CN109180556A - A kind of colored cyanines class fluorescent chemicals and its preparation method and application - Google Patents
A kind of colored cyanines class fluorescent chemicals and its preparation method and application Download PDFInfo
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- CN109180556A CN109180556A CN201811022803.1A CN201811022803A CN109180556A CN 109180556 A CN109180556 A CN 109180556A CN 201811022803 A CN201811022803 A CN 201811022803A CN 109180556 A CN109180556 A CN 109180556A
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- 239000000126 substance Substances 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000006933 amyloid-beta aggregation Effects 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 210000004556 brain Anatomy 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 4
- 230000000630 rising effect Effects 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- FLHJIAFUWHPJRT-UHFFFAOYSA-N 2,3,3-trimethylindole Chemical class C1=CC=C2C(C)(C)C(C)=NC2=C1 FLHJIAFUWHPJRT-UHFFFAOYSA-N 0.000 claims description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical group 0.000 claims description 2
- 238000003745 diagnosis Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 239000012047 saturated solution Substances 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
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- 125000006575 electron-withdrawing group Chemical group 0.000 abstract description 3
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- 230000008499 blood brain barrier function Effects 0.000 abstract description 2
- 210000001218 blood-brain barrier Anatomy 0.000 abstract description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract description 2
- -1 cyanine compound Chemical class 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 230000007935 neutral effect Effects 0.000 abstract description 2
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- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
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- 238000004220 aggregation Methods 0.000 description 8
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- OLQIKGSZDTXODA-UHFFFAOYSA-N 4-[3-(4-hydroxy-2-methylphenyl)-1,1-dioxo-2,1$l^{6}-benzoxathiol-3-yl]-3-methylphenol Chemical compound CC1=CC(O)=CC=C1C1(C=2C(=CC(O)=CC=2)C)C2=CC=CC=C2S(=O)(=O)O1 OLQIKGSZDTXODA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 2
- 206010002022 amyloidosis Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
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- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical class CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
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- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 1
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 description 1
- 208000003808 Amyloid Neuropathies Diseases 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 206010002025 Amyloidosis senile Diseases 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 description 1
- 244000178870 Lavandula angustifolia Species 0.000 description 1
- 235000010663 Lavandula angustifolia Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- XMLJCSFKQSJZLS-UHFFFAOYSA-L [K+].[K+].OC.[O-]C([O-])=O Chemical compound [K+].[K+].OC.[O-]C([O-])=O XMLJCSFKQSJZLS-UHFFFAOYSA-L 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940039856 aricept Drugs 0.000 description 1
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- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
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- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000000695 excitation spectrum Methods 0.000 description 1
- 229940108366 exelon Drugs 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 239000001102 lavandula vera Substances 0.000 description 1
- 235000018219 lavender Nutrition 0.000 description 1
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
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- 230000003340 mental effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940033872 namenda Drugs 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
- C09K2211/1033—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom with oxygen
Abstract
The invention belongs to specific molecular identification material fields, disclose a kind of colored cyanines class fluorescent chemicals and its preparation method and application.It spends shown in the general structure such as formula (I) of cyanines class fluorescent chemicals in the portion.Fluorescent chemicals of the invention, using classical flower cyanine type dye structure, the electron-withdrawing group of electroneutral is introduced in R base location, electron donating group and electron-withdrawing group in its structure is set to form the conjugated structure of push-pull electronic action, and increase the conjugated system of transition by carbon-carbon double bond, the fluorescence for generating compound molecule is mobile near infrared region, while the electron neutral group introduced solves the problems, such as that most of electrically charged cyanine compound can not pass through blood-brain barrier.The compound molecule has affinity to A β plaque block, can be used successfully to the near-infrared fluorescent imaging of A β plaque block, has many advantages, such as that safety is "dead", low in cost, background fluorescence interference is lower, penetration power is strong in biological tissues.
Description
Technical field
The invention belongs to specific molecular identification material fields, and in particular to a kind of colored cyanines class fluorescent chemicals and its system
Preparation Method and application.
Background technique
Alzheimer disease (Alzheimer ' s disease, AD), also known as senile dementia, are that one kind is mainly in 65 years old
The neurodegenerative disease of the above crowd, affects millions of people worldwide, annual 5000000 newly-increased.Clinical manifestation is progressive
Memory impairment, cognitive disorder, mental symptom and activity of daily living forfeiture, this brings to patient, family members and society
Serious stress and economic pressures.However, not having so far because the pathogenesis of alzheimer's disease is still indefinite
Effective drug can be with diagnosing and treating alzheimer's disease.So far, U.S. Food and Drug Administration (FDA) only criticizes
Quasi- 5 kinds of drug donepezils (Aricept), Rivastigmine (Exelon), galanthamine (Reminyl), Tacrine
(Cognex) and Memantine (Namenda) is used for the clinical treatment of AD, but this 5 kinds of drugs can only improve the symptom of AD patient, no
The state of an illness of AD can be slowed down, cannot fundamentally treat AD.
In AD patient's brain, it is AD pathologic mark the most significant that beta-amyloid protein (Amyloid, A β) deposits in brain
One of will.A β plaque block has started to occur for 5~10 years before the onset of AD, is the earliest nerve fiber degeneration mark of AD and important disease
Feature of science, therefore exploitation has important meaning to the early diagnosis of AD with the Small-molecule probe imaging agent that aβ protein is deposited as target spot
Justice.Other than AD, A β plaque block is existed in other diseases, such as Down Cotard, type-2 diabetes mellitus insulinoma, brain starch
Angiopathy, amyloidosis, amyloid polyneuropathy, systemic senile amyloidosis and the something lost with amyloidosis
Transmissibility cerebral hemorrhage etc..
Between the past several years, the molecular probe of the detection aβ protein in vitro and in vivo have been achieved for significantly into
Step.The image probe and method applied, including magnetic resonance imaging (MRI), positron emission tomography (PET), monochromatic light
Son transmitting computer tomography (SPECT) and optical image technology.Three kinds of PET probes of FDA approved[18F]FPIB,[18F]
AV-45 and[18F]AV-1, but the application of these PET preparations clinically is limited, and is examined because they cannot be used for confirmatory
Disconnected AD, and it is at high cost, need convolution of the special facility for radionuclide to accelerate.Under comparing, optical imagery tool
There are many advantages such as the "dead", data acquisition time of safety is short and low in cost, the in recent years application in medical diagnosis etc.
It is in widespread attention.Especially near-infrared fluorescence imaging technology, because its background fluorescence interferes lower, penetration power in biological tissues
By force, therefore, the near-infrared fluorescent imaging agent (molecular probe) that there is affinity to A β plaque block is researched and developed, will be anticipated with important science
Justice and real value.
Therefore, research and development have the A beta molecule probe of specific binding A β plaque block noticeable.In conjunction with A β fluorescence probe and divide
Sub- imaging technique carries out tracing in vivo and the detection, it can be achieved that noninvasive, real-time A β plaque block of imaging of A β plaque block, and then is AD
Equal Diseases are early diagnosed, the research of examination of curative effect and therapeutic agent etc. provides great convenience.
Summary of the invention
In place of the above shortcoming and defect of the existing technology, the primary purpose of the present invention is that providing a kind of flower
Cyanines class fluorescent chemicals.
Another object of the present invention is to provide the preparation methods that above-mentioned portion spends cyanines class fluorescent chemicals.
A further object of the present invention is to provide above-mentioned portions, and cyanines class fluorescent chemicals to be spent to prepare A β deposition related disease
Application in diagnostic reagent and therapeutic agent.
The object of the invention is achieved through the following technical solutions:
A kind of colored cyanines class fluorescent chemicals, shown in general structure such as formula (I):
Wherein, R is
Spend the preparation method of cyanines class fluorescent chemicals, including following preparation step in above-mentioned portion:
(1) 2,3,3- tri-methyl indoles and iodomethane are heated into reaction in ethanol, obtain intermediate 1:
(2) DMF and methylene chloride are uniformly mixed, ice bath and nitrogen protection, are added dropwise phosphorus oxychloride dropwise, stirring 20~
After 40min, cyclohexanone is added, temperature rising reflux reaction obtains intermediate 2:
(3) intermediate 1 and intermediate 2 are dissolved in organic solvent, are warming up to 80~130 DEG C of back flow reactions, obtain centre
Body 3:
(4) intermediate 3 and malononitrile are dissolved in organic solvent, the methanol saturated solution of piperidines or potassium carbonate, room is added
Temperature is stirred to react, and obtains intermediate 4
(5) intermediate 4 is dissolved in acetonitrile, potassium carbonate is added and corresponding R amine side chain is reacted, obtains with formula
(I) portion of structure spends cyanines class fluorescent chemicals.
The synthetic route chart of above-mentioned preparation method is as shown in Figure 1.
Preferably, the temperature that reaction is heated described in step (1) is 80 DEG C.
Preferably, the temperature of the reaction of temperature rising reflux described in step (2) is 80 DEG C.
Preferably, organic solvent described in step (3) is the mixed solvent of n-butanol and toluene.
Preferably, organic solvent described in step (4) is methanol.
Spend cyanines class fluorescent chemicals answering in the diagnostic reagent and therapeutic agent for preparing A β deposition related disease in above-mentioned portion
With.
Further, the A β deposition related disease refers to Alzheimer's disease or cerebral amyloid angiopathy.
Further, the diagnostic reagent and therapeutic agent include that the portion of formula (I) structure spends cyanines class fluorescent chemicals and medicine
Acceptable carrier on." pharmaceutically acceptable carrier " refers to various excipient or diluent.Such as water, physiology salt
Water, glycerol or ethyl alcohol.
The developing method of present invention offer A β plaque block.In the first step of this developing method, detectable amount is contained into formula
(I) diagnostic reagent and therapeutic agent that the portion of structure spends cyanines class fluorescent chemicals are by the way that well known to a person skilled in the art methods to draw
Enter in tissue or patient, formula (I) compound represented of detectable amount introduces patient and is being enough to make compound and A β plaque block
In conjunction with time after, atraumatic ground detection compound.Or formula (I) compound represented is introduced into patient, through it is enough when
Between so that compound and A β plaque agllutination close, take tissue sample from patient, and be detached from patient and detect compound in tissue.Or suffer from certainly
Person takes tissue sample and formula (I) compound represented is introduced the tissue sample.It is being enough that the compound is made to be bound to A β plaque
After the time of block, detection compound.
Formula (I) compound represented can be administered to patient by whole or local administration route.For example, can be with
Compound is administered to patient so that it is delivered to whole body.It is alternatively possible to which compound to be administered to the specific organ of concern
Or tissue.For example, needing the amyloid plaques of positioning and quantitative intracerebral to diagnose or track the process of the AD of patient.
Term " patient " refers to the mankind and other animals.Also known how to determine is enough to make compound those skilled in the art
The time closed with A β plaque agllutination.By the way that formula (I) compound represented of detectable amount is introduced patient, then upon administration each
The required time can be easily determined in detection compound at time.
Term " in conjunction with " refers to the chemical interaction between compound and A β plaque block.In conjunction with example include covalent bond,
Ionic bond, hydrophilic-hydrophilic interaction, hydrophobic-hydrophobic interaction and complex compound.
Compared with the existing technology, portion of the invention spends cyanines class fluorescent chemicals and application to have the following advantages that and beneficial to effect
Fruit:
Fluorescent chemicals of the invention introduce the suction electricity of electroneutral in R base location using classical flower cyanine type dye structure
Subbase group makes electron donating group and electron-withdrawing group in its structure form the conjugated structure of push-pull electronic action, and passes through
Carbon-carbon double bond increases the conjugated system of transition, and the fluorescence for generating compound molecule is mobile near infrared region, while the electricity introduced
Neutral group solves the problems, such as that most of electrically charged cyanine compound can not pass through blood-brain barrier；Based on the skeleton, draw
Enter electron donating group, enhance the fluorescence quantum yield of fluorescent chemicals, it is made to have high-fluorescence quantum yield, and launch wavelength is leaned on
Nearly near infrared region.Such compound is tested in vitro shows have affinity to A β plaque block, can be used successfully to A β plaque block
Near-infrared fluorescent imaging, has that safety "dead", low in cost, background fluorescence interference is lower, penetration power in biological tissues
The advantages that strong.
Detailed description of the invention
Fig. 1 is the synthetic route chart that portion of the present invention spends cyanines class fluorescent chemicals preparation method；
Fig. 2~10 are respectively to be after the resulting fluorescent chemicals D1~D9 of the embodiment of the present invention is acted on A β 1-42 aggregation
Fluorescence titration spectrogram.
Specific embodiment
Present invention will now be described in further detail with reference to the embodiments and the accompanying drawings, but embodiments of the present invention are unlimited
In this.
Following embodiment can refer to routine techniques progress for not specifically specified parameter.Nuclear-magnetism spectrum is using Germany
Bruker company Avance III 400MHz (600MHz) nmr determination, deuterated chloroform or deuterated DMSO make solvent.
Embodiment 1
The synthesis of the colored cyanines class fluorescent chemicals of a kind of of the present embodiment, specific synthesis step are as follows:
(1) synthetic intermediate 1
By the 2,3,3- tri-methyl indole (30mmol) of 4.77g and 3.22ml iodomethane (7.08g, 50mmol) in 60ml second
It is stirred evenly in alcohol, sealed pressure vessel, 80 DEG C of reaction 12h.After the reaction was completed, it is cooled to room temperature, solid is precipitated, filters, obtain
Solid 7.7g is precipitated to get lavender intermediate 1, yield 85%.Nuclear magnetic data is as follows: 1H NMR (400MHz, DMSO) δ
7.92-7.86(m,1H),7.85-7.78(m,1H),7.66-7.58(m,2H),3.96(s,3H),2.76(s,3H),1.52(s,
6H)。
(2) synthetic intermediate 2
17.5ml DMF (16.54g, 225mmol) is uniformly mixed with 18ml methylene chloride, under ice bath and nitrogen protection,
15ml phosphorus oxychloride (24.68g, 160mmol) slowly is added dropwise dropwise, after stirring 20-40min, 4.6ml cyclohexanone is added
(4.37g, 45mmol) is cooled to room temperature, reaction solution is poured slowly into ice water after being warming up to 80 DEG C of back flow reaction 4h, is precipitated solid
Body filters, obtains 7.5g yellow solid, i.e. intermediate 2, yield: 90.8%.Nuclear magnetic data is as follows:1H NMR(400MHz,
DMSO)δ2.51(s,1H),2.39-2.28(m,4H),1.62-1.52(m,2H)。
(3) synthetic intermediate 3
7.5g intermediate 1 (25mmol) and 7g intermediate 2 (40mmol) are dissolved in 140ml n-butanol to mix with 60ml toluene
In solvent, after being warming up to 80-130 DEG C of reaction 4h, solvent is removed, column chromatography for separation obtains 2.5g red intermediate 3, yield
25%.Nuclear magnetic data is as follows: 1H NMR (400MHz, CDCl3) δ 10.28 (s, 1H), 7.85 (d, J=12.5Hz, 1H), and 7.23
(t, J=3.5Hz, 1H), 7.22 (d, J=3.7Hz, 1H), 6.96 (t, J=7.3Hz, 1H), 6.75 (d, J=7.7Hz, 1H),
5.48 (d, J=12.6Hz, 1H), 3.25 (s, 3H), 2.61 (t, J=5.3Hz, 2H), 2.51 (t, J=5.6Hz, 2H), 1.83-
1.76(m,2H),1.68(s,6H)。
(4) synthetic intermediate 4
400mg intermediate 3 (1.2mmol) and 800 μ L malononitrile (12mmol) are dissolved in 32ml methanol, 320 μ are added
The potassium carbonate methanol solution of L saturation, is stirred overnight at room temperature, and filters, obtains blue solid 400mg to get intermediate 4, yield
88.9%.Nuclear magnetic data is as follows:1H NMR (400MHz, DMSO) δ 8.00 (d, J=13.8Hz, 1H), 7.82 (s, 1H), 7.48
(d, J=6.9Hz, 1H), 7.33 (t, J=7.7Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.10 (t, J=7.4Hz, 1H),
5.90 (d, J=12.9Hz, 1H), 3.47 (s, 3H), 2.81 (t, J=8.7Hz, 2H), 2.60 (t, J=9.3Hz, 2H), 1.85-
1.73(m,2H),1.60(s,6H)。
(5) fluorescent chemicals D1 is synthesized
190mg intermediate 3 (0.5mmol) is dissolved in 30mL anhydrous acetonitrile, 3-5 equivalent potassium carbonate solid is added, then
280 μ L N, N- dimethyl-ethylenediamines (2.5mmol) are added, room temperature reaction for 24 hours, filters and removes solid base, obtain red solid
80mg, yield 37%.Nuclear magnetic data is as follows:1H NMR(400MHz,CDCl3) δ 7.73 (d, J=12.4Hz, 1H), 7.26-7.13
(m, 2H), 6.94 (t, J=7.3Hz, 1H), 6.87 (s, 1H), 6.73 (d, J=7.9Hz, 1H), 5.38 (d, J=12.4Hz,
1H), 4.00 (t, J=6.3Hz, 2H), 3.23 (s, 3H), 2.68 (t, J=6.3Hz, 2H), 2.56 (t, J=6.5Hz, 2H),
2.30(s,6H),2.02(s,2H),1.81–1.71(m,2H),1.66(s,6H)。
(6) fluorescent chemicals D2 is synthesized
By N, N- dimethyl-ethylenediamine replaces with the fourth ammonia of equivalent, obtains D2 by the method for synthesizing fluorescent chemicals D1,
Obtain red solid 70mg, yield 32%.Nuclear magnetic data is as follows:1H NMR(400MHz,CDCl3) δ 7.73 (d, J=12.4Hz,
1H), 7.24-7.16 (m, 2H), 6.93 (t, J=6.4Hz, 1H), 6.80 (s, 1H), 6.72 (d, J=8.0Hz, 1H), 5.38
(d, J=12.4Hz, 1H), 3.90 (t, J=7.3Hz, 2H), 3.23 (s, 3H), 2.56 (t, J=6.6Hz, 2H), 2.30 (t, J
=8.0Hz, 2H), 1.82-1.71 (m, 4H), 1.66 (s, 6H), 1.39 (t, J=7.7Hz, 2H), 0.97 (t, J=7.3Hz,
3H)。
(7) fluorescent chemicals D3 is synthesized
D3 is obtained by the method for synthesizing fluorescent chemicals D1, obtains red solid 65mg, yield 29%.Nuclear magnetic data is such as
Under:1H NMR(400MHz,CDCl3) δ 7.72 (d, J=12.4Hz, 1H), 7.25-7.16 (m, 2H), 6.93 (t, J=7.4Hz,
1H), 6.91 (s, 1H), 6.72 (d, J=8.1Hz, 1H), 5.38 (d, J=12.4Hz, 1H), 3.96 (t, J=6.9Hz, 2H),
3.22 (s, 3H), 2.56 (t, J=6.7Hz, 2H), 2.30 (t, J=6.4Hz, 4H), 2.22 (s, 6H), 1.97-1.92 (t, J=
8.0Hz,2H),1.77(m,2H),1.66(s,6H)。
(8) fluorescent chemicals D4 is synthesized
D4 is obtained by the method for synthesizing fluorescent chemicals D1, obtains red solid 78mg, yield 39%.Nuclear magnetic data is such as
Under:1H NMR(400MHz,CDCl3) δ 7.75 (d, J=12.4Hz, 1H), 7.26-7.15 (m, 2H), 6.94 (t, J=7.3Hz,
1H), 6.81 (s, 1H), 6.73 (d, J=8.0Hz, 1H), 5.39 (d, J=12.4Hz, 1H), 3.87 (t, J=8.0Hz, 2H),
3.23 (s, 3H), 2.57 (t, J=5.9Hz, 2H), 2.30 (t, J=4.0Hz, 2H), 1.91-1.68 (m, 4H), 1.66 (s,
6H), 0.99 (t, J=7.3Hz, 3H).
(9) fluorescent chemicals D5 is synthesized
D5 is obtained by the method for synthesizing fluorescent chemicals D1, obtains red solid 80mg, yield 32%.Nuclear magnetic data is such as
Under:1H NMR(400MHz,CDCl3) δ 7.73 (d, J=12.4Hz, 1H), 7.20 (dt, J=7.2,3.8Hz, 2H), 7.00-
6.87 (m, 2H), 6.72 (d, J=8.0Hz, 1H), 5.38 (d, J=12.4Hz, 1H), 3.97 (t, J=6.7Hz, 2H), 3.75-
3.68 (m, 4H), 3.23 (s, 3H), 2.57 (t, J=6.0Hz, 2H), 2.43 (s, 4H), 2.39 (t, J=6.7Hz, 2H), 2.28
(t, J=4.0Hz, 2H), 2.03-1.96 (m, 2H), 1.79-1.73 (m, 2H), 1.66 (s, 6H).
(10) fluorescent chemicals D6 is synthesized
D6 is obtained by the method for synthesizing fluorescent chemicals D1, obtains red solid 76mg, yield 33%.Nuclear magnetic data is such as
Under:1H NMR(400MHz,CDCl3) δ 7.72 (d, J=12.4Hz, 1H), 7.26-7.15 (m, 2H), 6.93 (t, J=7.3Hz,
1H), 6.85 (s, 1H), 6.72 (d, J=8.0Hz, 1H), 5.37 (d, J=12.4Hz, 1H), 4.03 (t, J=6.5Hz, 2H),
3.22 (s, 3H), 2.85 (t, J=6.5Hz, 2H), 2.62-2.54 (m, 6H), 2.29 (t, J=4.0Hz, 2H), 1.81-1.74
(m,6H),1.66(s,6H)。
(11) fluorescent chemicals D7 is synthesized
D7 is obtained by the method for synthesizing fluorescent chemicals D1, has obtained orange solids 50mg, yield 25%.Nuclear magnetic data is such as
Under:1H NMR(400MHz,CDCl3) δ 7.78 (d, J=12.5Hz, 1H), 7.26-7.18 (m, 2H), 6.95 (t, J=7.4Hz,
1H), 6.80 (s, 1H), 6.75 (d, J=8.0Hz, 1H), 5.39 (d, J=12.5Hz, 1H), 4.11 (t, J=4.0Hz, 2H),
4.96 (t, J=4.0Hz, 2H), 3.25 (s, 3H), 2.58 (t, J=6.6Hz, 2H), 2.31 (t, J=4.0Hz, 2H), 1.79-
1.75(m,2H),1.66(s,6H)。
(12) fluorescent chemicals D8 is synthesized
D8 is obtained by the method for synthesizing fluorescent chemicals D1, obtains red solid 80mg, yield 32%.Nuclear magnetic data is such as
Under:1H NMR(400MHz,CDCl3) δ 8.42 (s, 1H), 7.73 (d, J=12.4Hz, 1H), 7.60 (d, J=7.8Hz, 1H),
7.37 (d, J=8.0Hz, 1H), 7.23-7.16 (m, 3H), 7.10 (t, J=7.2Hz, 1H), 6.98 (s, 1H), 6.93 (t, J=
7.4Hz, 1H), 6.72 (d, J=8.0Hz, 1H), 6.39 (s, 1H), 5.36 (d, J=12.4Hz, 1H), 4.18 (t, J=
6.8Hz, 2H), 3.26 (t, J=6.8Hz, 2H), 3.22 (s, 3H), 2.51 (t, J=5.9Hz, 2H), 2.05-2.01 (m, 2H),
1.68(s,6H),1.65–1.60(m,2H)。
(13) fluorescent chemicals D9 is synthesized
D9 is obtained by the method for synthesizing fluorescent chemicals D1, obtains red solid 52mg, yield 20%.Nuclear magnetic data is such as
Under:1H NMR(400MHz,CDCl3) δ 8.46 (s, 1H), 7.73 (d, J=12.4Hz, 1H), 7.25-7.17 (m, 3H), 7.04
(d, J=2.3Hz, 1H), 6.97-6.89 (dd, J=9.2,5.3Hz, 2H), 6.83 (dd, J=8.8,2.4Hz, 1H), 6.72
(d, J=7.9Hz, 1H), 6.35 (s, 1H), 5.36 (d, J=12.4Hz, 1H), 4.16 (t, J=6.7Hz, 2H), 3.83 (s,
3H), 3.26-3.17 (m, 5H), 2.50 (t, J=7.3
Hz,2H),2.02–1.97(m,2H),1.67(s,6H),1.63–1.57(m,2H)。
Embodiment 2
Maximum absorption wavelength (λ of the fluorescent chemicals D1~D9 probe in different solventsabs) and maximum emission wavelength (λem)
Experiment:
Experimental method: taking fluorescent chemicals D1~D9 to be dissolved in dimethyl sulfoxide, is configured to 10mM stock solution.Take above-mentioned solution
3 μ L are diluted to 3mL with organic solvent DCM, EtOH, ACN, MeOH, DMSO, PBS of opposed polarity respectively, obtain 10 μM molten
Liquid, with ultraviolet specrophotometer (UV-2450, SHIMADZU) and sepectrophotofluorometer (F-4500, Hitachi), measurement is simultaneously
Record the maximum absorption wavelength and maximum emission wavelength of fluorescent chemicals.
Fluorescence spectra of the fluorescent chemicals D9~D18 in different solvents is shown in Table 1 in the present embodiment.
Maximum absorption wavelength and launch wavelength of the 1 compound D9~D18 of table in different solvents
As can be seen from Table 1, the launch wavelength of fluorescent chemicals of the invention occurs red with the increase of solvent polarity
It moves, the launch wavelength in PBS solution is located substantially near near infrared region.
Embodiment 3
Fluorescence quantum yield measurement experiment of the fluorescent chemicals D1~D9 in DCM and PBS；
Experimental method: choosing cresol-purple acetic acid cresol-purple is that (in methyl alcohol, fluorescence quantum yield is reference compound
0.54), measured respectively on ultraviolet-uisible spectrophotometer and sepectrophotofluorometer respectively fluorescent chemicals D1~D9 and
The ultra-violet absorption spectrum and fluorescence emission spectrum of reference compound, according to Yu=Ys*Fu/Fs*As/AuOperation is carried out, obtains fluorescence
The fluorescence quantum yield of compound.Yu、YsFor test substance and the fluorescence quantum yield of reference standard substance, Fu、FsFor determinand
The integrated fluorescence intensities of matter and reference material, Au、AsFor test substance and reference material the excitation wavelength incident intensity.
Fluorescence quantum yield of the fluorescent chemicals D1~D9 in DCM and PBS is shown in Table 2 in the present embodiment.
Fluorescence quantum yield of the 2 fluorescent chemicals D1~D9 of table in DCM and PBS
It can be seen from 2 result of table the fluorescence quantum yield of fluorescence chemical combination of the invention with solvent polarity reduction, it is glimmering
Quantum yield increases.
Embodiment 4
Fluorescent chemicals D1~D9 probe and A β1-42The vitro binding assay of aggregation:
Experimental method: taking fluorescent chemicals D1~D9 to be dissolved in dimethyl sulfoxide, is configured to 10mM stock solution, uses PBS solution
It is diluted to the prepare liquid of 250nM.First measure the excitation and emission spectra property of probe.Select A β1-42Albumen is in 37 DEG C of water-baths
A beta-aggregation body is cultivated, for simulating the aβ protein aggregation in human brain.By the A β of probe and various concentration1-42Aggregation mixing,
And fluorescence detection is carried out with sepectrophotofluorometer.
Fluorescent chemicals D1~D9 probe and A β in the present embodiment1-42The fluorescence titration spectrogram point of aggregation mixing front and back
Fig. 2~10, external detection limit (LOD) and external binding constant (K are not seend) it is shown in Table 3.
3 fluorescent chemicals D1~D9 probe of table and A β1-42The outer detection limit of aggregation acting body and binding constant
Fluorescent chemicals of the invention and A β it can be seen from Fig. 2~101-42After aggregation combines, fluorescence intensity is obvious
Enhancing.As can be seen from Table 3, fluorescent chemicals vitro detection A β of the invention1-42The detection limit of aggregation reaches nanomole grade
Not, substantially below 10nM.Fluorescent chemicals and A β of the invention1-42The external binding constant of aggregation reaches nanomole grade
Not, other than D7, the external binding constant of other compounds is below hundred nanomoles, has medium binding force.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. a kind of colored cyanines class fluorescent chemicals, it is characterised in that spend the general structure such as formula of cyanines class fluorescent chemicals in the portion
(I) shown in:
Wherein, R is
2. the preparation method of a kind of described in claim 1 colored cyanines class fluorescent chemicals, it is characterised in that including following preparation
Step:
(1) 2,3,3- tri-methyl indoles and iodomethane are heated into reaction in ethanol, obtain intermediate 1:
(2) DMF and methylene chloride are uniformly mixed, phosphorus oxychloride is added dropwise in ice bath and nitrogen protection dropwise, stirs 20~40min
Afterwards, cyclohexanone is added, temperature rising reflux reaction obtains intermediate 2:
(3) intermediate 1 and intermediate 2 are dissolved in organic solvent, are warming up to 80~130 DEG C of back flow reactions, obtain intermediate 3:
(4) intermediate 3 and malononitrile are dissolved in organic solvent, the methanol saturated solution of piperidines or potassium carbonate is added, room temperature is stirred
Reaction is mixed, intermediate 4 is obtained
(5) intermediate 4 is dissolved in acetonitrile, potassium carbonate is added and corresponding R amine side chain is reacted, obtains with formula (I)
Spend cyanines class fluorescent chemicals in the portion of structure.
3. the preparation method of a kind of according to claim 2 colored cyanines class fluorescent chemicals, it is characterised in that: step (1)
Described in heat reaction temperature be 80 DEG C.
4. the preparation method of a kind of according to claim 2 colored cyanines class fluorescent chemicals, it is characterised in that: step (2)
Described in temperature rising reflux reaction temperature be 80 DEG C.
5. the preparation method of a kind of according to claim 2 colored cyanines class fluorescent chemicals, it is characterised in that: step (3)
Described in organic solvent be n-butanol and toluene mixed solvent.
6. the preparation method of a kind of according to claim 2 colored cyanines class fluorescent chemicals, it is characterised in that: step (4)
Described in organic solvent be methanol.
7. a kind of described in claim 1 colored cyanines class fluorescent chemicals are preparing the diagnostic reagent of A β deposition related disease and are controlling
Treat the application in drug.
8. a kind of according to claim 7 colored cyanines class fluorescent chemicals are in the diagnostic reagent for preparing A β deposition related disease
With the application in therapeutic agent, it is characterised in that: the A β deposition related disease refers to Alzheimer's disease or brain amyloid blood
Pipe disease.
9. a kind of according to claim 7 colored cyanines class fluorescent chemicals are in the diagnostic reagent for preparing A β deposition related disease
With the application in therapeutic agent, it is characterised in that: the diagnostic reagent and therapeutic agent include that the portion of formula (I) structure spends cyanines class glimmering
Optical compounds and pharmaceutically acceptable carrier.
10. a kind of according to claim 9 colored cyanines class fluorescent chemicals are in the diagnosis examination for preparing A β deposition related disease
Application in agent and therapeutic agent, it is characterised in that: the pharmaceutically acceptable carrier is water, physiological saline, glycerol or second
Alcohol.
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| CN114539215A (en) * | 2022-01-05 | 2022-05-27 | 温州大学 | Partially cyanine fluorescent probe, preparation method and application |
| US11420991B2 (en) | 2019-11-25 | 2022-08-23 | Zhejiang University Of Technology | Confined porphyrin Co(II) and preparation method and application thereof |
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