CN107629063B - The Phthalocyanine Zinc of acid-sensitive-Gefitinib complex and preparation method thereof and application in medicine - Google Patents
The Phthalocyanine Zinc of acid-sensitive-Gefitinib complex and preparation method thereof and application in medicine Download PDFInfo
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- CN107629063B CN107629063B CN201710874916.3A CN201710874916A CN107629063B CN 107629063 B CN107629063 B CN 107629063B CN 201710874916 A CN201710874916 A CN 201710874916A CN 107629063 B CN107629063 B CN 107629063B
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Abstract
Application the present invention relates to Phthalocyanine Zinc-Gefitinib complex of the ketal of slightly sour environment sensitive connection and preparation method thereof and in medicine.Particularly, the present invention relates to Phthalocyanine Zinc shown in logical formula (I)-Gefitinib complex, preparation method and contain the pharmaceutical composition of the complex, as well as the purposes of photosensitizer, purposes especially in treating cancer, each substituent group in formula of (I) are identical as the definition in specification.The influencing each other due to Phthalocyanine Zinc group and Gefitinib group under normal tissue environment, the complex has lower cytotoxicity, but outside tumor tissue cell under slightly sour environment, hydrolysis occurs for ketal, hydrolysate Phthalocyanine Zinc fragment shows high photosensitive activity, and another hydrolysate Gefitinib derivative can be used as EGF-R ELISA (EGFR) tyrosinase inhibitor, inhibit tumour growth.They can be prepared into the optical dynamic therapy and the double curative effect anticancer drugs of chemotherapy of slightly sour environment and the double targetings of EGFR tyrosine kinase outside tumour cell.
Description
Technical field
The invention belongs to field of medicaments, it is related to Phthalocyanine Zinc-Gefitinib complex and preparation method thereof and its in medicine
Application, the purposes that the invention discloses it as the double curative effect drugs of optical dynamic therapy-chemotherapy, 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 known as tumour chemistry diagnosis and treatment drug (
Claim photosensitizer, Photosensitizer, abbreviation PS).PDT therapy processes be by be injected intravenously photosensitizer is injected in vivo it is (right
Affected part can also be applied in skin), by using the light of specific wavelength to irradiate tumor tissues after a certain period of time, it is enriched in tumour
The photosensitizer of tissue generates a series of optical physics chemical reactions, the active oxygen of cytotoxicity is generated, to kill under the excitation of light
Dead cancer cell destruction tumor tissues.
It is approved by the fda in the United States within 1996 clinic, FDA in 1997 is included in five class basic skills of oncotherapy
One of (operation, radiotherapy, chemotherapy, light power, biochemical immunity).It is compared with traditional therapy, PDT therapy has 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 advantages such as appearance and vitals function, treatment time can be protected short.Photodynamic therapy has been successfully applied to lung at present
Cancer, gastric 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, neck
The treatment of portion's cancer, Eye tumor, uterine cancer and oophoroma.
In recent years with EGF-R ELISA (epidermal growth factor receptor, EGFR) target spot
Anticancer drug increasingly by concern.EGFR is a kind of membrane receptor, in Several Kinds of Malignancy such as neurogliocytoma, mammary gland
Have in cancer, lung cancer, oophoroma, G. cephalantha, cervical carcinoma, the cancer of the esophagus, prostate cancer, liver cancer, colon cancer, gastric cancer etc. excessively
Expression, activation EGFR can accelerate tumour cell breeding, promote Tumor Angiongesis, accelerate metastases, hinder tumor death.
A kind of EGFR tyrosine kinase inhibitor of Gefitinib is a kind of targeted drug for treating tumour.2002 for the first time
It is listed in Japan, in May, 2003 is approved as three line single therapy drugs in the U.S. and Australia for Advanced Non-Small Cell
Lung cancer.Clinical treatment Locally Advanced or Metastatic Nsclc formally are had been used in Discussion on Chinese Listed within 2005.
Micro-environmental hypoxia existing for tumor entity tissue site causes the extracellular pH value of the region tumors lower (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 tissue is swollen
The design of tumor targeted drug provides new strategy.
Phthalocyanine Zinc-the Ji Fei of slightly sour environment sensitive key connection outside the invention discloses a series of by tumor tissue cell
For Buddhist nun's complex.The influencing each other due to Phthalocyanine Zinc group and Gefitinib group under normal tissue environment, which has
Lower cytotoxicity, but outside tumor tissue cell under slightly sour environment, by hydrolysis while high photosensitive activity can be discharged
Phthalocyanine Zinc fragment point and high EGFR tyrosine-kinase enzyme inhibition activity Gefitinib derivative fragment.They can be prepared into tumour cell
The optical dynamic therapy and the double curative effect anticancer drugs of chemotherapy of outer slightly sour environment and the double targetings of EGFR tyrosine kinase.
Summary of the invention
The invention discloses the Phthalocyanine Zinc-Gefitinib complexs and its system of a series of connection of the ketal of slightly sour environment sensitives
Preparation Method and application in medicine.Particularly, the present invention relates to Phthalocyanine Zinc shown in logical formula (I)-Gefitinib complex, its
The purposes of preparation method and pharmaceutical composition as well as photosensitizer containing the complex, especially in treating cancer
Purposes.The influencing each other due to Phthalocyanine Zinc group and Gefitinib group under normal tissue environment, which has lower
Cytotoxicity, but outside tumor tissue cell under slightly sour environment, hydrolysis, hydrolysate Phthalocyanine Zinc fragment exhibition occur for ketal
Existing high photosensitive activity, and another hydrolysate Gefitinib derivative can be used as EGF-R ELISA (EGFR) junket
Propylhomoserin enzyme inhibitor inhibits tumour growth.They can be prepared into slightly sour environment and the double targets of EGFR tyrosine kinase outside tumour cell
To the double curative effect anticancer drugs of optical dynamic therapy and chemotherapy.A kind of logical formula (I) compound represented provided by the invention:
Wherein: n=1,2,3, or 4；
Or its pharmaceutically acceptable salt.
Logical hydrolysis chemical formula (1) of the formula (I) compound represented under the slightly sour environment of tumor tissues
Wherein: n=1,2,3, or 4；
--------------------------(1)
PH value is formula (I) chemical structure stable structure under 7.4 environment outside normal tissue cell.Due to Phthalocyanine Zinc group and
Gefitinib group influences each other, which has lower cytotoxicity.
But under lower (6.5 or so) environment of pH value outside tumor tissue cell, ketal key is unstable, leads to formula (I) energy
Hydrolysis obtains formula (IV) and formula (V).The structure of logical formula (IV) compound is identical as having compound structure reported in the literature and class
Like (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 compounds are thin in tumour
Born of the same parents' uptake ratio is high, shows very high photosensitive activity at very low concentrations.And compound (V) be with Gefitinib structure extremely
Similar compound can show EGF-R ELISA tyrosine kinase inhibitory activity, inhibit tumour growth.
The typical compound of the present invention includes, but are not limited to:
Or its pharmaceutically acceptable salt.
The present invention also provides a kind of methods for preparing logical formula (I) compound represented, and reaction equation is as follows, but not only limits
In following method:
Wherein: n=1,2,3, or 4；
In organic solvent and under alkaline condition, react to obtain formula (I) change with formula (II) compound and formula (III) compound
Close object.Wherein: described to there is solvent to be selected from benzene, toluene and tetrahydrofuran；The reaction carries out at a temperature of 10~120 DEG C；It is described
Alkaline condition is provided by being selected from pyridine, triethylamine, hydrofining, sodium hydride and 4-N, at least one of N- lutidines reagent；
The molar ratio of formula (II) compound and formula (III) compound is 1:0.5~4.
General formula compound (II) 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).
The invention discloses the preparation methods of main intermediate (III), this method comprises:
In organic solvent and under alkaline condition, react to obtain formula (III) with formula (VI) compound and formula (VII) compound
Compound.Wherein: described to there is solvent to select N ' dinethylformamide, ethyl alcohol, methanol and tetrahydrofuran；The reaction 40~
It is carried out at a temperature of 120 DEG C；The alkaline condition is by being selected from pyridine, triethylamine, potassium carbonate, sodium carbonate and 4-N, N- lutidines
At least one of reagent provide；The molar ratio of formula (VI) compound and formula (VII) compound is 1:0.2~4.
Formula (VI) compound bibliography method is easy to synthesis as raw material using Gefitinib and obtains (Tetrhedron
Letters,46(43),7381-7384)。
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 be with purifying compound by high performance liquid chromatography (HPLC).
The present invention also provides a kind of pharmaceutical compositions, the logical formula (I) compound represented containing therapeutically effective amount or or
Its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to logical formula (I) compound represented or its pharmaceutically acceptable salts, or the medicine group comprising it
It closes object and is preparing the purposes in photo-dynamical medicine or photosensitive drug.
The invention further relates to logical formula (I) compound represented or its pharmaceutically acceptable salts, or the medicine group comprising it
Close purposes of the object in the drug of preparation treating cancer.Wherein the cancer is selected from the wherein described cancer and 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, head-neck carcinoma
Disease, Eye tumor, uterine cancer and oophoroma.
The invention further relates to logical formula (I) compound represented or its pharmaceutically acceptable salts, or the medicine group comprising it
Object is closed, photo-dynamical medicine or photosensitive drug are used as.
The invention further relates to logical formula (I) compound represented or its pharmaceutically acceptable salts, or the medicine group comprising it
Object is closed, treating cancer is used for.Wherein the cancer is selected from lung cancer, gastric 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 oophoroma.
The invention further relates to a kind of methods for the treatment of cancer comprising gives the logical formula (I) of required bacterium
Compound represented or its pharmaceutically acceptable salt, or comprising its pharmaceutical composition, then with suitable light source irradiation.Institute
Suitable optical filter can be connected by ordinary light source to provide or be provided by the laser of specific wavelength, light source by stating suitable light source
Wave-length coverage be 550~900nm, preferably 620~750nm.
Compound according to the present invention can be administered orally, sublingual administration, parenteral administration, subcutaneous administration, intramuscular apply
With, intravenous application, transdermal administration, local application or rectal administration.
In medicinal compound of the invention, for oral administration, sublingual administration, parenteral administration, subcutaneous administration, intramuscular
For application, intravenous application, transdermal administration, local application or rectal administration, active constituent can be with conventional pharmaceutical carrier
It mixes, animals or humans is applied in the form of applying unit.Suitable application unit form include oral form such as
Tablet, gel capsule, pulvis, granule and oral solution or suspension, 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, cream
The mixing such as sugar, magnesium stearate, talcum, Arabic gum.Tablet can use sucrose or other suitable material coatings or with such as
This mode handle so that its with it is extended or delay activity and continuously discharge predetermined amount active constituent.
The mixture of acquisition is poured into soft or hard capsules by the way that active constituent and diluent are mixed merga pass
To obtain gel capsule preparation.
The preparation of syrup or tincture form may include active constituent together with sweetener, preservative and aromatic and fit
When colorant.
The pulvis or granule being dispersed in water may include active constituent, with dispersing agent, surfactant, wetting
It agent or suspending agent and is mixed with corrigent or sweetener.Contain Emulsifier EL-60 in its pharmaceutical composition and its spreads out
Biology, dimethyl sulfoxide, ethyl alcohol, glycerol, n,N-Dimethylformamide, Liquid Macrogol -3000, cyclodextrin, glucose, tween,
One or more of polyethylene glycol mono stearate.
Suppository is used for rectal administration, the adhesive melted under rectal temperature is used, 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 dispersing agent and/or wetting agent) for parenteral, intranasal or intraocularly application.Contain polyoxy second in its pharmaceutical composition
Alkene castor oil and its derivative, dimethyl sulfoxide, ethyl alcohol, glycerol, n,N-Dimethylformamide, Liquid Macrogol -3000, ring paste
One or more of essence, glucose, tween, polyethylene glycol mono stearate.
Active constituent (may be together with one or more additive carriers) can also be formulated into microcapsules.
The compound of the present invention can be come with the dosage between 0.01mg/ days and 5000mg/ days using with single dose
Amount/day mode is provided or is applied in a manner of dosage several in whole day, for example, same dose is twice daily.It is applied
Daily dose is advantageously between 0.1mg and 200mg, or even more advantageously between 2.5mg and 50mg.Using exceeding
The dosage of these ranges may be needed, and those skilled in the art itself will recognize this point.
In a specific embodiment of the invention, pharmaceutical composition can also be prepared for external application.It can
To be introduced in the common type (that is, especially lotion, foaming agent, gelling agent, dispersing agent, spray) of the application type,
The common type has excipient, and the excipient is particularly capable of penetrating skin, in order to improve the property of active constituent
And accessibility.Other than composition according to the present invention, these compositions usually further include 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, emulsifier, thickener, the other active components for generating complementary effect or possible synergy, micro-
Secondary element, essential oil, fragrance, colorant, collagen, chemistry or mineral filtering agent.
Definition
Unless stated to the contrary, otherwise following that there are following meanings 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
Object 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, is pharmaceutically may be used
(as herein defined) salt and its pharmacological activity for having expected parent compound received.This salt includes:
(1) and the acid-addition salts of the formation such as inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or such as with organic acid
Acetic acid, benzene sulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, ethyl alcohol
Acid, hydroxyl naphthoic acid, 2- ethylenehydrinsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2- naphthalene sulfonic acids, propionic acid,
The formation such as salicylic acid, succinic acid, dibenzoyl-L-tartaric, tartaric acid, p-methyl benzenesulfonic acid, trimethylace tonitric, trifluoroacetic acid
Acid-addition salts；With
(2) the acid 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, ethanol amine, 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 " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or
The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine
The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
" Ts " is p-methyl benzenesulfonic acid base.
" TsCl " is p-methyl benzenesulfonic acid acyl chlorides.
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.
Test method without specific conditions in the embodiment of the present invention, usually according to normal condition, or according to raw material or
Condition proposed by commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.General formula compound
(II) 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).Formula (VI) compound
Bibliography method is easy to synthesis as raw material using Gefitinib and obtains (Tetrhedron Letters, 46 (43), 7381-
7384)。
Nuclear Magnetic Resonance: Bruker ARX-400 type high-resolution high resolution NMR instrument.
Mass spectrum: QSTAR Elite series connection level four bars time of-flight mass spectrometer.
MTT detecting instrument: Thermo Scientific Multiskan GO all-wave length microplate reader.
PBS buffer solution: phosphate buffer.
The structure of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.Nmr chemical be displaced (δ) with
10-6(ppm) unit provides.Measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), inside it is designated as tetramethylsilane (TMS).It uses
Following abbreviations: s be it is 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
Peak, dd are double doublet etc..
Tlc silica gel plate uses Qingdao GF254 silica gel plate, 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 generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
In embodiment unless otherwise specified, reaction carries out under argon atmospher or nitrogen atmosphere.
In embodiment unless otherwise specified, the solution in reaction refers to 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).
Embodiment 1: the synthesis of compound 1
Step 1
In ice-water bath, compound formula (VIII) (1.64g, 10mmol), p-methyl benzenesulfonic acid acyl chlorides (1.9g, 10mmol)
Methylene chloride (45mL) is added with pyridine (1.6g, 20.2mmol), temperature is raised to room temperature, continues to be stirred to react 15 hours, stops
Water (300mL) is added into reaction solution in reaction, and stirring is stood, and collects organic phase, and organic phase is dry with anhydrous sodium sulfate, decompression
Distillation, crude product silica gel column chromatography column separating purification, eluant, eluent are methylene chloride/methanol (10:1), and obtaining white oil object is
Compound formula (VII) (1.79g, 56%).MS (ESI): m/z=319 [M+H]+。
Step 2
In ice-water bath, compound formula (VII) (1.59g, 5mmol), compound formula (VI) (2.16g, 5mmol) is added
Anhydrous potassium carbonate (1.38g, 10mmol) is added into reaction solution in n,N-Dimethylformamide (50mL), and reaction solution is heated to 90
DEG C, stop reaction after being stirred to react 15 hours.Methylene chloride is added in decompression removal organic solvent, crude product after reaction stops
100mL stirring and dissolving adds water 200mL stirring, and organic phase and, vacuum distillation dry with anhydrous sodium sulfate are collected after standing,
Crude product silica gel column chromatography column separating purification, eluant, eluent are methylene chloride/methanol (15:1), and obtaining brown solid is Formula
(III) (1.82g, 62%).1H NMR(400MHz,DMSO-d6): δ 9.50 (s, 1H, NH), 8.50 (s, 1H, Ar-H), 8.08-
8.15 (m, 1H, Ar-H), 7.70-7.83 (m, 2H, Ar-H), 7.38-7.49 (m, 1H, Ar-H), 7.20 (s, 1H, Ar-H),
4.10-4.26(m,4H,CH2),3.55-3.72(m,10H,CH2),2.44-2.55(m,2H,CH2),2.34-2.45(m,4H,
CH2),1.94-2.05(m,2H,CH2),1.41(s,6H,CH3).MS (ESI): m/z=579 [M]+。
Step 3
In ice-water bath, compound 1-1 (0.7g, 0.7mmol), compound formula (III) (1.1g, 1.9mmol) is added
Slowly hydrofining (0.14g, 3.5mmol) is added into reaction solution in benzene (30mL), and reaction solution, which is heated to 80 DEG C, to be continued to be stirred to react
6 hours, it is slowly added to 5 milliliters of water quenching reactions.It is added into reaction solution water (100mL), stirring is stood, and collects organic phase.
Organic phase is dry with anhydrous sodium sulfate, vacuum distillation, crude product silica gel column chromatography column separating purification, eluant, eluent be chloroform/
Methanol (10:1), obtaining brown solid is compound 1 (0.15g, 11%).1H NMR(400MHz,DMSO-d6):δ9.51(s,
2H, NH), 9.31-9.35 (m, 4H, Pc-Hα), 9.21-9.25 (m, 2H, Pc-Hα), 8.51 (s, 2H, Ar-H), 8.09-8.18
(m, 8H, Ar-H, Pc-Hβ),7.71-7.84(m,4H,Ar-H),7.51(s,2H,Pc-Hβ),7.39-7.48(m,2H,Ar-H),
7.20 (s, 2H, Ar-H), 4.95-5.06 (m, 4H, CH2),4.53-5.62(m,4H,CH2),4.11-4.26(m,12H,CH2),
3.56-3.86(m,16H,CH2),2.44-2.52(m,4H,CH2),2.33-2.44(m,8H,CH2),1.91-2.05(m,4H,
CH2),1.43(s,12H,CH3).MS (ESI): m/z=1820 [M]+。
Embodiment 2: the synthesis of compound 2
Compound formula (III) synthesizes obtain as described in Example 1.
In ice-water bath, compound 2-1 (0.7g, 0.6mmol), compound formula (III) (1.1g, 1.9mmol) is added
Slowly sodium hydride (0.12g, 5mmol) is added into reaction solution in toluene (40mL), and reaction solution is heated to 110 DEG C and continues stirring instead
It answers 5 hours, is slowly added to 5 milliliters of water quenching reactions.Water (100mL) is added into reaction solution, stirring is stood, and collects organic phase.
Organic phase is dry with anhydrous sodium sulfate, vacuum distillation, crude product silica gel column chromatography column separating purification, eluant, eluent be chloroform/
Methanol (10:1) obtains brown solid compound 2 (0.18g, 15%).1H NMR(400MHz,DMSO-d6): δ 9.50 (s, 2H,
NH), 9.30-9.34 (m, 4H, Pc-Hα), 9.20-9.24 (m, 2H, Pc-Hα), 8.50 (s, 2H, Ar-H), 8.08-8.1,9 (m,
8H, Ar-H, Pc-Hβ),7.73-7.84(m,4H,Ar-H),7.52(s,2H,Pc-Hβ),7.38-7.48(m,2H,Ar-H),7.20
(s, 2H, Ar-H), 4.95-5.07 (m, 4H, CH2),4.52-5.62(m,4H,CH2),4.10-4.26(m,12H,CH2),3.50-
3.81(m,32H,CH2),2.44-2.55(m,4H,CH2),2.33-2.44(m,8H,CH2),1.91-2.05(m,4H,CH2),
1.41(s,12H,CH3).MS (ESI): m/z=1996 [M]+。
Embodiment 3: the synthesis of compound 3
Compound formula (III) synthesizes obtain as described in Example 1.
In ice-water bath, compound 3-1 (1.27g, 1mmol), first is added in compound formula (III) (2.2g, 3.8mmol)
Slowly sodium hydride (0.12g, 5mmol) is added into reaction solution in benzene (30mL), and room temperature continues to be stirred to react 16 hours, slowly adds
Enter 5 milliliters of water quenching reactions.It is evaporated under reduced pressure out organic solvent, water (100mL) and methylene chloride are added into remaining solid
(100mL), stirring are stood, and collect organic phase.Organic phase is dry with anhydrous sodium sulfate, vacuum distillation, crude product silica gel column chromatography
Column separating purification, eluant, eluent are methylene chloride/methanol (10:1), obtain brown solid compound 3 (0.22g, 10%).1H NMR
(400MHz,DMSO-d6): δ 9.50 (s, 2H, NH), 9.31-9.36 (m, 4H, Pc-Hα), 9.22-9.26 (m, 2H, Pc-Hα),
8.50 (s, 2H, Ar-H), 8.08-8.20 (m, 8H, Ar-H, Pc-Hβ),7.73-7.85(m,4H,Ar-H),7.51(s,2H,Pc-
Hβ), 7.37-7.49 (m, 2H, Ar-H), 7.20 (s, 2H, Ar-H), 4.94-5.09 (m, 4H, CH2),4.51-5.63(m,4H,
CH2),4.06-4.30(m,12H,CH2),3.45-3.88(m,40H,CH2),2.43-2.54(m,4H,CH2),2.32-2.45
(m,8H,CH2),1.90-2.05(m,4H,CH2),1.41(s,12H,CH3).MS (ESI): m/z=2084 [M]+。
Test case 1: the hydrolysis of compound 2
It takes compound 2 (200mg, 0.1mmol) to be dissolved in 50mL tetrahydrofuran, it is slow to add 50mL pH6.5 phosphate
Fliud flushing (PBS solution).Keeping solution ph is 6.5, and reaction 24 hours is stirred at room temperature.Two are added after being evaporated under reduced pressure out organic solvent
Chloromethanes (200mL), concussion are stood, and collect organic phase.Organic phase is dry with anhydrous sodium sulfate, vacuum distillation, crude product silicon
Glue-line analyse column separating purification, eluant, eluent be methylene chloride/methanol (10:1), obtain blue solid compound 4 (65mg, 67%) and
Brown solid formula (V) compound (35mg, 73%).
Compound 4:1H NMR(400MHz,DMSO-d6): 9.41-9.49 (m, 4H, Pc-Hα), 9.39-9.42 (m, 2H,
Pc-Hα),8.12-8.18(m,6H,Pc-Hβ),7.57(s,2H,Pc-Hβ),4.94-5.07(m,4H,CH2),4.52-5.68(m,
4H,CH2),4.10-4.28(m,4H,CH2),3.78-3.86(m,4H,CH2),3.58-3.69(m,12H,CH2),3.48-3.54
(m,4H,CH2).MS (ESI): m/z=961 [M+H]+。
Formula (V) compound:1H NMR(400MHz,DMSO-d6): δ 9.50 (s, 1H, NH), 8.50 (s, 1H, Ar-H),
8.07-8.14 (m, 1H, Ar-H), 7.70-7.85 (m, 2H, Ar-H), 7.37-7.49 (m, 1H, Ar-H), 7.20 (s, 1H, Ar-
H),3.96-4.26(m,6H,CH2),3.55-3.72(m,4H,CH2),2.44-2.55(m,2H,CH2),2.34-2.45(m,4H,
CH2),1.94-2.05(m,2H,CH2).MS (ESI): m/z=477 [M+H]+。
Test case 2: the photosensitive experiment of extracorporeal anti-tumor cell
Test sample: the compounds of this invention 2, compound 4 and formula (V) compound
Test cell: human lung carcinoma cell PC9
Main agents: 1) mould DMEM complete culture solution: is added in 500mL DMEM liquid medium (GIBCO company)
Element/streptomysin 100,000 U, fetal calf serum 56mL are mixed.2) MTT solution (MTT:3- (4,5- dimethylthiazole -2) -2,5- hexichol
Base tetrazole bromide is purchased from MP company, the U.S.): powdery MTT is dissolved in PBS solution with the concentration of 5mg/mL, filtration sterilization is now matched
It is current.
Experimental method:
Test sample is made into the mother liquor that concentration is 1mM with DMSO；The mother liquor of 100 μ L1mg/mL is taken when experiment, is added
1.15mL 0.5% (w/w) Emulsifier EL-60 pH 7.4PBS and pH 6.5PBS buffer, is configured to 80 μ g/mL medical fluids,
And the medical fluid of various concentration is diluted to corresponding PBS buffer solution, keep medical fluid pH value constant in dilution, drug solution preparing
Cell dosing culture is carried out after being stored at room temperature 24 hours afterwards.The final concentration of DMSO is≤1% in each drug and negative control group.
The attached tumor cells for selecting logarithmic growth phase after being digested with pancreatin, are made into suitable with the DMEM culture medium containing 10% fetal calf serum
The cell suspension for closing concentration is seeded in 96 well culture plates at 37 DEG C, 5%CO2Under the conditions of cultivate 24 hours.It is then respectively adding
Test medicine, control drug, solvent and each 100 μ L of culture solution of various concentration, every group of 3 parallel holes.It is divided into illumination after mixing
Be protected from light two groups, dosing co-culture 2 hours after, discard culture medium, rejoin the culture medium without test sample set 37 DEG C,
5%CO2Under the conditions of continue culture 24 hours.After 24 hours, 5mg/mL MTT, 20 μ L, 37 DEG C, 5%CO are added in every hole2Under the conditions of
It after being incubated for 4 hours, inhales and abandons supernatant, 200 μ L DMSO are added in every hole, vibrate 10 minutes, and microplate reader detects light absorption value, measure wave
Long 570nm, excitation wavelength 630nm.Light source connects heat-insulated sink increasing by the halogen lamp of 200W and mentions in the optical filter of 610nm
For light dosage is 48J cm-2。
Calculation method of the drug to the inhibiting rate of growth of tumour cell: growth of tumour cell inhibiting rate (%)=[(negative right
According to a group OD mean value-administration group OD mean value)/negative control group OD mean value] × 100%.Half-inhibitory concentration IC50Calculating, use
The measurement of the logit Return Law.
Experimental result:
The IC of 1 drug of table human lung carcinoma cell PC9 in irradiation50(nM) value
| Drug | 7.4 medical fluid culture of cellular pH | 6.5 medical fluid culture of cellular pH |
| Compound 2 | >5000 | 23 |
| Compound 4 | 46 | 50 |
| Formula (V) compound | 85 | 78 |
Experimental result is shown, under light protected environment, the compound of all tests is not shown when at concentrations up to 5000nM
Cytotoxicity, but when irradiation situation compound 4 and formula (V) compound are in pH 6.5 and pH 7.4 to human lung carcinoma cell PC9's
Half lethal concentration IC50Value is mutually between 46-85nM.But compound 2 is in the medical fluid culture cell of pH 7.4, at concentrations up to
5000nM does not have photosensitive activity in irradiation, but compound 2 shows very high when the medical fluid of pH 6.5 carries out culture cell
Photosensitive activity, IC50Value is 23nM, this is because the hydrolysis of compound 2 obtains high cell toxicity chemical combination under the slightly sour environment of tumour
Object 4 and formula (V) compound.
It is known that all there is slightly sour environment in almost all of entity tumor, as lung cancer, gastric 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
There is slightly sour environment, compound disclosed in this patent or its pharmaceutically acceptable salt in the entity tumors such as oophoroma, or comprising
Its pharmaceutical composition can be prepared into photosensitive drug and treat above-mentioned cancer.
The above description is only an embodiment of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within principle.
Claims (8)
1. a kind of logical formula (I) compound represented:
Wherein: n=1,2,3, or 4；
Or its pharmaceutically acceptable salt.
2. logical formula (I) compound represented according to claim 1, is selected from:
3. a kind of method for preparing logical formula (I) compound represented according to claim 1, this method comprises:
Wherein: n=1,2,3, or 4；
It is characterized by: reacting to obtain with formula (II) compound and formula (III) compound in organic solvent and under alkaline condition
Formula (I) compound.
4. according to the method described in claim 3, wherein: described to there is solvent to be selected from benzene, toluene and tetrahydrofuran；The reaction exists
It is carried out at a temperature of 10~120 DEG C；The alkaline condition is by being selected from pyridine, triethylamine, hydrofining, sodium hydride and 4-N, N- dimethyl
At least one of pyridine reagent provides；The molar ratio of formula (II) compound and formula (III) compound is 1:0.5~4.
5. a kind of pharmaceutical composition, containing therapeutically effective amount according to claim 1~any one of 2 described in general formula
(I) compound represented and pharmaceutically acceptable carrier.
6. logical formula (I) compound represented described according to claim 1~any one of 2 or according to claim 5
Pharmaceutical composition preparing the purposes in photo-dynamical medicine or photosensitive drug.
7. logical formula (I) compound represented described according to claim 1~any one of 2 or according to claim 5
Pharmaceutical composition preparation treating cancer drug in purposes.
8. purposes according to claim 7, wherein the cancer is selected from lung cancer, gastric 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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| CN106749478A (en) * | 2016-11-11 | 2017-05-31 | 深圳市声光动力生物医药科技有限公司 | 1,4 pH sensitive Di-substituted phthalocyanine Zn complexes and preparation method thereof and in application pharmaceutically |
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| CN106565760A (en) * | 2016-11-11 | 2017-04-19 | 深圳市声光动力生物医药科技有限公司 | BODIPY derivatives and preparation method thereof, and application of BODIPY derivatives to medicine |
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