine complex that more has comparative advantages is necessity very as drug candidate.
Summary of the invention
The object of the present invention is to provide a kind of phthalocyanine metal complex that contains piperazine oxyethyl group modification group and preparation method thereof.Of the present inventionly provide phthalocyanine complex to have the photodynamic activity height, raw material is easy to get, prepares advantages such as easy, and in the physiology system, is difficult for characteristics such as gathering, stable height.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
The phthalocyanine metal complex that contains piperazine oxyethyl group modification group provided by the invention; Comprise the quaternary phthalocyanine metal complex of a kind of non-periphery, but called after 1,8 (11); 15 (18); 22 (25)-four [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, it is characterized in that: its structural formula is following:
In the following formula, the M representation metal ion, R represents substituted radical, and four substituted radicals all are in the non-peripheral position of phthalocyanine ring, claim a the position, i.e. 1 (4), 8 (11), 15 (18), 22 (25) positions, wherein M is Zn
2+, Co
2+, Ni
2+, Fe
2+Or Cu
2+, substituent group R is:
The phthalocyanine metal complex that contains piperazine oxyethyl group modification group provided by the invention; Comprise the quaternary phthalocyanine metal complex of a kind of non-periphery, but called after 1,8 (11); 15 (18); 22 (25)-four (2-piperazinyl oxyethyl group) phthalocyanine metal complex, or claim four-a-(2-piperazinyl oxyethyl group) phthalocyanine metal complex, it is characterized in that: its structural formula is following:
In the following formula, the M representation metal ion, R represents substituted radical, and four substituted radicals all are in the non-peripheral position of phthalocyanine ring, claim a the position, i.e. 1 (4), 8 (11), 15 (18), 22 (25) positions, wherein M is Zn
2+, Co
2+, Ni
2+, Fe
2+Or Cu
2+, substituent group R is:
The phthalocyanine metal complex that contains piperazine oxyethyl group modification group provided by the invention; Comprise the mono-substituted phthalocyanine metal complex of a kind of non-periphery; But called after 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex, it is characterized in that: its structural formula is following:
，
In the following formula, the M representation metal ion, R represents substituted radical, and wherein M is Zn
2+, Co
2+, Ni
2+, Fe
2+Or Cu
2+, substituent R is:
The phthalocyanine metal complex that contains piperazine oxyethyl group modification group provided by the invention comprises the mono-substituted phthalocyanine metal complex of a kind of non-periphery, but called after 1-(2-piperazinyl oxyethyl group) phthalocyanine complex, and it is characterized in that: its structural formula is following:
In the following formula, the M representation metal ion, R represents substituted radical, and wherein M is Zn
2+, Co
2+, Ni
2+, Fe
2+Or Cu
2+, substituent R is:
The preparation method of four-a-among the present invention [2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex may further comprise the steps:
(1) N-hydroxyethyl piperazine middle-end amino is protected through tertbutyloxycarbonyl: with N-hydroxyethyl piperazine and tert-Butyl dicarbonate is raw material; In the presence of triethylamine, be solvent with the methylene dichloride, 0 ℃ of stirring reaction 0.5 ~ 2 hour; 20 ~ 30 ℃ of stirring reactions 12 ~ 48 hours; Through the thin-layer chromatography monitoring, termination reaction when the N-hydroxyethyl piperazine is exhausted basically is through solvent method and extraction process purification of target product; In the above-mentioned reaction, the molar ratio of N-hydroxyethyl piperazine, tert-Butyl dicarbonate and triethylamine is 1:1 ~ 2.5:1 ~ 2, and the consumption of solvent is that every mmol N-hydroxyethyl piperazine needs 1 ~ 3ml;
(2) preparation 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile: the end amino that obtains with 3-nitro phthalic nitrile and step (1) is reactant by the N-hydroxyethyl piperazine of tertbutyloxycarbonyl protection; With N; The N N is a solvent; Under salt of wormwood existence and nitrogen protection, room temperature ~ 45 ℃ following stirring reaction 48 ~ 96 hours is monitored through thin-layer chromatography; Termination reaction when 3-nitro phthalic nitrile is exhausted basically is through solvent method, recrystallization method and extraction process purification of target product; In the above-mentioned reaction; 3-nitro phthalic nitrile is 1:1 ~ 1.5 with the amino molar ratio by the N-hydroxyethyl piperazine of tertbutyloxycarbonyl protection of end; Solvent load is that every mmol reactant 3-nitro phthalic nitrile needs 2 ~ 5ml, and the consumption of salt of wormwood is that every mmol reactant 3-nitro phthalic nitrile needs 1.5 ~ 3mmol;
(3) the quaternary phthalocyanine metal complex of the non-periphery of preparation: with 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile is raw material; Pentyl alcohol, N, dinethylformamide or dimethylethanolamine are solvent, add zinc chloride (or cobalt or nickel or ferrous or copper) or zinc sulfate (or cobalt or nickel or ferrous or copper) or zinc acetate (or cobalt or nickel or ferrous or copper); With 1; 8-diazabicylo [5.4.0] 11 carbon-7-alkene is catalyzer, and 130 ~ 150 ℃ of following stirring reactions 6 ~ 12 hours are through thin-layer chromatography monitoring reaction end; Generation contains a four substituted phthalocyanine title complexs of respective metal, and then through solvent method or chromatography purification title product; In the above-mentioned reaction, the molar ratio of 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile and metal-salt is 1:0.25 ~ 2; Catalyst consumption is that every mmol3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile needs 0.4 ~ 0.8ml; The consumption of solvent is that every mmol3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile needs 20 ~ 30ml.
The preparation method of four-a-among the present invention (2-piperazinyl oxyethyl group) phthalocyanine metal complex may further comprise the steps: under the nitrogen protection condition; Four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex is joined the tetrahydrofuran solution of tetrabutyl ammonium fluoride; Stirring and refluxing reaction 5 ~ 10 hours; Monitor reaction end through thin-layer chromatography, and carry out purifying through gel chromatography; In this reaction, the concentration of tetrabutyl ammonium fluoride is 0.5 ~ 2M, and 1mmol four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex needs the tetrahydrofuran solution 15 ~ 30ml of tetrabutyl ammonium fluoride.
The preparation method of 1-among the present invention [2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex may further comprise the steps:
(1) N-hydroxyethyl piperazine middle-end amino is protected through tertbutyloxycarbonyl: with N-hydroxyethyl piperazine and tert-Butyl dicarbonate is raw material; In the presence of triethylamine, be solvent with the methylene dichloride, 0 ℃ of stirring reaction 0.5 ~ 2 hour; 20 ~ 30 ℃ of stirring reactions 12 ~ 48 hours; Through the thin-layer chromatography monitoring, termination reaction when the N-hydroxyethyl piperazine is exhausted basically is through solvent method and extraction process purification of target product; In the above-mentioned reaction, the molar ratio of N-hydroxyethyl piperazine, tert-Butyl dicarbonate and triethylamine is 1:1 ~ 2.5:1 ~ 2, and the consumption of solvent is that every mmol N-hydroxyethyl piperazine needs 1 ~ 3ml;
(2) preparation 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile: the end amino that obtains with 3-nitro phthalic nitrile and step (1) is reactant by the N-hydroxyethyl piperazine of tertbutyloxycarbonyl protection; With N; The N N is a solvent; Under salt of wormwood existence and nitrogen protection, room temperature ~ 45 ℃ following stirring reaction 48 ~ 96 hours is monitored through thin-layer chromatography; Termination reaction when 3-nitro phthalic nitrile is exhausted basically is through solvent method, recrystallization method and extraction process purification of target product; In the above-mentioned reaction; 3-nitro phthalic nitrile is 1:1 ~ 1.5 with the amino molar ratio by the N-hydroxyethyl piperazine of tertbutyloxycarbonyl protection of end; Solvent load is that every mmol reactant 3-nitro phthalic nitrile needs 2 ~ 5ml, and the consumption of salt of wormwood is that every mmol reactant 3-nitro phthalic nitrile needs 1.5 ~ 3mmol;
(3) the mono-substituted phthalocyanine metal complex of the non-periphery of preparation: with 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile and phthalonitrile is raw material; With Pentyl alcohol, N; Dinethylformamide or dimethylethanolamine are solvent; Add zinc chloride (or cobalt or nickel or ferrous or copper) or zinc sulfate (or cobalt or nickel or ferrous or copper) or zinc acetate (or cobalt or nickel or ferrous or copper), with 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene is catalyzer; 100 ~ 150 ℃ of following stirring reactions 8 ~ 48 hours; Through thin-layer chromatography monitoring reaction end, generation contains the mono-substituted phthalocyanine complex in a position of respective metal, no substituted phthalocyanine and polysubstituted phthalocyanine complex, through solvent method or column chromatography or HPLC; Remove excessive raw material, do not have replacement or polysubstituted phthalocyanine and other impurity, obtain mono-substituted title product; In the above-mentioned reaction, the molar ratio of 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile, phthalonitrile and metal-salt is 1:3 ~ 6:0.25 ~ 2; Catalyst consumption is that every mmole 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile needs 0.3 ~ 0.7ml; The consumption of solvent is that [2-(N-tert-butoxycarbonyl-piperazine base) needs 20 ~ 35ml to every mmole 3-.
The preparation method of 1-among the present invention (2-piperazinyl oxyethyl group) phthalocyanine complex may further comprise the steps: under the nitrogen protection condition; 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex is joined the tetrahydrofuran solution of tetrabutyl ammonium fluoride; Back flow reaction 5 ~ 10 hours; Thin-layer chromatography monitoring reaction end carries out purifying through gel chromatography, obtains the mono-substituted phthalocyanine metal complex of non-periphery as claimed in claim 7; In this reaction, the concentration of tetrabutyl ammonium fluoride is 0.5 ~ 2M, and 1mmol1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine metal complex needs the tetrahydrofuran solution 15 ~ 30ml of tetrabutyl ammonium fluoride.
The phthalocyanine metal complex that contains piperazine oxyethyl group modification group provided by the invention can be used for preparing photo-dynamical medicine or photosensitive medicament.Said photosensitive medicament, or be called for short photosensitizers, or claim the photosensitive drug preparation, be called light power medicament again.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 an infectation of bacteria, or oral disease, or degeneration of macula illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.Described smooth power sterilization can be the light power sterilization purification of blood or blood derivatives, or the light power sterilization of water, or medical or life is sterilized with the light power of 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, dissolves phthalocyanine metal complex of the present invention; Be mixed with and contain certain density photosensitive medicament, the concentration of phthalocyanine metal complex is not higher than its saturation concentration; In the solution of processing, add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament;
Described other material is castor oil polyoxyethylene 35 ethers, methyl-sulphoxide, ethanol, glycerine, N, the miscellany of one or more in dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, the YMS 2.
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, and possess hydrophilic property is easy to be prepared into photosensitive medicament.The substituted phthalocyanine complex of 2-piperazinyl oxyethyl group 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 the phthalocyanine ring, and promptly so-called a introduces substituting group on the position.Introduce hydrophilic radical in a position,, can stop the phthalocyanine ring in Aquo System, to be assembled effectively, thereby improve photodynamic activity significantly than in the b position.
(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 superior to first-generation photosensitizers greatly.A provided by the invention position substituted phthalocyanine, with respect to corresponding b position substituted phthalocyanine, the maximum absorption spectrum red shift, this is favourable to optical dynamic therapy, because spectral red shift can improve the transmitance of used excitation light 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 the fungal cell and the cancer cells uptake ratio of phthalocyanine complex, thereby has improved the photodynamic activity of phthalocyanine complex.Select this group to confirm after through a large amount of comparative tests as non-peripheral substituting group; Introduce some other similar group; For example; Piperazinyl, oxyethyl group, ethanoyl piperazine oxyethyl group, ethanoyl piperazine phenoxy, kharophen phenoxy, 4-formic acid phenoxy, 3-formic acid phenoxy etc., the cellular uptake rate of raising phthalocyanine complex and the effect of photodynamic activity are all not as introducing 2-piperazinyl oxyethyl group.
(5) non-peripheral monosubstituted phthalocyanine metal complexes provided by the present invention, also asymmetric except possessing above-mentioned advantage because of having, and valuable especially in field of photodynamic.1-provided by the invention (2-piperazinyl oxyethyl group) Phthalocyanine Zinc had both shown that the high light power to cancer cells suppressed active, had shown that again the high light power to fungi suppresses active.Because cancer cells and fungal cell there are differences on the composition structure, the phthalocyanines photosensitizers does not generally possess the high reactivity of two aspects simultaneously, and 1-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc has special advantages in this respect.
(6) the preparation route of phthalocyanine complex provided by the present invention is rationally feasible, and synthesis material is easy to get, and is prone to industrialization.1,8 (11), 15 (18), 22 (25)-four (2-piperazinyl oxyethyl group) phthalocyanine metal complexes and 1-(the 2-piperazinyl oxyethyl group) synthetic route of phthalocyanine metal complex and the selection of technology just obtain through a large amount of creative experiments among the present invention.Conventional method is as midbody through preparation 3-[2-(piperazinyl) oxyethyl group] phthalic nitrile; And then through the synthetic target phthalocyanine complex of template, but in practice, find that the synthetic yield of 3-[2-(piperazinyl) oxyethyl group] phthalic nitrile is very low (mainly being because the amino in the piperazine has also been participated in nucleophilic substitution reaction); And with the amino in the piperazine through after the tertbutyloxycarbonyl protection; Can address this problem preferably, and the reduction of protection after product polarity, be easier to separation and purification.Obtained the phthalocyanine complex behind the amido protecting, how deprotection also is a key in the synthesis technique; Conventional deprotection method is included in trifluoroacetic acid, phosphoric acid and HCl etc. in differing temps and the solvent, all can not be when not destroying the phthalocyanine ring; Deprotection effectively; Through a large amount of contrast experiments, the present invention has adopted the tetra-tert Neutral ammonium fluoride as deprotecting regent, obtains effect preferably.
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 the 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 an infectation of bacteria, or oral disease, or degeneration of macula 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; Be used for the sterilization of light power; Described smooth power sterilization can be the light power sterilization purification of blood or blood derivatives, or the light power sterilization of water, or medical or life is sterilized with the light power of 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 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 is as solvent; Dissolve phthalocyanine metal complex according to the invention; Be mixed with and contain certain density photosensitive medicament, the concentration of phthalocyanine metal complex is not higher than its saturation concentration.Described other material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N; Dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, YMS 2.Also can be earlier with hydrochloric acid or sulfuric acid or etc. acidic substance two [4-(2-amino-ethyl) phenoxy] of the present invention silicon phthalocyanine is converted into the form of salt, use above-mentioned dissolution with solvents then.In the solution of processing, can add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament.
Preparation for topical is used can be dissolved in phthalocyanine metal complex of the present invention in the perviousness solvent, maybe will be injected in ointment, washing lotion or the gel.The aqueous solution of the preferred 5-35% of said perviousness solvent (wt%) methyl-sulphoxide.
Below adopt non-limiting example that the present invention is described further.
Embodiment 1
Synthetic and the physico-chemical property of 1,8 (11), 15 (18), 22 (25)-four [2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc
Formula (1)
This compound also can be claimed four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc, and its structure is suc as formula shown in (1), wherein:
(1) N-hydroxyethyl piperazine middle-end is amino through BOC (tertbutyloxycarbonyl) protection: at 20 ~ 60ml (preferred 30 ml) CH
2Cl
2In; Add 20mmolN-hydroxyethyl piperazine and 20 ~ 40mmol (preferred 30 mmol) triethylamine; Then slowly drip 20 ~ 50mmol (preferred 40 mmol) tert-Butyl dicarbonate, 0 ℃ of stirring reaction 0.5 ~ 2 hour (preferred 1 hour), 30 ℃ of stirring reactions then; Through thin-layer chromatography monitoring, termination reaction when the N-hydroxyethyl piperazine is exhausted basically.Revolve and boil off except that CH
2Cl
2And triethylamine, the pale yellow oily liquid body and function CH that obtains
2Cl
2Dissolving is washed three times, collects organic phase, anhydrous MgSO
4Drying is revolved to boil off and is desolventized, and obtains holding the N-hydroxyethyl piperazine of amino BOC protection.
(2) preparation 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile: the N-hydroxyethyl piperazine (10 ~ 15mmol, preferred 10mmol) with the amino BOC protection of the end of 3-nitro phthalic nitrile (10mmol) and above-mentioned acquisition is a reactant, with N; N N (DMF) is solvent (20 ~ 50ml; Preferred 25ml), at salt of wormwood (15 ~ 30mmol, preferred 22 mmol; Adding in three batches) under existence and the nitrogen protection; Stirring reaction is 48 ~ 96 hours under the room temperature ~ 45 ° C (preferred 45 ° of C), through thin-layer chromatography monitoring, termination reaction when 3-nitro phthalic nitrile is exhausted basically.Reaction mixture is used the micropore organic membrane filter, collects filtrating, joins this filtrating in the 500ml mixture of ice and water again, stirs; Separate out a large amount of lightpink depositions, leave standstill, centrifugal, washing; Collect solid, lyophilize gets the lightpink solid; And further separate out through diluted hydrochloric acid dissolution, sodium hydroxide solution and carry out purifying, obtain the white powder product behind the washing and drying, productive rate 80%.
The characterization data of product is following:
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) the quaternary phthalocyanine metal complex of the non-periphery of preparation: under protection of nitrogen gas; 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] the phthalic nitrile 1mmol that said process (1) is obtained joins 20-30ml Pentyl alcohol (or N; Dinethylformamide; Or dimethylethanolamine) (preferred Pentyl alcohol, 25ml), stirring heats up makes it to dissolve fully in.Add 0.25 ~ 2 mmol (preferred 0.5mmol) zinc acetate and 0.4 ~ 0.8ml (preferred 0.6ml) 1; 8-diazabicylo [5.4.0]+-carbene-7 (DBU); Continue logical nitrogen, and refluxing and stirring reaction response 6 ~ 12 hours (through thin-layer chromatography monitoring reaction end).Rotary evaporation in vacuo with a small amount of DMF solubilizing reaction product, joins in the 500ml frozen water after removing solvent; Filter and collect blue deposition, separate out through diluted hydrochloric acid dissolution, sodium hydroxide solution and carry out preliminary purification, behind the whiz; Use ETHYLE ACETATE/DMF (volume ratio 10:1) mixed solvent to be eluent, separate, collect the deep green elution fraction through silica gel column chromatography; Concentrate the back and be further purified through gel chromatography (S-X3 type), obtain after the vacuum-drying 60mg deep green product.The maximum absorption band of product in DMF is positioned at 701 nm places, and (Cremophor EL, wt%) maximum absorption wavelength in the aqueous solution is positioned at the 704nm place at 1% castor oil derivative.
The characterization data of product is following:
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 (and 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)-four (2-piperazinyl oxyethyl group) Phthalocyanine Zinc
This compound also can be claimed four-a-(2-piperazinyl oxyethyl group) Phthalocyanine Zinc, and its structure is suc as formula shown in (1), wherein:
Under the nitrogen protection condition; 0.25mmol four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc that embodiment 1 is obtained joins the tetrahydrofuran solution of 5 ml tetrabutyl ammonium fluorides (TBAF); The concentration of tetrabutyl ammonium fluoride is 0.5 ~ 2M (preferred 1M); Stirring and refluxing reaction 5 ~ 10 hours is through thin-layer chromatography monitoring reaction end.Revolve to boil off and desolventize washing, freezing drying under reduced pressure.Be that moving phase is crossed the gel column purifying then with THF, collect the deep green component, drying obtains the 122mg product, and productive rate is 45%.The maximum absorption band of product in DMF is positioned at 699 nm places, and (Cremophor EL, wt%) maximum absorption wavelength in the aqueous solution is positioned at the 703nm place at 1% castor oil derivative.
The characterization data of product is following:
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
Synthetic and the physico-chemical property of 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc
Formula (2)
The structure of this compound is suc as formula shown in (2), wherein:
(1) N-hydroxyethyl piperazine middle-end is amino through BOC (tertbutyloxycarbonyl) protection: at 20 ~ 60ml (preferred 30 ml) CH
2Cl
2In; Add 20mmolN-hydroxyethyl piperazine and 20 ~ 40mmol (preferred 30 mmol) triethylamine; Then slowly drip 20 ~ 50mmol (preferred 40 mmol) tert-Butyl dicarbonate, 0 ℃ of stirring reaction 0.5 ~ 2 hour (preferred 1 hour), 30 ℃ of stirring reactions then; Through thin-layer chromatography monitoring, termination reaction when the N-hydroxyethyl piperazine is exhausted basically.Revolve and boil off except that CH
2Cl
2And triethylamine, the pale yellow oily liquid body and function CH that obtains
2Cl
2Dissolving is washed three times, collects organic phase, anhydrous MgSO
4Drying is revolved to boil off and is desolventized, and obtains holding the N-hydroxyethyl piperazine of amino BOC protection.
(2) preparation 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile: the N-hydroxyethyl piperazine (10 ~ 15mmol, preferred 10mmol) with the amino BOC protection of the end of 3-nitro phthalic nitrile (10mmol) and above-mentioned acquisition is a reactant, with N; N N (DMF) is solvent (20 ~ 50ml; Preferred 25ml), at salt of wormwood (15 ~ 30mmol, preferred 22 mmol; Adding in three batches) under existence and the nitrogen protection; Stirring reaction is 48 ~ 96 hours under the room temperature ~ 45 ° C (preferred 45 ° of C), through thin-layer chromatography monitoring, termination reaction when 3-nitro phthalic nitrile is exhausted basically.Reaction mixture is used the micropore organic membrane filter, collects filtrating, joins this filtrating in the 500ml mixture of ice and water again, stirs; Separate out a large amount of lightpink depositions, leave standstill, centrifugal, washing; Collect solid, lyophilize gets the lightpink solid; And further separate out through diluted hydrochloric acid dissolution, sodium hydroxide solution and carry out purifying, obtain the white powder product behind the washing and drying, productive rate 80%.
The characterization data of product is following:
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) the mono-substituted phthalocyanine metal complex of the non-periphery of preparation: 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile and 3 ~ 6mmol (preferred 5mmol) phthalic nitrile of 1.0 mmol are joined in 20 ~ 35ml (preferred 25ml) Pentyl alcohol; Logical nitrogen; Stir and be warmed up to dissolving fully; Add 0.25 ~ 2 (preferred 2mmol) Glacial acetic acid zinc and 0.3 ~ 0.7ml (preferred 0.6ml) DBU again, stirring and refluxing reaction (through thin-layer chromatography monitoring reaction end).Rotary evaporation in vacuo with a small amount of DMF solubilizing reaction product, joins in the frozen water after removing solvent; Filter and collect blue deposition, separate out through diluted hydrochloric acid dissolution, sodium hydroxide solution and carry out preliminary purification, behind the whiz; Use ETHYLE ACETATE/DMF (volume ratio 10:1) mixed solvent to be eluent, separate, collect second blue elution fraction through silica gel column chromatography; Concentrate the back and be further purified through gel chromatography (S-X3 type), obtain after the vacuum-drying the 40mg blue product.The maximum absorption band of product in DMF is positioned at the 677nm place, and (Cremophor EL, wt%) maximum absorption wavelength in the aqueous solution is positioned at the 681nm place at 1% castor oil derivative.
The characterization data of product is following:
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 is suc as formula shown in (2), wherein:
Under the nitrogen protection condition; 0.25mmol1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] the Phthalocyanine Zinc 0.25mmol that embodiment 3 is obtained joins the tetrahydrofuran solution of 5 ml tetrabutyl ammonium fluorides (TBAF); The concentration of tetrabutyl ammonium fluoride is 0.5 ~ 2M (preferred 1M); Stirring and refluxing reaction 5 ~ 10 hours is through thin-layer chromatography monitoring reaction end.Revolve to boil off and desolventize washing, freezing drying under reduced pressure.Be that moving phase is crossed the gel column purifying then with THF, collect the deep green component, drying obtains the 70mg product, and productive rate is 40%.The maximum absorption band of product in DMF is positioned at 677 nm places, and (Cremophor EL, wt%) maximum absorption wavelength in the aqueous solution is positioned at the 680nm place at 1% castor oil derivative.
The characterization data of product is following:
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 among equimolar NSC 51149 alternate embodiment 1 and the embodiment 3; Can obtain the pairing substituted phthalocyanine cobalt of each embodiment (II), i.e. four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine cobalt and 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine cobalt.Four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc with in equimolar four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine cobalt alternate embodiment 2 can obtain four-a-(2-piperazinyl oxyethyl group) phthalocyanine cobalt.1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc with in equimolar 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] the phthalocyanine cobalt alternate embodiment 4 can obtain 1-(2-piperazinyl oxyethyl group) phthalocyanine cobalt.The structure of products therefrom is except that the Zn at phthalocyanine center replaces with the Co, the same with the phthalocyanine product described in the embodiment 1-4.
Embodiment 6
Central ion is Cu
2+Phthalocyanine complex synthetic
With the zinc acetate among equimolar anhydrous cupric chloride alternate embodiment 1 and the embodiment 3; Can obtain the pairing 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.Four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc with in equimolar four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] CuPc alternate embodiment 2 can obtain four-a-(2-piperazinyl oxyethyl group) CuPc.1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc with in equimolar 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] the CuPc alternate embodiment 4 can obtain 1-(2-piperazinyl oxyethyl group) CuPc.The structure of products therefrom is except that the Zn at phthalocyanine center replaces with the Cu, the same with the phthalocyanine product described in the embodiment 1-4.
Embodiment 7
Central ion is Fe
2+Phthalocyanine complex synthetic
With the zinc acetate among equimolar iron protochloride alternate embodiment 1 and the embodiment 3; Can obtain the pairing 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.Four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc with in equimolar four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] FePC alternate embodiment 2 can obtain four-a-(2-piperazinyl oxyethyl group) FePC.1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc with in equimolar 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] the FePC alternate embodiment 4 can obtain 1-(2-piperazinyl oxyethyl group) FePC.The structure of products therefrom is except that the Zn at phthalocyanine center replaces with the Fe, the same with the phthalocyanine product described in the embodiment 1-4.
Embodiment 8
Central ion is Ni
2+Phthalocyanine complex synthetic
With the zinc acetate among equimolar nickelous chloride alternate embodiment 1 and the embodiment 3; Can obtain the pairing substituted phthalocyanine nickel of each embodiment (II), i.e. four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine nickel and 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine nickel.Four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc with in equimolar four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalocyanine nickel alternate embodiment 2 can obtain four-a-(2-piperazinyl oxyethyl group) phthalocyanine nickel.1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc with in equimolar 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] the phthalocyanine nickel alternate embodiment 4 can obtain 1-(2-piperazinyl oxyethyl group) phthalocyanine nickel.The structure of products therefrom is except that the Zn at phthalocyanine center replaces with the Ni, the same with the phthalocyanine product described in the embodiment 1-4.
Embodiment 9
Substitute the zinc chloride (or cobalt or nickel or ferrous or copper) in the foregoing description with zinc sulfate (or cobalt or nickel or ferrous or copper) or zinc acetate (or cobalt or nickel or ferrous or copper), also can obtain corresponding phthalocyanine phthalocyanine title complex.
Embodiment 10
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 is as solvent; Dissolve phthalocyanine metal complex according to the invention; Be mixed with blue solution (being photosensitive medicament) uniformly, the concentration of phthalocyanine metal complex is 0.08mM in the photosensitive medicament.Described other material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N; Dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, YMS 2.Also can be earlier with hydrochloric acid or sulfuric acid or etc. acidic substance two [4-(2-amino-ethyl) phenoxy] of the present invention silicon phthalocyanine is converted into the form of salt, use above-mentioned dissolution with solvents then.In the solution of processing, can add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament.
Phthalocyanine metal complex of the present invention is dissolved in the aqueous solution of 5-35% (wt%) methyl-sulphoxide, can be used as the preparation that topical is used.
Embodiment 11
Photo-dynamical medicine, photosensitive medicament or photosensitizers that the present invention is prepared; At optical dynamic therapy; Or light power diagnosis; Or the method for use of the photosensitive medicament of the non-phthalocyanine of the present invention of utilization or porphyrin compound preparation in the method for use in the light power sterilization and the prior art or photosensitizers is identical, but the supporting suitable light source of need, and described suitable light source can be connected that suitable spectral filter provides or provided by the laser of specific wavelength by ordinary light source; The wavelength region of light source is 300-800nm, preferred 680-704nm.
Embodiment 12
The described phthalocyanine metal complex of claim 1 of the present invention is dissolved in 1% castor oil derivative, and (Cremophor EL wt%) in the aqueous solution, processes 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 the cell culture fluid, processes the cell culture fluid that contains phthalocyanine complex of different concns.Cancer cells was cultivated 2 hours in the nutrient solution of the phthalocyanine complex that contains different concns respectively, abandoned nutrient solution thereafter, behind PBS cleaning cell, add new nutrient solution (not containing phthalocyanine metal complex).Illumination experimental group, pair cell are carried out red light irradiation, and (used exciting light sources is the ruddiness of wavelength greater than 610nm, shines 30 minutes, and the power of irradiates light is 15mw * cm
-2); The irradiation group did not place the dark place 20 minutes with cell.After illumination or the not illumination, the survival rate of cell adopts mtt assay to investigate.Concrete experimental procedure referring to "
Bioorganic & Medicinal Chemistry Letters ", 2006,16,2450-2453.
Above-mentioned wavelength is that halogen lamp through 500W connects the spectral filter that heat insulation tank adds greater than 610nm and provides greater than the ruddiness of 610nm.
The result shows that if do not carry out illumination, the described phthalocyanine complex of embodiment 1-8 does not does not then kill and wound and the growth-inhibiting effect people's cancer of the stomach BGC823, shows that they do not have dark toxicity; If but carrying out red light irradiation, the described phthalocyanine complex of embodiment 1-8 has shown different photodynamic activities, wherein, the toxic limit medium dose (IC of four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc
50, promptly 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, the IC of 1-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] 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 described other phthalocyanine complexes of embodiment 1-8
50Value is all greater than 20 * 10
-6Mol/L.
Embodiment 13
The described phthalocyanine complex of claim 1-4 of the present invention is dissolved in 1% castor oil derivative, and (Cremophor EL wt%) in the PBS damping fluid, processes the photosensitive medicament of 0.1mM, tests their light power inhibition activity to fungi.
Used fungi is Candida albicans CMCC (F) C1a (Candida albicans, C. albicans), at first prepares the saline water bacteria suspension of Candida albicans, and concentration is controlled at 1-10 * 10
6CFU/ml.The photosensitive medicament of 0.1mM is diluted in the bacteria suspension, processes the nutrient solution that contains the different concns phthalocyanine complex.Cultivate after 3 hours, the illumination experimental group, bacteria suspension is carried out red light irradiation, and (used exciting light sources is the ruddiness of wavelength greater than 610nm, shines 30 minutes, and the power of irradiates light is 15mw * cm
-2); The irradiation group did not place the dark place 20 minutes with bacteria suspension.After illumination or the not illumination, get 20 μ L bacteria suspensions, dilute 100 times, quantitatively pipette 20 μ L with liquid-transfering gun again and be uniformly coated on SDA plate media surface, 37 ℃ of lucifuges of constant temperature are inverted and are cultivated, and 48h observes the colony count of Candida albicans at interval.Bacteriostasis rate clicks the formula counting: bacteriostasis rate=100% * (1-experimental group colony count MV/control group colony count MV).
The result shows that the described phthalocyanine complex of claim 1-4 of the present invention has significant light restraining effect to Candida albicans, and solvent control group, an administration irradiation group, not administration of an irradiation group all do not influence the growth of Candida albicans.Wherein, the toxic limit medium dose (IC of four-a-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] Phthalocyanine Zinc
50, promptly 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 fully.
Above-mentioned wavelength is that halogen lamp through 500W connects the spectral filter that heat insulation tank adds greater than 610nm and provides greater than the ruddiness of 610nm.
The above is merely preferred embodiment of the present invention, and all equalizations of doing according to claim of the present invention change and modify, and all should belong to covering scope of the present invention.
Claims (8)
1. quaternary phthalocyanine metal complex of non-periphery, it is characterized in that: its structural formula is following:
In the following formula, the M representation metal ion, R represents substituted radical, and four substituted radicals all are in the non-peripheral position of phthalocyanine ring, claim a the position, i.e. 1 (4), 8 (11), 15 (18), 22 (25) positions, wherein M is Zn
2+, Co
2+, Ni
2+, Fe
2+Or Cu
2+, substituent group R is:
2. the preparation method of the quaternary phthalocyanine metal complex of non-periphery as claimed in claim 1, it is characterized in that: described preparation method may further comprise the steps:
(1) N-hydroxyethyl piperazine middle-end amino is protected through tertbutyloxycarbonyl: with N-hydroxyethyl piperazine and tert-Butyl dicarbonate is raw material; In the presence of triethylamine, be solvent with the methylene dichloride, 0 ℃ of stirring reaction 0.5 ~ 2 hour; 20 ~ 30 ℃ of stirring reactions 12 ~ 48 hours; Through the thin-layer chromatography monitoring, termination reaction when the N-hydroxyethyl piperazine is exhausted basically is through solvent method and extraction process purification of target product;
In the above-mentioned reaction, the molar ratio of N-hydroxyethyl piperazine, tert-Butyl dicarbonate and triethylamine is 1:1 ~ 2.5:1 ~ 2, and the consumption of solvent is that every mmol N-hydroxyethyl piperazine needs 1 ~ 3ml;
(2) preparation 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile: the end amino that obtains with 3-nitro phthalic nitrile and step (1) is reactant by the N-hydroxyethyl piperazine of tertbutyloxycarbonyl protection; With N; The N N is a solvent; Under salt of wormwood existence and nitrogen protection, room temperature ~ 45 ℃ following stirring reaction 48 ~ 96 hours is monitored through thin-layer chromatography; Termination reaction when 3-nitro phthalic nitrile is exhausted basically is through solvent method, recrystallization method and extraction process purification of target product;
In the above-mentioned reaction; 3-nitro phthalic nitrile is 1:1 ~ 1.5 with the amino molar ratio by the N-hydroxyethyl piperazine of tertbutyloxycarbonyl protection of end; Solvent load is that every mmol reactant 3-nitro phthalic nitrile needs 2 ~ 5ml, and the consumption of salt of wormwood is that every mmol reactant 3-nitro phthalic nitrile needs 1.5 ~ 3mmol;
(3) the quaternary phthalocyanine metal complex of the non-periphery of preparation: with 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile is raw material; Pentyl alcohol, N, dinethylformamide or dimethylethanolamine are solvent, add chlorate, vitriol or the acetate of zinc, cobalt, nickel, ferrous or copper; With 1; 8-diazabicylo [5.4.0] 11 carbon-7-alkene is catalyzer, and 130 ~ 150 ℃ of following stirring reactions 6 ~ 12 hours are through thin-layer chromatography monitoring reaction end; Generation contains a four substituted phthalocyanine title complexs of respective metal, and then through solvent method or chromatography purification title product;
In the above-mentioned reaction, the molar ratio of 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile and metal-salt is 1:0.25 ~ 2; Catalyst consumption is that every mmol3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile needs 0.4 ~ 0.8ml; The consumption of solvent is that every mmol3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile needs 20 ~ 30ml.
3. quaternary phthalocyanine metal complex of non-periphery, it is characterized in that: its structural formula is following:
In the following formula, the M representation metal ion, R represents substituted radical, and four substituted radicals all are in the non-peripheral position of phthalocyanine ring, claim a the position, i.e. 1 (4), 8 (11), 15 (18), 22 (25) positions, wherein M is Zn
2+, Co
2+, Ni
2+, Fe
2+Or Cu
2+, substituent group R is:
4. the preparation method of the quaternary phthalocyanine metal complex of non-periphery as claimed in claim 3, it is characterized in that: described preparation method may further comprise the steps:
Under the nitrogen protection condition; The quaternary phthalocyanine metal complex of the described non-periphery of claim 1 is joined the tetrahydrofuran solution of tetrabutyl ammonium fluoride; Stirring and refluxing reaction 5 ~ 10 hours; Through thin-layer chromatography monitoring reaction end, carry out purifying through gel chromatography, obtain the quaternary phthalocyanine metal complex of non-periphery as claimed in claim 3;
In this reaction, the concentration of tetrabutyl ammonium fluoride is 0.5 ~ 2M, and the quaternary phthalocyanine metal complex of the described non-periphery of 1mmol claim 1 needs the tetrahydrofuran solution 15 ~ 30ml of tetrabutyl ammonium fluoride.
5. mono-substituted phthalocyanine metal complex of non-periphery, it is characterized in that: its structural formula is following:
，
In the following formula, the M representation metal ion, R represents substituted radical, and wherein M is Zn
2+, Co
2+, Ni
2+, Fe
2+Or Cu
2+, substituent R is:
6. the preparation method of the mono-substituted phthalocyanine metal complex of non-periphery as claimed in claim 5, it is characterized in that: described preparation method may further comprise the steps:
(1) N-hydroxyethyl piperazine middle-end amino is protected through tertbutyloxycarbonyl: with N-hydroxyethyl piperazine and tert-Butyl dicarbonate is raw material; In the presence of triethylamine, be solvent with the methylene dichloride, 0 ℃ of stirring reaction 0.5 ~ 2 hour; 20 ~ 30 ℃ of stirring reactions 12 ~ 48 hours; Through the thin-layer chromatography monitoring, termination reaction when the N-hydroxyethyl piperazine is exhausted basically is through solvent method and extraction process purification of target product;
In the above-mentioned reaction, the molar ratio of N-hydroxyethyl piperazine, tert-Butyl dicarbonate and triethylamine is 1:1 ~ 2.5:1 ~ 2, and the consumption of solvent is that every mmol N-hydroxyethyl piperazine needs 1 ~ 3ml;
(2) preparation 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile: the end amino that obtains with 3-nitro phthalic nitrile and step (1) is reactant by the N-hydroxyethyl piperazine of tertbutyloxycarbonyl protection; With N; The N N is a solvent; Under salt of wormwood existence and nitrogen protection, room temperature ~ 45 ℃ following stirring reaction 48 ~ 96 hours is monitored through thin-layer chromatography; Termination reaction when 3-nitro phthalic nitrile is exhausted basically is through solvent method, recrystallization method and extraction process purification of target product;
In the above-mentioned reaction; 3-nitro phthalic nitrile is 1:1 ~ 1.5 with the amino molar ratio by the N-hydroxyethyl piperazine of tertbutyloxycarbonyl protection of end; Solvent load is that every mmol reactant 3-nitro phthalic nitrile needs 2 ~ 5ml, and the consumption of salt of wormwood is that every mmol reactant 3-nitro phthalic nitrile needs 1.5 ~ 3mmol;
(3) the mono-substituted phthalocyanine metal complex of the non-periphery of preparation: with 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile and phthalonitrile is raw material; With Pentyl alcohol, N, dinethylformamide or dimethylethanolamine are solvent, add chlorate, vitriol or the acetate of zinc, cobalt, nickel, ferrous or copper; With 1; 8-diazabicylo [5.4.0] 11 carbon-7-alkene is catalyzer, and 100 ~ 150 ℃ of following stirring reactions 8 ~ 48 hours are through thin-layer chromatography monitoring reaction end; Generation contains the mono-substituted phthalocyanine complex in a position of respective metal, no substituted phthalocyanine and polysubstituted phthalocyanine complex; Through solvent method or column chromatography or HPLC, remove excessive raw material, do not have replacement or polysubstituted phthalocyanine and other impurity, obtain mono-substituted title product;
In the above-mentioned reaction, the molar ratio of 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile, phthalonitrile and metal-salt is 1:3 ~ 6:0.25 ~ 2; Catalyst consumption is that every mmole 3-[2-(N-tert-butoxycarbonyl-piperazine base) oxyethyl group] phthalic nitrile needs 0.3 ~ 0.7ml; The consumption of solvent is that [2-(N-tert-butoxycarbonyl-piperazine base) needs 20 ~ 35ml to every mmole 3-.
7. mono-substituted phthalocyanine metal complex of non-periphery, it is characterized in that: its structural formula is following:
In the following formula, the M representation metal ion, R represents substituted radical, and wherein M is Zn
2+, Co
2+, Ni
2+, Fe
2+Or Cu
2+, substituent R is:
8. the preparation method of the mono-substituted phthalocyanine metal complex of non-periphery as claimed in claim 7, it is characterized in that: described preparation method may further comprise the steps:
Under the nitrogen protection condition; The mono-substituted phthalocyanine metal complex of the described non-periphery of claim 5 is joined the tetrahydrofuran solution of tetrabutyl ammonium fluoride; Back flow reaction 5 ~ 10 hours; Thin-layer chromatography monitoring reaction end carries out purifying through gel chromatography, obtains the mono-substituted phthalocyanine metal complex of non-periphery as claimed in claim 7;
In this reaction, the concentration of tetrabutyl ammonium fluoride is 0.5 ~ 2M, and the mono-substituted phthalocyanine metal complex of the described non-periphery of 1mmol claim 5 needs the tetrahydrofuran solution 15 ~ 30ml of tetrabutyl ammonium fluoride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210176672.9A CN102675325B (en) | 2012-06-01 | 2012-06-01 | Phthalocyanine metal complex containing piperazine ethyoxyl modification group and preparing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210176672.9A CN102675325B (en) | 2012-06-01 | 2012-06-01 | Phthalocyanine metal complex containing piperazine ethyoxyl modification group and preparing method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102675325A true CN102675325A (en) | 2012-09-19 |
| CN102675325B CN102675325B (en) | 2014-06-25 |
Family
ID=46807936
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210176672.9A Active CN102675325B (en) | 2012-06-01 | 2012-06-01 | Phthalocyanine metal complex containing piperazine ethyoxyl modification group and preparing method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102675325B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262350A (en) * | 2014-10-09 | 2015-01-07 | 福州大学 | Phthalocyanine metal complex as well as preparation method and application thereof |
| CN105994358A (en) * | 2016-05-25 | 2016-10-12 | 武汉纺织大学 | Preparation method of composite nanometer antibacterial agent |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0906758A1 (en) * | 1997-08-14 | 1999-04-07 | MOLTENI L. & C. dei Fratelli Alitti Società di Esercizio S.P.A. | Zinc-phthalocyanines and corresponding conjugates, their preparation and use in photodynamic therapy and as diagnostic agents |
| CN101212987A (en) * | 2005-06-29 | 2008-07-02 | 阿利提兄弟有限公司L.莫太尼公司 | Self-sterilizing products |
-
2012
- 2012-06-01 CN CN201210176672.9A patent/CN102675325B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0906758A1 (en) * | 1997-08-14 | 1999-04-07 | MOLTENI L. & C. dei Fratelli Alitti Società di Esercizio S.P.A. | Zinc-phthalocyanines and corresponding conjugates, their preparation and use in photodynamic therapy and as diagnostic agents |
| CN101212987A (en) * | 2005-06-29 | 2008-07-02 | 阿利提兄弟有限公司L.莫太尼公司 | Self-sterilizing products |
Non-Patent Citations (4)
| Title |
|---|
| 《Dyes and Pigments》 20070902 Ziyang Huang，等 The syntheses, characterization and properties of some metallophthalocyanine complexes substituted by (N-(2-hydroxyethyl)piperazine)-N'-2-ethane sulfonic acid (HEPES) 第584-589页 1-4 第77卷, 第3期 * |
| ZIYANG HUANG，等: "The syntheses, characterization and properties of some metallophthalocyanine complexes substituted by (N-(2-hydroxyethyl)piperazine)-N’-2-ethane sulfonic acid (HEPES)", 《DYES AND PIGMENTS》, vol. 77, no. 3, 2 September 2007 (2007-09-02), pages 584 - 589, XP022361799, DOI: doi:10.1016/j.dyepig.2007.08.009 * |
| 黄剑东，等: "四乙酰哌嗪苯氧基酞菁锌及其蛋白质复合物的制备、表征与光动力活性", 《无机化学学报》, vol. 22, no. 3, 31 March 2006 (2006-03-31), pages 435 - 442 * |
| 黄紫洋，等: "含哌嗪取代酞菁金属配合物的合成及其对癌细胞的光灭活作用", 《无机化学学报》, vol. 24, no. 1, 31 January 2008 (2008-01-31), pages 55 - 60 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262350A (en) * | 2014-10-09 | 2015-01-07 | 福州大学 | Phthalocyanine metal complex as well as preparation method and application thereof |
| CN104262350B (en) * | 2014-10-09 | 2017-01-18 | 福州大学 | Phthalocyanine metal complex as well as preparation method and application thereof |
| CN105994358A (en) * | 2016-05-25 | 2016-10-12 | 武汉纺织大学 | Preparation method of composite nanometer antibacterial agent |
| CN105994358B (en) * | 2016-05-25 | 2018-07-06 | 武汉纺织大学 | A kind of preparation method of composite nano antibacterial agent |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102675325B (en) | 2014-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101023945B (en) | Use of non-periphery substituted phthalocyaniu metal complex | |
| CN104262350B (en) | Phthalocyanine metal complex as well as preparation method and application thereof | |
| CN103755714B (en) | A kind of Phthalocyanine-hydrocomplex complex and its preparation method and application | |
| CN108948060B (en) | Triphenylamine branch ligand substituted silicon phthalocyanine and preparation method and application thereof | |
| CN103755713B (en) | A kind of eight sulfonic phthalocyanin and its preparation method and application | |
| Farajzadeh et al. | Photophysicochemical, sonochemical, and biological properties of novel hexadeca-substituted phthalocyanines bearing fluorinated groups | |
| CN104230944B (en) | Bi-zinc-phthalocyanine coordination compound and preparation method and application thereof | |
| CN103435639B (en) | Silicon phthalocyanine of the asymmetric modification of a kind of axial nucleosides and its preparation method and application | |
| CN105622682B (en) | A kind of carboxyl zinc phthalocyanine-adriamycin conjugate and its preparation and application | |
| CN113150298B (en) | Covalent organic polymer based on porphyrin and preparation method and application thereof | |
| CN104844645B (en) | A kind of silicon phthalocyanine of axial ALA modifications and its preparation method and application | |
| CN102675325B (en) | Phthalocyanine metal complex containing piperazine ethyoxyl modification group and preparing method thereof | |
| CN110372754A (en) | A kind of novel metal complex of iridium and its preparation method and application | |
| CN102702210B (en) | Application of phthalocyanine metal complex containing piperazine ethyoxyl modified groups | |
| CN116726194A (en) | Porphyrin-antibiotic supermolecule nanoparticle, preparation method and application thereof | |
| CN102643280B (en) | Folic-acid-modified phthalocyanino-silicon, and preparation method and application thereof | |
| CN102659793B (en) | Phthalocyanine silicon modified by amino ethyl groups and phenoxy groups as well as preparation method and application thereof | |
| CN116354954A (en) | Targeted lysosome AIE probe and preparation method and application thereof | |
| CN103254223B (en) | Silicon phthalocyanine axially modified by aminoethyl phenoxyl and polyethylene glycol oligomer | |
| CN104650129A (en) | Silicon phthalocyanine axially bonded with piperidine or morpholine derivative with ester bond | |
| CN112028901B (en) | Cetyl ammonium group modified phthalocyanine, preparation method thereof and application thereof as photodynamic medicament | |
| CN109456334B (en) | Cyclo-monosubstituted amphiphilic phthalocyanine photosensitizer and preparation and application thereof | |
| CN113214297B (en) | Organic boron photosensitizer based on aggregation-induced emission and application thereof in treating multiple drug-resistant bacterial infection | |
| CN102827228B (en) | Silicon phthalocyanine modified by cytidine derivative and preparation method and application thereof | |
| CN102827226B (en) | Silicon phthalocyanine modified by uridine derivatives and preparation method and application of silicon phthalocyanine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |