CN104650129B - A kind of silicon phthalocyanine of axial ester bond connection piperidines or morpholine derivative - Google Patents
A kind of silicon phthalocyanine of axial ester bond connection piperidines or morpholine derivative Download PDFInfo
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Abstract
Silicon phthalocyanine the invention discloses a kind of axial ester bond connection piperidines or morpholine derivative and its preparation method and application, belongs to photo-dynamical medicine or sensitising agent preparation field.The silicon phthalocyanine that the present invention is provided can be used for light power antibacterial, light power anticancer, optical dynamic therapy other diseases, photodynamic disinfection and light power diagnosis as sensitising agent, the advantage such as preparation is simple, maximum absorption spectrum is located near infrared region, photosensitization is strong that it has.
Description
Technical field
The invention belongs to photo-dynamical medicine or sensitising agent preparation field, and in particular to a kind of axial ester bond connection piperidines or
Silicon phthalocyanine of quinoline derivant and its preparation method and application.
Background technology
Phthalocyanine complex is the important functional material of a class, and different purposes can be developed into by different structural modifications
Functional material.Suitable substituent and central ion are introduced on phthalocyanine ring, it is possible to which it is oxidation catalyst, desulfurization catalyst to develop
Agent, nonlinear optical material, photosensitive drug, liquid crystal material, optical recording material or light-guide material, but how regulate and control substitution base and
Central ion obtains objective function compound, is but to need creative work.
Phthalocyanine complex is as sensitising agent in optical dynamic therapy（Photodynamic Therapy）In application prospect draw
People attractes attention.So-called optical dynamic therapy（Or PDT）, it is sensitising agent substantially（Or photosensitive drug）Photosensitizer
React the application in medical domain.Its mechanism is sensitising agent first to be injected into body, after a period of time（When this section is waited
Between be to allow medicine relative enrichment in target body）, with the light irradiation target body of specific wavelength（Can be by optical fiber etc. to endoceliac target
Interventional technique imports light source）, the sensitising agent being enriched in target body inspired a series of optical physics photochemistry anti-in the case where light is excited
Should, active oxygen is produced, and then destroy target body（Such as cancer cell and cancerous tissue）.
In some developed countries, optical dynamic therapy has turned into the 4th kind of conventional method for the treatment of cancer.With traditional therapy,
As surgical operation, chemotherapy, radiotherapy are compared, photodynamic therapy biggest advantage is can to carry out selective destruction to cancerous tissue
Without performing surgical operation, and Small side effects, thus get most of the attention.
Meanwhile, research in recent years is also shown that PDT can also effectively treat bacterium infection, mouth disease, Huang
The non-Cancerous diseases such as spot denaturation illness in eye, artery sclerosis, wound infection and skin disease.Sensitising agent can be also used for light power and disappear
Poison, most importantly for the sterilization of water body, blood and blood derivatives.Meanwhile, the photoluminescent property using sensitising agent enters
Row light power diagnosis, are also an important use of photosensitive drug.
Optical dynamic therapy it is critical only that sensitising agent, and light power curative effect depends on the quality of sensitising agent.Controlled based on light power
The potentiality in terms for the treatment of tumour and Other diseases, scientific circles are treated it is believed that optical dynamic therapy will turn into the important of 21 century
Therapy, then, the sensitising agent as optical dynamic therapy core will turn into an important and tempting new high-tech industry.
So far, it is approved the sensitising agent predominantly hematoporphyrin derivative for clinically formally using.In the U.S., Canada, moral
The states such as state, Japan, use Photofrin（U.S. FDA is used for clinical treatment cancer in nineteen ninety-five official approval Photofrin
Disease）, it is the mixture of the haematoporphyrin oligomer for extracting and carrying out chemical modification from cow blood.Hematoporphyrin derivative shows
Show certain curative effect, but also expose critical defect：Maximum absorption wavelength（380-420nm）Not to tissue transmitance
Preferably red light district (650-800nm), skin phototoxicity is big, is mixture, constitutes unstable etc., thus clinical practice limited
System, so exploitation New Generation Optical dynamical medicine（Sensitising agent）It is international study hotspot.
The features such as due to being located at red light region and the strong photosensitizer ability easily through tissue with maximum absorption wavelength,
Phthalocyanine complex has drawn attention as the application of sensitising agent.In various phthalocyanine complexes, due to the fact that silicon phthalocyanine is made
For the application of novel photosensitive agent is highly valued：（1）Silicon phthalocyanine can be axially introduced into two substitution bases, so as to more effective
Ground prevents the aggregation of phthalocyanine ring, it is ensured that the performance of phthalocyanine photosensitizer ability；（2）The biocompatibility of silicon is higher, without dark toxicity.The U.S.
The axial substituted phthalocyanine silicon that Case Western Reserve universities develop（Pc4）High light photodynamic activity is shown, is had been enter into
Phase I clinical trial.But, the complex synthetic route of Pc4, preparation cost is high, and stability is poor.Therefore, it is new in the urgent need to screening
Photosensitive activity is high, prepare easy, low cost axial direction modification silicon phthalocyanine sensitising agent.In addition, the phthalocyanine of clinical test at present is photosensitive
Agent maximum absorption spectrum is all located near 670nm greatly, how to make the further red shift of Phthalocyanines maximum absorption band, so as to enter one
Step improves the tissue penetration of action spectrum, is also to be currently needed for the problem that emphasis overcomes.
The Chinese invention patent of Patent No. ZL200410013289.7 and ZL200610200598.4 describes a series of
Axial substituted silicon phthalocyanine complex, its preparation and its application in optical dynamic therapy（The invention is same hair with the application
A person of good sense）.But, due to sensitising agent and the potential tremendous economic social value of optical dynamic therapy, great range of application and control
The refinement of focus is treated, it is very must as drug candidate to prepare more axial substituted silicon phthalocyanine complexs with photosensitive activity
Want.
What is particularly worth mentioning is that, the state such as America and Europe, Japan increases to the input of novel photosensitive agent and intellectual property one after another
Infiltration dynamics, in this case, only pays much attention to possess the exploitation of independent intellectual property right medicine and accelerates patent protection step
Cut down, just can guarantee that China in optical dynamic therapy the autonomy of this important medical field and commanding elevation.
The content of the invention
It is an object of the invention to provide silicon phthalocyanine and its preparation of a kind of axial ester bond connection piperidines or morpholine derivative
Methods and applications.The silicon phthalocyanine that the present invention is provided can be used for light power antibacterial, light power anticancer, optical dynamic therapy as sensitising agent
Other diseases, photodynamic disinfection and light power diagnosis, it has, and preparation is simple, maximum absorption spectrum is located near infrared region, photosensitive
The advantage such as strong is acted on, belongs to photo-dynamical medicine or sensitising agent preparation field.
To achieve the above object, the present invention is adopted the following technical scheme that：
A kind of structural formula of the silicon phthalocyanine of axial ester bond connection piperidines or morpholine derivative is as follows：
What above formula was represented is the silicon phthalocyanine complex of axial substituted, silicon phthalocyanine or silicon phthalocyanine, is that central ion is silicon
Phthalocyanine complex, phthalocyanine, English name phthalocyanine is the abbreviation of four benzo tetraazatetradecane porphyrins, and axial substituted base is
Connected by silicon oxygen bond, wherein axial substituted base R is respectively selected from following group：
The method for preparing the silicon phthalocyanine of ester bond connection piperidines in axial direction as described above or morpholine derivative is comprised the following steps：
（1）With phthalocyanine silicon dichloride and the above-mentioned acid containing piperidines or morpholine group as reactant, both molar ratios are
1:4~10（It is preferred that 1:8）；
（2）With toluene, dimethylbenzene or dioxane as solvent, solvent load is that 1mmol phthalocyanine silicon dichlorides need 50 ~ 125ml
Solvent, under the protection of nitrogen, reacts 16 ~ 48 hours at 100 ~ 130 DEG C, is cleaned by solvent and extract and separate removes excess
Raw material and impurity, obtain the silicon phthalocyanine that described axial ester bond connects piperidines or morpholine derivative.
The silicon phthalocyanine of axial direction ester bond connection piperidines as described above or morpholine derivative be applied to prepare photo-dynamical medicine or
Sensitising agent.The sensitising agent, photosensitive medicament, or photosensitive drug preparation are can be described as in biomedicine field, are also called light power
Medicament.Prepared photo-dynamical medicine or sensitising agent can be used for optical dynamic therapy, light power diagnosis or photodynamic disinfection.Described
Optical dynamic therapy can be the optical dynamic therapy of malignant tumour, or carcinoid optical dynamic therapy, or leukaemia bone
Marrow ex-vivo photodynamic purification treatment, or non-Cancerous disease optical dynamic therapy.Described non-Cancerous disease, can be bacterium sense
Dye, or mouth disease, or macular degeneration illness in eye, or artery sclerosis, or wound infection, or skin disease, or disease
Poison infection.Described photodynamic disinfection can be the light power sterilization purification of blood or blood derivatives, or water light power
Sterilization, or medical or life device photodynamic disinfection.
Preparing the method for photo-dynamical medicine or sensitising agent is：With water, or water and other materials mixed solution, wherein other
The mass fraction of material is not higher than 10%, and used as solvent, the silicon phthalocyanine of the axial ester bond connection piperidines of dissolving or morpholine derivative is matched somebody with somebody
It is made containing certain density photosensitive medicament, the concentration of silicon phthalocyanine is not higher than its saturated concentration；Antioxygen is added in the solution being made
Agent, buffer and isotonic agent are as additive keeping the chemical stability and biocompatibility of photosensitive medicament；Described its
Its material is castor oil derivative（Cremophor EL）, dimethyl sulfoxide, ethanol, glycerine, N,N-dimethylformamide, poly- second
The mixture of one or more in glycol 300-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
Beneficial effects of the present invention and outstanding advantage are：
（1）The silicon phthalocyanine that the present invention is provided is axially symmetric substitution silicon phthalocyanine, axially contains piperidines or morpholine group, is had
Excellent is amphipathic.
（2）The silicon phthalocyanine that the present invention is provided maximum absorption wavelength in aqueous is at 690-700nm, and mole suction
Receive coefficient big（Up to 105The order of magnitude）, its spectral quality is not only significantly better than first generation sensitising agent, and better than carrying out clinic
Other phthalocyanine complexes of experiment.For example, the maximum absorption wavelength of the silicon phthalocyanine compound of present invention offer is relative to the U.S.
Pc4 red shifts 15nm, that is, treating spectrum can be with red shift 15nm, and the tissue penetration for treating light is further enhanced, and this is right
In optical dynamic therapy and light power diagnosis be highly beneficial.
（3）The silicon phthalocyanine that the present invention is provided is to be used as modification group by axial ester bond connection piperidines or morpholine derivative,
Relative to the corresponding silicon phthalocyanine that piperidines or morpholine derivative are connected axially through ehter bond, it has following significant advantage：（a）Prepare
In need not be prepared easier using the catalyst such as NaH；（b）Maximum absorption wavelength red shift 10-20nm, positioned at near-infrared
Area（690-700nm）, treat light tissue penetration be further enhanced, this is examined for optical dynamic therapy and light power
Disconnected is highly beneficial.
（4）The present invention provide phthalocyanine complex structure clearly, in the absence of position isomer.The present invention is to phthalocyanine parent knot
The chemical modification of structure, be by axially realizing rather than introducing substituted radical on the periphery of phthalocyanine ring in phthalocyanine ring, thus
Target compound structure clearly, in the absence of isomers.If substitution base is introduced on the periphery of phthalocyanine ring, due to the periphery of phthalocyanine ring
In the presence of 16 possible the position of substitution, then there may be multiple isomers, product is caused to contain isomers or separation costs increase.
（5）The present invention selects silicon as the central ion of phthalocyanine complex, and the biological safety and biocompatibility of silicon will
It is good in other common ions（Zinc, aluminium, magnesium and gallium）, and silicon phthalocyanine produces the quantum yield of active oxygen high.
（6）The silicon phthalocyanine that the present invention is provided is obtained by substantial amounts of screening test, and there is high light power to live for it
Property.Under red light irradiation, the compound of 80nM can 100% growth for suppressing Human gastric careinoma cells BGC823.Substantial amounts of contrast test table
Bright, the photodynamic activity for Human gastric careinoma cells BGC823 of the silicon phthalocyanine that the present invention is provided is significantly higher than other similar chemical combination
Thing, for example, two [2- (N- morpholines) ethyoxyl] silicon phthalocyanines, two [2- (N- piperidines) ethyoxyl] silicon phthalocyanines, two [2- (N- methyl-N-
Piperidines) ethyoxyl] silicon phthalocyanine diiodide, two [2- (N- methyl-N- morpholines) ethyoxyl] silicon phthalocyanine diiodides, two (4- second
Acylamino- phenoxy group) silicon phthalocyanine, two [4- (4- Acetylpiperazines) phenoxy group] silicon phthalocyanines, two [4- (3- carboxypropyls) benzene
Epoxide] silicon phthalocyanine, two (4- formic acid phenoxy group) silicon phthalocyanines, two (3- formic acid phenoxy group) silicon phthalocyanines, two (3,5- dioctyl phthalate benzene
Epoxide) silicon phthalocyanine, two (1- adamantane-methoxyl group) silicon phthalocyanines, two (2- adamantane-ethyoxyl) silicon phthalocyanines, four-α-
[4- (4- Acetylpiperazines) phenoxy group] ZnPc, four-α-(4- formic acid phenoxy group) ZnPc.
Specific embodiment
The preparation method of the silicon phthalocyanine of a kind of axial ester bond connection piperidines of the present invention or morpholine derivative, it is characterised in that：
（1）With phthalocyanine silicon dichloride and the above-mentioned acid containing piperidines or morpholine group as reactant, both molar ratios are 1:4~10（It is excellent
Select 1:8）；（2）With toluene, dimethylbenzene or dioxane as solvent, solvent load is that 1mmol phthalocyanine silicon dichlorides need 50 ~ 125ml molten
Agent, under the protection of nitrogen, reacts 16 ~ 48 hours at 100 ~ 130 DEG C, is cleaned by solvent and column chromatography for separation removes excess
Raw material and impurity, obtain the silicon phthalocyanine that described a kind of axial ester bond connects piperidines or morpholine derivative.
The silicon phthalocyanine that the present invention is provided can be used to prepare photo-dynamical medicine or photosensitive medicament, be applied to optical dynamic therapy or light
In power diagnosis, optical dynamic therapy of the present invention can be the optical dynamic therapy of malignant tumour, or carcinoid light
Dynamic therapy, or leukaemia ex vivo bone marrow light power purification treatment, or non-Cancerous disease optical dynamic therapy.The present invention
Described non-Cancerous disease, can be bacterium infection, or mouth disease, or macular degeneration illness in eye, or artery sclerosis, or
It is wound infection, or skin disease, or virus infection.
The silicon phthalocyanine that the present invention is provided can be used to prepare photosensitive medicament, for photodynamic disinfection, described photodynamic disinfection
Can be the light power sterilization purification of blood or blood derivatives, or water light power sterilization, or medical or life
With the photodynamic disinfection of device.
Application of the silicon phthalocyanine that the present invention is provided in optical dynamic therapy, light power diagnosis and photodynamic disinfection, need to match somebody with somebody
The suitable light source of set, described suitable light source can connect suitable optical filter to provide or by specific wavelength by ordinary light source
Laser provide, the wave-length coverage of light source is 600~800nm, preferably 690-700nm.
Photo-dynamical medicine is prepared using silicon phthalocyanine of the present invention（I.e. photosensitive medicament）Basic skills be：Using water,
Or the mixed solution of water and other materials（The content of other materials is not higher than 10%（wt%））As solvent, institute of the present invention is dissolved
Silicon phthalocyanine is stated, is configured to containing certain density photosensitive medicament, the concentration of silicon phthalocyanine is not higher than its saturated concentration.Other described things
Matter can be the following mixing of one or more：Castor oil derivative（Cremophor EL）, dimethyl sulfoxide, ethanol, glycerine, N,
Dinethylformamide, Liquid Macrogol -3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.Also may be used
First with hydrochloric acid or sulfuric acid or wait acidic materials that silicon phthalocyanine of the present invention is converted into the form of salt, it is then molten with above-mentioned solvent
Solution.Antioxidant, buffer and isotonic agent can be added as additive to keep the chemistry of photosensitive medicament in the solution being made
Stability and biocompatibility.
For the preparation of local administrable, silicon phthalocyanine of the present invention can be dissolved in penetrating solvents, or will
It is injected into ointment, washing lotion or gel.The preferred 5-35% of penetrating solvents（wt%）The aqueous solution of dimethyl sulfoxide.
Hereinafter using non-limiting example, the invention will be further described.
Embodiment 1
Two [3- (N- piperidines) propyl ester base] silicon phthalocyanines（Structure is shown below）Synthesis and physicochemical property：
Under nitrogen protection, by phthalocyanine silicon dichloride (244.7mg, 0.4mmol), 3- (N- piperidines) propionic acid 1.2-
2.4mmol (preferably 2.0mmol) is added in toluene or dimethylbenzene or dioxane 20-50ml (preferably toluene, 30ml),
Backflow 20-36 hours（It is preferred that 24 hours）.Rotary evaporation in vacuo removes solvent, is dissolved using 100ml dichloromethane, and centrifugation is removed
Insoluble matter, dichloromethane solution is gone to extract (3 × 100ml) with water, then collected organic layer uses watery hydrochloric acid（0.1-0.5
mmol）Extraction, collects water layer.With blue precipitate in 1M NaOH and water layer, is separated out, centrifugation, washing, vacuum drying obtains blue
Color product, yield 45%.Maximum absorption band of the product in DMF is located at 682 nm, maximum absorption wave in aqueous
Length is at 693-700nm.
The structural characterization data of product are as follows：HR-MS (ESI) m/z: 853.3375 [M+H]+；1H NMR (CDCl3,
400MHz, ppm): δ9.61~9.79 (m, 8H, Pc-Hα), δ8.30~8.44 (m, 8H, Pc-Hβ), δ0.89~1.01
(s, 12H, 4,5-H), δ0.67~0.88 (s, 8H, 3-H), δ0.08~0.21 (t, 4H, 2-H), δ-0.56~-
0.42 (t, 4H, 1-H).
Embodiment 2
Two [3- (N- methyl-N- piperidines) propyl ester base] silicon phthalocyanine diiodides（Structure is shown below）Synthesis and physics and chemistry
Property：
Under nitrogen protection, by two [3- (N- piperidines) propyl ester base] silicon phthalocyanines (0.023mmol), excess iodomethane is added to
In chloroform (20ml), flow back 1 ~ 4 hour（It is preferred that 2 hours）After be stirred at room temperature 16 ~ 48 hours（It is preferred that 24 hours）.Filtering, filter cake
With 50ml chloroforms three times, vacuum drying obtains final product product, yield 73%.Maximum absorption band of the product in DMF is located at 684
At nm, maximum absorption wavelength in aqueous is at 691-700nm.
The structural characterization data of product are as follows：HR-MS (ESI) m/z: 441.1888 [M-2I]2+；1H NMR
(DMSO-d6, 400MHz, ppm): δ9.70~9.82 (m, 8H, Pc-Hα), δ8.55~8.66 (m, 8H, Pc-Hβ),
δ2.14~2.25 (m, 4H, 3-H), δ1.98~2.09 (m, 4H, 3-H), δ1.74~1.85 (s, 6H, CH3), δ
1.37~1.48 (t, 4H, 2-H), δ0.99~1.13 (m, 6H, 4,5-H), δ0.78~0.90 (m, 6H, 4,5-H),
δ-0.27~-0.15 (t, 4H, 1-H).
Embodiment 3
Two [3- (N- morpholines) propyl ester base] silicon phthalocyanines（Structure is shown below）Synthesis：
Under nitrogen protection, by phthalocyanine silicon dichloride (244.7mg, 0.4mmol), 3- (N- morpholines) propionic acid 1.2-
2.4mmol (preferably 2.0mmol) is added in toluene or dimethylbenzene or dioxane 20-50ml (preferably toluene, 30ml),
Backflow 20-36 hours（It is preferred that 24 hours）.Rotary evaporation in vacuo removes solvent, is dissolved using 100ml dichloromethane, and centrifugation is removed
Insoluble matter, dichloromethane solution is gone to extract (3 × 100ml) with water, then collected organic layer uses watery hydrochloric acid（0.1-0.5
mmol）Extraction, collects water layer.With blue precipitate in 1M NaOH and water layer, is separated out, centrifugation, washing, vacuum drying obtains blue
Color product, yield 43%.Maximum absorption band of the product in DMF is located at 681 nm, maximum absorption wave in aqueous
Length is at 691-700nm.
The structural characterization data of product are as follows：MS (ESI) m/z: 856 [M]+
Embodiment 4
Two [3- (N- methyl-N- morpholines) propyl ester base] silicon phthalocyanine diiodides（Structure is shown below）Synthesis：
Under nitrogen protection, by two [3- (N- morpholines) propyl ester base] silicon phthalocyanines (0.023mmol), excess iodomethane is added to
In chloroform (20ml), flow back 1 ~ 4 hour（It is preferred that 2 hours）After be stirred at room temperature 16 ~ 48 hours（It is preferred that 24 hours）.Filtering, filter cake
With 50ml chloroforms three times, vacuum drying obtains final product product, yield 69%.Maximum absorption band of the product in DMF is located at
At 683nm, maximum absorption wavelength in aqueous is at 693-700nm.
The characterize data of product is as follows：MS (ESI) m/z: 872.3 [M-2I]2+。
Embodiment 5
Two [2- (N- morpholines) ethyoxyl] silicon phthalocyanines（Structure is shown below）Synthesis and physicochemical property：
Under nitrogen protection, by phthalocyanine silicon dichloride (244.7mg, 0.4mmol), 2- (N- morpholines) ethanol 0.8-
4.0mmol (preferably 1.6mmol) is added in toluene or dimethylbenzene or dioxane 20-50ml (preferably toluene, 30ml),
In the presence of sodium hydride（Every mole of phthalocyanine silicon dichloride need to add 2~6 molar sodium, preferably 3 moles）Backflow（It is preferred that 70
℃）10-24 hours（It is preferred that 12 hours）.Rotary evaporation in vacuo removes solvent, is dissolved using 100ml dichloromethane, is centrifuged off
Insoluble matter, dichloromethane solution extracts (3 × 100ml) with water, collected organic layer.Rotary evaporation in vacuo removes solvent, using silicon
Glue-line analyses column separating purification, collects key component, and solvent evaporated obtains blue solid for target product, product in DMF most
Big absworption peak is at 674nm.
The characterize data of product is as follows：MS (ESI) m/z:800[M]+。
Embodiment 6
Two [2- (N- methyl-N- morpholines) ethyoxyl] silicon phthalocyanine diiodides（Structure is shown below）Synthesis and physics and chemistry
Property：
Under nitrogen protection, by two [2- (N- morpholines) ethyoxyl] silicon phthalocyanines (0.023mmol), excess iodomethane is added to
In chloroform (20ml), flow back 1 ~ 6 hour（It is preferred that 4 hours）, there are a large amount of insoluble matters to separate out.Filtering, filter cake 50ml chloroforms
Three times, vacuum drying obtains final product product.Maximum absorption band of the product in DMF is located at 678 nm, maximum in aqueous
Absorbing wavelength is at 683nm.
The characterize data of product is as follows：MS (ESI) m/z: 830.3 [M-2I]2+。
Embodiment 7
Two [2- (N- piperidines) ethyoxyl] silicon phthalocyanines（Structure is shown below）Synthesis and physicochemical property：
Under nitrogen protection, by phthalocyanine silicon dichloride (244.7mg, 0.4mmol), 2- (N- piperidines) ethanol 0.8-
4.0mmol (preferably 1.6mmol) is added in toluene or dimethylbenzene or dioxane 20-50ml (preferably toluene, 30ml),
In the presence of sodium hydride（Every mole of phthalocyanine silicon dichloride need to add 2~6 molar sodium, preferably 3 moles）Backflow（It is preferred that 70
℃）10-24 hours（It is preferred that 16 hours）.Rotary evaporation in vacuo removes solvent, is dissolved using 100ml dichloromethane, is centrifuged off
Insoluble matter, dichloromethane solution extracts (3 × 100ml) with water, collected organic layer.Rotary evaporation in vacuo removes solvent, using silicon
Glue-line analyses column separating purification, collects key component, and solvent evaporated obtains blue solid for target product, yield 40%.Product exists
Maximum absorption band in DMF is at 673nm.
The characterize data of product is as follows：MS (ESI) m/z:797.6[M+H]+。
Embodiment 8
Two [2- (N- methyl-N- piperidines) ethyoxyl] silicon phthalocyanine diiodides（Structure is shown below）Synthesis and physics and chemistry
Property：
Under nitrogen protection, by two [2- (N- piperidines) ethyoxyl] silicon phthalocyanines (0.023mmol), excess iodomethane is added to
In chloroform (20ml), flow back 1 ~ 3 hour（It is preferred that 1 hour）, it is cooled to and is stirred at room temperature 8 ~ 24 hours（It is preferred that 12 hours）, there is a large amount of
Insoluble matter is separated out.Filtering, filter cake 50ml chloroforms three times, vacuum drying obtains final product product, yield 66%.Product is in DMF
Maximum absorption band be located at 678 nm and locate, maximum absorption band in aqueous is at 683 nm.
The characterize data of product is as follows：MS (ESI) m/z: 938.8 [M-Me-I]-。
Embodiment 9
Photo-dynamical medicine is prepared using silicon phthalocyanine of the present invention（I.e. photosensitive medicament）Method be：Use water, or water
With the mixed solution of other materials（The content of other materials is not higher than 10%（wt%））As solvent, phthalein of the present invention is dissolved
Cyanines silicon, prepares the uniform solution of au bleu（I.e. photosensitive medicament）, the concentration of silicon phthalocyanine is 0.08mM in photosensitive medicament.Described its
Its material can be the following mixing of one or more：Castor oil derivative（Cremophor EL）, it is dimethyl sulfoxide, ethanol, sweet
Oil, DMF, Liquid Macrogol -3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
Also first with hydrochloric acid or sulfuric acid or can wait acidic materials that silicon phthalocyanine of the present invention is converted into the form of amine salt, then with above-mentioned
Solvent dissolves.Antioxidant, buffer and isotonic agent can be added as additive to keep photosensitive medicament in the solution being made
Chemical stability and biocompatibility.
Silicon phthalocyanine of the present invention is dissolved in 5-35%（wt%）The aqueous solution of dimethyl sulfoxide, can be used as local administration
Preparation.
Embodiment 10
Photo-dynamical medicine, photosensitive medicament or sensitising agent prepared by the present invention, in optical dynamic therapy, or light power diagnosis,
Or prepared with the phthalocyanine or porphyrin compound described in non-invention in the application method in photodynamic disinfection and prior art
The application method of photosensitive medicament or sensitising agent is identical, but needs supporting suitable light source, and described suitable light source can be by common
Light source connects suitable optical filter to provide or provided by the laser of specific wavelength, and the wave-length coverage of light source is 300-
800nm, preferably 690-700nm.
Embodiment 11
Silicon phthalocyanine is dissolved in 1% castor oil derivative（Cremophor EL, wt%）In the aqueous solution, the light of 0.08mM is made
Quick medicament.Test their dark toxicities and photodynamic activity to Human gastric careinoma cells BGC823.
The photosensitive medicament of 0.08mM is diluted in cell culture fluid, be made various concentrations containing the thin of silicon phthalocyanine compound
Born of the same parents' nutrient solution.Cancer cell is cultivated 2 hours in the nutrient solution of the silicon phthalocyanine compound containing various concentrations respectively, training is abandoned thereafter
Nutrient solution, after PBS cell, adds new nutrient solution（Without silicon phthalocyanine compound）.Illumination experiment group, is carried out red to cell
Light irradiation（Exciting light sources used are feux rouges of the wavelength more than 610nm, are irradiated 30 minutes, and the power of irradiation light is 15mwcm-2）；Irradiation group, dark place is not placed in 20 minutes by cell.After illumination or not illumination, the survival rate of cell is investigated using mtt assay.Tool
Body experimental procedure referring to《Bioorganic & Medicinal Chemistry Letters》, 2006,16,2450-
2453。
Feux rouges of the above-mentioned wavelength more than 610nm is that the filter in 610nm is increased by the Halogen lamp LED heat-insulated tank of connection of 500W
Mating plate is provided.
Result shows, when by silicon phthalocyanine solution described in embodiment 1-4 be diluted to concentration for 1000-80nM (i.e. 1-0.08 ×
10-6 When mol/L), if not carrying out illumination, Human gastric careinoma cells BGC823 is not killed and growth inhibition effect, show them
There is no dark toxicity；But if carrying out red light irradiation, the silicon phthalocyanine described in the claims in the present invention 1 is more than 80nM when drug concentration
When, can 100% killing cancer cell.Illustrate that the silicon phthalocyanine described in the claims in the present invention 1 has high photodynamic activity.
Under similarity condition, the silicon phthalocyanine described in embodiment 5-8, the drug concentration needed for 100% killing cancer cell need to be more than 300nM.This
The silicon phthalocyanine that piperidines or morpholine derivative are connected axially through ester bond of present invention offer is provided（Chemical combination described in embodiment 1-4
Thing）, relative to the corresponding silicon phthalocyanine that piperidines or morpholine derivative are connected axially through ehter bond（Compound described in embodiment 5-8）Tool
There is significantly higher light power active anticancer.
By above-mentioned 1% castor oil derivative（Cremophor EL, wt%）The aqueous solution changes 1% castor oil derivative into
（Cremophor EL, wt%）PBS (PBS), also can obtain same experimental result.
Embodiment 12
Silicon phthalocyanine compound described in the claims in the present invention 1 is dissolved in 1% castor oil derivative（Cremophor EL,
wt%）In PBS, the photosensitive medicament of 0.050mM is made, tests their light power inhibitory activity to fungi.Fungi
It is Candida albicans CMCC (F) C1a（Candida albicans, C. albicans）.Under red light irradiation（Exciting light used
Light source is feux rouges of the wavelength more than 610nm, is irradiated 30 minutes, and the power of irradiation light is 15mwcm-2）, the claims in the present invention 1
Described silicon phthalocyanine compound can kill Candida albicans with 100%, and solvent control group, only administration irradiation group, an irradiation be not
Administration group does not influence the growth of Candida albicans.
Embodiment 13
Testing the silicon phthalocyanine compound described in the claims in the present invention 1 is used for the effect of photodynamic disinfection as sensitising agent
Really.
First, the phthalocyanine complex is dissolved in 1% castor oil derivative（Cremophor EL, wt%）In the aqueous solution, system
Into the photosensitive medicament of the photosensitive medicament of 0.1mM.It is then added into the water containing Escherichia coli, the content for making phthalocyanine is
0.01mM, contains the water of Escherichia coli with red light irradiation after 2 hours.The survival condition of Escherichia coli before and after inspection irradiation, as a result
Show under red light irradiation, two described in the claims in the present invention a kind silicon phthalocyanine compound can kill 95% Escherichia coli.
The foregoing is only presently preferred embodiments of the present invention, all impartial changes done according to scope of the present invention patent with
Modification, should all belong to covering scope of the invention.
Claims (5)
1. a kind of axial ester bond connects the silicon phthalocyanine of piperidines or morpholine derivative, it is characterised in that：Its structural formula is as follows：
,
Wherein axial substituted base R is respectively selected from following group：
。
2. it is a kind of to prepare the method that axial direction ester bond as claimed in claim 1 connects the silicon phthalocyanine of piperidines or morpholine derivative, its
It is characterised by：Comprise the following steps：
（1）With phthalocyanine silicon dichloride and the acid containing piperidines or morpholine group is as reactant, both molar ratios are 1:4~10；
（2）With toluene, dimethylbenzene or dioxane as solvent, solvent load is that 1mmol phthalocyanine silicon dichlorides need 50 ~ 125mL solvents,
Under the protection of nitrogen, reacted 16 ~ 48 hours at 100 ~ 130 DEG C, cleaned by solvent and extract and separate removes excessive raw material
And impurity, obtain the silicon phthalocyanine that described axial ester bond connects piperidines or morpholine derivative.
3. method according to claim 2, it is characterised in that：Step（1）Middle phthalocyanine silicon dichloride and containing piperidines or morpholinyl
The sour molar ratio of group is 1:8.
4. a kind of application of the silicon phthalocyanine of axial ester bond connection piperidines as claimed in claim 1 or morpholine derivative, its feature
It is：For preparing photo-dynamical medicine or sensitising agent.
5. application according to claim 4, it is characterised in that：Preparing the method for photo-dynamical medicine or sensitising agent is：With water,
Or the mixed solution of water and other materials, the mass fraction of wherein other materials is not higher than 10%, as solvent, dissolves silicon phthalein
Cyanines, are configured to photosensitive medicament, and the concentration of silicon phthalocyanine is not higher than its saturated concentration；Antioxidant is added in the solution being made, is delayed
Electuary and isotonic agent are as additive keeping the chemical stability and biocompatibility of photosensitive medicament；
Described other materials are castor oil derivative, dimethyl sulfoxide, ethanol, glycerine, N, N-dimethylformamide, poly- second two
The mixture of one or more in alcohol 300-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
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| CN106866721B (en) * | 2017-03-10 | 2019-03-26 | 江苏省原子医学研究所 | A kind of silicon phthalocyanine derivative and its application for preparing biotin acceptor targeting silicon phthalocyanine photosensitizer |
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| US5484778A (en) * | 1990-07-17 | 1996-01-16 | University Hospitals Of Cleveland | Phthalocyanine photosensitizers for photodynamic therapy and methods for their use |
| CN1861603A (en) * | 2006-06-21 | 2006-11-15 | 福州大学 | Silicon phthalocyanine compound and composite, their preparation and application thereof |
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|---|---|---|---|---|
| US5484778A (en) * | 1990-07-17 | 1996-01-16 | University Hospitals Of Cleveland | Phthalocyanine photosensitizers for photodynamic therapy and methods for their use |
| US5484778C1 (en) * | 1990-07-17 | 2001-05-08 | Univ Cleveland Hospitals | Phthalocynine photosensitizers for photodynamic therapy and methods for their use |
| CN1861603A (en) * | 2006-06-21 | 2006-11-15 | 福州大学 | Silicon phthalocyanine compound and composite, their preparation and application thereof |
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