CN1861603A - Silicon phthalocyanine compound and composite, their preparation and application thereof - Google Patents
Silicon phthalocyanine compound and composite, their preparation and application thereof Download PDFInfo
- Publication number
- CN1861603A CN1861603A CN 200610200598 CN200610200598A CN1861603A CN 1861603 A CN1861603 A CN 1861603A CN 200610200598 CN200610200598 CN 200610200598 CN 200610200598 A CN200610200598 A CN 200610200598A CN 1861603 A CN1861603 A CN 1861603A
- Authority
- CN
- China
- Prior art keywords
- oxyethyl group
- silicon phthalocyanine
- phthalocyanine
- silicon
- 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
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- -1 Silicon phthalocyanine compound Chemical class 0.000 title claims description 68
- 238000002360 preparation method Methods 0.000 title claims description 25
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- JACPFCQFVIAGDN-UHFFFAOYSA-M sipc iv Chemical compound [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].C=1C=CC=C(C(N=C2[N-]C(C3=CC=CC=C32)=N2)=N3)C=1C3=CC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 JACPFCQFVIAGDN-UHFFFAOYSA-M 0.000 claims description 214
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 claims description 127
- BUMGIEFFCMBQDG-UHFFFAOYSA-N dichlorosilicon Chemical compound Cl[Si]Cl BUMGIEFFCMBQDG-UHFFFAOYSA-N 0.000 claims description 96
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- MWZPENIJLUWBSY-VIFPVBQESA-N methyl L-tyrosinate Chemical compound COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-VIFPVBQESA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
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- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
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- 229960005489 paracetamol Drugs 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 229920000136 polysorbate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
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- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An axially substituted silicon-phthalocyanin match and its composition are disclosed, which have high optical spectrum characteristics and can be used as the photosensitizer used for photodynamic therapy to tumor and the diseases other than cancer, photodynamic diagnosis and photodynamic disinfecting.
Description
Invention field
The present invention relates to silicon phthalocyanine compound and mixture thereof and their preparation and application.The invention still further relates to them as the application of photosensitizers in optical dynamic therapy, light power diagnosis and the sterilization of light power.
Background technology:
Phthalocyanine complex is a class important functional material, and it is applied to corresponding high-tech sector as advanced person's light-guide material, optical recording material, catalytic material.Recently, phthalocyanine complex is noticeable as the application prospect of photosensitizers in optical dynamic therapy (PhotodynamicTherapy), has showed huge social, economic benefit in the near future.
So-called optical dynamic therapy (or claim photodynamic therapy) in fact, is the application that the photosensitization of photosensitizers (with claiming photosensitive drug) is reflected at medical field.Its mechanism is, earlier photosensitizers is injected body, (this section waiting time be allow medicine relatively enrichment in target body) after a period of time, rayed target body (can import light source by interventional techniques such as optical fiber) with specific wavelength 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 as surgical operation, chemotherapy, radiotherapy, the photodynamic therapy biggest advantage is to carry out selective destruction and needn't perform surgical operation cancerous tissue, and side effect is little, thereby gets most of the attention.
Simultaneously, research in recent years shows that also photodynamic therapy also can be treated non-Cancerous diseases such as infectation of bacteria, oral disease, macular degeneration 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 blood and blood derivatives.Simultaneously, utilizing the photoluminescent property of photosensitizers to carry out light power diagnosis, also is an important use of medical photosensitive agent.
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, use be that Photofrin Guo Lan Duck DA is in nineteen ninety-five official approval Photofrin
Extend protectionThe storehouse pest wooden dipper iii of the Drung nationality is consulted in gruel
Condemning the deep and remote brown punishment of general Q rises abruptly〉try to gain 13. and thank to the difficult plan of Ц man edge and scoop up mace curtain ancient type of banner hoisted on a featherdecked mast rank an ancient spear T on the way with a dustpan and annotate this of tomb and take off ひ flute core gram difficult plan (5) Huang He that falls from the sky or outer space? obtained Ministry of Health's approval clinic trial in 998 years.More than the photosensitizers of clinical use shown certain curative effect, but also exposed critical defect, for example, 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 exploitation s-generation anticancer photosensitizer is international research focus.
In the various novel photosensitive agents that are worth further exploitation, phthalocyanine complex is subjected to very big attention, and this is because metal phthalocyanine complex has following characteristics: the skeleton structure similar to haematoporphyrin, but it is more stable to form structure; The photosensitization ability is strong (when the center ion is Si
4+, Al
3+, Zn
2+Deng the time); Maximum absorption wavelength is positioned at the easy ruddiness zone that sees through tissue etc.From literature search as can be known: the axial substituted phthalocyanine Pc4 of U.S. Case Western Reserve university development has significantly high photodynamic activity, has entered the I clinical trial phase.One of characteristics of Pc4 are to have axial substituting group.In general, the phthalocyanine that the axial phthalocyanine that replaces replaces than the plane is more difficult formation aggregate (because effect of axial substituent steric effect) in solution, and the formation of aggregate can reduce the photodynamic activity of photosensitizers significantly; And because silicon has excellent biological compatibility, therefore, axially the silicon phthalocyanine that replaces will become crucial s-generation photosensitizers.But, the complex synthetic route of Pc4, the preparation cost height, the axial group of Pc4 is not the best to the avidity of target, the more important thing is, and Pc4 is not the medicine that China has independent intellectual property right.Therefore, press for the new photosensitive activity height of screening, the axial phthalocyanine photosensitizers that preparation is easy, cost is low, and declare patent as early as possible to capture the commanding elevation of China in this field.Application number is to have introduced a kind of new axial substituted phthalocyanine title complex, its preparation and the application in optical dynamic therapy (this invention and the application are same contriver) thereof for the Chinese invention patent of CN1583762 CN200410013289.7, open (bulletin) number.But because the huge economic society of photosensitizers and optical dynamic therapy potential is worth, the refinement of range of application and treatment focus greatly, prepare the axial replacement silicon phthalocyanine title complexs with photosensitive activity is very necessary as drug candidate more.
In addition, in order further to improve the bioavailability and the cancer cells target of photosensitizers, photosensitizers should come into one's own with the mixture that the carrier compound with specific recognition biological target is formed, yet above-mentioned PC4 and patent do not relate to this point.
Based on above-mentioned analysis, the present invention has synthesized the axial replacement silicon phthalocyanine title complex and the mixture thereof of a series of novelties, and they are applied to optical dynamic therapy (or light power diagnosis or the sterilization of light power) as photosensitizers important and distinct advantage.
What deserves to be mentioned is; states such as America and Europe, Japan strengthen one after another to the input of novel photosensitive agent and the infiltration dynamics of intellecture property; in this case; have only and pay much attention to have the exploitation of independent intellectual property right medicine and accelerate the patent protection paces, could guarantee autonomy and the commanding elevation of China at this important medical field of optical dynamic therapy.
Summary of the invention:
The present invention has overcome the existing defective of existing photosensitizers, and its primary and foremost purpose is that new axial replacement silicon phthalocyanine title complex and the mixture thereof with photosensitive activity will be provided.
The structural formula of silicon phthalocyanine title complex of the present invention is as follows:
What following formula was represented is the silicon phthalocyanine title complex that axially replaces, silicon phthalocyanine or title silicon phthalocyanine, be that central ion is the phthalocyanine complex of silicon, phthalocyanine, English name phthalocyanine, be the abbreviation of four benzo tetraazatetradecane porphyrins, axially substituting group connects by siloxane bond, and wherein axially substituent R is selected from following group:
Silicon phthalocyanine title complex provided by the present invention is following compound:
Two [(2-methoxyl group) oxyethyl group] silicon phthalocyanine
Two [(2-oxyethyl group) oxyethyl group] silicon phthalocyanine
Two [2-(2-methoxy ethoxy) oxyethyl group] silicon phthalocyanine
Two octyloxy silicon phthalocyanines
Two 2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } silicon phthalocyanine
Two 2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } silicon phthalocyanine
Two 2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } silicon phthalocyanine
Two 2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } silicon phthalocyanine
Two 2-{2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-{2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-{2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-{2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine
Two (4-piperidines oxygen base) silicon phthalocyanine
Two (N-methyl-4-piperidines oxygen base) silicon phthalocyanine
Two (N, N-dimethyl-4-piperidine oxygen base) silicon phthalocyanine diiodide
Two [2-(4-piperidyl) oxyethyl group] silicon phthalocyanine
Two [2-(N-piperazinyl) oxyethyl group] silicon phthalocyanine
Two [2-(piperazine oxyethyl group) oxyethyl group] silicon phthalocyanine
Two [2-(N-morpholinyl) oxyethyl group] silicon phthalocyanine
Two [2-(N-methyl-N-morpholinyl) oxyethyl group] silicon phthalocyanine diiodide
Two [2-(N-piperidyl) oxyethyl group] silicon phthalocyanine
Two [2-(N-methyl-N-piperidyl) oxyethyl group] silicon phthalocyanine diiodide
Two [3-(N-piperidyl) propoxy-] silicon phthalocyanine
Two [3-(N-methyl-N-piperidyl) propoxy-] silicon phthalocyanine diiodide
Two [2-imidazoles oxygen base] silicon phthalocyanine
Two [1-methyl-2-imidazoles oxygen base] silicon phthalocyanine
Two [1,1-dimethyl-2-imidazoles oxygen base] silicon phthalocyanine diiodide
Two [2-benzoglyoxaline oxygen base] silicon phthalocyanine
Two [1-benzotriazole oxygen base] silicon phthalocyanine
Two (2-cyclohexyl oxyethyl group) silicon phthalocyanine
Two (2-phenyl ethoxy) silicon phthalocyanine
Two (4-glycyl phenoxyl) silicon phthalocyanine
Two (4-kharophen phenoxy group) silicon phthalocyanine
Two [4-(2-amino-2-methoxycarbonyl-ethyl) phenoxy group] silicon phthalocyanine
Two [4-(4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine
Two [4-(1-methyl-4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine diiodide
Two [4-(3-carboxyl propyl group) phenoxy group] silicon phthalocyanine
Two (4-formic acid phenoxy group) silicon phthalocyanine
Two (3-formic acid phenoxy group) silicon phthalocyanine
Two (3,5-dioctyl phthalate phenoxy group) silicon phthalocyanine
Two (2,4-dimethyl-6-2-pyrimidinyl oxy) silicon phthalocyanine
Two (2-amino-5-bromo-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine
Two (2-sec.-propyl-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine
Two (1-isobutyl--2,2-dimethyl-3-isobutyl boc-propoxy-) silicon phthalocyanine
Two (1-diamantane-methoxyl group) silicon phthalocyanine
Two (2-diamantane-oxyethyl group) silicon phthalocyanine
Two [(12-crown-4) ylmethoxy] silicon phthalocyanine
Two [(15-hat-5) ylmethoxy] silicon phthalocyanine
Two [(18-hat-6) ylmethoxy] silicon phthalocyanine
Second purpose of the present invention is to provide the preparation method of above-mentioned axial replacement silicon phthalocyanine title complex.
The preparation method of silicon phthalocyanine title complex of the present invention is characterised in that: (a) alcohol derivate with phthalocyanine silicon dichloride and the described substituted radical of claim 1-2 is a reactant, and both molar ratios are 1: 2～10; (b) reaction needs to carry out in the presence of sodium hydride or salt of wormwood, and every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides or salt of wormwood; (c) at 70 Fei to the temperature between the reflux temperature of reaction solvent, reacted 3 hours～36 hours; (d) after reaction finishes,, remove excessive raw material and impurity, the purification of target product by solvent method or column chromatography or high performance liquid chromatography.
The 3rd purpose of the present invention is to provide above-mentioned axial replacement silicon phthalocyanine title complex and mixture thereof as the application of photosensitizers in optical dynamic therapy, light power diagnosis and 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 macular degeneration 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 light power sterilization medical or that live and use device.
Novel silicon phthalocyanine complex provided by the invention is applied to have following significant advantage in optical dynamic therapy or light power diagnosis or the sterilization of light power as photosensitizers:
(a) be difficult for forming aggregate because of having axial substituting group, guaranteed to have stronger photosensitive activity.Common photosensitizers easily forms aggregate in aqueous solution, the formation of aggregate has weakened the photosensitization ability of photosensitizers greatly, cause the photosensitizers inactivation at last, how overcoming quick dose of easy accumulative behavior and being needs the problem that solves in the practical application, the invention provides effective solution.Than all ring substituents, axially substituting group can stop the phthalocyanine ring to gather by Intermolecular Forces significantly effectively.
(b) phthalocyanine complex structure provided by the invention clearly, location isomer not.The present invention is to the chemically modified of phthalocyanine precursor structure, be by the phthalocyanine ring axially rather than introduce substituted radical at the periphery of phthalocyanine ring and realize, thereby clearly, there is not isomer in the target compound structure.If the periphery at the phthalocyanine ring is introduced substituting group, because there are 16 possible the position of substitution in the periphery of phthalocyanine ring, then may produce a plurality of isomer, cause product to contain isomer or separation costs sharp increase, this is the weak point that chow ring substituted phthalocyanine title complex is used as photosensitive drug.
(b) owing to selected common pharmacophoric group and drug modification group as axial substituting group, they are ethylenedioxies, or oxyethyl group, or amino acid derivative, or pyrimidine ring, or piperidyl, or piperazinyl, or carboxyl, or diamantane, or crown ether, thereby phthalocyanine complex of the present invention has good biological safety and biocompatibility.
(c) the present invention selects the central ion of silicon as phthalocyanine complex, and it is good for other common ion (zinc, aluminium, magnesium and gallium) that the biological safety of silicon and biocompatibility are wanted, and silicon phthalocyanine produces the quantum yield height of active oxygen.
(d) substituted radical raw material of the present invention is easy to get.
(e) phthalocyanine complex photosensitizers provided by the invention prepares easyly, easy to operate, and preparation speed is fast, and preparation cost is low, and productive rate is higher.
(f) maximum absorption wavelength of phthalocyanine complex provided by the 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.This is very favourable for optical dynamic therapy.
(h) the invention provides various types of silicon phthalocyanine photosensitizerss, or amphipathic phthalocyanine, or the negatively charged ion phthalocyanine, or cationic phthalocyanine, thereby can be suitable for dissimilar focuses and disease, subject range is wide.
(i) the invention provides positively charged ion and replace the silicon phthalocyanine photosensitizers, have the anti-gram of selectivity-/+activity of bacterium.
Simultaneously, mixture provided by the present invention is applied to optical dynamic therapy and light power diagnosis as photosensitizers, its special feature is: in the advantage as photosensitive drug that keeps above-mentioned silicon phthalocyanine title complex, also have the ability of unitransport and selective binding biological target, promptly have target.
Embodiment
The preparation method of silicon phthalocyanine title complex of the present invention, it is characterized in that: (a) alcohol derivate with phthalocyanine silicon dichloride and the described substituted radical of claim 1-2 is a reactant, both molar ratios are 1: 2～10, preferred toluene of reaction solvent or N, N-dicarboximide or 2-methyl ethyl ether; (b) reaction needs to carry out in the presence of sodium hydride or salt of wormwood, and every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides or salt of wormwood; (c) at 70 Fei to the temperature between the reflux temperature of reaction solvent, reacted 3 hours～36 hours; (d) after reaction finishes,, remove excessive raw material and impurity, the purification of target product by solvent method or column chromatography or high performance liquid chromatography.
The preparation method of silicon phthalocyanine title complex of the present invention, it is characterized in that: for the substituent silicon phthalocyanine of axial cation, prepare by corresponding neutral silicon phthalocyanine title complex, the characteristics of this preparation are to utilize alkylating agent (alkyl iodide) to be converted into quaternary ammonium salt amino, be reflected in the organic solvent, carry out under in room temperature to the temperature between the reflux temperature, the reaction times is 1 hour～48 hours.
The mixture photosensitizers that the present invention also provides a class to have target function, promptly by above-mentioned silicon phthalocyanine title complex with have the mixture that the carrier compound of specific recognition biological target is formed, the mol ratio of silicon phthalocyanine title complex and carrier compound is 1: 1～20.Carrier compound with specific recognition biological target is selected from glucosides, amino acid, polypeptide, protein and antibody.Silicon phthalocyanine title complex and the bonding force of carrier compound that can discern biological target comprise electrostatic interaction, hydrogen bond, Van der Waals force, hydrophobicity effect, charge transfer compound action and coordination mainly from intermolecular interaction in the mixture.The axial substituting group of silicon phthalocyanine of the present invention can strengthen these interactions.
The preferred a kind of mixture in following of the present invention: be about to the mixture that title complex is formed with bovine serum albumin (BSA) respectively; Or the mixture that title complex is formed with bovine serum albumin (HSA) respectively; Or the mixture that title complex is formed with Transferrins,iron complexes respectively; Or the mixture that title complex is formed with low-density lipoprotein respectively; Or the mixture that title complex is formed with antibody CD52 respectively; Or the mixture that title complex is formed with antibody CD33 respectively.
Title complex provided by the invention or mixture can be used as good photosensitive drug and are 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 macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.
Title complex provided by the invention or mixture also can be used for the sterilization of light power, and described smooth 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 that live and use device.
The application in optical dynamic therapy, light power diagnosis and the sterilization of light power of title complex of the present invention or mixture, 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, the wavelength region of light source is 600～800nm, preferred 670～750nm.
Title complex preparation method's of the present invention specific embodiment is as follows:
Embodiment 1
Synthetic and the physico-chemical property of two [(2-methoxyl group) oxyethyl group] silicon phthalocyanine: phthalocyanine silicon dichloride and the methyl glycol molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent.In the presence of sodium hydride (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides, preferred 3 moles), reflux temperature is 3 hours～36 hours (preferred 12 hours) of reaction down.After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed the silica gel column chromatography column separating purification, collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 29%.The maximum absorption band of the uv-vis spectra of product is 672nm (in a DMF solution), mass spectrum (ESI) m/z:713[M+Na]
+The DMF of indication is N among the present invention, the N-dicarboximide.
Change poly-middle reaction solvent toluene of above-mentioned synthetic step into DMF, temperature of reaction changes 130 Fei into, and other condition is identical, also can realize the synthetic of two [(2-methoxyl group) oxyethyl group] silicon phthalocyanine.
Embodiment 2
Synthetic and the physico-chemical property of two [(2-oxyethyl group) oxyethyl group] silicon phthalocyanine: phthalocyanine silicon dichloride and the glycol monoethyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent.In the presence of sodium hydride (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides, preferred 3 moles), reflux temperature is 3 hours～36 hours (preferred 12 hours) of reaction down.React completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed the silica gel column chromatography column separating purification, collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid.The maximum absorption band of the uv-vis spectra of product is 672nm (in a DMF solution), mass spectrum (ESI) m/z:741[M+Na]
+
Embodiment 3
Synthetic and the physico-chemical property of two [2-(2-methoxy ethoxy) oxyethyl group] silicon phthalocyanine: phthalocyanine silicon dichloride and the diethylene glycol dimethyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent.In the presence of sodium hydride (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides, preferred 3 moles), reflux temperature is 3 hours～36 hours (preferred 12 hours) of reaction down.React completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed the silica gel column chromatography column separating purification, collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of the uv-vis spectra of product is 674nm (in a DMF solution), mass spectrum (ESI) m/z:801[M+Na]
+
All apparently higher than two [2-(2-butoxy oxyethyl group) oxyethyl group] silicon phthalocyanine, the former synthetic yield is 40% for wetting ability of described two [2-(2-methoxy ethoxy) oxyethyl group] silicon phthalocyanine and synthetic yield, and the latter is 22%.
Embodiment 4
Synthetic and the physico-chemical property of two octyloxy silicon phthalocyanines: phthalocyanine silicon dichloride and the n-Octanol molar ratio according to 1: 4 is distributed in the dry toluene solvent, in the presence of sodium hydride, refluxed 14 hours, react completely, the decompression rotary evaporation removes and desolvates, washing is filtered, and filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of uv-vis spectra is 673nm (in a DMF solution), mass spectrum (ESI) m/z:799[M]
-
Embodiment 5
Synthetic and the physico-chemical property of two { 2-[2-(2-methoxy ethoxy) oxyethyl group] oxyethyl group } silicon phthalocyanine: phthalocyanine silicon dichloride and the triethylene glycol monomethyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent.In the presence of sodium hydride (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides, preferred 3 moles), reflux temperature is 3 hours～36 hours (preferred 12 hours) of reaction down.After reaction finished, the decompression rotary evaporation removed and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 40%.The maximum absorption band of product uv-vis spectra is 674nm (in a DMF solution).
Embodiment 6
Synthetic and the physico-chemical property of two { 2-[2-(2-ethoxy ethoxy) oxyethyl group] oxyethyl group } silicon phthalocyanine: phthalocyanine silicon dichloride and the triethylene glycol one ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent.In the presence of sodium hydride (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides, preferred 3 moles), reflux temperature is 3 hours～2 days (preferred 12 hours) of reaction down.After reaction finished, the decompression rotary evaporation removed and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 60%.The maximum absorption band of product uv-vis spectra is 674nm (in a DMF solution), mass spectrum (ESI) m/z:894[M]
-
With the above-mentioned synthetic step poly-in reaction solvent toluene change the 2-methyl ethyl ether into, other condition is identical, { 2-[2-(2-ethoxy ethoxy) oxyethyl group] oxyethyl group } silicon phthalocyanine of also can realizing two synthetic.
Embodiment 7
Synthetic and the physico-chemical property of two { 2-[2-(2-propoxy-oxyethyl group) oxyethyl group] oxyethyl group } silicon phthalocyanine: phthalocyanine silicon dichloride and the triethylene glycol one propyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent.In the presence of sodium hydride (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides, preferred 3 moles), reflux temperature is 3 hours～36 hours (preferred 12 hours) of reaction down.After reaction finished, the decompression rotary evaporation removed and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 40%.The maximum absorption band of product uv-vis spectra is 674nm (in a DMF solution).
Embodiment 8
Synthetic and the physico-chemical property of two { 2-[2-(2-butoxy oxyethyl group) oxyethyl group] oxyethyl group } silicon phthalocyanine: phthalocyanine silicon dichloride and the triethylene glycol monobutyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent.In the presence of sodium hydride (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides, preferred 3 moles), reflux temperature is 3 hours～2 days (preferred 24 hours) of reaction down.After reaction finished, the decompression rotary evaporation removed and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 35%.The maximum absorption band of product product uv-vis spectra is 675nm (in a DMF solution).
Embodiment 9
Two { 2-{2-[2-(2-methoxy ethoxy) oxyethyl group] oxyethyl group } oxyethyl group } the synthetic and physico-chemical property of silicon phthalocyanine: phthalocyanine silicon dichloride and the TEG monomethyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), back flow reaction 3 hours～36 hours (preferred 16 hours).After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 50%.The maximum absorption band of product uv-vis spectra is 674nm (in a DMF solution), mass spectrum (ESI) m/z:954[M]
-
With the above-mentioned synthetic step poly-in reaction solvent toluene change the 2-methyl ethyl ether into, other condition is identical, { 2-{2-[2-(2-methoxy ethoxy) oxyethyl group] oxyethyl group } oxyethyl group of also can realizing two } silicon phthalocyanine synthetic.
Embodiment 10
Two { 2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] oxyethyl group } oxyethyl group } the synthetic and physico-chemical property of silicon phthalocyanine: phthalocyanine silicon dichloride and the TEG one ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), back flow reaction 3 hours～36 hours (preferred 10 hours).After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 30%.The maximum absorption band of product uv-vis spectra is 675nm (in a DMF solution)
Embodiment 11
Two { 2-{2-[2-(2-propoxy-oxyethyl group) oxyethyl group] oxyethyl group } oxyethyl group } the synthetic and physico-chemical property of silicon phthalocyanine: phthalocyanine silicon dichloride and the TEG one propyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), back flow reaction 3 hours～36 hours (preferred 11 hours).After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 30%.The maximum absorption band of product uv-vis spectra is 675nm (in a DMF solution).
Embodiment 12
Two { 2-{2-[2-(2-butoxy oxyethyl group) oxyethyl group] oxyethyl group } oxyethyl group } the synthetic and physico-chemical property of silicon phthalocyanine: phthalocyanine silicon dichloride and the TEG monobutyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), back flow reaction 3 hours～36 hours (preferred 14 hours).After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 30%.The maximum absorption band of product uv-vis spectra is 675nm (in a DMF solution).
Embodiment 13
Two { 2-{2-{2-[2-(2-methoxy ethoxy) oxyethyl group] oxyethyl group } oxyethyl group } oxyethyl group } the synthetic and physico-chemical property of silicon phthalocyanine: phthalocyanine silicon dichloride and the five ethylene glycol monomethyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), back flow reaction 3 hours～36 hours (preferred 20 hours).After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid.The maximum absorption band of product uv-vis spectra is 675nm (in a DMF solution).
Embodiment 14
Two { 2-{2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] oxyethyl group } oxyethyl group } oxyethyl group } the synthetic and physico-chemical property of silicon phthalocyanine: phthalocyanine silicon dichloride and the five ethylene glycol list ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), back flow reaction 3 hours～36 hours (preferred 20 hours).After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid.The maximum absorption band of product uv-vis spectra is 675nm (in a DMF solution).
Embodiment 15
Two { 2-{2-{2-[2-(2-propoxy-oxyethyl group) oxyethyl group] oxyethyl group } oxyethyl group } oxyethyl group } the synthetic and physico-chemical property of silicon phthalocyanine: phthalocyanine silicon dichloride and the five ethylene glycol list propyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), back flow reaction 3 hours～36 hours (preferred 20 hours).After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid.The maximum absorption band of product uv-vis spectra is 675nm (in a DMF solution).
Embodiment 16
Two { 2-{2-{2-[2-(2-butoxy oxyethyl group) oxyethyl group] oxyethyl group } oxyethyl group } oxyethyl group } the synthetic and physico-chemical property of silicon phthalocyanine: phthalocyanine silicon dichloride and the five ethylene glycol monobutyl ether molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), back flow reaction 3 hours～36 hours (preferred 20 hours).After reacting completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, and filter cake is crossed silica gel column chromatography column separating purification (ethyl acetate is an eluent), collects main ingredient, and it is target product that solvent evaporated obtains the mazarine solid.The maximum absorption band of product uv-vis spectra is 675nm (in a DMF solution).
Hydrophilic lipotropy test shows, the described silicon phthalocyanine title complex of embodiment 5-16 has amphipathic, contain 6-10 oxyethyl group in two axial substituting groups of the described silicon phthalocyanine title complex of embodiment 5-16, it is superior amphipathic that 6-10 suitable oxyethyl group causes title complex to have, their wetting ability is greater than the class title complex that contains 5-1 oxyethyl group in the axial substituting group, and lipotropy is greater than the class title complex that contains in the axial substituting group greater than 11 oxyethyl groups.The described silicon phthalocyanine title complex of the amphipathic embodiment of making 5-16 is suitable for the focus at multiple position and the optical dynamic therapy of polytype cancer cells, and active significantly high, has wide especially range of application.
Embodiment 17
Synthetic and the physico-chemical property of two (4-piperidines oxygen base) silicon phthalocyanine: phthalocyanine silicon dichloride and the 4-hydroxy piperidine molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 90 Fei reaction 8 hours, the decompression rotary evaporation removes and desolvates, filter cake CHCl is filtered in washing
3Filtrate is collected in dissolving, and it is target product that solvent evaporated obtains the mazarine solid, and productive rate is 40%.The Q band maximum absorption band of product uv-vis spectra is 672nm (in a DMF solution), mass spectrum (ESI) m/z:641.3[M-C
5H
10NO]
+
Embodiment 18
Synthetic and the physico-chemical property of two (N-methyl-4-piperidines oxygen base) silicon phthalocyanine: phthalocyanine silicon dichloride and the N-methyl-4-hydroxy piperidine molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 80 Fei reaction 7～12 hours, the decompression rotary evaporation removes and desolvates, filter cake CHCl is filtered in washing
3Filtrate is collected in dissolving, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 40%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:769.4[M+H]
+
Embodiment 19
Synthetic and the physico-chemical property of two (N, N-dimethyl-4-piperidine oxygen base) silicon phthalocyanine diiodide: two (N-methyl-4-piperidines oxygen base) silicon phthalocyanine is dissolved in CHCl
3In, be made into saturated solution, add excessive MeI, stir 1～12 hour (preferred 6 hours), there is a large amount of insolubless to separate out, filter, obtaining the atropurpureus solid is target product, productive rate 91%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 676nm, mass spectrum (ESI) m/z:399.9[M-2I]
2+
Embodiment 20
Synthetic and the physico-chemical property of two [2-(4-piperidyl) oxyethyl group] silicon phthalocyanine: phthalocyanine silicon dichloride and 2-(4-piperidines) the ethanol molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 16 hours) of (preferred 90 Fei) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, filter cake CHCl is filtered in washing
3Filtrate is collected in dissolving, and it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:797.3[M+H]
+
Embodiment 21
Synthetic and the physico-chemical property of two [2-(N-piperazinyl) oxyethyl group] silicon phthalocyanine: phthalocyanine silicon dichloride and N-(2-hydroxyl) the ethyl piperazidine molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 12 hours) of (preferred 90 Fei) reaction under 70 Fei～reflux temperature, after reacting completely, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 40%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 674nm, mass spectrum (ESI) m/z:799[M]
+
Embodiment 22
Synthetic and the physico-chemical property of two [2-(piperazine oxyethyl group) oxyethyl group] silicon phthalocyanine: phthalocyanine silicon dichloride and the 1-hydroxyethyl oxyethyl group piperazine molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 8 hours) of (preferred 90 Fei) reaction under 70 Fei～reflux temperature, after reacting completely, the decompression rotary evaporation removes and desolvates, washing, filter filter cake CHCl
3Filtrate is collected in dissolving, and it is target product that solvent evaporated obtains the mazarine solid, productive rate 30%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:886.0[M]
+
Embodiment 23
Synthetic and the physico-chemical property of two [2-(N-morpholinyl) oxyethyl group] silicon phthalocyanine: phthalocyanine silicon dichloride and N-(2-hydroxyl) the ethyl morpholine molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～24 hours (preferred 12 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 674nm, mass spectrum (ESI) m/z:800[M]
+
Embodiment 24
Synthetic and the physico-chemical property of two [2-(N-methyl-N-morpholinyl) oxyethyl group] silicon phthalocyanine diiodide: two [2-(N-morpholinyl) oxyethyl group] silicon phthalocyanine is dissolved in CHCl
3In, be made into saturated solution, add excessive MeI, back flow reaction 4 hours has a large amount of insolubless to separate out, and filters, and obtaining black solid is target product.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 678nm, mass spectrum (ESI) m/z:830.3[M-2I]
2+
Embodiment 25
Synthetic and the physico-chemical property of two [2-(N-piperidyl) oxyethyl group] silicon phthalocyanine: phthalocyanine silicon dichloride and 2-(N-piperidines) the ethanol molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～24 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 40%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:797.6[M+H]
+
Embodiment 26
Synthetic and the physico-chemical property of two [2-(N-methyl-N-piperidyl) oxyethyl group] silicon phthalocyanine diiodide: two [2-(N-piperidyl) oxyethyl group] silicon phthalocyanine is dissolved in CHCl
3In, be made into saturated solution, add excessive MeI, refluxed 1 hour, be cooled to stirring at room 12 hours, there is a large amount of insolubless to separate out, filter, obtaining black solid is target product, productive rate 66%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 678nm, mass spectrum (ESI) m/z:938.8[M-Me-I]
-
Embodiment 27
Synthetic and the physico-chemical property of two [2-(N-piperidyl) propoxy-] silicon phthalocyanine: phthalocyanine silicon dichloride and 3-(N-piperidines) the propyl alcohol molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～24 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 45%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm.
Embodiment 28
Synthetic and the physico-chemical property of two [2-(N-methyl-N-piperidyl) propoxy-] silicon phthalocyanine diiodide: two [2-(N-piperidyl) propoxy-] silicon phthalocyanine is dissolved in CHCl
3In, be made into saturated solution, add excessive MeI, refluxed 1 hour, be cooled to stirring at room 12 hours, there is a large amount of insolubless to separate out, filter, obtaining black solid is target product, productive rate 66%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 679nm.
Embodiment 29
Synthetic and the physico-chemical property of two [2-imidazoles oxygen base] silicon phthalocyanine: phthalocyanine silicon dichloride and the 2-hydroxyl imidazoles molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～24 hours (preferred 20 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 683nm.
Embodiment 30
Synthetic and the physico-chemical property of two [1-methyl-2-imidazoles oxygen base] silicon phthalocyanine: phthalocyanine silicon dichloride and the 1-methyl-2-hydroxyl imidazoles molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～24 hours (preferred 10 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 683nm.
Embodiment 31
Synthetic and the physico-chemical property of two [1,1-dimethyl-2-imidazoles oxygen base] silicon phthalocyanine diiodide: two [1-methyl-2-imidazoles oxygen base] silicon phthalocyanine is dissolved in CHCl
3In, be made into saturated solution, add excessive MeI, stirred 48 hours under the room temperature,, filter, obtaining black solid is target product, productive rate 66%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 687nm.
Embodiment 32
Synthetic and the physico-chemical property of two [2-benzoglyoxaline oxygen base] silicon phthalocyanine: phthalocyanine silicon dichloride and the 2-hydroxy benzo imidazoles molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 70 Fei～reflux temperature reacted 8～24 hours down, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 683nm.
Embodiment 33
Synthetic and the physico-chemical property of two [1-benzotriazole oxygen base] silicon phthalocyanine: phthalocyanine silicon dichloride and the 1-hydroxy benzo three imidazoles molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 70 Fei～reflux temperature reacted 8～12 hours down, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 685nm.
Embodiment 34
Synthetic and the physico-chemical property of two (2-cyclohexyl oxyethyl group) silicon phthalocyanine: phthalocyanine silicon dichloride and the 2-cyclohexyl ethanol molar ratio according to 1: 4 is distributed in the dry toluene solvent, in the presence of sodium hydride, refluxed 20 hours, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collects main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 38%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:795.8[M]
-
Embodiment 35
Synthetic and the physico-chemical property of two (2-phenyl ethoxy) silicon phthalocyanine: phthalocyanine silicon dichloride and the 2-phenylethyl alcohol molar ratio according to 1: 4 is distributed in the dry toluene solvent, in the presence of sodium hydride, refluxed 12 hours, react completely, the decompression rotary evaporation removes and desolvates, and washing is filtered, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 32%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:782.8[M]
+
Embodiment 36
Synthetic and the physico-chemical property of two (4-glycyl phenoxyl) silicon phthalocyanine: phthalocyanine silicon dichloride and the 4-hydroxybenzene ethanamide molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent; (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride; preferred 3 moles); 10～24 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature; the decompression rotary evaporation removes and desolvates; washing; filter; filter cake is crossed silica gel column chromatography column separating purification (eluent is DMF); collect main ingredient; it is target product that solvent evaporated obtains the mazarine solid, productive rate 46%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 680nm, mass spectrum (ESI) m/z:840.9[M]
-
Embodiment 37
Synthetic and the physico-chemical property of two (4-kharophen phenoxy group) silicon phthalocyanine: phthalocyanine silicon dichloride and the paracetamol molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～24 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 37%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 681nm, mass spectrum (ESI) m/z:840.8[M]
-
Embodiment 38
Synthetic and the physico-chemical property of two [4-(2-amino-2-methoxycarbonyl-ethyl) phenoxy group] silicon phthalocyanine: phthalocyanine silicon dichloride and the L-Tyrosine methyl ester molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～24 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, filter cake is crossed silica gel column chromatography column separating purification (eluent is an acetone), collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 60%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 681nm, mass spectrum (ESI) m/z:929.3[M+H]
+
Embodiment 39
Synthetic and the physico-chemical property of two [4-(4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine: phthalocyanine silicon dichloride and 1-ethanoyl-4-(4-hydroxy phenyl) piperazine molar ratio according to 1: 4 is distributed in the dry toluene solvent; in the presence of sodium hydride, refluxed 12 hours; react completely; the decompression rotary evaporation removes and desolvates; add 100ml water, filter, filter cake is crossed the silica gel column chromatography column separating purification; collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 680nm, mass spectrum (ESI) m/z:980.8[M+H]
+
Sodium hydride with the above-mentioned synthetic step in poly-changes Anhydrous potassium carbonate into, and other condition is identical, also can realize the synthetic of two [4-(4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine.
Embodiment 40
Synthetic and the physico-chemical property of two [4-(1-methyl-4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine diiodide: two [4-(4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine is dissolved in CHCl
3In, be made into saturated solution, add excessive MeI, refluxed 12 hours, there is a large amount of insolubless to separate out, filter, obtaining blue solid is target product.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 685nm, mass spectrum (ESI) m/z:540.8[M-2I]
2+
Embodiment 41
Synthetic and the physico-chemical property of two [4-(3-carboxyl propyl group) phenoxy group] silicon phthalocyanine: phthalocyanine silicon dichloride and 3-(4-hydroxyphenoxy) the propionic acid molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 24 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, adding weak acid separates out, filter, the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 39%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 680nm, mass spectrum (ESI) m/z:870.3[M]
-
Embodiment 42
Synthetic and the physico-chemical property of two (4-formic acid phenoxy group) silicon phthalocyanine: phthalocyanine silicon dichloride and the P-hydroxybenzoic acid molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 24 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, adding weak acid separates out, filter, through the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 45%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 682nm, mass spectrum (ESI) m/z:813.5[M]
-
Embodiment 43
Synthetic and the physico-chemical property of two (3-formic acid phenoxy group) silicon phthalocyanine: phthalocyanine silicon dichloride and the m-Salicylic acid molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 24 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, adding weak acid separates out, filter, through the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 45%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 682nm, mass spectrum (ESI) m/z:813.5[M]
-
Embodiment 44
Two (3,5-dioctyl phthalate phenoxy group) the synthetic and physico-chemical property of silicon phthalocyanine: the molar ratio of dioctyl phthalate between phthalocyanine silicon dichloride and 4-hydroxyl according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 24 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, adding weak acid separates out, filter,, collect main ingredient through the silica gel column chromatography column separating purification, it is target product that solvent evaporated obtains the mazarine solid, productive rate 10%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 677nm, mass spectrum (ESI) m/z:902.3[M]
-
Embodiment 45
Two (2,4-dimethyl-6-2-pyrimidinyl oxy) the synthetic and physico-chemical property of silicon phthalocyanine: with phthalocyanine silicon dichloride and 2,4-dimethyl-6-hydroxy pyrimidine is distributed in the dry toluene solvent according to the molar ratio of 1: 2～10 (preferred 1: 4), (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 24 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, through silica gel column chromatography column separating purification (elutriant is THF), collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 683nm, mass spectrum (ESI) m/z:786.9[M]
+
The described title complex two (2 of present embodiment, 4-methyl-6-2-pyrimidinyl oxy) silicon phthalocyanine and two (6-amino-2-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine is compared and had following remarkable advantages: the photosensitization ability is significantly high, and (quantum yield that the former photosensitization produces single line oxygen is 0.73, and the quantum yield of the latter's single line oxygen is 0.44), amino in latter's substituting group has the photosensitization ability of title complex and subtracts the effect of going out, and present embodiment is amino by substituting with methyl, has significantly improved the photosensitization ability of title complex; Separation costs is low, and the existence of the latter's amino causes title complex separating difficulty height on silica gel column chromatography; The depolymerization ability is significantly high, owing to use the bigger methyl of steric hindrance, the depolymerization ability of the described title complex of present embodiment in aqueous solution is significantly higher than two (6-amino-2-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine.
Embodiment 46
Synthetic and the physico-chemical property of two (2-amino-5-bromo-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine: phthalocyanine silicon dichloride and 2-amino-5-bromo-4-hydroxyl-6-methylpyrimidine are distributed in the dry toluene solvent according to the molar ratio of 1: 2～10 (preferred 1: 4), (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 24 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, through silica gel column chromatography column separating purification (elutriant is THF), collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 686nm, mass spectrum (ESI) m/z:744.4[M]
+
The described title complex two of present embodiment (2-amino-5-bromo-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine and two (6-amino-2-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine is compared has following remarkable advantages: because of the introducing of bromine atoms, the fat-soluble of the described title complex of present embodiment significantly improves, and make it more appropriate to treat brain tumor.
Embodiment 47
Synthetic and the physico-chemical property of two (2-sec.-propyl-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine: phthalocyanine silicon dichloride and the 2-sec.-propyl-6-methyl-4-hydroxy pyrimidine molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 24 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, through silica gel column chromatography column separating purification (elutriant is an acetone), collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 683nm, mass spectrum (ESI) m/z:842.9[M]
+
Dry toluene solvent with the above-mentioned synthetic step in poly-changes the 2-methyl ethyl ether into, and other condition is identical, also can realize the synthetic of two (2-sec.-propyl-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine.
The described title complex two of present embodiment (2-sec.-propyl-6-methyl-6-2-pyrimidinyl oxy) silicon phthalocyanine and two (6-amino-2-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine is compared has following remarkable advantages: the photosensitization ability is significantly high, and (quantum yield that the former photosensitization produces single line oxygen is 0.56, and the quantum yield of the latter's single line oxygen is 0.44), amino in latter's substituting group has the photosensitization ability of title complex and subtracts the effect of going out, and present embodiment is amino by substituting with sec.-propyl, has significantly improved the photosensitization ability of title complex; Separation costs is low, and the existence of the latter's amino causes its separating difficulty height on silica gel column chromatography; The depolymerization ability is significantly high, owing to use the bigger sec.-propyl of steric hindrance, the depolymerization ability of the described title complex of present embodiment in aqueous solution is significantly higher than two (6-amino-2-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine.
Embodiment 48
Two (1-isobutyl esters-2,2-dimethyl-3-isobutyl boc-propoxy-) the synthetic and physico-chemical property of silicon phthalocyanine: with phthalocyanine silicon dichloride and 2,2,4-trimethylammonium-1,3-pentanediol-1-isobutyl ester is distributed in the dry toluene solvent according to the molar ratio of 1: 2～10 (preferred 1: 4), (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 24 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter,, collect main ingredient through the silica gel column chromatography column separating purification, it is target product that solvent evaporated obtains the mazarine solid, productive rate 53%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:755.6[M-C
12H
23O
3]
+
Embodiment 49
Synthetic and the physico-chemical property of two (1-diamantane methoxyl group) silicon phthalocyanine: phthalocyanine silicon dichloride and the 1-diamantane methyl alcohol molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, through the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 65%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:871.1[M+H]
+
Embodiment 50
Synthetic and the physico-chemical property of two (2-diamantane oxyethyl group) silicon phthalocyanine: phthalocyanine silicon dichloride and the 2-diamantane ethanol molar ratio according to 1: 2～10 (preferred 1: 4) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, through the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 56%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 674nm, mass spectrum (ESI) m/z:898.4[M]
+
Embodiment 51
Synthetic and the physico-chemical property of two [(12-crown-4) ylmethoxy] silicon phthalocyanine: phthalocyanine silicon dichloride and the 2-hydroxymethyl-12-crown-4 molar ratio according to 1: 2～10 (preferred 1: 2) is distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, through the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid, productive rate 22%.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 673nm, mass spectrum (ESI) m/z:950.6[M]
-
Embodiment 52
Synthetic and the physico-chemical property of two [(15-hat-5) ylmethoxy] silicon phthalocyanine: phthalocyanine silicon dichloride and 2-hydroxymethyl-15-hat-5 molar ratios according to 1: 2～10 (preferred 1: 2) are distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, through the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 674nm.
Embodiment 53
Synthetic and the physico-chemical property of two [(15-hat-5) ylmethoxy] silicon phthalocyanine: phthalocyanine silicon dichloride and 2-hydroxymethyl-15-hat-5 molar ratios according to 1: 2～10 (preferred 1: 2) are distributed in the dry toluene solvent, (every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides in the presence of sodium hydride, preferred 3 moles), 10～36 hours (preferred 16 hours) of (preferred reflux temperature) reaction under 70 Fei～reflux temperature, the decompression rotary evaporation removes and desolvates, washing, filter, through the silica gel column chromatography column separating purification, collect main ingredient, it is target product that solvent evaporated obtains the mazarine solid.The Q band maximum absorption band of product uv-vis spectra is (in DMF solution) 675nm.
Preparation method's specific embodiment of mixture of the present invention is as follows:
Embodiment 54
The preparation of mixture: with embodiment 6 described title complexs two { 2-[2-(2-ethoxy ethoxy) oxyethyl group] oxyethyl group } silicon phthalocyanine and low-density lipoprotein in the aqueous solution or PBS damping fluid with mol ratio (20～1: 1) mix, 37 Fei stir (or vibration) 2～24 hours (preferred 24 hours) down, obtain mixture, by gel infiltration or film dialysis purifying, freeze-drying is preserved.
Repeat said process, just change the type of title complex and carrier compound in the mixing solutions, just can obtain claim 5 and 6 described mixtures.
Mixture after the freeze-drying has water-soluble, can directly be dissolved in to make medicament in the water for injection and be used for optical dynamic therapy.
It is as follows to adopt mixture of the present invention to prepare the specific embodiment of relevant preparation:
Embodiment 55
Silicon phthalocyanine title complex provided by the present invention and mixture thereof before using, must be made appropriate formulation.
For the preparation of used for intravenous injection, make the mixed solution of water or water and other material be mixed with the preparation that contains photosensitizers.Described other material can be following one or more mixed: methyl-sulphoxide, ethanol, glycerine, N, N-dicarboximide, Liquid Macrogol-3000, cyclodextrin, glucose, castor oil derivative, tween, polyethylene glycol mono stearate.In the solution of making, can add antioxidant, buffer reagent and isotonic agent as chemical stability and the biocompatibility of additive with the maintenance photosensitive drug.
For the preparation that local application uses, can be mixed with washing lotion or the ointment or the perviousness solvent of the silicon phthalocyanine title complex that contains sufficient quantity.
For the preparation that the preparation or the local application of used for intravenous injection uses, all can be made into the liposome form of photosensitizers.
Adopt mixture of the present invention as follows to the specific embodiment of the dark toxicity of human liver cancer cell HepG2 and photodynamic activity test:
Embodiment 56
Following silicon phthalocyanine title complex is made the aqueous solution of 2% castor oil derivative Cremophor EL (v/v), test their dark toxicity and photodynamic activities to human liver cancer cell HepG2, cell survival rate adopts mtt assay to investigate.
The result shows, when being 1.0 * 10 with the phthalocyanine complex solution dilution to concentration
-6Mol Bo
-1The time, if do not carry out illumination, then human liver cancer cell HepG2 is not is not killed and wounded and the growth-inhibiting effect, show that they do not have dark toxicity; If (used exciting light sources is the ruddiness of wavelength greater than 610nm, and irradiates light dosage is 80J Outside-Island m but carry out red light irradiation
-2), following silicon phthalocyanine title complex all shows significantly high photodynamic activity, can reach 90%-100% to the kill rate of cancer cells.
Change the aqueous solution of above-mentioned 2% castor oil derivative Cremophor EL (v/v) into 10% polyethylene glycol mono stearate (wt/wt) aqueous solution or 10% polyoxyethylene glycol 550 (wt/wt) aqueous solution or 10% polyoxyethylene glycol 750 (wt/wt) aqueous solution, also can obtain same experimental result.
Above-mentioned wavelength is that halogen lamp by 500W connects the spectral filter that heat insulation tank adds greater than 610nm and provides greater than the ruddiness of 610nm.
Described following silicon phthalocyanine title complex is a kind of of following title complex: two [(2-methoxyl group) oxyethyl group] silicon phthalocyanine; two [(2-oxyethyl group) oxyethyl group] silicon phthalocyanine; two [2-(2-methoxy ethoxy) oxyethyl group] silicon phthalocyanine; two octyloxy silicon phthalocyanines; two 2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } silicon phthalocyanine; two 2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } silicon phthalocyanine; two 2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } silicon phthalocyanine; two 2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } silicon phthalocyanine; two 2-{2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine; two 2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine; two 2-{2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine; two 2-{2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine; two 2-{2-{2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine; two 2-{2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine; two 2-{2-{2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine; two 2-{2-{2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine; two (4-piperidines oxygen base) silicon phthalocyanine; two (N-methyl-4-piperidines oxygen base) silicon phthalocyanine; two (N; N-dimethyl-4-piperidine oxygen base) silicon phthalocyanine diiodide; two [2-(4-piperidyl) oxyethyl group] silicon phthalocyanine; two [2-(N-piperazinyl) oxyethyl group] silicon phthalocyanine; two [2-(piperazine oxyethyl group) oxyethyl group] silicon phthalocyanine; two [2-(N-piperidyl) oxyethyl group] silicon phthalocyanine; two [2-(N-methyl-N-piperidyl) oxyethyl group] silicon phthalocyanine diiodide; two [3-(N-piperidyl) propoxy-] silicon phthalocyanine; two [3-(N-methyl-N-piperidyl) propoxy-] silicon phthalocyanine diiodide; two [4-(1-methyl-4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine diiodide; two [2-imidazoles oxygen base] silicon phthalocyanine; two [1-methyl-2-imidazoles oxygen base] silicon phthalocyanine; two [1; 1-dimethyl-2-imidazoles oxygen base] the silicon phthalocyanine diiodide; two [2-benzoglyoxaline oxygen base] silicon phthalocyanine; two [1-benzotriazole oxygen base] silicon phthalocyanine; two (4-glycyl phenoxyl) silicon phthalocyanine; two [4-(2-amino-2-methyl esters-ethyl) phenoxy group] silicon phthalocyanine; two (3-formic acid phenoxy group) silicon phthalocyanine; two [4-(3-carboxyl propyl group) phenoxy group] silicon phthalocyanine; two (4-formic acid phenoxy group) silicon phthalocyanine; two (3-formic acid phenoxy group) silicon phthalocyanine; two (3; 5-dioctyl phthalate phenoxy group) silicon phthalocyanine; two (2; 4-methyl-6-2-pyrimidinyl oxy) silicon phthalocyanine; two (2-sec.-propyl-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine; two (1-isobutyl-s-2; 2-dimethyl-3-isobutyl boc-propoxy-) silicon phthalocyanine, two [(12-crown-4) ylmethoxy] silicon phthalocyanine.
Claims (10)
1. silicon phthalocyanine title complex, it is characterized in that: its structural formula is as follows:
What following formula was represented is the silicon phthalocyanine title complex that axially replaces, silicon phthalocyanine or title silicon phthalocyanine, be that central ion is the phthalocyanine complex of silicon, phthalocyanine, English name phthalocyanine, be the abbreviation of four benzo tetraazatetradecane porphyrins, axially substituting group connects by siloxane bond, and wherein axially substituent R is selected from following a kind of group:
2. silicon phthalocyanine title complex according to claim 1 is characterized in that: be following compound:
Two [(2-methoxyl group) oxyethyl group] silicon phthalocyanine
Two [(2-oxyethyl group) oxyethyl group] silicon phthalocyanine
Two [2-(2-methoxy ethoxy) oxyethyl group] silicon phthalocyanine
Two octyloxy silicon phthalocyanines
Two 2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } silicon phthalocyanine
Two 2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } silicon phthalocyanine
Two 2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } silicon phthalocyanine
Two 2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } silicon phthalocyanine
Two 2-{2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-{2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-{2-[2-(2-propoxy-oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine
Two 2-{2-{2-[2-(2-butoxy oxyethyl group) oxyethyl group] and oxyethyl group } oxyethyl group } oxyethyl group } silicon phthalocyanine
Two (4-piperidines oxygen base) silicon phthalocyanine
Two (N-methyl-4-piperidines oxygen base) silicon phthalocyanine
Two (N, N-dimethyl-4-piperidine oxygen base) silicon phthalocyanine diiodide
Two [2-(4-piperidyl) oxyethyl group] silicon phthalocyanine
Two [2-(N-piperazinyl) oxyethyl group] silicon phthalocyanine
Two [2-(piperazine oxyethyl group) oxyethyl group] silicon phthalocyanine
Two [2-(N-morpholinyl) oxyethyl group] silicon phthalocyanine
Two [2-(N-methyl-N-morpholinyl) oxyethyl group] silicon phthalocyanine diiodide
Two [2-(N-piperidyl) oxyethyl group] silicon phthalocyanine
Two [2-(N-methyl-N-piperidyl) oxyethyl group] silicon phthalocyanine diiodide
Two [3-(N-piperidyl) propoxy-] silicon phthalocyanine
Two [3-(N-methyl-N-piperidyl) propoxy-] silicon phthalocyanine diiodide
Two [2-imidazoles oxygen base] silicon phthalocyanine
Two [1-methyl-2-imidazoles oxygen base] silicon phthalocyanine
Two [1,1-dimethyl-2-imidazoles oxygen base] silicon phthalocyanine diiodide
Two [2-benzoglyoxaline oxygen base] silicon phthalocyanine
Two [1-benzotriazole oxygen base] silicon phthalocyanine
Two (2-cyclohexyl oxyethyl group) silicon phthalocyanine
Two (2-phenyl ethoxy) silicon phthalocyanine
Two (4-glycyl phenoxyl) silicon phthalocyanine
Two (4-kharophen phenoxy group) silicon phthalocyanine
Two [4-(2-amino-2-methoxycarbonyl-ethyl) phenoxy group] silicon phthalocyanine
Two [4-(4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine
Two [4-(1-methyl-4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine diiodide
Two [4-(3-carboxyl propyl group) phenoxy group] silicon phthalocyanine
Two (4-formic acid phenoxy group) silicon phthalocyanine
Two (3-formic acid phenoxy group) silicon phthalocyanine
Two (3,5-dioctyl phthalate phenoxy group) silicon phthalocyanine
Two (2,4-dimethyl-6-2-pyrimidinyl oxy) silicon phthalocyanine
Two (2-amino-5-bromo-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine
Two (2-sec.-propyl-6-methyl-4-2-pyrimidinyl oxy) silicon phthalocyanine
Two (1-isobutyl--2,2-dimethyl-3-isobutyl boc-propoxy-) silicon phthalocyanine
Two (1-diamantane-methoxyl group) silicon phthalocyanine
Two (2-diamantane-oxyethyl group) silicon phthalocyanine
Two [(12-crown-4) ylmethoxy] silicon phthalocyanine
Two [(15-hat-5) ylmethoxy] silicon phthalocyanine
Two [(18-hat-6) ylmethoxy] silicon phthalocyanine.
3. the preparation method of silicon phthalocyanine title complex according to claim 1 and 2 is characterized in that: (a) alcohol derivate with phthalocyanine silicon dichloride and the described substituted radical of claim 1-2 is a reactant, and both molar ratios are 1: 2～10; (b) reaction needs to carry out in the presence of sodium hydride or salt of wormwood, and every mole of phthalocyanine silicon dichloride need add 2～6 moles of sodium hydrides or salt of wormwood; (c) at 70 Fei to the temperature between the reflux temperature of reaction solvent, reacted 3 hours～36 hours; (d) after reaction finishes,, remove excessive raw material and impurity, the purification of target product by solvent method or column chromatography or high performance liquid chromatography.
4. the preparation method of silicon phthalocyanine title complex according to claim 1 and 2, it is characterized in that: for the substituent silicon phthalocyanine of axial cation, prepare by corresponding neutral silicon phthalocyanine title complex, the characteristics of this preparation are to utilize alkylating agent (alkyl iodide) to be converted into quaternary ammonium salt amino, be reflected in the organic solvent, carry out under in room temperature to the temperature between the reflux temperature, the reaction times is 1 hour～48 hours.
5. the mixture of silicon phthalocyanine title complex according to claim 1 and 2 and carrier compound composition with specific recognition biological target, it is characterized in that: the carrier compound with specific recognition biological target is selected from glucosides, amino acid, polypeptide, protein and antibody, and the mol ratio of silicon phthalocyanine title complex and carrier compound is 1: 1～20.
6. mixture according to claim 5 is characterized in that: a kind of mixture in can be preferably following: be about to the mixture that title complex is formed with bovine serum albumin (BSA) respectively; Or the mixture that title complex is formed with bovine serum albumin (HSA) respectively; Or the mixture that title complex is formed with Transferrins,iron complexes respectively; Or the mixture that title complex is formed with low-density lipoprotein respectively; Or the mixture that title complex is formed with antibody CD52 respectively; Or the mixture that title complex is formed with antibody CD33 respectively.
7. according to claim 2 or 6 described title complexs or the application of mixture in optical dynamic therapy or light power diagnosis, 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.
8. non-Cancerous disease according to claim 7 can be an infectation of bacteria, or oral disease, or macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.
9. the application in the sterilization of light power according to described title complex of claim 1-6 and mixture thereof, described 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 that live and use device.
10. the application in optical dynamic therapy according to described title complex of claim 7-9 or mixture, 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, the wavelength region of light source is 600～800nm, preferred 670～750nm.
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| CN102643280A (en) * | 2012-05-18 | 2012-08-22 | 福州大学 | Folic-acid-modified phthalocyanino-silicon, and preparation method and application thereof |
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2006
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