WO2010126077A1 - Composé fluorescent proche infrarouge - Google Patents

Composé fluorescent proche infrarouge Download PDF

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WO2010126077A1
WO2010126077A1 PCT/JP2010/057541 JP2010057541W WO2010126077A1 WO 2010126077 A1 WO2010126077 A1 WO 2010126077A1 JP 2010057541 W JP2010057541 W JP 2010057541W WO 2010126077 A1 WO2010126077 A1 WO 2010126077A1
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group
alkyl group
substituent
compound
mmol
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PCT/JP2010/057541
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Japanese (ja)
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哲雄 長野
泰照 浦野
裕一郎 小出
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国立大学法人 東京大学
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Priority to JP2011511433A priority Critical patent/JP5526124B2/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen

Definitions

  • the present invention relates to a novel near infrared fluorescent compound.
  • a wavelength region of 650 nm to 900 nm is called a “biological window” and is a wavelength region in which a living tissue has high permeability.
  • Probes having fluorescence in the near infrared region are considered to be very useful due to advantages in bioimaging such as low cytotoxicity and small scattered light.
  • NIR near infrared region
  • cyanine compounds are mainly used for in vivo imaging among compounds having fluorescence in the near infrared region.
  • low stability due to the structure such as photofading and instability to bases, may be a problem for cyanine dyes.
  • Another problem is that cyanine dyes are difficult to chemically modify due to their structural instability. From such a viewpoint, provision of a novel compound having fluorescence in the near infrared region is desired.
  • Rhodamine is a fluorescent dye widely used in the field of chemical biology due to its excellent fluorescence properties such as high fluorescence quantum yield and light fading resistance, and various chemical modifications have been applied. Less known rhodamine compounds have fluorescence in the region. Recently, a compound in which the ring-constituting oxygen atom at the 10-position of the xanthene ring in the rhodamine skeleton is replaced with a silicon atom has been reported (China Patent Application No. 200610045944.6, published on August 2, 2006).
  • This compound has a feature that the fluorescence wavelength is shifted to the longer wavelength side by about 90 nm compared to the conventional rhodamine, and the fluorescence in the near infrared region can be used.
  • this compound cannot be said to have sufficiently long-wavelength fluorescence, and the provision of a new fluorescent compound having absorption and fluorescence maximum points in the near-infrared region of about 680 to 750 nm. It is desired.
  • An object of the present invention is to provide a novel fluorescent compound having a maximum point of absorption and fluorescence in the near infrared region of about 680 nm to 750 nm by chemically modifying the rhodamine skeleton.
  • the present inventors have replaced the ring-constituting oxygen atom at the 10-position of the xanthene ring in the rhodamine skeleton of the rhodamine skeleton with a silicon atom and utilized the amino group of the rhodamine skeleton.
  • a compound with two ring structures in the ring is ideal for having absorption and fluorescence maximum points in the near infrared region of about 680 nm to 750 nm while maintaining the high fluorescence quantum yield and light fading resistance of rhodamine. It has been found that it has excellent fluorescence characteristics.
  • the present invention has been completed based on the above findings.
  • R 1 represents a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent
  • R 2 , R 3 , R 4 and R 5 are Each independently represents a hydrogen atom, an optionally substituted alkyl group, a hydroxyl group, or a halogen atom
  • R 6 and R 7 each independently represent an optionally substituted alkyl group
  • R 8 and R 9 are each independently a hydrogen atom or a substituent
  • X represents an alkyl group that may have, or an aryl group that may have a substituent
  • R 8 and R 9 may combine with each other to form a ring structure
  • R 1 is an optionally substituted phenyl group
  • R 2 , R 3 , R 4 , and R 5 are hydrogen atoms
  • R 6 and R 7 are An alkyl group
  • Z is Si (R 8 ) (R 9 ) (wherein R 8 and R 9 each independently represents an alkyl group)
  • a compound represented by the above general formula (I) or a residue of the compound for use in the production of a fluorescent probe capable of detecting protons, metal ions, reactive oxygen species, or enzymes, or the like and a compound represented by the above general formula (I) or a residue of the compound, or a salt thereof for use in the production of a fluorescent labeling reagent.
  • a fluorescent probe capable of detecting protons, metal ions, reactive oxygen species, or enzymes, which includes a residue of the compound represented by the general formula (I); protons, metal ions, active oxygen
  • a fluorescent probe capable of detecting a species or an enzyme for example, a substitution for capturing a residue of a compound represented by the above general formula (I) and a proton, a metal ion, a reactive oxygen species, or an enzyme
  • a fluorescent probe comprising a chemical structure bonded to a group; a fluorescent labeling reagent comprising a residue of the compound represented by the general formula (I); and a fluorescent labeling reagent, wherein Also provided by the present invention is a fluorescent labeling reagent comprising a chemical structure in which a residue of a compound represented by formula (I) is bonded to a substituent capable of binding to a biological substance.
  • the compound represented by the above general formula (I) or a salt thereof provided by the present invention absorbs in the near infrared region of about 680 nm to 750 nm while maintaining the high fluorescence quantum yield and light fading resistance of rhodamine. -Since it has an ideal fluorescence characteristic having a maximum point of fluorescence, it is extremely useful as a mother nucleus compound for producing a fluorescent probe capable of detecting, for example, protons, metal ions, or reactive oxygen species.
  • alkyl group includes an alkyl group composed of linear, branched, cyclic, or a combination thereof.
  • an alkyl group having 1 to 18 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, and still more preferably about 1 to 6 carbon atoms can be used.
  • halogen atom include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • aryl group means a monocyclic or polycyclic aromatic group, and the aryl group has a hetero atom (for example, an oxygen atom, a nitrogen atom, or a sulfur atom) as a ring-constituting atom. You may have one or two or more. When having two or more heteroatoms, they may be the same or different. As the aryl group, a phenyl group can be preferably used.
  • a functional group when a functional group is defined as “may have a substituent”, the type of substituent, the substitution position, and the number of substituents are not particularly limited, and two When having the above substituents, they may be the same or different.
  • the substituent group include, but are not limited to, an alkyl group, an alkoxy group, a hydroxyl group, a carboxyl group, a halogen atom, a sulfo group, an amino group, an alkoxycarbonyl group, and an oxo group. These substituents may further have a substituent. Examples of such include, but are not limited to, a halogenated alkyl group, a dialkylamino group, and the like.
  • R 1 represents a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent.
  • the alkyl group represented by R 1 for example, an alkyl group having about 1 to 6 carbon atoms can be used, and as the aryl group represented by R 1 , for example, a phenyl group or the like can be used.
  • the alkyl group or aryl group represented by R 1 may be unsubstituted or may have a substituent.
  • alkyl group or aryl group represented by R 1 has a substituent
  • substituents include an alkyl group, an alkoxy group, a hydroxyl group, a halogen atom, an amino group, a sulfo group, and a carboxyl group. It is not limited to.
  • R 1 is preferably an aryl group which may have a substituent, and more preferably R 1 is a phenyl group which may have a substituent.
  • R 1 is a phenyl group having a substituent
  • the alkyl group for example, an alkyl group having 1 to 6 carbon atoms
  • an alkoxy group for example, an alkoxy group having 1 to 6 carbon atoms
  • a carboxyl group are selected. More preferred is a phenyl group having about 1 to 3 substituents selected.
  • 2-alkylphenyl group 2-alkyl-4-carboxyphenyl group, 2-alkyl-4-alkoxyphenyl group, 2-carboxyphenyl group, 4-alkyl-2-carboxyphenyl group, etc.
  • alkyl group is a methyl group as a substituent of the phenyl group
  • a 2-methylphenyl group is preferable.
  • R 2 , R 3 , R 4 , and R 5 each independently represent a hydrogen atom, an alkyl group that may have a substituent, a hydroxyl group, or a halogen atom.
  • the alkyl group which may have a substituent is the same as that described for R 1 .
  • R 2 , R 3 , R 4 , and R 5 may be unsubstituted or may have a substituent.
  • R 2, R 3, R 4 and although R 5 that is preferably both hydrogen atoms, in R 2, R 3, R 4 , and any one or more hydrogen atoms of the R 5 And the remainder is preferably an alkyl group (for example, an alkyl group having 1 to 6 carbon atoms), a hydroxyl group, or a halogen atom such as a chlorine atom.
  • R 6 and R 7 each independently represents an alkyl group which may have a substituent.
  • the alkyl group which may have a substituent is the same as that described for R 1 .
  • R 6 and R 7 may be an unsubstituted alkyl group or an alkyl group having a substituent. In the case of an alkyl group having a substituent, it preferably has a hydrophilic substituent such as a sulfo group, a carboxyl group, or a hydroxyl group.
  • R 6 and R 7 are preferably unsubstituted alkyl groups (eg, alkyl groups having 1 to 6 carbon atoms), and more preferably R 6 and R 7 are both methyl groups.
  • Z represents Si (R 8 ) (R 9 ), Ge (R 8 ) (R 9 ), or Sn (R 8 ) (R 9 ), wherein R 8 and R 9 are each independently a hydrogen atom,
  • R 8 and R 9 are each independently a hydrogen atom
  • the alkyl group which may have a substituent, or the aryl group which may have a substituent is shown.
  • the alkyl group which may have a substituent represented by R 8 and R 9 or the aryl group which may have a substituent is the same as described for R 1 above.
  • R 8 and R 9 can be selected from the group consisting of an alkyl group (for example, an alkyl group having 1 to 6 carbon atoms) and a phenyl group, and the alkyl group or the phenyl group is used as a substituent, for example, an alkyl group , An alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a sulfo group and the like may be present.
  • R 8 and R 9 are preferably both alkyl groups (eg, alkyl groups having 1 to 6 carbon atoms), and it is more preferable that both R 8 and R 9 are methyl groups.
  • R 8 and R 9 may be bonded to each other to form a ring structure.
  • R 8 and R 9 are both alkyl groups
  • R 8 and R 9 can be bonded to each other to form a spiro carbocycle.
  • the ring formed is preferably about 5 to 8 membered ring, for example.
  • the alkyl group which may have a substituent represented by R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 is the same as that described for R 1 above. is there.
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are preferably hydrogen atoms, but R 10 , R 11 , R 12 , R 13 , R 14 , R It is also preferred that any one or more of 15 , 16 and R 17 is an alkyl group (for example, an alkyl group having 1 to 6 carbon atoms).
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are an alkyl group (for example, an alkyl group having 1 to 6 carbon atoms), the alkyl group is a sulfo group. It is also preferable to have a hydrophilic substituent such as a hydroxyl group or a carboxyl group.
  • the compound represented by the general formula (I) may have an appropriate counter ion X so as to form a quaternary ammonium salt.
  • the counter ion include, but are not limited to, halogen ions, cyan ions, acetate ions, trifluoroacetate ions, and the like.
  • the compound represented by the general formula (I) may form an intramolecular counter ion with a quaternary nitrogen cation and an acidic group (for example, carboxyl group or sulfo group) present in the molecule.
  • the compound of the present invention represented by the above general formula (I) can exist in the form of a salt.
  • Examples of the base addition salt include metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt, and organic amine salts such as ammonium salt and triethylamine salt.
  • Acid addition salts include hydrochloride, sulfuric acid, and the like. Examples thereof include mineral acid salts such as salts and nitrates, and organic acid salts such as p-toluenesulfonate, methanesulfonate, maleate and oxalate.
  • a salt with an amino acid such as glycine may be formed.
  • the compound of the present invention represented by the above general formula (I) or a salt thereof may exist as a hydrate or a solvate, and any of these substances is included in the scope of the present invention.
  • the compound of the present invention represented by the above general formula (I) may have one or two or more asymmetric carbons depending on the type of substituent.
  • stereoisomers such as diastereoisomers based on two or more asymmetric carbons
  • any mixture of stereoisomers, racemates and the like are included in the scope of the present invention.
  • the compound of the present invention represented by the above general formula (I) or a salt thereof specifically measures protons, metal ions, reactive oxygen species, enzymes, etc. (hereinafter, these may be referred to as “measurement objects”). Therefore, it is extremely useful as a mother nucleus structure of a fluorescent probe.
  • the compound of the present invention represented by the above general formula (I) or a salt thereof is extremely useful as a mother nucleus structure of a fluorescent labeling reagent for fluorescent labeling of biological components.
  • the residue of the compound represented by the above general formula (I) can be used.
  • the term “residue” means the remaining chemical structure obtained by removing one or more hydrogen atoms from the compound represented by the above general formula (I).
  • a residue of the compound represented by the above general formula (I) is typically bonded to a substituent for capturing a proton, a metal ion, a reactive oxygen species, an enzyme, or the like.
  • Fluorescent probes containing chemical structures can be manufactured.
  • the metal ions include alkali metal ions such as sodium ions and lithium ions, alkaline earth metal ions such as calcium ions, magnesium ions, and zinc ions.
  • the active oxygen species include nitric oxide, hydroxy radical, singlet oxygen, superoxide, peroxynitrite, and hypochlorous acid.
  • the measurement object is not limited to these.
  • a substituent for capturing an object to be measured that has been conventionally used in a fluorescent probe for measuring protons, metal ions, or reactive oxygen species may be introduced onto an aryl group represented by R 1 , preferably a phenyl group. it can. Two substituents introduced on the aryl group may be bonded to each other to form a ring structure to form a substituent for capturing a proton, metal ion, or reactive oxygen species.
  • R 1 aryl group represented by R 1
  • R 1 A substituent introduced into the group or a ring structure condensed with the phenyl group, wherein R is an arbitrary substituent.
  • the position of the substituent for capturing the proton, metal ion, or reactive oxygen species introduced on the aryl group represented by R 1 , preferably the phenyl group, is not particularly limited. In addition to these substituents, any substituent may be present on the aryl group represented by R 1 , preferably the phenyl group.
  • substituents for capturing the measurement object have been proposed and can be appropriately selected by those skilled in the art depending on the type of the measurement object. For example, JP-A-10-226688, International Publication WO 99/51586, JP-A 2000-239272, International Publication WO 01/62755, and the like can be referred to.
  • substituted for capturing a proton, metal ion, or reactive oxygen species means that the substituent chelates a metal ion without causing a substantial chemical change with respect to an object to be measured. This should be interpreted in the broadest sense, including the case where the chemical structure of the substituent changes due to a chemical reaction with the measurement object, in addition to the case of capturing by chemicalization, etc. must not.
  • one or both of the two groups introduced onto the aryl group represented by R 1 are represented by the following formula (A ): (Wherein, X 1 , X 2 , X 3 , and X 4 each independently represent a hydrogen atom, an alkyl group, or a 2-pyridylmethyl group, and m and n each independently represent 0 or 1). It is preferred that
  • both aryl groups represented by R 1 preferably two groups introduced on the phenyl group, independently represent groups represented by the above formula (A), and m and n Is 0 and these two groups are substituted at adjacent positions on the aryl ring.
  • any one of the two groups introduced onto the aryl group represented by R 1 preferably the phenyl group, is a group represented by the above formula (A), and the other is A hydrogen atom is preferred.
  • X 1 , X 2 , X 3 , and X 4 are preferably 2 -pyridylmethyl groups, and X 1 and X 2 are more preferably 2-pyridylmethyl groups. Further, m is 0, n is 1, and X 4 is preferably a hydrogen atom. In this case, both X 1 and X 2 are preferably 2-pyridylmethyl groups.
  • an aryl group represented by R 1 preferably two adjacent groups introduced on the phenyl group are bonded to each other to form a ring structure represented by the following formula (B): : (Wherein R 18 represents an alkyl group, an alkoxy group, or a carboxyl group, and R 19 and R 20 each independently represents an alkyl group or an aryl group).
  • R 19 and R 20 are preferably each independently a phenyl group which may have a substituent, and more preferably both are phenyl groups.
  • the substituents for capturing protons, metal ions, or reactive oxygen species described above are exemplary, and the substituents for capturing protons, metal ions, or reactive oxygen species are not limited thereto. This will be readily understood by those skilled in the art. In addition, those skilled in the art can easily understand that the introduction site of a substituent for capturing protons, metal ions, or reactive oxygen species is not limited to the aryl group represented by R 1 , preferably the benzene ring of the phenyl group. It is possible to design various fluorescent probes using the residue of the compound of the present invention represented by the general formula (I).
  • a side chain containing a chemical structure that is specifically recognized by the enzyme and undergoes a chemical change and the residue of the compound represented by the above general formula (I) It is common to design a fluorescent probe that binds to each other.
  • R 6 and / or R 7 is hydrogen
  • an amino acid or peptide that acts as an enzyme substrate is introduced into the residue of the compound represented by the general formula (I) obtained by removing the hydrogen
  • a fluorescent probe for measuring an enzyme can be produced.
  • a fluorescent probe specific for caspase 3 can be produced by introducing a group represented by —CO—CH (NH 2 ) —CH 2 —COOH.
  • the fluorescent probe for measuring the enzyme is not limited to the above example.
  • compounds having a photodegradable protecting group are applied to the analysis of dynamic biological signal transmission as so-called caged compounds.
  • protecting groups of the o-nitrobenzyl type are widely used (for example, ⁇ -carboxy-2-nitrobenzyl group, 1- (2-nitrophenyl) ethyl group, 4,5- Dimethoxy-2-nitrobenzyl group, 1- (4,5-dimethoxy-2-nitrophenyl) ethyl group, 5-carboxymethoxy-2-nitrobenzyl group, etc .: Molecular Probes catalog (Handbook of Fluorescent Probes and Research Chemicals, ninth Edition), Chapter 17 (caging groups and their photolysis), and photodegradable protecting groups described in JP-A-2006-241133).
  • a caged compound can be produced by introducing such a photodegradable protecting group into the residue of the compound represented by the general formula (I).
  • R 6 and / or R 7 is hydrogen
  • capturing the measurement target aryl group represented by R 1 as a fluorescent probe compound is substantially nonfluorescent before, preferably have a substantially high electron density on the benzene ring of the phenyl group, and compound after acquisition of the measurement object It is desirable to select a combination of substituents that substantially lowers the electron density of the aryl group represented by R 1 , preferably the benzene ring of the phenyl group, so that is substantially fluorescent.
  • Information on the electron density of the benzene ring of the aryl group represented by R 1 can be easily obtained, for example, by calculating the oxidation potential of the aryl ring according to a quantum chemical technique.
  • the design concept of such a fluorescent probe is disclosed in, for example, International Publication No. WO2005 / 24049. For example, by referring to FIG. Is possible to understand. All of the above international disclosures are incorporated herein by reference.
  • the compound represented by the general formula (I) emits fluorescence in the state of a quaternary salt, but is substantially non-fluorescent or weakly fluorescent when the nitrogen atom forming the quaternary salt becomes tertiary nitrogen. It becomes.
  • the nitrogen forming the quaternary salt is modified by amidation or the like so that the quaternary salt cannot be taken into a tertiary nitrogen atom, which is substantially non-fluorescent or weak.
  • a fluorescent probe that is substantially non-fluorescent or weakly fluorescent can be designed before capture of the measurement target substance. This technique is widely used in rhodamine derivatives.
  • the measurement method of an object to be measured using a fluorescent probe generally includes (A) a residue of the compound of the present invention represented by the above general formula (I) and a proton, metal ion, reactive oxygen species, or enzyme A step of reacting a measurement object with a fluorescent probe combined with a substituent for capturing a group, and the like, and (B) a step of measuring the fluorescence of the compound after supplementation generated in the step (A). It is out.
  • Fluorescence measurement means using a fluorescent probe is not particularly limited, but a method of measuring a fluorescence spectrum in vitro, a method of measuring a fluorescence spectrum in vivo using a bioimaging technique, or the like can be adopted. .
  • a method of measuring a fluorescence spectrum in vitro a method of measuring a fluorescence spectrum in vivo using a bioimaging technique, or the like can be adopted.
  • the fluorescent component can be labeled with the biological component.
  • a fluorescent labeling reagent can be produced.
  • biological components include, but are not limited to, amino acids, oligopeptides, proteins, lipids, saccharides, nucleic acids, and the like.
  • a reactive functional group capable of binding to an amino group, carboxyl group, thiol group, hydroxyl group, etc. present in a biological component can be used.
  • a maleimide group for example, a maleimide group, a succinimide group, 1
  • Various reactive functional groups have been proposed depending on the type of amino group, carboxyl group, thiol group, or hydroxyl group to be modified, such as 1,3-thiazolidine-2-thione group, and those skilled in the art will select as appropriate. It is possible.
  • the anti-tumor antibody is labeled using a fluorescent labeling reagent in which a residue of the compound of the present invention represented by the above general formula (I) and a reactive functional group reactive with a biological component are bound.
  • a fluorescent labeling reagent in which a residue of the compound of the present invention represented by the above general formula (I) and a reactive functional group reactive with a biological component are bound.
  • the presence of cancer cells or cancer tissue can be proved by bringing the labeled antibody into contact with the tissue or organ.
  • tissue sections and the like may be fixed by an appropriate method such as a paraffin method and observed under a microscope, but biological tissues can also be stained immunochemically using an endoscope and observed. .
  • Various fluorescence imaging methods using near-infrared fluorescent materials have been proposed (for example, JP-A-9-309845; J. Neurosurg., 87, pp. 738-745, 1997; medical electronics and biotechnology, 34, pp.316-322, 1996, etc.), the
  • the above-mentioned fluorescent probe or fluorescent labeling reagent may be used as a composition by blending additives usually used for the preparation of the reagent as necessary.
  • additives such as solubilizers, pH adjusters, buffers, and isotonic agents can be used as additives for using the reagent in a physiological environment, and the amount of these additives is appropriately selected by those skilled in the art. Is possible.
  • These compositions are provided as a composition in an appropriate form such as a mixture in a powder form, a lyophilized product, a granule, a tablet, or a liquid.
  • Example 1 The compound SiR680 of the present invention was prepared according to the following scheme.
  • the reaction solution was returned to room temperature and stirred overnight. 2 N HCl was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous NaHCO 3 solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in dichloromethane (20 mL) and a sufficient amount of chloranil was added. After the mixture was stirred for 2 hours, the solvent was distilled off again. The residue was purified by HPLC to obtain the desired product (SiR680, 20.9 mg, 0.0370 mmol, yield 16%).
  • Example 2 The compounds SiX700, 2-Me-4-COOH SiR700, and SiR700 of the present invention were prepared according to the following scheme.
  • Example 3 The compounds SiX720 and SiR720 of the present invention were prepared according to the following scheme.
  • Example 4 Absorption spectra and fluorescence spectra of the compounds of the present invention (SiR680, SiR700, and SiR720), the compound described in Chinese Patent Application No. 200610045944.6 (SiR650), and the cyanine compound (Cy5.5) were measured.
  • SiR680, SiR700, and Cy5.5 were irradiated with light (40 mW / cm 2 , Cy5 filter) for 10 minutes, 20 minutes, and 30 minutes, and the light fading resistance was examined.
  • SiR680, SiR700, and Cy5.5 were excited at 650 nm, 670 nm, and 650 nm, respectively.
  • the compound of the present invention was more excellent in light fading resistance than the comparative compound Cy5.5.

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Abstract

Cette invention concerne un composé fluorescent de formule (I), qui a un pic d'absorption/fluorescence dans la région proche infrarouge d'environ 680 nm à 750 nm. [R1 représente un atome d'hydrogène, un groupe alkyle ou un groupe aryle ; R2 à R5 représentent chacun un atome d'hydrogène, un groupe alkyle, un group hydroxy ou un atome d'halogène ; R6 et R7 représentent chacun un groupe alkyle ; Z représente Si(R8)(R9), Ge(R8)(R9) ou Sn(R8)(R9) (R8 et R9 étant chacun un atome d'hydrogène, un groupe alkyle ou un groupe aryle) ; X et Y représentent chacun –C(R10)(R11)-, -C(R12)(R13)-C(R14)(R15)- ou –C(R16)=C(R17)- (R10 à R17 étant chacun un atome d'hydrogène, un groupe alkyle, un groupe hydroxy ou un atome d'halogène) ; et M- représente un anion lorsqu'un contre-ion est présent.]
PCT/JP2010/057541 2009-04-30 2010-04-28 Composé fluorescent proche infrarouge WO2010126077A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012099218A1 (fr) * 2011-01-20 2012-07-26 国立大学法人 東京大学 Sonde fluorescente
WO2012111818A1 (fr) * 2011-02-18 2012-08-23 国立大学法人 東京大学 Sonde fluorescente
WO2012111817A1 (fr) * 2011-02-18 2012-08-23 国立大学法人 東京大学 Sonde fluorescente
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WO2013122189A1 (fr) * 2012-02-17 2013-08-22 国立大学法人 東京大学 Sonde fluorescente
WO2014106957A1 (fr) * 2013-01-07 2014-07-10 国立大学法人 東京大学 SYNTHÈSE DE RHODAMINE Si ASYMÉTRIQUE ET DE RHODOL
CN104262378A (zh) * 2014-08-28 2015-01-07 中国人民解放军第二军医大学 一种硅基罗丹明衍生物及其制备方法和应用
WO2015083799A1 (fr) * 2013-12-04 2015-06-11 国立大学法人 東京大学 Groupe de désactivation proche infrarouge
WO2015194606A1 (fr) * 2014-06-17 2015-12-23 国立大学法人大阪大学 Sonde fluorescente, agent de détection d'oxygène singulet, et procédé de détection d'oxygène singulet
CN105482807A (zh) * 2015-11-24 2016-04-13 中国人民解放军第二军医大学 具有溶酶体定位功能的硅基罗丹明铜离子荧光探针及其制备方法和应用
JP2016521254A (ja) * 2013-03-15 2016-07-21 ビセン メディカル， インコーポレイテッド ｉｎｖｉｔｒｏおよびｉｎｖｉｖｏイメージングおよび検出のための置換シラキサンテニウム赤色〜近赤外蛍光色素
EP3431480A1 (fr) * 2012-01-30 2019-01-23 The University Of Hong Kong Sondes fluorogènes à base de diarylamine utilisables en vue de la détection de péroxynitrite
CN110204568A (zh) * 2019-07-02 2019-09-06 华东师范大学 一类硅基取代香豆素衍生物及其合成方法
CN111303111A (zh) * 2020-03-23 2020-06-19 华东理工大学 一类新型黄菁近红外二区染料、制备方法及荧光成像应用
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US9714260B2 (en) 2013-01-07 2017-07-25 The University Of Tokyo Asymmetrical Si rhodamine and rhodol synthesis
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