CN107629063A - Phthalocyanine Zinc Gefitinib complex of acid-sensitive and preparation method thereof and application in medicine - Google Patents
Phthalocyanine Zinc Gefitinib complex of acid-sensitive and preparation method thereof and application in medicine Download PDFInfo
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- CN107629063A CN107629063A CN201710874916.3A CN201710874916A CN107629063A CN 107629063 A CN107629063 A CN 107629063A CN 201710874916 A CN201710874916 A CN 201710874916A CN 107629063 A CN107629063 A CN 107629063A
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Abstract
Phthalocyanine Zinc Gefitinib complex connected the present invention relates to the ketal of slightly sour environment sensitive and preparation method thereof and application in medicine.Especially, the present invention relates to the Phthalocyanine Zinc Gefitinib 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.The influencing each other due to Phthalocyanine Zinc group and Gefitinib group under normal structure environment, the complex has relatively low 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, suppress tumour growth.They can be prepared into the optical dynamic therapy and the double curative effect cancer therapy drugs of chemotherapy of the double targetings of slightly sour environment and EGFR EGFR-TK 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 invention discloses it as the double curative effect medicines of optical dynamic therapy-chemotherapy, 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 has been successfully applied to lung at present
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, 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
Cancer therapy drug is 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, stomach 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 inhibitors of Gefitinib, it is a kind of targeted drug for treating tumour.2002 first
Listed in Japan, be approved in May, 2003 to be used for Advanced Non-Small Cell as three line single therapy medicines in the U.S. and Australia
Lung cancer.Formally clinical treatment Locally Advanced or Metastatic Nsclc 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 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.
The invention discloses it is a series of by tumor tissue cell outside slightly sour environment sensitive key connection Phthalocyanine Zinc-Ji Fei
For Buddhist nun's complex.The influencing each other due to Phthalocyanine Zinc group and Gefitinib group under normal structure environment, the complex has
Relatively low cytotoxicity, but outside tumor tissue cell under slightly sour environment, high photosensitive activity can be discharged by hydrolysis simultaneously
Phthalocyanine Zinc fragment point and high EGFR tyrosine-kinases enzyme inhibition activity Gefitinib derivative fragment.They can be prepared into tumour cell
The optical dynamic therapy and the double curative effect cancer therapy drugs of chemotherapy of the outer double targetings of slightly sour environment and EGFR EGFR-TK.
The content of the invention
Phthalocyanine Zinc-Gefitinib the complex and its system connected the invention discloses a series of ketal of slightly sour environment sensitives
Preparation Method and application in medicine.Especially, the present invention relates to the Phthalocyanine Zinc shown in logical formula (I)-Gefitinib complex, its
Preparation method and the pharmaceutical composition containing the complex, as well as the purposes of sensitising agent, particularly in treating cancer
Purposes.The influencing each other due to Phthalocyanine Zinc group and Gefitinib group under normal structure environment, the complex has relatively low
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, suppress tumour growth.They can be prepared into the double targets of slightly sour environment and EGFR EGFR-TK outside tumour cell
To the double curative effect cancer therapy drugs of optical dynamic therapy and chemotherapy.Compound shown in a kind of logical formula (I) provided by the invention：
Wherein：N=1,2,3, or 4；
Or its pharmaceutically acceptable salt.
Hydrolysis chemical formula (1) of the compound under the slightly sour environment of tumor tissues shown in logical formula (I)
Wherein：N=1,2,3, or 4；
--------------------------(1)
PH value is formula (I) chemical constitution Stability Analysis of Structures under 7.4 environment outside normal tissue cell.Due to Phthalocyanine Zinc group and
Gefitinib group influences each other, and the complex has relatively low cytotoxicity.
But under relatively low (6.5 or so) environment of pH value outside tumor tissue cell, ketal key is unstable, lead to formula (I) energy
Hydrolysis obtains formula (IV) and formula (V).The structure of logical formula (IV) compound is identical with the compound structure of document report 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, EGF-R ELISA TYR kinase inhibitory activity can be showed, suppress tumour growth.
Typical compound of the invention includes, but are not limited to：
Or its pharmaceutically acceptable salt.
The present invention also provides a kind of method for preparing the compound shown in logical formula (I), and reaction equation is as follows, but not only limits
In following method:
Wherein：N=1,2,3, or 4；
In organic solvent with alkalescence condition, react to obtain formula (I) with formula (II) compound and formula (III) compound and change
Compound.Wherein：It is described to there is solvent to be selected from benzene, toluene and tetrahydrofuran；The reaction is carried out at a temperature of 10~120 DEG C；It is described
Alkalescence condition selected from least one of pyridine, triethylamine, hydrofining, sodium hydride and 4-N, N- lutidines reagent by providing；
The mol 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 main intermediate (III) preparation method, this method includes：
In organic solvent with alkalescence condition, react to obtain formula (III) with formula (VI) compound and formula (VII) compound
Compound.Wherein：It is described to there is solvent to select N ' dinethylformamides, ethanol, methanol and tetrahydrofuran；The reaction 40~
Carried out at a temperature of 120 DEG C；The alkalescence condition is by selected from pyridine, triethylamine, potassium carbonate, sodium carbonate and 4-N, N- lutidines
At least one of reagent provide；The mol 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 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.
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.
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 620~750nm.
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.
" TsCl " is p-methyl benzenesulfonic acid acyl chlorides.
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.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)。
NMR：Bruker ARX-400 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 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 are 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).
Embodiment 1：The synthesis of compound 1
1st step
In ice-water bath, compound formula (VIII) (1.64g, 10mmol), p-methyl benzenesulfonic acid acyl chlorides (1.9g, 10mmol)
Dichloromethane (45mL) is added with pyridine (1.6g, 20.2mmol), temperature is raised to room temperature, continues stirring reaction 15 hours, stops
Reaction, water (300mL) 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 methylene chloride/methanol (10:1), obtaining white oil thing is
Compound formula (VII) (1.79g, 56%).MS(ESI):M/z=319 [M+H]+。
2nd step
In ice-water bath, compound formula (VII) (1.59g, 5mmol), compound formula (VI) (2.16g, 5mmol) adds
DMF (50mL), Anhydrous potassium carbonate (1.38g, 10mmol) is added into reaction solution, reaction solution is heated to 90
DEG C, stirring reaction stops reaction after 15 hours.Decompression removes organic solvent after reaction stops, and crude product adds dichloromethane
100mL stirring and dissolvings, add water 200mL stirrings, organic phase are collected after standing and with anhydrous sodium sulfate drying, vacuum distillation,
Crude product silica gel column chromatography column separating purification, eluant, eluent are methylene chloride/methanol (15:1) it is Formula, to obtain brown solid
(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]+。
3rd step
In ice-water bath, compound 1-1 (0.7g, 0.7mmol), compound formula (III) (1.1g, 1.9mmol) adds
Benzene (30mL), slowly adds hydrofining (0.14g, 3.5mmol) into reaction solution, and reaction solution is heated to 80 DEG C of continuation stirring reactions
6 hours, it is slowly added to 5 milliliters of water quenchings and goes out reaction.Water (100mL) is added into reaction solution, stirring is stood, and collects organic phase.
Organic phase anhydrous sodium sulfate drying, be evaporated under reduced pressure, crude product silica gel column chromatography column separating purification, eluant, eluent be chloroform/
Methanol (10:1) it is compound 1 (0.15g, 11%), to obtain brown solid.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 to obtain as described in Example 1.
In ice-water bath, compound 2-1 (0.7g, 0.6mmol), compound formula (III) (1.1g, 1.9mmol) adds
Toluene (40mL), slowly adds sodium hydride (0.12g, 5mmol) into reaction solution, and reaction solution is heated to 110 DEG C and continues stirring instead
Answer 5 hours, be slowly added to 5 milliliters of water quenchings and go out reaction.Water (100mL) is added into reaction solution, stirring is stood, and collects organic phase.
Organic phase anhydrous sodium sulfate drying, be evaporated under reduced pressure, crude product silica gel column chromatography column separating purification, eluant, eluent be chloroform/
Methanol (10:1) brown solid compound 2 (0.18g, 15%), is obtained.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 to obtain as described in Example 1.
In ice-water bath, compound 3-1 (1.27g, 1mmol), compound formula (III) (2.2g, 3.8mmol) adds first
Benzene (30mL), sodium hydride (0.12g, 5mmol) is slowly added into reaction solution, room temperature continues stirring reaction 16 hours, slowly adds
Enter 5 milliliters of water quenchings to go out reaction.Organic solvent is evaporated under reduced pressure out, water (100mL) and dichloromethane are added into remaining solid
(100mL), stirring are stood, and collect organic phase.Organic phase anhydrous sodium sulfate drying, it is evaporated under reduced pressure, crude product silica gel column chromatography
Column separating purification, eluant, eluent are methylene chloride/methanol (10:1) brown solid compound 3 (0.22g, 10%), is obtained.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
Take compound 2 (200mg, 0.1mmol) to be dissolved in 50mL tetrahydrofurans, add 50mL pH6.5 phosphate and delay
Fliud flushing (PBS solution).It is 6.5 to keep solution ph, 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 anhydrous sodium sulfate drying, it is evaporated under reduced pressure, crude product silicon
Glue-line analyses column separating purification, and eluant, eluent is 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) DMEM complete culture solutions：Mould is added in 500mL DMEM liquid mediums (GIBCO companies)
Element/streptomysin 100,000 U, hyclone 56mL, mix.2) MTT solution (MTT：3- (4,5- dimethylthiazole -2) -2,5- hexichol
Base tetrazole bromide, it is purchased from MP companies of the U.S.)：Powdery MTT is dissolved in PBS solution with 5mg/mL concentration, filtration sterilization, now matched somebody with somebody
It is current.
Experimental method：
Test sample is made into the mother liquor that concentration is 1mM with DMSO；100 μ L1mg/mL mother liquor is taken during experiment, is added
1.15mL 0.5% (w/w) Emulsifier EL-60 pH 7.4PBS and pH 6.5PBS buffer solutions, are configured to 80 μ g/mL decoctions,
And the decoction of various concentrations is diluted to corresponding PBS, keep decoction pH value constant in dilution, drug solution preparing
Cell dosing culture is carried out after being stored at room temperature 24 hours afterwards.DMSO final concentration is≤1% in each medicine and negative control group.
From the attached tumor cells of exponential phase, after being digested with pancreatin, it is made into the DMEM culture mediums containing 10% hyclone suitable
The cell suspension of concentration is closed, 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 nutrient solution of various concentrations, every group of 3 parallel holes.It is divided into illumination after mixing
With two groups of lucifuge, dosing co-culture 2 hours after, discard culture medium, rejoin the culture medium without test sample put 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 per hole2Under the conditions of
After being incubated 4 hours, supernatant is abandoned in suction, and 200 μ L DMSO are added per hole, is vibrated 10 minutes, ELIASA detection light absorption value, determines ripple
Long 570nm, excitation wavelength 630nm.Light source connects the optical filter that heat-insulated tank increased in 610nm by 200W Halogen lamp LED and carried
For light dosage is 48J cm-2。
Computational methods of the medicine to the inhibiting rate of growth of tumour cell：Growth of tumour cell inhibiting rate (%)=[(negative right
According to a group OD averages-administration group OD averages)/negative control group OD averages] × 100%.Half-inhibition concentration IC50Calculating, use
The logit Returns Law determine.
Experimental result：
The medicine of table 1 human lung carcinoma cell PC9 in irradiation IC50(nM) value
| Medicine | The decoction culture of cellular pH 7.4 | The decoction culture of cellular pH 6.5 |
| 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 pH 7.4 decoction culture cell, at concentrations up to
5000nM, there is no photosensitive activity in irradiation, but compound 2 shows very high when pH 6.5 decoction carries out culture cell
Photosensitive activity, IC50It is worth for 23nM, this is due to that the hydrolysis of compound 2 obtains high cell toxicity chemical combination under the slightly sour environment of tumour
Thing 4 and formula (V) compound.
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)
- A kind of 1. compound shown in logical formula (I)：Wherein：N=1,2,3, or 4；Or its pharmaceutically acceptable salt.
- 2. the compound shown in logical formula (I) according to claim 1, it is selected from：
- 3. a kind of method for preparing the compound shown in logical formula (I) according to claim 1, this method include：Wherein：N=1,2,3, or 4；It is characterized in that：In organic solvent with alkalescence condition, react to obtain with formula (II) compound and formula (III) compound Formula (I) compound.
- 4. the method according to claim 11, wherein：It is described to there is solvent to be selected from benzene, toluene and tetrahydrofuran；The reaction exists Carried out at a temperature of 10~120 DEG C；The alkalescence condition is by selected from pyridine, triethylamine, hydrofining, sodium hydride and 4-N, N- dimethyl At least one of pyridine reagent provides；The mol ratio of formula (II) compound and formula (III) compound is 1:0.5~4.
- 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. 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. 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. 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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| 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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Effective date of registration: 20231109 Address after: No. 101, No. 12 Beihuan North Third Lane, Guantian Community, Shiyan Street, Bao'an District, Shenzhen City, Guangdong Province, 518000 Patentee after: SHENZHEN DAVOOS SCIENCE AND TECHNOLOGY LTD. Address before: D703, 7th Floor, Silver Star Technology Building, No. 1301, Sightseeing Road, Dabuxiang Community, Guanlan Street, Longhua District, Shenzhen City, Guangdong Province, 518000 Patentee before: SHENZHEN SONO-PHOTODYNAMIC BIO-MED TECHNOLOGY Ltd. |
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