CN106565763B - Axial substituted silicon phthalocyanine complex sensitive pH and preparation method thereof and application in medicine - Google Patents

Axial substituted silicon phthalocyanine complex sensitive pH and preparation method thereof and application in medicine Download PDF

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CN106565763B
CN106565763B CN201610995706.5A CN201610995706A CN106565763B CN 106565763 B CN106565763 B CN 106565763B CN 201610995706 A CN201610995706 A CN 201610995706A CN 106565763 B CN106565763 B CN 106565763B
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compound
cancer
logical formula
formula
medicine
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CN106565763A (en
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蒋雄杰
黄华静
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SHENZHEN DAVOOS SCIENCE AND TECHNOLOGY LTD.
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Shenzhen Acousto-Optic Dynamic Biological Medicine Science And Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/025—Silicon compounds without C-silicon linkages

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Abstract

Application the present invention relates to cholesterol silicon phthalocyanine complex of ketal connection sensitive pH and preparation method thereof and in medicine.Especially, the present invention relates to the silicon phthalocyanine complex shown in logical formula (I), its preparation method and pharmaceutical composition containing the complex, as well as the purposes of sensitising agent, purposes particularly in treating cancer, each substituent in its formula of (I) are identical with the definition in specification.Due to the presence of cholesterol group, the serial complex is difficult by tumour cell and normal cell intake, but outside tumor tissue cell under slightly sour environment, hydrolysis occurs for ketal key, the hydrolysis derivative of silicon phthalocyanine can be easy to be absorbed by cancer cell, and showing high photosensitive activity, they can be prepared into slightly sour environment Targeted Photosensitizer outside tumour cell.

Description

Axial substituted silicon phthalocyanine complex sensitive pH and preparation method thereof and in medicine Using
Technical field
The invention belongs to field of medicaments, it is related to silicon phthalocyanine complex and preparation method thereof and its application in medicine, this Disclosure of the invention its as sensitising agent, the purposes for treating cancer.
Technical background
Optical dynamic therapy (Photodynamic Therapy, abbreviation PDT), also known as photoradiation therapy (Photoradiation Therapy, abbreviation PRT) or photochemotherapy (Photochemotherapy), are that one kind is based on The treatment method of the photochemical reaction principle of particular chemicals.Chemical substance used be referred to as tumour chemistry diagnosis and treatment medicine ( Claim sensitising agent, Photosensitizer, abbreviation PS).PDT therapy processes be by be injected intravenously sensitising agent is injected in vivo it is (right Affected part can also be applied in skin), the light irradiation tumor tissues of specific wavelength are used after certain time, are enriched in tumour The sensitising agent of tissue produces a series of optical physics chemical reactions under the exciting of light, the active oxygen of cytotoxicity is produced, so as to kill Dead cancer cell destruction tumor tissues.
Clinic is approved by the fda in the United States within 1996, FDA in 1997 is included in five class basic skills of oncotherapy One of (operation, radiotherapy, chemotherapy, light power, biochemical immunity).Compared with traditional therapy, PDT therapies have wound very little, poison Property it is humble, selectivity is good, applicability is good, repeatable treatment, can palliative treatment, operation can be cooperateed with to improve curative effect, recessiveness can be eliminated Carninomatosis stove, the advantage such as appearance and vitals function, treatment time can be protected short.
Photodynamic therapy can also effectively treat bacterium infection, mouth infection, macular degeneration illness in eye, artery sclerosis, wound The non-Cancerous disease such as sentiment dye and skin disease.Sensitising agent can be also used for photodynamic disinfection, most importantly for blood and The sterilization of blood derivatives.Meanwhile carry out light power diagnosis, and medical photosensitive agent using the photoluminescent property of sensitising agent One important use.
The key of optical dynamic therapy is 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 are treated, scientific circles are it is believed that optical dynamic therapy will be important as 21 century Therapy.The sensitising agent that clinic is mainly applied now is porphin Fei Muna (Porfimer sodium, Photofin), and the medicine is first Afterwards in 28 countries and regions listings such as Holland, Canada, Japan, the U.S., France, Germany, Britain.China is in optical dynamic therapy (PDT) it is slower that the research in terms of starts to walk compared with states such as the U.S., Japan, but progressive very fast.Early 1980s so far, for develop light Dynamic therapy is done a lot of work, and compared with the achievement of foreign countries' report, its depth and range have no too big gap.Chongqing Huading shows Develop, produced to treat the haematoporphyrin of tumour (Hematoporphyrin, happiness pool point) for bio-pharmaceuticals Co., Ltd, Produced and sold via state food drug administration (SFDA) official approval and be applied to clinic.Xi Bofenshi China is unique The anticancer photosensitizer of listing, it is the porphin Fei Muna analogs of external listing, is hematoporphyrin derivative, belongs to first generation anticancer Photosensitive drug.
Although porphin Fei Muna and happiness pool point clinically achieve success, its complicated components, various composition is in light power Effect in damage does not also understand fully that the non-active ingredient for accounting for medicine total amount more than 20% not only can not be to the target tissue of lesion so far Effective Photodynamic polymer effect is produced, turns into the chief culprit for causing normal structure that photosensitized reaction occurs on the contrary.Other first generation light Sensitizing drug is not strong to the targeting of tumour, and the photosensitive drug with tumor-targeting of research efficiently, less toxic is nearest grinds Study carefully focus.
Micro-environmental hypoxia existing for tumor entity tissue site causes the extracellular pH value of the region tumors relatively low (6.5 Left and right), and the outer pH value of normal tissue cell is 7.4 or so.PH value difference between tumor entity tissue and normal structure is swollen The design of knurl targeted drug provides new strategy.Inventor herein reports the sensitive photosensitive medicines of multiple serial pH in recent years Thing, such as axial aminoderivative substitution silicon phthalocyanine, pass through degree of ionization Different Effects light of the amino under different pH environment It is quick activity (Jiang,X.-J.et.al,Chem.Commun.,2010,46,3188–3190)；Axial phenyl derivatives substitute silicon Phthalocyanine, by the aggregation extent Different Effects photosensitive activity of Phthalocyanine under pH environment (Jiang,X.-J.et.al, Chem.Eur.J.,2010,16,4777–4783)；Pass through the azole derivatives of fluorine boron two of ketal key connection sensitive pH and two cyclopentadienyls Iron derivative, because ferrocene is fluorescence quenching, Photo-induced electron transfer (photoinduced electron can be passed through Transfer, PET) photosensitive activities of the azole derivatives of fluorine boron two is quenched in process, but under slightly sour environment, the fracture of ketal key, two The photosensitive activity of azole derivatives be restored (Jiang,X.-J.et.al,Chem.Eur.J.2016,22,8273–8281)。 But the medicine of these compounds and the most of pH sensitivities reported at present is not slightly sour environment targeted drug outside tumour cell, this It is due to the aobvious acidity of subcellular organization such as mitochondria, lysosome etc. of tumour cell and normal cell, the pH value of lysosome is more Can be with as little as 5.These compounds, can be by the sour exciting light in subcellular organization after by tumour cell and normal cell intake Quick activity, injuring tumor cell and normal cell.
The invention discloses the structure of a series of silicon phthalocyanine complex of ketals connection and cholesterol derivative, synthesis and answer With.Due to the presence of cholesterol group, medicine is difficult to be absorbed by tumour cell and normal cell, but micro- outside tumor tissue cell Under acid environment, hydrolysis occurs for ketal, and silicon phthalocyanine hydrolysis derivative can be easy to be absorbed by cancer cell, shows high photosensitive Activity, they are slightly sour environment Targeted Photosensitizers outside tumour cell.
The content of the invention
The invention discloses a series of slightly sour environment Targeted Photosensitizer outside tumour cells.Disclose a series of ketal connections Silicon phthalocyanine complex and cholesterol derivative structure, synthesis and application.In silicon phthalocyanine axially introduced into cholesterol group, silicon phthalein With the ketal key connection of acid-sensitive between cyanines complex and cholesterol, non-polar character and big steric hindrance due to cholesterol, Silicon phthalocyanine-cholesterol complexes are difficult to be absorbed by cancer cell and normal cell, but slightly sour outside tumor entity tissue cancer cell Under environment, hydrolysis occurs for ketal key, and cholesterol group comes off, and silicon phthalocyanine hydrolysis derivative can be absorbed and showed by cancer cell High photosensitive activity, they are slightly sour environment Targeted Photosensitizers outside tumour cell.
Compound shown in a kind of logical formula (I) provided by the invention：
Wherein：N=2,3, or 4；X=O or NH；
Or its pharmaceutically acceptable salt.
Hydrolysis chemical formula (1) of the compound under slightly sour environment shown in logical formula (I)
The hydrolysate of the shown compound of logical formula (I) is the change of the structure and existing document report of logical formula (VI) compound Compound structure it is similar (Jiang,X.-J.et.al.,J.Med.Chem.2011,54,320–330；Huang Jiandong,Jiang is of exceptional abilityDeng, in State's patent 200610200598.4), these compounds are high in tumour cell uptake ratio, show at very low concentrations very high Photosensitive activity.
Typical compound of the invention includes, but are not limited to：
Or its pharmaceutically acceptable salt, wherein
The present invention also provides a kind of method for preparing the compound shown in logical formula (I), and this method includes：
Wherein：N=2,3, or 4；X=O or NH；
1st step, the solvent are selected from DMF, dimethyl sulfoxide (DMSO), dichloromethane, chloroform and tetrahydrochysene Furans；The reaction is carried out at a temperature of -5~80 DEG C；The alkalescence condition by selected from pyridine, triethylamine, sodium hydride and 4-N, The reagents such as N- lutidines provide；The logical formula (II) compound and the mol ratio of cholesterol formyl chloride are 1:0.2~2.
2nd step, the solvent are selected from DMF, dimethyl sulfoxide (DMSO), dichloromethane, chloroform and tetrahydrochysene Furans；The reaction is carried out at a temperature of -5~80 DEG C；The alkalescence condition by selected from pyridine, triethylamine, sodium hydride and 4-N, The reagents such as N- lutidines provide；The mol ratio of the logical formula (III) compound and logical formula (IV) compound is 1:0.3~3.
3rd step, the solvent are selected from toluene, dimethylbenzene；The reaction is carried out at a temperature of 80~160 DEG C；The alkalescence Condition selected from reagents such as pyridine, triethylamine, sodium hydride and 4-N, N- lutidines by providing；The phthalocyanine silicon dichloride and formula (V) mol ratio of compound is 1:0.5~10.
If it is necessary, by method well known to those skilled in the art, such as by distillation, by silica gel column chromatography or Person can also purifying compound by high performance liquid chromatography (HPLC).
The present invention also provides a kind of pharmaceutical composition, its contain compound shown in the logical formula (I) of therapeutically effective amount or or Its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to the compound shown in logical formula (I) or its pharmaceutically acceptable salt, or include its medicine group Purposes of the compound in photo-dynamical medicine or photosensitive drug is prepared.
The invention further relates to the compound shown in logical formula (I) or its pharmaceutically acceptable salt, or include its medicine group Purposes of the compound in the medicine for preparing treating cancer.Wherein described cancer is selected from wherein described cancer and is selected from lung cancer, stomach Cancer, the cancer of the esophagus, breast cancer, carcinoma of urinary bladder, prostate cancer, cancer of pancreas, cholangiocarcinoma, the carcinoma of the rectum, colon cancer, cutaneum carcinoma, incidence cancer Disease, Eye tumor, uterine cancer and oophoroma, excellent breast cancer.
The invention further relates to the compound shown in logical formula (I) or its pharmaceutically acceptable salt, or include its medicine group Compound, it is used as photo-dynamical medicine or photosensitive drug.
The invention further relates to the compound shown in logical formula (I) or its pharmaceutically acceptable salt, or include its medicine group Compound, it is used for treating cancer.Wherein described cancer is selected from lung cancer, stomach cancer, the cancer of the esophagus, breast cancer, carcinoma of urinary bladder, prostate Cancer, cancer of pancreas, cholangiocarcinoma, the carcinoma of the rectum, colon cancer, cutaneum carcinoma, incidence cancer, Eye tumor, uterine cancer and oophoroma, it is preferably newborn Gland cancer.
The invention further relates to a kind of method for the treatment of cancer, and it includes giving the logical formula (I) of required bacterium Shown compound or its pharmaceutically acceptable salt, or its pharmaceutical composition is included, then irradiated with suitable light source.Institute Suitable optical filter can be connected to provide or be provided by the laser of specific wavelength, light source by ordinary light source by stating suitable light source Wave-length coverage be 550~900nm, preferably 620~720nm.
It can be administered orally, sublingual administration, parenteral administration, subcutaneous administration, intramuscular applied according to the compound of the present invention With, intravenous administration, applied dermally, local application or rectal administration.
In the medicinal compound of the present invention, for orally administering, sublingual administration, parenteral administration, subcutaneous administration, intramuscular Using, for intravenous administrations, applied dermally, local application or rectal administration, active component can be with conventional pharmaceutical carrier Mix, animals or humans is applied in the form of applying unit.Suitable unit form of applying includes oral form such as Tablet, gel capsule, pulvis, granule and oral solution or supensoid agent, sublingual or oral administration form, parenteral, Subcutaneously, intramuscular, intravenous, intranasal or intraocular administration form and rectal administration form.
When solid composite is prepared to tablet form, main active and pharmaceutical carrier such as gelatin, starch, breast Sugar, magnesium stearate, talcum, Arabic gum etc. mix.Tablet can use sucrose or other suitable material coatings or with such as This mode is handled so that it has active component that is extending or delay active and continuously discharging scheduled volume.
The mixture of acquisition is poured into soft or hard capsules by the way that active component and diluent are mixed into merga pass To obtain gel capsule preparation.
The preparation of syrup or tincture form can include active component together with sweetener, preservative and aromatic and fit When colouring agent.
The pulvis or granule being dispersed among in water can include active component, itself and dispersant, surfactant, wetting Agent or suspending agent and mixed with flavouring or sweetener.Contain Emulsifier EL-60 in its drug regimen and its spread out Biology, dimethyl sulfoxide, ethanol, glycerine, DMF, Liquid Macrogol -3000, cyclodextrin, glucose, tween, One or more in polyethylene glycol mono stearate.
Suppository is used for rectal administration, and it uses the adhesive melted under rectal temperature, for example, cocoa butter or polyethylene glycol To prepare.
(it includes pharmacology for aqueous suspension, isotonic normal saline solution agent or sterile and injectable solution Upper compatible dispersant and/or wetting agent) it is used for parenteral, the administration of intranasal or intraocular.Contain polyoxy second in its drug regimen Alkene castor oil and its derivative, dimethyl sulfoxide, ethanol, glycerine, DMF, Liquid Macrogol -3000, ring paste One or more in essence, glucose, tween, polyethylene glycol mono stearate.
Active component (may be together with one or more additive carriers) can also be formulated into microcapsules.
The compound of the present invention can be used with the dosage between 0.01mg/ days and 5000mg/ days, with single dose The mode in amount/day is provided or applied in a manner of some dosage in whole day, for example, same dose is twice daily.Applied Daily dose is advantageously between 0.1mg and 200mg, or even more advantageously between 2.5mg and 50mg.Using beyond The dosage of these scopes is probably needs, and those skilled in the art itself will be appreciated that this point.
In the particular of the present invention, pharmaceutical composition can also be formulated for external application.It can To be introduced in the common type (that is, particularly lotion, foaming agent, gel, dispersant, spray) that this applies type, The common type has excipient, and the excipient is particularly capable of penetrating skin, in order to improve the property of active component And accessibility.In addition to the composition according to the present invention, these compositions are generally further comprising physiologically acceptable Medium, the medium generally comprise water or solvent, for example, alcohol, ether or ethylene glycol.The composition can also include surface-active It is agent, preservative, stabilizer, emulsifying agent, thickener, the other active components for producing complementary effect or possible synergy, micro- Secondary element, essential oil, spices, colouring agent, collagen, chemistry or mineral filtering agent.
Definition
Unless stated to the contrary, it is otherwise following that there are following implications with term in the specification and in the claims.
In the present invention, " pharmaceutically acceptable " is understood to mean it and is used to prepare pharmaceutical composition, the combination Thing is usually safety, nontoxic, meets needs in terms of biology or other and the composition can be acceptable for Beasts and human pharmaceutical use.
In the present invention, " pharmaceutically acceptable salt " of compound is understood to refer to following salt, and it is pharmaceutically may be used Receive (as herein defined) salt and it possess the pharmacological activity of expected parent compound.This salt includes：
(1) with the acid-addition salts of the inorganic acid such as formation such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or with organic acid such as Acetic acid, benzene sulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, ethanol Acid, hydroxyl naphthoic acid, 2- ethylenehydrinsulfonic acids, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2- naphthalene sulfonic acids, propionic acid, The formation such as salicylic acid, butanedioic acid, dibenzoyl-L-tartaric, tartaric acid, p-methyl benzenesulfonic acid, trimethylace tonitric, trifluoroacetic acid Acid-addition salts；With
(2) the sour proton present in the parent compound is by metal ion, for example, alkali metal ion is (for example, Na+、K+Or Li+), alkaline-earth metal ions (such as Ca2+Or Mg2+) or aluminium ion replacement；Or the salt formed when being coordinated with organic base or inorganic base. Acceptable organic base includes diethanol amine, monoethanolamine, N-METHYL-ALPHA-L-GLUCOSAMINE, triethanolamine, tromethamine etc..Acceptable nothing Machine alkali includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or Pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine The purpose of compositions is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.
" Ts " is p-methyl benzenesulfonic acid base.
Embodiment
By reading the following example, those skilled in the art will be better understood the present invention.These embodiments are only used It is of the invention in explaining.
The experimental method of unreceipted actual conditions in the embodiment of the present invention, generally according to normal condition, or according to raw material or Condition proposed by commodity manufacturer.The reagent in unreceipted specific source, for the conventional reagent of market purchase.
NMR：Bruker ARX-300 type high-resolution high resolution NMR instrument.
Mass spectrum：QSTAR Elite series connection level Four bar time of-flight mass spectrometers.
MTT detecting instruments：Thermo Scientific Multiskan GO all-wave length ELIASAs
PBS：Phosphate buffer
The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).Nmr chemical displacement (δ) with 10-6(ppm) unit provides.Measure solvent is deuterated chloroform (CD3Cl), inside it is designated as tetramethylsilane (TMS).Under use Row abbreviation：For s to be unimodal, bs is width unimodal, and d is doublet, and t is triplet, and qdt is quartet, and m is multiplet or a large amount of peaks, Dd is double doublet etc..
Tlc silica gel plate uses Qingdao GF254 silica gel plates, the rule that the silica gel plate that thin-layered chromatography (TLC) uses uses Lattice are 0.15mm~0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.
In embodiment unless otherwise specified, reaction is carried out under argon atmospher or blanket of nitrogen.
In embodiment unless otherwise specified, the solution in reaction refers to the aqueous solution.
In embodiment unless otherwise specified, the temperature of reaction is room temperature.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC).
The synthesis of the compound 1 of embodiment 1
1st step
In ice-water bath, compound 1-1 (1.62g, 10mmol), chloro-carbonic acid cholesterol (2.2g, 4.9mmol) and three second Amine (2g, 20mmol) adds dichloromethane (30mL), continues stirring reaction 3 hours, stops reaction, water is added into reaction solution (200mL), stirring are stood, and are collected organic phase, organic phase anhydrous sodium sulfate drying, are evaporated under reduced pressure, crude product silica gel column chromatography Column separating purification, eluant, eluent are chloroform/methanol (9:1) white solid 1-2 (1.45g, 51%), is obtained.MS(ESI):m/z =598 [M+Na]+。
2nd step
In ice-water bath, compound 1-2 (1.2g, 2.1mmol), compound 1-3 (0.52g, 1.5mmol), pyridine (1.1g, 14mmol) adds dichloromethane (35mL), withdraws from ice-water bath, and temperature, which is warmed to room temperature, continues stirring reaction 6 hours, stops Reaction, water (100mL) is added into reaction solution, stirring is stood, and collects organic phase, organic phase anhydrous sodium sulfate drying, decompression Distillation, crude product silica gel column chromatography column separating purification, eluant, eluent is chloroform/methanol (9:1) white oil thing 1-4, is obtained (0.55g, 47%).MS(ESI):M/z=774 [M+Na]+。
3rd step
Phthalocyanine silicon dichloride (0.61g, 1mmol), compound 1-4 (0.7g, 9.4mmol) are added in toluene (30mL), to Sodium hydride (0.2g, 8.3mmol) is slowly added into reaction solution, temperature rises to 110 DEG C and reacted 12 hours, and decompression steams solvent, Solid residue adds 100 milliliters of chloroforms and 100 milliliters of water, extraction, collects organic phase, with anhydrous sodium sulfate drying, decompression Distillation, crude product silica gel column chromatography column separating purification, eluant, eluent is chloroform, obtains green solid 1 (0.22g, 16%).1H NMR(300MHz,CDCl3):δ9.61-9.64(m,8H,Pc-Hα),8.33-8.36(m,8H,Pc-Hβ), 5.36 (d, J= 4.5Hz,2H,Chol-6-CH),4.40-4.44(m,2H,Chol-3-CH),3.41-3.65(m,12H,CH2),3.10-3.25 (m,8H,CH2), 2.95 (t, J=5.1Hz, 4H, CH2),2.65-2.73(m,8H,CH2), 2.44 (t, J=4.8Hz, 4H, CH2), 1.66-2.36 (m, 16H, Chol), 1.65 (t, J=5.1Hz, 4H, CH2),0.83-1.55(m,76H,Chol,CH3), 0.68(s,6H,Chol-18-CH3), 0.38 (t, J=5.4Hz, 4H, CH2), -1.93 (t, J=5.4Hz, 4H, CH2)。MS (ESI):M/z=2042 [M+H]+。
The synthesis of the compound 2 of embodiment 2
1st step
In ice-water bath, compound 2-1 (0.57g, 3.5mmol), chloro-carbonic acid cholesterol (1.55g, 3.5mmol) and pyrrole Pyridine (0.8g, 10.1mmol) adds dichloromethane (35mL), and temperature is raised to room temperature, continues stirring reaction 2 hours, stops reaction, Water (100mL) is added into reaction solution, stirring is stood, and is collected organic phase, organic phase anhydrous sodium sulfate drying, is evaporated under reduced pressure, Crude product silica gel column chromatography column separating purification, eluant, eluent are chloroform/methanol (15:1), obtain white solid 2-2 (0.92g, 46%).MS(ESI):M/z=599 [M+Na]+。
2nd step
In ice-water bath, compound 2-2 (0.9g, 1.6mmol), compound 2-3 (0.9g, 3.0mmol) adds tetrahydrochysene Furans (30mL), sodium hydride (0.3g, 12.5mmol) is slowly added into reaction solution, withdraws from ice-water bath, temperature is warmed to room temperature Continue stirring reaction 6 hours, stop reaction, water (100mL) is added into reaction solution, stirring is stood, and collects organic phase, organic phase With anhydrous sodium sulfate drying, it is evaporated under reduced pressure, crude product silica gel column chromatography column separating purification, eluant, eluent is chloroform/methanol (9: 1) white oil thing 1-4 (0.74g, 63%), is obtained.MS(ESI):M/z=708 [M+H]+。
3rd step
Phthalocyanine silicon dichloride (0.21g, 0.34mmol), compound 1-4 (0.45g, 0.6mmol) and pyridine (2g, 25.4mmol) it is added in toluene (30mL), temperature rises to 140 DEG C and reacted 24 hours, and decompression steams solvent, and solid residue adds 100 milliliters of chloroforms and 100 milliliters of water, extraction, organic phase is collected, with anhydrous sodium sulfate drying, be evaporated under reduced pressure, crude product is used Silica gel column chromatography column separating purification, eluant, eluent are chloroform, obtain green solid 2 (0.12g, 19%).1H NMR(300MHz, CDCl3):δ9.58-9.63(m,8H,Pc-Hα),8.30-8.34(m,8H,Pc-Hβ), 5.35 (d, J=4.5Hz, 2H, Chol-6- CH),4.38-4.40(m,2H,Chol-3-CH),4.20-4.25(m,4H,CH2),4.65-3.55(m,8H,CH2),3.44(t,J =5.1Hz, 4H, CH2), 3.22 (t, J=5.1Hz, 4H, CH2), 2.92 (t, J=5.1Hz, 4H, CH2), 2.43 (t, J= 4.8Hz,4H,CH2), 1.63-2.33 (m, 16H, Chol), 1.65 (t, J=5.1Hz, 4H, CH2),0.84-1.55(m,76H, Chol,CH3),0.68(s,6H,Chol-18-CH3), 0.38 (t, J=5.4Hz, 4H, CH2), -1.91 (m, J=5.4Hz, 4H, CH2).MS(ESI):M/z=1957 [M+H]+。
The synthesis of the compound 3 of embodiment 3
1st step
In ice-water bath, compound 1-2 (1.2g, 2.1mmol), compound 3-1 (0.5g, 2.4mmol), pyridine (0.8g, 10.1mmol) adds dichloromethane (25mL), and temperature, which is warmed to room temperature, continues stirring reaction 8 hours, stops reaction, to anti- Answer and water (100mL) is added in liquid, stirring is stood, and is collected organic phase, organic phase anhydrous sodium sulfate drying, is evaporated under reduced pressure, thick production Product silica gel column chromatography column separating purification, eluant, eluent are chloroform/methanol (9:1), obtain pale yellow oil 3-2 (0.85g, 62%).MS(ESI):M/z=663 [M]+.2nd step
Phthalocyanine silicon dichloride (0.21g, 0.34mmol), compound 1-4 (1.5g, 2.2mmol) and pyridine (1g, 12.7mmol) It is added in toluene (30mL), temperature rises to 120 DEG C and reacted 24 hours, and decompression steams solvent, and solid residue adds 100 milliliter three Chloromethanes and 100 milliliters of water, extraction, organic phase is collected, with anhydrous sodium sulfate drying, be evaporated under reduced pressure, crude product silica gel column chromatography Column separating purification, eluant, eluent are chloroform, obtain green solid 3 (0.85g, 13%).1H NMR(300MHz,CDCl3):δ 9.62-9.64(m,8H,Pc-Hα),8.33-8.35(m,8H,Pc-Hβ), 5.35 (d, J=4.2Hz, 2H, Chol-6-CH), 4.35-4.39(m,2H,Chol-3-CH),3.55-3.60(m,4H,CH2),3.14-3.19(m,8H,CH2),2.27-2.25(m, 4H,CH2),1.73-2.32(m,16H,Chol),1.67-1.73(m,8H,CH2),0.86-1.56(m,76H,Chol,CH3), 0.68(s,6H,Chol-18-CH3),0.37-0.40(m,4H,CH2),-1.87--1.89(m,4H,CH2).MS(ESI):M/z= 1865[M+H]+。
Test case：The photosensitive experiment of extracorporeal anti-tumor cell
Test sample：The compounds of this invention 2
Positive reference substance：Hematoporphyrine Injection (English name：Hematoporphyrin Injection；Trade name：Happiness pool Point, Huading Modern Biopharmaceutical Co., Ltd., Chongqing City's production).
Test cell：Human breast cancer cell line Bcap-37
Main agents：1) RPMI-1640 complete culture solutions：In 500mL RPMI-1640 liquid mediums (GIBCO companies) It is middle to add penicillin/streptomycin 100,000 U, hyclone 56mL, mix.2) MTT solution (MTT：3- (4,5- dimethylthiazoles- 2) -2,5- diphenyltetrazolium bromide bromides, MP companies of the U.S. are purchased from)：Powdery MTT is dissolved in PBS solution, mistake with 5mg/mL concentration Filter sterilization, it is now with the current.
Experimental method：
1) test sample compound method：Test sample is made into the mother liquor that concentration is 1mM with DMSO；100 μ L1mg/ are taken during experiment ML mother liquor, 1.15mL 0.5% (w/w) Emulsifier EL-60 pH 7.4PBS and pH 6.5PBS buffer solutions are added, are configured to 80 μ g/mL decoctions, and the decoction of various concentrations is diluted to corresponding PBS, decoction pH value is kept in dilution It is constant, cell dosing culture is carried out after drug solution preparing at once.DMSO final concentration is≤1% in each medicine and negative control group. Happiness pool sweet smell is 5mL liquid solutions preparation containing 25mg, concentration 5mg/mL.100 μ L 5mg/mL preparation is taken, adds 4.90mL pH 7.4PBS or pH 6.5PBS buffer solutions, and the decoction of various concentrations is diluted to corresponding PBS, in dilution Keep decoction pH value constant, carry out cell dosing culture after drug solution preparing at once.
2) attached tumor cells of exponential phase are selected, after being digested with pancreatin, with the RPMI containing 10% hyclone L640 culture mediums are made into the cell suspension of suitable concentration, are seeded in 96 well culture plates.100 μ L are inoculated with per hole, often add a row Cell suspension is shaken, is added and is gently horizontally rotated culture plate after cell and cell is evenly dispersed in ware hole surface, 96 holes The sterile PBS of collar aperture addition around plate, 37 DEG C, 5%CO2Culture 24 hours.Be then respectively adding various concentrations test medicine, Positive drug, solvent and each 100 μ L of nutrient solution, every group of 3 parallel holes.It is divided into two groups of illumination and lucifuge after mixing, in dosing After co-culturing 2 hours, culture medium is discarded, the culture medium without test sample is rejoined and puts 37 DEG C, 5%CO2Under the conditions of continue to train Support 24 hours.After 24 hours, 5mg/mL MTT, 20 μ L, 37 DEG C, 5%CO are added per hole2Under the conditions of be incubated 4 hours after, carefully inhale Supernatant is abandoned, 200 μ L DMSO are added per hole, is vibrated 10 minutes, is made to be formed after formazan particles fully dissolve, ELIASA detection Light absorption value, determine wavelength 570nm, reference wavelength 630nm.Light source by 200W Halogen lamp LED connect heat-insulated tank increase in 610nm optical filter provides, and light dosage is 48J cm-2。
3) computational methods of the medicine to the inhibiting rate of growth of tumour cell：Growth of tumour cell inhibiting rate (%)=[(negative Control group OD averages-administration group OD averages)/negative control group OD averages] × 100%.Half-inhibition concentration IC50Calculating, adopt Determined with the logit Returns Law.
Experimental result：
The IC of the compound 2 of table 1 and happiness pool point human breast cancer cell line Bcap-37 in irradiation50(ng/mL) value
Photosensitive drug The decoction culture of cellular pH 7.4 The decoction culture of cellular pH 6.5
Compound 2 >8000 46
Happiness pool point 3800 4100
Experimental result is shown, under light protected environment, the compound of all tests does not have when at concentrations up to 5000ng/mL Show cytotoxicity, but half cause when happiness pool point is in pH 6.5 and pH 7.4 in the case of irradiation to human breast cancer cell line Bcap-37 Dead concentration IC50Value is more or less the same, between 3800-4100ng/mL.But compound 2 is in pH 7.4 decoction culture cell, dense Degree is up to 8000ng/mL, does not have photosensitive activity completely in irradiation, but decoction of the compound 2 in pH 6.5 carries out culture cell When, show very high photosensitive activity, IC50It is worth for 46ng/mL, shows obviously slightly sour environment targeting outside tumour cell Property.
It is known that slightly sour environment all be present in almost all of entity tumor, as lung cancer, stomach cancer, the cancer of the esophagus, breast cancer, Carcinoma of urinary bladder, prostate cancer, cancer of pancreas, cholangiocarcinoma, the carcinoma of the rectum, colon cancer, cutaneum carcinoma, incidence cancer, Eye tumor, uterine cancer and There is slightly sour environment in the entity tumors such as oophoroma, compound disclosed in this patent or its pharmaceutically acceptable salt, or comprising Its pharmaceutical composition can be prepared into photosensitive drug and treat above-mentioned cancer.
The foregoing is only embodiments of the invention, be not intended to limit the invention, it is all the present invention spirit and All any modification, equivalent and improvement made within principle etc., should be included in the scope of the protection.

Claims (8)

  1. A kind of 1. compound shown in logical formula (I)：
    Wherein：N=2,3, or 4；X=O or NH；
    Or its pharmaceutically acceptable salt.
  2. 2. the compound shown in logical formula (I) according to claim 1, it is selected from：
    Wherein
  3. 3. a kind of method for preparing the compound shown in logical formula (I) according to claim 1, this method include：
    Wherein：N=2,3, or 4；X=O or NH；
    1st step, in organic solvent, under alkaline environment, logical formula (II) compound and cholesterol formyl chloride containing acetal bonds Reaction obtains logical formula (III) compound；
    2nd step, in organic solvent, in the basic conditions, lead to formula (IV) compound and reacted with logical formula (III) compound, obtained Logical formula (V) compound；
    3rd step, in organic solvent, in the basic conditions, lead to formula (V) compound and reacted with phthalocyanine silicon dichloride, obtain logical formula (I) Compound.
  4. 4. the method according to claim 11, wherein：
    1st step, the solvent are selected from DMF, dimethyl sulfoxide (DMSO), dichloromethane, chloroform and tetrahydrochysene furan Mutter；The reaction is carried out at a temperature of -5~80 DEG C；The alkalescence condition is by selected from pyridine, triethylamine, sodium hydride and 4-N, N- A kind of reagent in lutidines provides；The logical formula (II) compound and the mol ratio of cholesterol formyl chloride are 1:0.2~ 2；
    2nd step, the solvent are selected from DMF, dimethyl sulfoxide (DMSO), dichloromethane, chloroform and tetrahydrochysene furan Mutter；The reaction is carried out at a temperature of -5~80 DEG C；The alkalescence condition is by selected from pyridine, triethylamine, sodium hydride and 4-N, N- A kind of reagent in lutidines provides；The mol ratio of the logical formula (III) compound and logical formula (IV) compound is 1:0.3 ~3；
    3rd step, the solvent are selected from toluene, dimethylbenzene；The reaction is carried out at a temperature of 80~160 DEG C；The alkalescence condition There is provided by a kind of reagent in pyridine, triethylamine, sodium hydride and 4-N, N- lutidines；The phthalocyanine silicon dichloride is with leading to The mol ratio of formula (V) compound is 1:0.5~10.
  5. 5. a kind of pharmaceutical composition, it contains the formula according to any one in claim 1~2 of therapeutically effective amount (I) compound and pharmaceutically acceptable carrier shown in.
  6. 6. compound shown in logical formula (I) according to any one in claim 1~2 or according to claim 5 Purposes of the pharmaceutical composition in photo-dynamical medicine or photosensitive drug is prepared.
  7. 7. compound shown in logical formula (I) according to any one in claim 1~2 or according to claim 5 Pharmaceutical composition prepare treating cancer medicine in purposes.
  8. 8. purposes according to claim 7, wherein described cancer is selected from lung cancer, stomach cancer, the cancer of the esophagus, breast cancer, bladder Cancer, prostate cancer, cancer of pancreas, cholangiocarcinoma, the carcinoma of the rectum, colon cancer, cutaneum carcinoma, incidence cancer, Eye tumor, uterine cancer and ovary Cancer.
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