CN106749478A - 1,4 pH sensitive Di-substituted phthalocyanine Zn complexes and preparation method thereof and in application pharmaceutically - Google Patents
1,4 pH sensitive Di-substituted phthalocyanine Zn complexes and preparation method thereof and in application pharmaceutically Download PDFInfo
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- CN106749478A CN106749478A CN201611039671.4A CN201611039671A CN106749478A CN 106749478 A CN106749478 A CN 106749478A CN 201611039671 A CN201611039671 A CN 201611039671A CN 106749478 A CN106749478 A CN 106749478A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to pH sensitive cholesterol phthalocyanine Zn complex of ketal connection and preparation method thereof and in application pharmaceutically.Especially, pharmaceutical composition the present invention relates to the phthalocyanine Zn complex shown in logical formula (I), its preparation method and containing the complex, and it is used as the purposes of sensitising agent, purposes particularly in treating cancer, each substitution base in its formula of (I) is identical with the definition in specification.Due to the presence of cholesterol group, the series compound is difficult to be absorbed by tumour cell and normal cell, but under micro- acid environment outside tumor tissue cell, there is hydrolysis in ketal, the hydrolysis derivative of Phthalocyanine Zinc can be easy to be absorbed by cancer cell, and representing high photosensitive activity, they can be prepared into the outer micro- acid environment Targeted Photosensitizer of tumour cell.
Description
Technical field
The invention belongs to field of medicaments, it is related to phthalocyanine Zn complex and preparation method thereof and its in application pharmaceutically, this
Disclosure of the invention its as sensitising agent, for the purposes for the treatment of 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), by the light irradiation tumor tissues after certain hour with specific wavelength, it is 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 is listed in five class basic skills of oncotherapy within 1997
One of (operation, radiotherapy, chemotherapy, light power, biochemical immunity).Compared with traditional therapy, PDT therapies have wound very little, poison
Property 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.
PDT 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, light power diagnosis are carried out using the photoluminescent property of sensitising agent, it is also medical photosensitive agent
One important use.
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.The sensitising agent of now clinical main application is porphin Fei Muna (Porfimer sodium, Photofin), the medicine elder generation
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) research in terms of starts to walk relatively late compared with states such as the U.S., Japan, but progressive very fast.Early 1980s are development light so far
Dynamic therapy is done a lot of work, and compared with the achievement of external report, its depth and range have no too big gap.Chongqing Huading shows
Developed for bio-pharmaceuticals Co., Ltd, production is used to treat the haematoporphyrin (Hematoporphyrin, happiness pool point) of tumour,
Produce and sell and be applied to clinic via state food drug administration (SFDA) official approval.Xi Bofenshi China is unique
The anticancer photosensitizer of listing, 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 are clinically achieved successfully, its complicated components, various composition is in light power
Effect in damage does not 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 yet
Effective Photodynamic polymer is produced to act on, on the contrary as the chief culprit for causing normal structure that photosensitized reaction occurs.Other first generation light
Sensitizing drug is not strong to the targeting of tumour, and research is efficient, the photosensitive drug with tumor-targeting of low toxicity is nearest grinding
Study carefully focus.
The micro-environmental hypoxia that tumor entity tissue site is present 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 photosensitizer of the pH sensitivities of multiple series in recent years
Compound, such as axial aminoderivative substitution silicon phthalocyanine, by degree of ionization Different Effects of the amino under different pH environment
Photosensitive activity (Jiang,X.-J.et.al,Chem.Commun.,2010,46,3188–3190)；Axial phenyl derivatives substitution
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)；The azole derivatives of fluorine boron two and two cyclopentadienyls for connecing are bonded by the sensitive ketals of pH
Iron derivative, because ferrocene is fluorescence quenching, can be by Photo-induced electron transfer (photoinduced electron
Transfer, PET) process is quenched the photosensitive activity of the azole derivatives of fluorine boron two, but under micro- acid environment, it is anti-that ketal occurs hydrolysis
Should, the ferrocene group of donor properties comes off, the photosensitive activity of two azole derivatives be restored (Jiang,X.- J.et.al,Chem.Eur.J.2016,22,8273–8281).But most of pH sensitivities of these compounds and at present report
Medicine is not the outer micro- acid environment targeted drug of tumour cell, this be due to tumour cell and normal cell subcellular organization such as
Mitochondria, lysosome etc. show acidity, and the pH value of lysosome more can as little as 5.These compounds are by tumour cell and normally
After cellular uptake, photosensitive activity, injuring tumor cell and normal cell can be excited by the acid in subcellular organization.
The content of the invention
The invention discloses a series of outer micro- acid environment Targeted Photosensitizer of tumour cells.Disclose a series of ketal connections
Phthalocyanine Zn complex and cholesterol derivative structure, synthesis and apply.Cholesterol group, phthalein are introduced in Phthalocyanine Zinc Isosorbide-5-Nitrae position
It is bonded with the ketal of acid-sensitive between cyanines Zn complex and cholesterol and is connect, because the non-polar character of cholesterol and big steric hindrance is made
With Phthalocyanine Zinc-cholesterol complexes are difficult to be absorbed by cancer cell and normal cell, but micro- outside tumor entity tissue cancer cell
Under acid environment, there is hydrolysis in ketal key, and cholesterol group is come off, and Phthalocyanine Zinc hydrolysis derivative can be absorbed and opened up by cancer cell
Existing high photosensitive activity, they are the outer micro- acid environment Targeted Photosensitizers of tumour cell.
The compound shown in a kind of logical formula (I) that the present invention is provided：
Wherein：N=1,2,3, or 4；X=O or NH；
Or its pharmaceutically acceptable salt.
Lead to hydrolysis chemical formula (1) of the compound shown in formula (I) under micro- acid environment
The hydrolysate of the shown compound of logical formula (I) is the change of the structure with existing document report of logical formula (V) compound
Compound structure it is identical and similar (Liu, J.-Y.,Jiang,X.-J.et.al.,Org.Biomol.Chem.,2008,6,4560–
4566；Liu,J.-Y.,lo,P.-C.,Jiang,X.-J., et.al., Dalton Trans., 2009,4129-4135), these
Compound is high in tumour cell uptake ratio, and photosensitive activity very high is represented at very low concentrations.
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 the method includes：
Wherein：N=1,2,3, or 4；X=O or NH；
1st step, the solvent is 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 are provided；The logical formula (II) compound is 1 with the mol ratio of cholesterol formyl chloride:0.2~2.
2nd step, the solvent is 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 are provided；The logical formula (IV) compound is 1 with the mol ratio of logical formula (III) compound:0.5~5.
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, compound shown in its logical formula (I) for containing therapeutically effective amount or or
Its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to lead to compound or its pharmaceutically acceptable salt shown in formula (I), or the medicine group comprising it
Purposes of the compound in photo-dynamical medicine or photosensitive drug is prepared.
The invention further relates to lead to compound or its pharmaceutically acceptable salt shown in formula (I), or the medicine group comprising it
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, the cancer of the uterus and oophoroma, excellent breast cancer.
The invention further relates to lead to compound or its pharmaceutically acceptable salt shown in formula (I), or the medicine group comprising it
Compound, it is used as photo-dynamical medicine or photosensitive drug.
The invention further relates to lead to compound or its pharmaceutically acceptable salt shown in formula (I), or the medicine group comprising it
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, the cancer of the uterus and oophoroma, preferably breast
Gland cancer.
The invention further relates to a kind of method for the treatment of cancer, its logical formula (I) for including giving required bacterium
Shown compound or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, are then irradiated with suitable light source.Institute
Stating suitable light source can connect suitable optical filter to provide or provided by the laser of specific wavelength, light source by ordinary light source
Wave-length coverage be 550~900nm, preferably 620~720nm.
Compound of the invention can be administered orally, sublingual administration, parenteral administration, subcutaneous administration, intramuscular are applied
With, intravenous administration, applied dermally, local application or rectal administration.
In medicinal compound of the invention, for Orally administered, sublingual administration, parenteral administration, subcutaneous administration, intramuscular
For, intravenous administration, 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 administration unit form includes oral form such as
Tablet, gel capsule, pulvis, granule and oral solution or supensoid agent, sublingual or oral administration form, parenteral,
Subcutaneous, 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 materials to be coated or with such as
This mode is processed so that it has active component that is extension or delay active and continuously discharging scheduled volume.
In the mixed merga pass of active component and diluent poured into soft or hard capsules by the mixture of acquisition
To obtain gel capsule preparation.
The preparation of syrup or tincture form can be comprising active component is together with sweetener, preservative and aromatic and fits
When colouring agent.
The pulvis or granule being dispersed among in water can be comprising active components, 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 aseptic and injectable solution
Upper compatible dispersant and/or wetting agent) applied for parenteral, 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 carrier) can also be formulated into microcapsules.
Compound of the 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 the way of some dosage in whole day, for example, same dose is twice daily.Applied
Daily dose advantageously between 0.1mg and 200mg, or even more advantageously between 2.5mg and 50mg.Using exceeding
The dosage of these scopes is probably needs, and those skilled in the art itself will be appreciated that this point.
In a particular of the 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) using 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 composition of the invention, these compositions are generally further comprising physiologically acceptable
Medium, the medium generally comprises 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, otherwise following term in the specification and in the claims has following implications.
In the present invention, " pharmaceutically acceptable " is understood to mean it and is used to prepare pharmaceutical composition, the combination
Thing is usually safe, and nontoxic, in terms of biology or other meeting needs 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
(as herein defined) salt and its pharmacological activity for possessing expected parent compound for receiving.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,
Salicylic acid, butanedioic acid, dibenzoyl-L-tartaric, tartaric acid, p-methyl benzenesulfonic acid, trimethylace tonitric, trifluoroacetic acid etc. are formed
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 is including 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 NaOH.
" pharmaceutical composition " represent containing one or more compound described herein or its physiologically/pharmaceutically useful salt or
The mixture of pro-drug and other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine
The purpose of compositions is administration of the promotion to organism, absorption and then performance bioactivity beneficial to active component.
" Ts " is p-methyl benzenesulfonic acid base.
Specific 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 technique 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, is the conventional reagent of market purchase.General formula compound
(IV) bibliography method is easy to synthesis and obtains (New J.Chem., 2013,37,1746-1752；
Org.Biomol.Chem.,2008,6,4560–4566；Dalton Trans.,2009,4129–4135).
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 is given.Measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), inside it is designated as tetramethylsilane (TMS).Use
Following abbreviations：S is unimodal, and 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
Peak, 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) is used is used
Lattice are 0.15mm~0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.
It is carrier that column chromatography generally uses 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 the 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), cholesterol acyl chlorides (2.2g, 4.9mmol) and triethylamine
(2g, 20mmol) adds dichloromethane (50mL), continues stirring reaction 2 hours, stops reaction, to adding water in reaction solution
(100mL), stirring stands, and collects organic phase, organic phase anhydrous sodium sulfate drying, vacuum distillation, crude product silica gel column chromatography
Column separating purification, eluant, eluent is chloroform/methyl alcohol (9:1) white solid 1-2 (1.53g, 55%), is obtained.MS(ESI):m/z
=598 [M+Na]+。
2nd step
In ice-water bath, compound 1-3 (1.27g, 1mmol), 1-2 (1.55g, 2.7mmol) and pyridine (0.8g,
Chloroform (25mL) 10.1mmol) is added, continues stirring reaction 2 hours, stop reaction, to adding water in reaction solution
(120mL), stirring stands, and collects organic phase, organic phase anhydrous sodium sulfate drying, vacuum distillation, crude product silica gel column chromatography
Column separating purification, eluant, eluent is chloroform/methyl alcohol (20:1) green solid 1 (1.18g, 57%), is obtained.1H NMR
(300MHz,DMSO-d6):δ 9.33-9.37 (m, 4H, Pc-Hα), 9.21-9.25 (m, 2H, Pc-Hα),8.15-8.20(m,6H,
Pc-Hβ),7.53(s,2H,Pc-Hβ),5.28-5.37(m,2H,chol-6-CH),4.82-4.90(m,4H,CH2),4.35-
4.49(m,6H,CH2,chol-3-CH),3.85-4.10(m,8H,CH2),3.41-3.75(m,32H,CH2),1.72-2.35(m,
16H,chol),0.85-1.58(s,76H,chol,CH3),0.68(s,6H,chol-18-CH3).MS(ESI):M/z=2077 [M
+H]+。
The synthesis of the compound 2 of embodiment 2
1st step
In ice-water bath, compound 2-1 (1.64g, 10mmol), cholesterol acyl chlorides (1.55g, 3.5mmol) and pyridine
(0.8g, 10.1mmol) adds dichloromethane (25mL), and temperature is raised to room temperature, continues stirring reaction 2 hours, stops reaction, to
Water (100mL) is added in reaction solution, stirring stands, collection organic phase, organic phase anhydrous sodium sulfate drying, vacuum distillation, slightly
Product silica gel column chromatography column separating purification, eluant, eluent is chloroform/methyl alcohol (15:1), obtain white solid 2-2 (1.02g,
49%).MS(ESI):M/z=599 [M+Na]+。
2nd step
In ice-water bath, compound 2-3 (0.7g, 0.6mmol), 2-2 (1.6g, 2.8mmol) adds tetrahydrofuran
(30mL), slowly to sodium hydride (0.1g, 4.2mmol) is added in reaction solution, continues stirring reaction 2 hours, is slowly added to 2 milliliters
Water quenching is gone out reaction, and to water (100mL) is added in reaction solution, stirring stands, and collects organic phase, and organic phase is dry with anhydrous sodium sulfate
It is dry, vacuum distillation, crude product silica gel column chromatography column separating purification, eluant, eluent is chloroform/methyl alcohol (20:1), obtain blue solid
Body 2 (0.25g, 22%).1H NMR(300MHz,DMSO-d6):δ 9.32-9.36 (m, 4H, Pc-Hα), 9.20-9.25 (m, 2H,
Pc-Hα),8.12-8.2(m,6H,Pc-Hβ),7.51(s,2H,Pc-Hβ),5.30-5.37(m,2H,chol-6-CH),4.81-
4.91(m,4H,CH2),4.32-4.48(m,10H,CH2,chol-3-CH),3.85-4.12(m,8H,CH2),3.41-3.75(m,
20H,CH2),1.70-2.35(m,16H,chol),0.83-1.57(s,76H,chol,CH3),0.67(s,6H,chol-18-
CH3).MS(ESI):M/z=1992 [M]+。
The synthesis of the compound 3 of embodiment 3
In ice-water bath, compound 3-3 (0.6g, 5.5mmol), 2-2 (0.8g, 1.4mmo) adds tetrahydrofuran
(30mL), slowly to sodium hydride (0.1g, 4.2mmol) is added in reaction solution, continues stirring reaction 2 hours, is slowly added to 2 milliliters
Water quenching is gone out reaction, and to water (100mL) is added in reaction solution, stirring stands, and collects organic phase, and organic phase is dry with anhydrous sodium sulfate
It is dry, vacuum distillation, crude product silica gel column chromatography column separating purification, eluant, eluent is chloroform/methyl alcohol (20:1), obtain blue solid
Body 3 (0.22g, 21%).1H NMR(300MHz,DMSO-d6):δ 9.35-9.49 (m, 6H, Pc-Hα),8.12-8.2(m,6H,
Pc-Hβ),7.58(s,2H,Pc-Hβ),5.31-5.35(m,2H,chol-6-CH),4.81-4.98(m,4H,CH2),4.32-
4.56(m,10H,CH2,chol-3-CH),4.10-4.20(m,4H,CH2),3.41-3.75(m,12H,CH2),1.70-2.35
(m,16H,chol),0.80-1.62(s,76H,chol,CH3),0.66(s,6H,chol-18-CH3).MS(ESI):M/z=
1904[M]+。
The synthesis of the compound 4 of embodiment 4
In ice-water bath, compound 4-3 (0.7g, 0.7mmol), 1-2 (1.33g, 2.1mmol) and triethylamine (2g,
Chloroform (30mL) 20mmol) is added, continues stirring reaction 2 hours, stop reaction, to addition water (100mL) in reaction solution,
Stirring stands, and collects organic phase, and organic phase anhydrous sodium sulfate drying, vacuum distillation, crude product is pure with silica gel column chromatography post separation
Change, eluant, eluent is chloroform/methyl alcohol (20:1) blue solid 4 (0.25g, 20%), is obtained.1H NMR(300MHz,DMSO-
d6):δ 9.33-9.53 (m, 6H, Pc-Hα),8.10-8.18(m,6H,Pc-Hβ),7.58(s,2H,Pc-Hβ),5.36-5.40(m,
2H,chol-6-CH),4.73-4.80(m,4H,CH2),4.38-4.60(m,2H,chol-3-CH),3.35-3.85(m,20H,
CH2),1.73-2.40(m,16H,chol),0.84-1.65(s,76H,chol,CH3),0.68(s,6H,chol-18-CH3)。MS
(ESI):M/z=1813 [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, are purchased from MP companies of the U.S.)：Powdery MTT is dissolved in PBS solution, mistake with the concentration of 5mg/mL
Filter sterilization, it is now with the current.
Experimental technique：
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
The mother liquor of mL, adds 1.15mL 0.5% (w/w) Emulsifier EL-60 pH 7.4PBS and pH 6.5PBS buffer solutions, is configured to
80 μ g/mL liquids, and the liquid of various concentrations is diluted to corresponding PBS, liquid pH value is kept in dilution
It is constant, cell dosing culture is carried out after drug solution preparing at once.The final concentration of DMSO is≤1% in each medicine and negative control group.
It is 5mL liquid solution preparations containing 25mg, concentration 5mg/mL that happiness pool is fragrant.The preparation of 100 μ L 5mg/mL is taken, 4.90mL pH are added
7.4PBS or pH 6.5PBS buffer solutions, and the liquid of various concentrations is diluted to corresponding PBS, in dilution
Keep liquid pH value constant, carry out cell dosing culture after drug solution preparing at once.
2) from the attached tumor cells of exponential phase, 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, a row is often added
Cell suspension is shaken, is added and gently horizontally rotate culture plate after cell and cell is evenly dispersed in ware hole surface, 96 holes
A collar aperture adds aseptic PBS, 37 DEG C, 5%CO around plate2Culture 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, rejoin the culture medium without test sample and put 37 DEG C, 5%CO2Under the conditions of continue 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, vibrated 10 minutes, made to be formed after formazan particles fully dissolve, ELIASA detection
Light absorption value, determines wavelength 570nm, reference wavelength 630nm.Light source by the Halogen lamp LED of 200W connect heat-insulated tank increase in
The optical filter of 610nm is provided, and light dosage is 48J cm-2。
3) computational methods of the inhibiting rate of drug on tumor cell growth：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 liquid culture of cellular pH 7.4 | The liquid culture of cellular pH 6.5 |
| Compound 2 | >8000 | 95 |
| Happiness pool point | 3800 | 4100 |
Experimental result shows, under light protected environment, the compound of all tests does not have when at concentrations up to 5000ng/mL
Display cytotoxicity, but half cause when pool point is liked 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 the liquid cultured cells of pH 7.4, dense
Degree is up to 8000ng/mL, and in irradiation completely without photosensitive activity, but compound 2 carries out cultured cells in the liquid of pH 6.5
When, represent photosensitive activity very high, IC50It is 95ng/mL to be worth, and represents the outer micro- acid environment targeting of obviously tumour cell
Property.
It is known that all there is micro- acid environment in almost all of entity tumor, such 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, the cancer of the uterus and
There is micro- acid 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 it is of the invention spirit and
Any modification, equivalent and improvement for being made within principle etc., should be included within the scope of the present invention.
Claims (8)
1. the compound shown in a kind of logical formula (I)：
Wherein：N=1,2,3, or 4；X=O or NH；Or its is pharmaceutically acceptable
Salt.
2. the compound shown in logical formula (I) according to claim 1, it is selected from：
Wherein
3. a kind of method for preparing the compound shown in logical formula (I) according to claim 1, the method includes：
Wherein：N=1,2,3, 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, Zinc phthalocyanine derivative leads to formula (IV) compound and logical formula (III) chemical combination
Thing reacts, and obtains logical formula (I) compound.
4. method according to claim 3, wherein：
1st step, the solvent is 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-
The reagents such as lutidines are provided；The logical formula (II) compound is 1 with the mol ratio of cholesterol formyl chloride:0.2~2.
2nd step, the solvent is 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-
The reagents such as lutidines are provided；The logical formula (IV) compound is 1 with the mol ratio of logical formula (III) compound:0.5~5.
5. a kind of pharmaceutical composition, its formula according to any one in claim 1~2 for containing therapeutically effective amount
(I) compound and pharmaceutically acceptable carrier, diluent or excipient shown in.
6. compound shown in the 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. compound shown in the 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. 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, the cancer of the uterus and ovary
Cancer, preferably breast cancer.
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| CN107629063A (en) * | 2017-09-25 | 2018-01-26 | 深圳市声光动力生物医药科技有限公司 | Phthalocyanine Zinc Gefitinib complex of acid-sensitive and preparation method thereof and application in medicine |
| WO2019056374A1 (en) * | 2017-09-25 | 2019-03-28 | 深圳市声光动力生物医药科技有限公司 | Acid-sensitive boron subphthalocyanine-gefitinib complex and preparation method therefor and medical use thereof |
| CN110628049A (en) * | 2019-10-22 | 2019-12-31 | 西华师范大学 | Photoresponse antibacterial self-repairing collagen gel and preparation method thereof |
| CN114621309A (en) * | 2022-03-03 | 2022-06-14 | 宁德师范学院 | Phthalocyanine ammonium salt liquid crystal supermolecule antistatic material, intermediate, preparation and application |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107629063A (en) * | 2017-09-25 | 2018-01-26 | 深圳市声光动力生物医药科技有限公司 | Phthalocyanine Zinc Gefitinib complex of acid-sensitive and preparation method thereof and application in medicine |
| CN107629063B (en) * | 2017-09-25 | 2019-03-19 | 深圳市声光动力生物医药科技有限公司 | The Phthalocyanine Zinc of acid-sensitive-Gefitinib complex and preparation method thereof and application in medicine |
| WO2019056374A1 (en) * | 2017-09-25 | 2019-03-28 | 深圳市声光动力生物医药科技有限公司 | Acid-sensitive boron subphthalocyanine-gefitinib complex and preparation method therefor and medical use thereof |
| CN110628049A (en) * | 2019-10-22 | 2019-12-31 | 西华师范大学 | Photoresponse antibacterial self-repairing collagen gel and preparation method thereof |
| CN114621309A (en) * | 2022-03-03 | 2022-06-14 | 宁德师范学院 | Phthalocyanine ammonium salt liquid crystal supermolecule antistatic material, intermediate, preparation and application |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018086241A1 (en) | 2018-05-17 |
| CN106749478B (en) | 2017-11-07 |
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