WO2022163377A1 - Photosensibilisateur - Google Patents

Photosensibilisateur Download PDF

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WO2022163377A1
WO2022163377A1 PCT/JP2022/001035 JP2022001035W WO2022163377A1 WO 2022163377 A1 WO2022163377 A1 WO 2022163377A1 JP 2022001035 W JP2022001035 W JP 2022001035W WO 2022163377 A1 WO2022163377 A1 WO 2022163377A1
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group
formula
photosensitizer
carbon atoms
cation
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篤志 白石
双葉 川上
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サンアプロ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/06—Aluminium compounds
    • 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 System
    • C07F7/02—Silicon compounds
    • 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 System
    • C07F7/30—Germanium compounds
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • 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
    • C09K3/00—Materials not provided for elsewhere

Definitions

  • the present invention involves a photosensitizer containing a metal complex having a specific structure, which is sensitive to light in the visible to infrared region, a conjugate formed by combining this with an antibody, and light irradiation using the same. Regarding treatment methods.
  • Phthalocyanines, porphyrins, and analogues thereof are used in fields such as bioimaging, for example, due to their ability to emit high fluorescence when irradiated with visible light.
  • active species such as radicals and singlet oxygen are generated from the excited state by light irradiation.
  • photosensitizers Such compounds are called "photosensitizers", and cytotoxic active oxygen that induces apoptosis, necrosis or autophagy of nearby cells by irradiation with light of a specific wavelength.
  • Excitation light in the near-infrared (NIR) region itself is said to be harmless to cells, but when using current non-targeted photosensitizers, it is taken up by normal cells, which can cause serious side effects. be. Therefore, conventional photodynamic therapy, in which cells are killed in combination with non-ionized physical energy using the above-mentioned photosensitizer, may be of limited use.
  • a compound having a drug action is chemically bound to a protein or the like to be specifically bound to the surface of a specific cell, and the compound is accumulated in the target cell during use to provide more effective treatment.
  • photosensitizers used in light-based therapeutic methods are units for specifically binding to specific cell surfaces with the aim of localizing them on target cells, such as Antibodies and their fragments are used.
  • Patent Document 4 discloses a method for killing cells, wherein an antibody to which one or more IR-700 molecules, which are photosensitizers, is bound to a cell containing a cell surface protein is used.
  • a method which involves binding a therapeutically effective amount specifically to a cell surface protein, irradiating with light of a wavelength of 660-740 nm, and killing the cells with another agent after irradiation.
  • Patent Document 5 in a method for inducing cytotoxicity in a subject suffering from a pathological condition, a drug containing a photosensitizer unit of a phthalocyanine derivative bound to a probe that specifically binds to the target cell is administered to induce cell death.
  • a method is disclosed comprising illuminating said cells with a suitable excitation light in an amount suitable for induction.
  • near-infrared light is irradiated to a complex in which a compound in which an IR-700 molecule, which is a photosensitizer, is bound to an antibody or the like is specifically bound to a specific target cell.
  • a method is disclosed in which a portion of the IR-700 molecule is bound and dissociated by the reaction, thereby changing from a hydrophilic molecule to a hydrophobic molecule, thereby aggregating the complex and removing a specific target cell. ing.
  • a portion of the IR-700 molecule is hydrolyzed by irradiation with near-infrared light, and is changed to be hydrophobic, thereby causing the aggregation.
  • the problem to be solved by the present invention is a photosensitizer having a specific structure, and in the case of causing a rapid change from hydrophilic to hydrophobic by light irradiation as described above, it has higher sensitivity than before. It is the provision of a photosensitizer.
  • a photosensitizer for example, in a method of use in which an antibody conjugate, in which the photosensitizer and an antibody are bound, agglutinates a complex formed by specifically binding to a specific target cell by irradiation with visible light to infrared light. , to provide a photosensitizer having higher sensitivity than conventional ones.
  • the present invention has general formula (1) or A photosensitizer containing a metal complex represented by the general formula (2).
  • R 1 to R 8 are substituents on the cyclic ligand, and R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 are bonded to each other.
  • Y is a nitrogen atom, CR 9 or may be directly bonded
  • R 9 is a hydrogen atom or an aromatic hydrocarbon having 6 to 14 carbon atoms
  • M is selected from the group of Al, Ga, In, Si, Ge, Sn, Fe, Ti, Co and Mn
  • L 1 and L 2 are axially coordinated to metal M and represented by formula (3) and only L 1 when M is Al, Ga, In, Fe, Co or Mn.
  • Formula (2) represents the case where the central metal M is cationic, R 1 to R 8 , Y, L 1 and L 2 are the same as in Formula (1), and M is P, Sb or Bi. is selected from the group X 2 - represents a monovalent counter anion corresponding to the central metal cation;
  • D represents an oxygen atom or a sulfur atom
  • E represents alkylene having 1 to 8 carbon atoms, alkenylene having 2 to 8 carbon atoms, alkynylene having 2 to 8 carbon atoms or arylene having 6 to 14 carbon atoms.
  • a + is a monovalent onium cation
  • X 1 ⁇ represents a monovalent counter anion corresponding to the onium cation.
  • R 10 and R 11 in formula (4) are alkyl groups having 1 to 3 carbon atoms or groups selected from the group represented by the following formula (5). However, when both R 10 and R 11 are alkyl groups having 1 to 3 carbon atoms, it has a monovalent counter anion X 3 — corresponding to the ammonio group.
  • L 3 is methylene, ethylene or propylene
  • X 4 - is an anion selected from the group represented by carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid and phosphonic acid.
  • R 10 and R 11 have formula (5), either one of X 4 - has a hydrogen ion or a monovalent metal cation.
  • the present invention is an antibody conjugate in which the photosensitizer containing an antibody is bound to at least one of the substituents on the cyclic ligand.
  • the present invention is a method of using the photosensitizer, characterized in that detachment of the axial ligand is accelerated by irradiation with light of 500 to 1500 nm.
  • the photosensitizer of the present invention is sensitive to light in the visible to infrared region with a wavelength of 500 nm to 1500 nm to efficiently generate protons, and the action of the protons promotes desorption of the axial ligand. can be done.
  • the agglutination action is more efficient than that of conventional photosensitizers. can be done.
  • the photosensitizer of the present invention has the general formula It contains a metal complex represented by (1) or general formula (2).
  • R 1 to R 8 are substituents on the cyclic ligand, and R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 are bonded to each other.
  • Y is a nitrogen atom, CR 9 or may be directly bonded
  • R 9 is a hydrogen atom or an aromatic hydrocarbon having 6 to 14 carbon atoms
  • M is selected from the group of Al, Ga, In, Si, Ge, Sn, Fe, Ti, Co and Mn
  • L 1 and L 2 are axially coordinated to metal M and represented by formula (3) and only L 1 when M is Al, Ga, In, Fe, Co or Mn.
  • Formula (2) represents the case where the central metal M is cationic, R 1 to R 8 , Y, L 1 and L 2 are the same as in formula (1), and M is P, Sb or Bi. is selected from the group X 2 - represents a monovalent counter anion corresponding to the central metal cation;
  • D represents an oxygen atom or a sulfur atom
  • E represents alkylene having 1 to 8 carbon atoms, alkenylene having 2 to 8 carbon atoms, alkynylene having 2 to 8 carbon atoms or arylene having 6 to 14 carbon atoms.
  • ammonio group represented by formula (4) in the main chain of these groups, and further an ether group, a sulfide group, a ketone group, an amide group, an ester group, a thioester group, a urea group, a sulfone group, It may contain a silyl group or a phenylene group, A + is a monovalent onium cation, and X 1 - represents a monovalent counter anion corresponding to the onium cation.
  • R 10 and R 11 in formula (4) are a methyl group, an ethyl group, or a group selected from the group represented by the following formula (5). However, when both R 10 and R 11 are a methyl group or an ethyl group, it has a monovalent counter anion X 3 — corresponding to the ammonio group.
  • L 3 is methylene, ethylene or propylene
  • X 4 - is an anion selected from the group represented by carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid and phosphonic acid.
  • R 10 and R 11 have formula (5), either one of X 4 - has a hydrogen ion or a monovalent metal cation.
  • the cyclic ligand having a ring structure in which pyrrole rings are connected directly or by ⁇ conjugation is a ligand moiety for the central metal element in the metal complex constituting the photosensitizer of the present invention, and has four is a compound in which the pyrrole rings of are bonded directly or through one carbon atom or nitrogen atom while maintaining a ⁇ bond to form a ring structure.
  • Porphyrins, polyphyrazines, coroles, phthalocyanines, and chlorins are specific examples of compounds useful as cyclic ligands from the viewpoint of availability of raw materials and ease of synthesis. Porphyrins and phthalocyanines are preferred.
  • the axial ligand having an onium salt structure in the present invention is a ligand coordinated to the central metal of the metal complex of the present invention, and , represents a ligand coordinated in the vertical direction, and the axial ligand has an onium salt structure.
  • Y may be a nitrogen atom, CR 9 or a direct bond.
  • the direct bond means that the pyrrole rings are directly bonded to form a ring structure connected by ⁇ conjugation.
  • R 9 is a hydrogen atom or an aromatic hydrocarbon having 6-14 carbon atoms.
  • M represented by formula (1) is the central metal of the metal complex having the cyclic ligand and is selected from the group consisting of Al, Ga, In, Si, Ge, Sn, Fe, Ti, Co and Mn, Al, Si, Ge and Sn are preferred from the viewpoint of photoreactivity.
  • M represented by formula (2) has a cyclic ligand, represents a central metal that forms a cationic metal complex, is selected from the group of P, Sb and Bi, and P is preferable from the viewpoint of photoreactivity. .
  • R 1 to R 8 are substituents on the cyclic ligands and are each independently an aryl group having 6 to 30 carbon atoms or a heteroaryl group having 4 to 30 carbon atoms. , an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms or an alkynyl group having 2 to 30 carbon atoms, a hydroxy group, an alkoxy group having 1 to 18 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, an alkylcarbonyl group having 2 to 19 carbon atoms, an arylcarbonyl group having 7 to 11 carbon atoms, an alkoxycarbonyl group having 2 to 19 carbon atoms, an aryloxycarbonyl group having 7 to 11 carbon atoms, and an arylthiocarbonyl group having 7 to 11 carbon atoms group, acyloxy group having 2 to 19 carbon atoms, arylthio group having 6 to 20 carbon
  • the aryl group having 6 to 30 carbon atoms includes monocyclic aryl groups such as phenyl group and biphenylyl group, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, chrysenyl, naphthacenyl, benzanthracenyl, anthraquinolyl, fluorenyl, naphthoquinone and anthraquinone. and condensed polycyclic aryl groups such as
  • heteroaryl groups having 4 to 30 carbon atoms include cyclic groups containing 1 to 3 heteroatoms such as oxygen, nitrogen and sulfur, which may be the same or different.
  • is a monocyclic heteroaryl group such as thienyl, furanyl, pyranyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl; , carbazolyl, acridinyl, phenothiazinyl, phenazinyl, xanthenyl, thianthrenyl, phenoxazinyl, phenoxathiinyl, chromanyl, isochromanyl, dibenzothienyl, xanthonyl, thioxanthonyl, dibenzofuranyl, and other fused polycyclic heteroaryl groups.
  • alkyl groups having 1 to 30 carbon atoms include linear alkyl groups such as methyl, ethyl, propyl, butyl, hexadecyl and octadecyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and isohexyl. and cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Alkenyl groups having 2 to 30 carbon atoms include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl and the like.
  • alkynyl groups having 2 to 30 carbon atoms examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl and the like. mentioned.
  • the alkoxy groups having 1 to 18 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, dodecyloxy and the like.
  • aryloxy groups having 6 to 10 carbon atoms include phenoxy and naphthyloxy.
  • Alkylcarbonyl groups having 2 to 19 carbon atoms include acetyl, trifluoroacetyl, propionyl, butanoyl, 2-methylpropionyl, heptanoyl, 2-methylbutanoyl, 3-methylbutanoyl, octanoyl and the like.
  • Arylcarbonyl groups having 7 to 11 carbon atoms include benzoyl, 4-tert-butylbenzoyl, naphthoyl and the like.
  • the alkoxycarbonyl group having 2 to 19 carbon atoms includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like.
  • the aryloxycarbonyl group having 7 to 11 carbon atoms includes phenoxycarbonyl, naphthoxycarbonyl and the like.
  • the arylthiocarbonyl group having 7 to 11 carbon atoms includes phenylthiocarbonyl, naphthoxythiocarbonyl and the like.
  • Acyloxy groups having 2 to 19 carbon atoms include acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy, octadecylcarbonyloxy and the like.
  • Arylthio groups having 6 to 20 carbon atoms include phenylthio, biphenylylthio, methylphenylthio, chlorophenylthio, bromophenylthio, fluorophenylthio, hydroxyphenylthio, methoxyphenylthio, naphthylthio, 4-[4-(phenylthio) benzoyl]phenylthio, 4-[4-(phenylthio)phenoxy]phenylthio, 4-[4-(phenylthio)phenyl]phenylthio, 4-(phenylthio)phenylthio, 4-benzoylphenylthio, 4-benzoyl-chlorophenylthio, 4- benzoyl-methylthiophenylthio, 4-(methylthiobenzoyl)phenylthio, 4-(p-tert-butylbenzoyl)phenylthio and the like.
  • alkylthio groups having 1 to 18 carbon atoms include methylthio, ethylthio, propylthio, tert-butylthio, neopentylthio and dodecylthio.
  • the alkylsulfinyl group having 1 to 18 carbon atoms includes methylsulfinyl, ethylsulfinyl, propylsulfinyl, tert-pentylsulfinyl, octylsulfinyl and the like.
  • the arylsulfinyl group having 6 to 10 carbon atoms includes phenylsulfinyl, tolylsulfinyl, naphthylsulfinyl and the like.
  • alkylsulfonyl groups having 1 to 18 carbon atoms include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and octylsulfonyl.
  • the arylsulfonyl groups having 6 to 10 carbon atoms include phenylsulfonyl, tolylsulfonyl, naphthylsulfonyl and the like.
  • Halogen groups include fluoro, chloro, bromo and iodo.
  • X 2 - is a monovalent counter anion corresponding to the central metal cation.
  • L 1 and L 2 are axial ligands represented by formula (3) that coordinate to the metal, and in formula (3), X 1 - is a monovalent It is the monovalent counter anion for the onium cation A + .
  • X 1 - and X 2 - are not restricted except that they are halogen anions and monovalent polyatomic anions such as F ⁇ , Cl ⁇ , Br ⁇ , I ⁇ , BY a ⁇ , PY a ⁇ , SbY a ⁇ , (Rf) b PF 6-b ⁇ , R 12 c BY 4-c ⁇ , R 12 c GaY 4-c ⁇ , R 13 SO 3 ⁇ , (R 13 SO 2 ) 3 C ⁇ and (R An anion represented by 13 SO 2 ) 2 N- is exemplified.
  • P represents a phosphorus atom
  • B a boron atom
  • Sb an antimony atom
  • F a fluorine atom
  • Ga gallium atom
  • Y represents a halogen atom (preferably a fluorine atom).
  • S represents a sulfur atom
  • O represents an oxygen atom
  • C represents a carbon atom
  • N represents a nitrogen atom.
  • Rf represents an alkyl group (preferably an alkyl group having 1 to 8 carbon atoms) in which 80 mol % or more of the hydrogen atoms are substituted with fluorine atoms.
  • Alkyl groups to be Rf by fluorine substitution include straight-chain alkyl groups (methyl, ethyl, propyl, butyl, pentyl, octyl, etc.), branched-chain alkyl groups (isopropyl, isobutyl, sec-butyl, tert-butyl, etc.) and cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like.
  • the ratio of hydrogen atoms of these alkyl groups substituted with fluorine atoms in Rf is preferably 80 mol% or more, more preferably 90 mol%, based on the number of moles of hydrogen atoms possessed by the original alkyl groups. % or more, particularly preferably 100%.
  • the substitution ratio with fluorine atoms is within these preferred ranges, the photosensitivity of the sulfonium salt is further improved.
  • Rf include CF 3 ⁇ , CF 3 CF 2 ⁇ , (CF 3 ) 2 CF ⁇ , CF 3 CF 2 CF 2 ⁇ , CF 3 CF 2 CF 2 ⁇ , (CF 3 ) 2 CFCF 2 ⁇ , CF 3 CF 2 (CF 3 )CF — and (CF 3 ) 3 C — .
  • the b Rf's are independent of each other and therefore may be the same or different.
  • R 12 represents a phenyl group in which some of the hydrogen atoms have been replaced with at least one element or electron-withdrawing group. Examples of such single elements include halogen atoms and include fluorine, chlorine, and bromine atoms. Electron-withdrawing groups include a trifluoromethyl group, a nitro group, a cyano group, and the like. Among these, a phenyl group in which one hydrogen atom is substituted with a fluorine atom or a trifluoromethyl group is preferred.
  • the c R 12 are independent of each other and therefore may be the same or different.
  • R 13 represents an alkyl group having 1 to 20 carbon atoms, a perfluoroalkyl group having 1 to 20 carbon atoms or an aryl group having 6 to 20 carbon atoms, and the alkyl group and perfluoroalkyl group are linear or branched. or cyclic, and the aryl group may be unsubstituted or substituted.
  • a represents an integer of 4 to 6; b is an integer of 1-5, preferably 2-4, more preferably 2 or 3; c is an integer of 1 to 4, preferably 4;
  • Examples of anions represented by (Rf) b PF 6-b - include (CF 3 CF 2 ) 2 PF 4 - , (CF 3 CF 2 ) 3 PF 3 - , ((CF 3 ) 2 CF) 2 PF 4 ⁇ , ((CF 3 ) 2 CF) 3 PF 3 ⁇ , (CF 3 CF 2 CF 2 ) 2 PF 4 ⁇ , (CF 3 CF 2 CF 2 ) 3 PF 3 ⁇ , ((CF 3 ) 2 CFCF 2 ) 2PF 4 ⁇ , ((CF 3 ) 2 CFCF 2 ) 3 PF 3 ⁇ , (CF 3 CF 2 CF 2 ) 2 PF 4 ⁇ and ( CF 3 CF 2 CF 2 CF 2 ) 3 PF 3 ⁇ Anions such as Of these, (CF 3 CF 2 ) 3 PF 3 ⁇ , (CF 3 CF 2 CF 2 ) 3 PF 3 ⁇ , ((CF 3 CF 2
  • Examples of anions represented by R 12 c BY 4-c - include (C 6 F 5 ) 4 B - , ((CF 3 ) 2 C 6 H 3 ) 4 B - , (CF 3 C 6 H 4 ) 4 Anions represented by B ⁇ , (C 6 F 5 ) 2 BF 2 ⁇ , C 6 F 5 BF 3 ⁇ and (C 6 H 3 F 2 ) 4 B ⁇ are exemplified. Among these, anions represented by (C 6 F 5 ) 4 B — and ((CF 3 ) 2 C 6 H 3 ) 4 B — are preferred.
  • Examples of anions represented by R 12 c GaY 4-c - include (C 6 F 5 ) 4 Ga - , ((CF 3 ) 2 C 6 H 3 ) 4 Ga - , (CF 3 C 6 H 4 ) 4 Examples include anions represented by Ga ⁇ , (C 6 F 5 ) 2 GaF 2 ⁇ , C 6 F 5 GaF 3 ⁇ and (C 6 H 3 F 2 ) 4 Ga ⁇ .
  • anions represented by (C 6 F 5 ) 4 Ga — and ((CF 3 ) 2 C 6 H 3 ) 4 Ga — are preferred.
  • Anions represented by R 13 SO 3 — include trifluoromethanesulfonate anion, pentafluoroethanesulfonate anion, heptafluoropropanesulfonate anion, nonafluorobutanesulfonate anion, pentafluorophenylsulfonate anion, and p-toluene.
  • Examples include sulfonate anion, benzenesulfonate anion, camphorsulfonate anion, methanesulfonate anion, ethanesulfonate anion, propanesulfonate anion and butanesulfonate anion.
  • trifluoromethanesulfonate anion trifluoromethanesulfonate anion, nonafluorobutanesulfonate anion, methanesulfonate anion, butanesulfonate anion, camphorsulfonate anion, benzenesulfonate anion and p-toluenesulfonate anion are preferred.
  • Anions represented by (R 13 SO 2 ) 3 C - include (CF 3 SO 2 ) 3 C - , (C 2 F 5 SO 2 ) 3 C - , (C 3 F 7 SO 2 ) 3 C - and anions represented by (C 4 F 9 SO 2 ) 3 C-.
  • Anions represented by (R 13 SO 2 ) 2 N ⁇ include (CF 3 SO 2 ) 2 N ⁇ , (C 2 F 5 SO 2 ) 2 N ⁇ , (C 3 F 7 SO 2 ) 2 N ⁇ and anions represented by (C 4 F 9 SO 2 ) 2 N-.
  • the monovalent polyatomic anions include BY a ⁇ , PY a ⁇ , SbY a ⁇ , (Rf) b PF 6-b ⁇ , R 12 c BY 4-c ⁇ , R 12 c GaY 4-c ⁇ , R
  • perhalate anions ClO 4 - , BrO 4 - etc.
  • halogenated sulfones acid anions FSO 3 - , ClSO 3 - etc.
  • sulfate anions CH 3 SO 4 - , CF 3 SO 4 - , HSO 4 - etc.
  • carbonate anions HCO 3 - , CH 3 CO 3 - etc.
  • aluminum acid anions AlCl 4 ⁇ , AlF 4 ⁇ , ( t- C 4 F 9 O) 4 Al ⁇ etc.
  • L 1 and L 2 represented by formulas (1) and (2) are axial ligands represented by formula (3) that coordinate to the central metal M, and depending on the type of M, the axial ligand different number of If M is Al, Ga, In, Fe, Co or Mn, it has only L1. When there are two axial ligands (L 1 and L 2 ), they may be the same or different.
  • D is directly bonded to the central metal M and represents an oxygen atom or a sulfur atom.
  • E is a divalent group that bonds D and the onium cation A + and is alkylene having 1 to 8 carbon atoms, alkenylene having 2 to 8 carbon atoms, alkynylene having 2 to 8 carbon atoms, or carbon Representing arylene of numbers 6 to 14, containing at least one ammonio group represented by formula (4) in the main chain of these groups, further ether group, sulfide group, ketone group, amide group, ester group, thioester group , a urea group, a sulfone group, a silyl group or a phenylene group.
  • the main chain is the main skeleton that connects D and the onium cation A + .
  • alkylene having 1 to 8 carbon atoms examples include linear alkylene such as methylene, ethylene, trimethylene, tetramethylene, hexamethylene, octamethylene, 1-methylethyl, 1-methylethylidene, 1,1-dimethylethylene, 1,2-dimethyl
  • Examples include branched alkylenes such as ethylene and 1-methylpropylidene, and cyclic alkylenes such as cyclopropylene, cyclobutylene, cyclopentylene, cyclopentylidene, cyclohexylene and cyclohexylidene.
  • alkenylene having 2 to 8 carbon atoms examples include vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-hexenylene, cyclohexenylene, 1,3-butadienylene, 1,3- Hexadienylene, 2,4,6-octatrienylene and the like are included.
  • alkynylene having 2 to 8 carbon atoms include ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene, 1,3-butadienylene, hexane-1-en-3-ynylene, and the like. be done.
  • Arylenes having 6 to 14 carbon atoms include phenylene, naphthylene, anthracenylene, and biphenylene.
  • the main chain contains at least one ammonio group represented by formula (4), which improves the water solubility of the entire compound.
  • R 10 and R 11 in formula (4) are alkyl groups having 1 to 3 carbon atoms or groups selected from the group represented by formula (5). However, when both R 10 and R 11 are alkyl groups having 1 to 3 carbon atoms, it has a monovalent counter anion X 3 — corresponding to the ammonio group.
  • the anions X 3 - mentioned here are the same as those exemplified for the above X 1 - or X 2 - .
  • ammonio group represented by formula (4) include the following. * indicates the binding position.
  • those having carboxylic acid or sulfonic acid are preferable from the viewpoint of ease of synthesis, and sulfonic acid and salts thereof having a high degree of dissociation are more preferable from the viewpoint of improving water solubility.
  • the main chain may further contain an ether group, a sulfide group, a ketone group, an amide group, an ester group, a thioester group, a urea group, a sulfone group, a silyl group or a phenylene group.
  • an ether group a sulfide group, a ketone group, an amide group, an ester group, a thioester group, a urea group, a sulfone group, a silyl group or a phenylene group.
  • * indicates the binding position.
  • a + is a monovalent onium cation bound to the metal via D and E as axial ligands.
  • a + in the present invention decomposes the energy received by the cyclic ligand by light absorption according to a photochemical process (electron transfer, energy transfer, etc.) to generate protons, and ammonio represented by the above formula (4) base is not included.
  • a monovalent onium cation is a cation that is produced by coordinating a proton or a cation-type atomic group (such as an alkyl group) to a compound containing an element having a lone pair of electrons, and is a monovalent onium cation. Examples include the following cations.
  • pyrilinium cations (4-methylpyrilinium cations and 2,6-diphenylpyrilinium cations, etc.); Chromenium cations (2,4-dimethylchromenium cations, etc.); isochromenium cations (1,3-dimethylisochromenium cations, etc.); pyridinium cations (N-methylpyridinium cation, N-methoxypyridinium cation, N-butoxypyridinium cation, N-benzyloxypyridinium cation, N-benzylpyridinium cation, etc.); imidazolium cations (such as N,N'-dimethylimidazolium cations and 1-ethyl-3-methylimidazolium cations); quinolium cations (such as N-methylquinolium cations and N-benzylquinolium cations); isoquinolium cations (N-methylisoquino
  • sulfonium cation ⁇ triphenylsulfonium cation, diphenylmethylsulfonium cation, phenyldimethylsulfonium cation, 4-(phenylthio)phenyldiphenylsulfonium cation, and 4-hydroxyphenylmethylbenzylsulfonium cation, etc. ⁇ ; sulfoxonium cations (such as triphenylsulfoxonium); Thianthrenium cations [5-(4-methoxyphenyl)thianthrenium, 5-phenylthianthrenium and 5-tolylthianthrenium cations]; thiophenium cations (2-naphthyltetrahydrothiophenium, etc.); iodonium cations [such as diphenyliodonium cation, di-p-tolyliodonium cation and 4-isopropylphenyl(p-tolyl)
  • onium cations sulfonium cations, iodonium cations, and diazonium cations are preferred from the viewpoint of photoresponsiveness.
  • preferred axial ligands L 1 and L 2 represented by formula (3) containing sulfonium cations include the following.
  • preferred axial ligands L 1 and L 2 represented by formula (3) containing iodonium cations include the following.
  • preferred axial ligands L 1 and L 2 represented by formula (3) containing diazonium cations include the following.
  • the photosensitizer (target product) represented by the general formula (1) of the present invention can be produced by a known method. That is, the metal complex precursor (a) having the target aromatic heterocyclic compound as a cyclic ligand and an onium structure formed by forming a ring structure in which pyrrole rings are connected directly or by ⁇ conjugation, and the target A desired compound can be obtained by synthesizing axial ligand precursors (b) each having an anion and combining them. As an example, the manufacturing method is shown by the following chemical formula.
  • the metal complex precursor (a) can be produced in various ways by known methods (methods for synthesizing porphyrins and phthalocyanines are described, for example, in KARL M. Kadis H Kevin M. Smith Roger Guilard, The Porphyrin Handbook VOL.1-10, ACADEMIC PRESS (2000) and VOL.
  • M is the same as the central metal M and represents the valence m.
  • X represents a halogen atom and has the same number of halogen atoms as the valence of the metal M.
  • L 5 and L 6 are halogen atoms or hydroxyl [Onium] is the same as A in formula (3), and X 1 is the same as X 1 in formula (3).
  • the photosensitizer (object) represented by the general formula (2) of the present invention is a cationic metal complex
  • the target compound can be obtained by combining with the ligand precursor (b).
  • the target is achieved by exchanging in the presence of an equal amount or more of an alkali metal salt, alkaline earth metal salt, etc. of the X2 anion, which is the raw material.
  • a metal complex is obtained.
  • M is the same as the central metal M and represents the valence m.
  • X represents a halogen atom and has the same number of halogen atoms as the valence of the metal M.
  • L 5 and L 6 are halogen atoms or hydroxyl [Onium] is the same as A in formula (3), X 1 is the same as X 1 in formula (3), M' represents an alkali metal or alkaline earth metal, X2 is the same as X2 in formula ( 2 ).
  • the onium cation structure used in the axial ligand precursor (b) of the present invention can be produced by a metathesis method.
  • the metathesis method is, for example, Shin Experimental Chemistry Course 14-I (1978, Maruzen) p-448; Advance in Polymer Science, 62, 1-48 (1984); Shin Experimental Chemistry Course 14-III (1978, Maruzen) ) pp1838-1846; Organosulfur Chemistry (Synthetic Reaction Edition, 1982, Kagaku Dojin), Chapter 8, pp237-280; Nihon Kagaku Zasshi, 87, (5), 74 (1966); JP-A-64-45357 , JP-A-61-212554, JP-A-61-100557, JP-A-5-4996, JP-A-7-82244, JP-A-7-82245, JP-A-58-210904, JP-A-6- No.
  • halogen ion salts of onium cations such as F ⁇ , Cl ⁇ , Br ⁇ , I ⁇ ; OH ⁇ salts; ClO 4 ⁇ salts; FSO 3 ⁇ , ClSO 3 ⁇ , CH 3 Salts with sulfonate ions such as SO 3 ⁇ , C 6 H 5 SO 3 ⁇ , CF 3 SO 3 ⁇ ; salts with sulfate ions such as HSO 4 ⁇ , SO 4 2- ; HCO 3 ⁇ , CO 3 2- , salts with carbonate ions such as H 2 PO 4 ⁇ , HPO 4 2- , PO 4 3- , and the like salts with phosphate ions, etc., to form the desired onium salt.
  • halogen ion salts of onium cations such as F ⁇ , Cl ⁇ , Br ⁇ , I ⁇ ; OH ⁇ salts; ClO 4 ⁇ salts; FSO 3 ⁇ , ClSO
  • Organic solvents include hydrocarbons (hexane, heptane, toluene, xylene, etc.), cyclic ethers (tetrahydrofuran, dioxane, etc.), chlorinated solvents (chloroform, dichloromethane, etc.), alcohols (methanol, ethanol, isopropyl alcohol, etc.), ketones ( acetone, methyl ethyl ketone and methyl isobutyl ketone), nitriles (such as acetonitrile) and polar organic solvents (such as dimethylsulfoxide, dimethylformamide and N-methylpyrrolidone). These solvents may be used alone or in combination of two or more.
  • the desired photosensitizer thus obtained can be purified by a method such as column chromatography using silica gel or the like, recrystallization, or washing with water or a solvent, if necessary.
  • Purification by recrystallization involves dissolving the desired photosensitizer in a small amount of water or an organic solvent, and separation from the water or organic solvent involves direct application to a water or organic solvent solution containing the desired photosensitizer. (or after concentration), another poor solvent is added to precipitate the desired photosensitizer.
  • the poor solvents used here include chain ethers (diethyl ether, dipropyl ether, etc.), esters (ethyl acetate, butyl acetate, etc.), aliphatic hydrocarbons (hexane, cyclohexane, etc.) and aromatic hydrocarbons (toluene and xylene, etc.).
  • Purification can also be carried out by utilizing the difference in solubility due to temperature. Purification can be carried out by recrystallization (a method of utilizing the difference in solubility due to cooling, a method of precipitating by adding a poor solvent, or a combination thereof).
  • the photosensitizer is an oily substance (when it does not crystallize), it can be purified by a method of washing the oily substance with water or a poor solvent.
  • the structure of the photosensitizer thus obtained can be analyzed by general analytical methods such as nuclear magnetic resonance spectra of 1 H, 13 C, 19 F, 31 P, infrared absorption spectra, mass spectrometry, or It can be identified by elemental analysis or the like.
  • the photosensitizer of the present invention changes from a water-soluble form to a hydrophobic form by light irradiation and is applied to a method of use for the purpose of aggregation.
  • At least one of R 8 is preferably represented by the following general formula (6).
  • (G) represents a biomolecule (probe), and L4 represents a divalent group that bonds (G) to a photosensitizer molecule. ]
  • (G) represents a biomolecule (hereinafter referred to as probe), including natural or synthetic molecules for use in biological systems.
  • probes include proteins, peptides, small molecules, ligands, enzyme substrates, hormones, antibodies, antigens, haptens, avidin, streptavidin, biotin, oligosaccharides, polysaccharides, nucleic acids, deoxynucleic acids, ribonucleic acids, nucleotide triphosphates, etc. is mentioned.
  • L 4 is a divalent group that binds the probe (G) and the photosensitizer molecule of the present invention, and is not particularly limited, from carbon, oxygen, nitrogen, sulfur and phosphorus atoms Consists of a selected straight chain, branched chain, or cyclic chain having 1 to 60 atoms, and a part of the chain may contain a double bond, a triple bond, or a bonding group represented by the following chemical formula. . * indicates the binding position.
  • L4 is the same as in formula ( 6 ), and (G') is a reactive group for binding the probe (G) in formula (6).
  • Specific examples of (G') include an activated ester group (here, a carboxylic acid ester having a good leaving group, such as a succinimidyloxy group and a sulfosuccinimidyloxy group).
  • halogenated acyl group halogenated alkyl group, amino group, acid anhydride, carboxylic acid, carbodiimide group, hydroxy group, iodoacetamide group, isocyanate group, isothiocyanate group, maleimide group, phosphoramidite group, sulfonic acid ester group, thiol group and the like.
  • the carboxyl group, amino group, thiol group, etc. contained in (G) may be reacted with the reactive group (G') to bond.
  • the amino group of (G) reacts with the succinimidyl oxyester group of (G') to form an amide bond, and the thiol group of (G) and the maleimide group of (G') to form a sulfide bond.
  • the probe (G) and the photosensitizer of the present invention are bound.
  • the decomposable onium salt bound to the axial ligand decomposes, and the action of protons generated thereby causes elimination of the axial ligand.
  • the wavelength of the light to be irradiated is not particularly limited as long as it is within the range of wavelengths that can be absorbed by the present photosensitizer. In particular, from the viewpoint of the effect on cells and photoresponsiveness, it is more preferable to irradiate with light of 650 to 1200 nm, which is in the near-infrared region.
  • Aggregation of the photosensitizer of the present invention occurs due to a change from hydrophilicity to hydrophobicity due to detachment of the axial ligand upon irradiation with light. That is, for example, when used in a therapeutic method for killing specific target cells (e.g., cancer cells) by light irradiation, the photosensitizer of the present invention and a probe for binding to specific target cells ( (preferably an antibody) is introduced in advance, and by administering this, a complex that specifically binds to the target cell is formed, and for example, by irradiation with near-infrared light, the axial ligand is detached.
  • specific target cells e.g., cancer cells
  • a probe for binding to specific target cells preferably an antibody
  • the photosensitizer of the present invention When the photosensitizer of the present invention is bound to an antibody, it acts on a protein or the like for specific binding to a specific cell surface, so that it can be accumulated in target cells. Therefore, the photosensitizer-bound antibody conjugate of the present invention can be used for molecular target therapy, as is the case with antibody conjugates conjugated with compounds having other drug actions.
  • monoclonal antibodies are preferably used.
  • Basiliximab and the like are specifically exemplified.
  • it can be suitably used for affinity chromatography, light irradiation molecule inactivation method (CALI and FALI), etc., which are analytical methods and purification methods that utilize the specific binding of antibodies.
  • % means % by weight.
  • the structure of the metal complex precursor (a) is shown below.
  • reagents purchased from Aldrich Co. were used for all of the metal complex precursors other than the above production examples.
  • Production Example 6 Synthesis of Axial Ligand Precursor (b-1/PF 6 ) Production Example 5 was carried out except that 10.6 g of K(C 2 F 5 ) 3 PF 3 was replaced with 4.0 g of KPF 6 . Following the method described in Example 5, 4.9 g (58% yield) of a pale yellow solid was obtained. 1 H, 19 F and 31 P-NMR confirmed that this slightly yellow solid was the axial ligand precursor (b-1/PF 6 ).
  • Production Example 11 Synthesis of Axial Ligand Precursor (b-3/TfO) Described in Production Example 10 except that 0.66 g of silver trifluoroacetate was replaced with 0.77 g of silver trifluoromethanesulfonate. 0.49 g (59% yield) of a white solid was obtained according to the method of 1 H, 19 F-NMR confirmed that this white solid was the axial ligand precursor (b-3/TfO).
  • Production Example 16 Synthesis of Axial Ligand Precursor (b-7/TfO) Described in Production Example 15 except that 0.66 g of silver trifluoroacetate was replaced with 0.77 g of silver trifluoromethanesulfonate. 0.22 g (28% yield) of a pale yellow solid was obtained according to the method of . 1 H, 19 F-NMR confirmed that this white solid was the axial ligand precursor (b-7/TfO).
  • reaction mixture was poured into 100 mL of 10% sodium trifluoromethanesulfonate aqueous solution. After stirring at room temperature for 2 hours, the mixture was extracted with 50 mL of dichloromethane, washed with water 5 times, and concentrated. Recrystallization was performed with dichloromethane-hexane to obtain 6.1 g of a slightly yellow solid (yield 86%). 1 H, 19 F-NMR confirmed that this slightly yellow solid was (Intermediate-16).
  • Production Example 21 Synthesis of axial ligand precursor (b-11/CF 3 CO 2 )
  • axial ligand precursor (b-3/Cl) instead of 0.5 g of axial ligand precursor (b-3/Cl), 0.39 g of a pale yellow solid (yield 44%) was obtained according to the method described in Production Example 10, except that the compound (b-11/Br) was 0.9 g. 1 H, 19 F-NMR confirmed that this pale yellow solid was an axial ligand precursor (b-11/CF 3 CO 2 ).
  • Synthesis method (I) (for metal complexes with two axial ligands) Examples 1-17, 23-32, 38-43
  • the metal complex precursor (a) and the axial ligand precursor (b) were mixed in a reaction vessel at a molar ratio of 1:2 in an acetonitrile solvent at room temperature, reacted for 6 hours while blowing nitrogen, and acetonitrile was distilled off under reduced pressure.
  • the desired product photosensitizer
  • Synthesis method (III) (in the case of a metal complex with one axial ligand) Examples 33-37
  • the metal complex precursor (a) and the axial ligand precursor (b) were mixed in a reaction vessel at a molar ratio of 1:1 in an acetonitrile solvent at room temperature, reacted for 6 hours while blowing nitrogen, and acetonitrile was distilled off under reduced pressure.
  • the desired product (photosensitizer) was obtained.
  • H-3 1:1 (molar ratio) mixture of H-1 and triphenylsulfonium bromide
  • H-4 1:1 (molar ratio) mixture of H-2 and diphenyliodonium chloride
  • the photosensitizers of the present invention exhibit good solubility even in hydrophilic solvents, particularly buffer solvents used in the biotechnology field. Further, as shown in Examples 44 to 86, the photosensitizer of the present invention is hydrophobized by light irradiation and can be effectively aggregated. Although the photosensitizers of Comparative Examples 1 and 2 are excellent in solubility, there is almost no aggregation effect due to hydrophobization, and as in Comparative Examples 3 and 4, the photosensitizer and the onium salt structure are separately blended. It can be seen that, when there is no solubility, it is not suitable for hydrophobization by light irradiation.
  • Production Example-26 Synthesis of Metal Complex Precursor (a-11) According to Production Example 1, instead of octaethylporphyrin, 5-(4-methoxycarbonylphenyl)-10,15,20-triphenylporphyrin (manufactured by Tokyo Kasei) and tetrachlorosilane to synthesize the title compound (a-11).
  • Examples 87-91 Synthesis of Intermediate I According to the synthesis method (I), the metal complex precursor (a-10) and the axial ligand precursor (b) were mixed in an acetonitrile solvent at a molar ratio of 1:2 at room temperature in a reaction vessel, and nitrogen was blown into the reaction vessel. The mixture was allowed to react for several hours, and acetonitrile was distilled off under reduced pressure to obtain the desired intermediate I.
  • Examples 92-96 Synthesis of Intermediate I According to the synthesis method (I), the metal complex precursor (a-11) and the axial ligand precursor (b) were mixed in an acetonitrile solvent at a molar ratio of 1:2 at room temperature in a reaction vessel, and nitrogen was blown into the reaction vessel. The mixture was allowed to react for several hours, and acetonitrile was distilled off under reduced pressure to obtain the desired intermediate I.
  • Photosensitizers (PS-Ra and PS-Rb) having reactive groups on the side chains obtained in Examples 87-96 were used, and biotin was labeled as a probe according to the following flow, which is a known method.
  • Sensitizers (PS-Ba) and (PS-Bb) were synthesized.
  • Table 5 shows the structures of the synthesized photosensitizers (PS-Ba1-5 and PS-Bb1-5).
  • Examples 97-101 0.1 mmol of (PS-Ra) was dissolved in 10 mL of dimethylsulfoxide in a reaction vessel, and 0.1 mmol of N-biotinyl-3,6-dioxaoctane-1,8-diamine (manufactured by Tokyo Kasei) and diphosphate were added thereto. 10 mL of sodium buffer solution (pH 8.4) was added and stirred at room temperature for 24 hours. The reaction mixture was concentrated and washed with acetonitrile and methanol to obtain the desired product (PS-Ba).
  • Examples 102-106 0.1 mmol of (PS-Rb) was dissolved in 10 mL of dimethylsulfoxide in a reaction vessel, and 0.1 mmol of N-biotinyl-3,6-dioxaoctane-1,8-diamine (manufactured by Tokyo Kasei) and diphosphate were added thereto. 10 mL of sodium buffer solution (pH 8.4) was added and stirred at room temperature for 24 hours. The reaction solution was concentrated and washed with acetonitrile and methanol to obtain the desired product (PS-Bb).
  • the photosensitizers bound to the probes of the present invention exhibit good solubility even in hydrophilic solvents, especially buffer solvents used in the biotechnology field. Furthermore, as shown in Examples 107 to 116, the photosensitizer bound to the probe of the present invention is hydrophobized by light irradiation and can be effectively aggregated. That is, even if the photosensitizer of the present invention is in the form of binding various probes, it can be aggregated with a change in hydrophilicity and hydrophobicity by light irradiation without impairing its effect.
  • the photosensitizers (PS-Ra) and (PS-Rb) having a reactive group on the side chain, which are precursors thereof, can also obtain an aggregating effect by light irradiation.
  • the photosensitizer of the present invention uses light (particularly in the visible region to the infrared region) to agglutinate a complex specifically bound to a specific target cell by light irradiation. , and is suitably used for therapeutic purposes as a pharmaceutical (photodynamic therapy, photoimmunotherapy, etc.). In addition, it can be suitably used for affinity chromatography, light irradiation molecule inactivation method (CALI and FALI), etc., which are analytical methods and purification methods that utilize specific binding of antibodies.
  • CALI and FALI light irradiation molecule inactivation method

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Abstract

L'invention concerne un photosensibilisateur qui a une structure spécifique, et qui a une sensibilité plus élevée que les photosensibilisateurs existants lorsque l'irradiation de lumière provoque un changement rapide de l'hydrophilie en hydrophobicité. La présente invention concerne : un photosensibilisateur contenant un complexe métallique qui est représenté par la formule générale (1) ou la formule générale (2) et qui a un ligand cyclique qui forme une structure cyclique dans laquelle des cycles pyrrole sont liés directement ou par conjugaison π, et un ligand axial ayant une structure de sel d'onium ; un conjugué d'anticorps auquel ledit photosensibilisateur se lie ; un procédé d'utilisation dudit photosensibilisateur, le procédé étant caractérisé en ce que le détachement d'un ligand axial est favorisé par irradiation avec de la lumière ayant une longueur d'onde de 500-1500 nm ; et un procédé d'utilisation utilisant ledit photosensibilisateur à des fins thérapeutiques.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2283980A (en) * 1993-11-10 1995-05-24 Sandoz Ltd Cationic aluminium-phthalocyanine dyestuffs
WO2005099689A1 (fr) * 2004-04-01 2005-10-27 Case Western Reserve University Apport topique de phtalocyanines
RU2282646C1 (ru) * 2005-05-31 2006-08-27 Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" (ФГУП "ГНЦ "НИОПИК") Фотосенсибилизаторы для фотодинамической терапии

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2283980A (en) * 1993-11-10 1995-05-24 Sandoz Ltd Cationic aluminium-phthalocyanine dyestuffs
WO2005099689A1 (fr) * 2004-04-01 2005-10-27 Case Western Reserve University Apport topique de phtalocyanines
RU2282646C1 (ru) * 2005-05-31 2006-08-27 Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" (ФГУП "ГНЦ "НИОПИК") Фотосенсибилизаторы для фотодинамической терапии

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZAIDI SYED, AGARWAL RAJESH, EICHLER GUIDO, RIHTER BORIS D., KENNEY MALCOLM E., MUKHTAR HASAN: " Photodynamic Effects of New Silicon Phthalocyanines: In vitro Studies Utilizing Rat Hepatic Microsomes and Human Erythrocyte Ghosts as Model Membrane Sources", PHOTOCHEMISTRY AND PHOTOBIOLOGY, vol. 58, no. 2, 1 August 1993 (1993-08-01), US , pages 204 - 210, XP055953514, ISSN: 0031-8655, DOI: 10.1111/j.1751-1097.1993.tb09550.x *

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