WO2022163377A1

WO2022163377A1 - Photosensitizer

Info

Publication number: WO2022163377A1
Application number: PCT/JP2022/001035
Authority: WO
Inventors: 篤志白石; 双葉川上
Original assignee: サンアプロ株式会社
Priority date: 2021-02-01
Filing date: 2022-01-14
Publication date: 2022-08-04
Also published as: JPWO2022163377A1

Abstract

Provided is a photosensitizer which has a specific structure, and has higher sensitivity than existing photosensitizers when light irradiation causes a rapid change from hydrophilicity to hydrophobicity. The present invention pertains to: a photosensitizer containing a metal complex which is represented by general formula (1) or general formula (2) and has a cyclic ligand that forms a ring structure in which pyrrole rings are linked directly or via π conjugation, and an axial ligand having an onium salt structure; an antibody conjugate to which said photosensitizer binds; a method of using said photosensitizer, the method being characterized in that the detachment of an axial ligand is promoted through irradiation with light having a wavelength of 500-1,500 nm; and a usage method in which said photosensitizer is used for therapeutic purpose.

Description

Photosensitizer

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. In addition, it is known that active species such as radicals and singlet oxygen are generated from the excited state by light irradiation. There is a therapeutic method in which the substance is administered into the body by ingestion or injection and irradiated with light. 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. (See Patent Documents 1 to 3).

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.

In order to avoid side effects such as those described above, attention has been focused on molecular target therapy, particularly in therapeutic methods. 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. Based on the above idea, in recent years 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.

For example, 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 is disclosed 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. In 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.

Furthermore, in Patent Document 6, 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. According to this method, 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.

Japanese Patent Publication No. 09-504811 Patent No. 2532368 Japanese Patent Application Publication No. 2014-522881 Patent No. 6127045 Patent No. 6741599 Japanese translation of PCT publication No. 2017-524002

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.
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.

As a result of intensive studies aimed at solving the above problems, the present inventors have found that a photosensitizer having a specific structure has excellent effects on the above problems.
That is, the present invention has general formula (1) or A photosensitizer containing a metal complex represented by the general formula (2).

In formula (1), 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. may form a condensed polycyclic aromatic structure, 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, and 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;

In formula (3), 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. and containing at least one ammonio group represented by the following 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 , 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 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.

In formula (5), L ³ is methylene, ethylene or propylene, and X ₄ ^- is an anion selected from the group represented by carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid and phosphonic acid. However, when both R ¹⁰ and R ¹¹ have formula (5), either one of X ₄ ^- has a hydrogen ion or a monovalent metal cation.

Furthermore, 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.

Further, 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. As a result, in a method of use in which a complex specifically bound to a specific target cell is agglutinated by irradiation with visible light to infrared light, the agglutination action is more efficient than that of conventional photosensitizers. can be done.

Hereinafter, embodiments of the present invention will be described in detail.

The photosensitizer of the present invention has the general formula It contains a metal complex represented by (1) or general formula (2).

In formula (3), 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. and at least one 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.

The cyclic ligand having a ring structure in which pyrrole rings are connected directly or by π 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 π 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.

In formulas (1) and (2), Y may be a nitrogen atom, CR ⁹ or a direct bond. Here, the direct bond means that the pyrrole rings are directly bonded to form a ring structure connected by π 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. .

In formulas (1) and (2), 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 atoms, alkylthio group having 1 to 18 carbon atoms, alkylsulfinyl group having 1 to 18 carbon atoms, arylsulfinyl group having 6 to 10 carbon atoms, carbon alkylsulfonyl groups having ₁ to 18 carbon atoms, arylsulfonyl groups having ₆ to ₁₀ carbon atoms, alkyleneoxy groups, amino groups, cyano groups _, nitro groups and halogen groups; , R ₅ and R ₆ , R ₇ and R ₈ may be bonded to each other to form a condensed polycyclic aromatic structure.

In the above, 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

Examples of 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.

Examples of 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.

Examples of alkynyl groups having 2 to 30 carbon atoms 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.

Examples of 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.

Examples of 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.

Examples of 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.

Among the substituents R ¹ to R ⁸ on these cyclic ligands, preferably an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, a carbon an alkylcarbonyl group having 2 to 6 carbon atoms, an arylcarbonyl group having 7 to 11 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an arylthio group having 6 to 14 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, a chloro group, a fluoro group, more preferably an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group having 4 to 14 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or 2 to 6 carbon atoms are an alkylcarbonyl group, a benzoyl group, an aryloxy group having 6 to 10 carbon atoms, and a fluoro group.

In formula (2), X ₂ ^- is a monovalent counter anion corresponding to the central metal cation.
In formulas (1) and (2), 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, and Ga a 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, and 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%. When the substitution ratio with fluorine atoms is within these preferred ranges, the photosensitivity of the sulfonium salt is further improved. Particularly preferred examples of 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 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 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 ) ₂ CF) ₃ PF ₃ ⁻ , ((CF ₃ ) ₂ CF) ₂ The anions represented by PF ₄ ^- , ((CF ₃ ) ₂ CFCF ₂ ) ₃ PF ₃ ^- and ((CF ₃ ) ₂ CFCF ₂ ) ₂ PF ₄ ^- are preferred.

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 ⁻ . Among these, 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. Among these, 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 In addition to the anions represented by ¹³ SO ₃ ^- , (R ¹³ SO ₂ ) ₃ C ^- or (R ¹³ SO ₂ ) ₂ N ^- , 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.), hexafluorobismuthate anions (BiF ₆ ⁻ ), carboxylate anions (CH ₃ COO ⁻ , CF ₃ COO ⁻ , C ₆ H ₅ COO ⁻ , CH ₃ C ₆ H ₄ COO ⁻ , C ₆ F ₅ COO ⁻ , CF ₃ C ₆ H ₄ COO ⁻ , etc.), arylborate anions (B(C ₆ H ₅ ) ₄ ⁻ , CH ₃ CH ₂ CH ₂ CH ₂ B(C ₆ H ₅ ) ₃ ^- , etc.), thiocyanate anion (SCN ⁻ ), nitrate anion (NO ₃ ⁻ ), and the like can be used.

Among these anions, F ⁻ , Cl ⁻ , Br ⁻ , I ⁻ , BF ₄ ⁻ , SbF ₆ ⁻ , PF ₆ ⁻ , (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 ⁻ , (R ¹³ SO ₂ ) ₂ N ⁻ and carboxylate ions (CH ₃ COO ⁻ , CF ₃ COO ⁻ , C ₆ H ₅ COO ⁻ , CH ₃ C ₆ H ₄ COO ⁻ , C ₆ F ₅ COO ⁻ , CF ₃ C ₆ H ₄ COO ⁻ etc.) are preferred, and Cl ⁻ , Br ⁻ , I ⁻ , BF ₄ ⁻ , PF ₆ ⁻ , (CF ₃ CF ₂ ) ₃ PF ₃ ⁻ , ((CF ₃ ) ₂ CF) ₃ PF ₃ ⁻ , (CF ₃ CF ₂ CF ₂ ) ₃ PF ₃ ⁻ , trifluoromethanesulfonate anion, nonafluoro The butanesulfonate anions, CH ₃ COO ⁻ , CF ₃ COO ⁻ , (CF ₃ SO ₂ ) ₃ C ⁻ and (CF ₃ SO ₂ ) ₂ N ⁻ are soluble in water and polar solvents (such as dimethyl sulfoxide). is more preferable. When two or more anions are present in the same molecule, they may be the same or different.

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.

In formula (3), D is directly bonded to the central metal M and represents an oxygen atom or a sulfur atom.

In formula (3), 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.
Here, the main chain is the main skeleton that connects D and the onium cation A ⁺ .
Examples of alkylene having 1 to 8 carbon atoms 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.
Examples of alkenylene having 2 to 8 carbon atoms 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.
Examples of 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 ^- .

Specific examples of the ammonio group represented by formula (4) include the following.
* indicates the binding position.

Among these, 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. The following are mentioned. * indicates the binding position.

In formula (3), 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-methylisoquinolium, etc.);
thiazonium cations (such as benzylbenzothiazonium cations);
acridium cations (such as benzyl acridium cation and phenacylacridium cation);
diazonium cations (phenyldiazonium cation, 2,4,6-trimethoxyphenyldiazonium cation, 2,4,6-triethoxyphenyldiazonium cation and 4-anilinophenyldiazonium cation, etc.);
Phosphonium cations [quaternary phosphonium cations (tetraphenylphosphonium cation, tetra-p-tolylphosphonium cation, triphenylbenzylphosphonium cation, triphenylbutyl cation, tetraethylphosphonium cation, tetrabutylphosphonium cation, etc.) and the like].
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)iodonium cation];

Among the above onium cations, sulfonium cations, iodonium cations, and diazonium cations are preferred from the viewpoint of photoresponsiveness.

Specific examples of preferred axial ligands L ¹ and L ² represented by formula (3) containing sulfonium cations include the following.

Specific examples of preferred axial ligands L ¹ and L ² represented by formula (3) containing iodonium cations include the following.

Specific examples of 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 π 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. (Here, the aromatic heterocyclic compound is defined as porphyrin.) 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.

(In the formula, 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).)

When the photosensitizer (object) represented by the general formula (2) of the present invention is a cationic metal complex, an axis containing the cationic metal complex precursor (a′) and an onium structure and having an anion of interest The target compound can be obtained by combining with the ligand precursor (b). _At that time, in order to introduce X2, which is the counter anion of the central metal cation, 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.

(In the formula, 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. 184170, etc., first, 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. Solvents and aqueous solutions containing anionic alkali metal salts, alkaline earth metal salts or quaternary ammonium salts and, if necessary, other anionic components such as KPF ₆ , KBF ₄ and NaB(C ₆ F ₅ ) ₄ in a theoretical amount or more. Add it inside and make it double decompose. Water or an organic solvent can be used as the solvent. 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). Moreover, when 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.

In particular, 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).

[In formula (6), (G) represents a biomolecule (probe), and L4 represents a ^divalent group that bonds (G) to a photosensitizer molecule. ]

In formula (6), (G) represents a biomolecule (hereinafter referred to as probe), including natural or synthetic molecules for use in biological systems. Preferred 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.

In formula (6), 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.

In order to introduce the probe (G), it is convenient to introduce a group represented by the following general formula (7) into at least one of R ¹ to R ⁸ which are substituents of the cyclic ligand. is preferred.

[In formula (7), L4 is the same as in formula ( ⁶ ), and (G') represents a reactive group for binding the probe (G) in formula (6). ]

In formula (7), 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). , 1-benzotriazolyl group, 4-nitrophenyloxy, pentafluorophenyloxy group, etc.), 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.

In order to introduce the probe (G), the carboxyl group, amino group, thiol group, etc. contained in (G) may be reacted with the reactive group (G') to bond. As an example, 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. Thus, the probe (G) and the photosensitizer of the present invention are bound.

When the photosensitizer of the present invention is irradiated with light, 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. It aggregates with a change in hydrophilicity and hydrophobicity due to , and can destroy target cells.
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. In particular, when applying the sensitizer of the present invention to target cancer cells, monoclonal antibodies are preferably used. Basiliximab and the like are specifically exemplified. 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 the specific binding of antibodies.

The present invention will be further described below with reference to Examples, but the present invention is not intended to be limited to these. In addition, unless otherwise specified below, % means % by weight.

Production Example 1 Synthesis of Metal Complex Precursor (a-1) Synthesis of Octaethyl Porphyrinatosilicon (IV) Dichloride (a-1). W. Buchler, et. al. , Chem. Ber. 1973, 106, 2710, the title compound (a-1) was synthesized from octaethylporphyrin and tetrachlorosilane.

Production Example 2 Synthesis of Metal Complex Precursor (a-4) Synthesis of Phthalocyanatogermanium (IV) Dichloride 150 g of n-pentanol, 23 g of 1,2-dicyanobenzene and 10 g of germanium tetrachloride were added to a reaction vessel. 27 g of DBU (1,8-diazabicyclo[5.4.0]-7-undecene) was added and mixed. The mixture was heated to 140° C. and reacted under reflux for 12 hours. After cooling to room temperature, the reaction solution was gradually added dropwise to 1,500 g of methanol/water=1/2 (weight ratio) while stirring to obtain a slurry. This was filtered, and the filtrate was washed five times with 100 g of methanol/water=1/2 (weight ratio) and dried to obtain 18.9 g of a dark blue solid. ¹ H-NMR confirmed that this dark blue solid was the metal complex precursor (a-4).

The structure of the metal complex precursor (a) is shown below. In addition, reagents purchased from Aldrich Co. were used for all of the metal complex precursors other than the above production examples.

Production Example 3 Synthesis of Axial Ligand Precursor (b-1/Cl) (1) Intermediate-1: Synthesis of 3,5-dimethyl-4-hydroxyphenyldiphenylsulfonium chloride salt 2,6-dimethyl 7.3 g of phenol, 50 g of methanesulfonic acid and 7 g of diphosphorus pentoxide were added and stirred. 10 g of diphenyl sulfoxide was added thereto and reacted at 45° C. for 6 hours. The reaction solution was gradually added to 100 mL of 20% saline solution with stirring while being cooled in an ice bath. An additional 100 mL of dichloromethane was added and stirred for 1 hour. After standing, the aqueous layer was removed by liquid separation, and the organic layer was washed with 50 mL of water five times and concentrated. Recrystallization was performed with acetone to obtain 15.2 g of a white solid. This white solid was confirmed to be (Intermediate-1) by ¹ H-NMR.
(2) Intermediate-2: Synthesis of 4-chloroethoxy-3,5-dimethylphenyldiphenylsulfonium chloride salt Into a reaction vessel (Intermediate-1) 3.4 g, THF 20 mL, potassium carbonate 1.5 g, 1-bromo- 14 g of 2-chloroethane was added and reacted at 60° C. for 6 hours. After the reaction, concentration under reduced pressure was performed using an evaporator, extraction was performed by adding 50 mL of dichloromethane to the residue, and washing with water was performed 5 times with 50 mL of water. After that, the organic layer was concentrated under reduced pressure using an evaporator and recrystallized with dichloromethane-hexane to obtain 3.2 g of a white solid. This white solid was confirmed to be (Intermediate-2) by ¹ H-NMR.
(3) Synthesis of Axial Ligand Precursor (b-1/Cl) 4.1 g of (Intermediate-2), 20 mL of acetonitrile, and 1.8 g of N,N-dimethylethanolamine were added to a reaction vessel and heated at 60°C. The reaction was allowed to proceed for 12 hours. After the reaction, concentration under reduced pressure was performed using an evaporator, extraction was performed by adding 50 mL of dichloromethane to the residue, and washing with water was performed five times with 50 mL of water. After that, the organic layer was concentrated under reduced pressure using an evaporator and recrystallized with dichloromethane-hexane to obtain 2.5 g of a slightly yellow solid (yield: 51%). It was confirmed by ¹ H-NMR that this slightly yellow solid was the axial ligand precursor (b-1/Cl).

Production Example 4 Synthesis of Axial Ligand Precursor (b-1/Br) 0.5 g of silver acetate was dissolved in 100 mL of water. A solution prepared by adding and dissolving .5 g and 10 mL of acetonitrile was added little by little, and the mixture was stirred for 1 hour. The resulting precipitate was removed by centrifugation, 0.5 g of potassium bromide was added to the solution portion, and the mixture was stirred at room temperature for 6 hours. Extraction was performed by adding 50 mL of dichloromethane, and washing was performed 5 times with 50 mL of water. After that, the organic layer was concentrated under reduced pressure using an evaporator and recrystallized with dichloromethane-hexane to obtain 0.35 g of a slightly yellow solid (yield 60%). It was confirmed by ¹ H-NMR that this slightly yellow solid was the axial ligand precursor (b-1/Br).

Production Example 5 Synthesis of Axial Ligand Precursor (b-1/(C ₂ F ₅ ) ₃ PF ₃ ) 4.9 g of axial ligand precursor (b-1/Cl) was added to a reaction vessel, and 100 mL of dichloromethane was added. Dissolved. An aqueous solution prepared by previously dissolving 10.6 g of K(C ₂ F ₅ ) ₃ PF ₃ in 100 mL of water was added thereto and stirred for 6 hours. The aqueous layer was removed by liquid separation. It was washed with 50 mL of water five times, and the organic layer was concentrated. Recrystallization was performed with dichloromethane-hexane to obtain 5.7 g of a slightly yellow solid (yield 44%). ¹ H, ¹⁹ F and ³¹ P-NMR confirmed that this slightly yellow solid was the axial ligand precursor (b-1/(C ₂ F ₅ ) ₃ PF ₃ ).

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 7 Synthesis of Axial Ligand Precursor (b-2/I) (1) Intermediate-3: Synthesis of 4-phenylthiophenyl-2-bromoethyl ether 4.0 g of 4-phenylthiophenol in a reaction vessel , THF 50 mL, potassium carbonate 3.0 g, and 1,2-dibromoethane 15 g were added and reacted at 60° C. for 6 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. 50 mL of dichloromethane was added to the residue for extraction, and the extract was washed with 50 mL of water five times. After that, the organic layer was concentrated under reduced pressure using an evaporator and purified by silica gel column chromatography to obtain 5.2 g of pale yellow oil (yield: 84%). ¹ H-NMR confirmed that this pale yellow oil was (Intermediate-3).
(2) Intermediate-4: Synthesis of 4-(2-bromoethoxy)phenylphenylmethylsulfonium iodide 3.1 g of (Intermediate-3), 20 mL of chloroform, and 1.6 g of iodomethane were added to a reaction vessel and heated at 50°C. It was reacted for 5 hours. After the reaction, the mixture was washed with 30 mL of water five times, and then the organic layer was concentrated under reduced pressure using an evaporator and purified by silica gel column chromatography to obtain 3.1 g of a pale yellow solid (yield: 69%). It was confirmed by ¹ H-NMR that this pale yellow solid was (Intermediate-4).
(3) Intermediate-5: Synthesis of 4-(2-[N-{3-(ethoxydimethylsilyl)propyl}amino]ethoxy)phenylphenylmethylsulfonium iodide Into a reaction vessel (Intermediate-4) 4.5 g , 50 mL of acetone, 5 g of sodium carbonate, and 1.6 g of 3-aminopropyldimethylethoxysilane were added and reacted under reflux for 18 hours. The reaction mixture was poured into 100 mL of water. The extract was extracted with 50 mL of dichloromethane, washed with water five times, and concentrated. Purification by silica gel column chromatography gave 2.7 g of pale yellow solid (yield 51%). It was confirmed by ¹ H-NMR that this pale yellow solid was (Intermediate-5).
(4) Synthesis of Axial Ligand Precursor (b-2/I) 5.3 g of (Intermediate-5), 20 mL of acetone, 5 g of sodium carbonate, and 5.0 g of iodomethane were added to a reaction vessel and reacted under reflux for 5 hours. let me A solid precipitated after the reaction was filtered off, and the filtrate was added to 100 mL of a 50% aqueous iodic acid solution. The mixture was stirred at room temperature for 3 hours and extracted with 50 mL of dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, washed with water five times, and concentrated. Recrystallization was performed with dichloromethane-hexane to obtain 2.5 g of pale yellow solid (yield 38%). ¹ H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-2/I).

Production Example 8 Synthesis of Axial Ligand Precursor (b-2/PF ₆ ) / _I ) _6.6 g _, _6.1 g of slightly yellow solid ₍ yield: 88%) was obtained. ¹ H, ¹⁹ F and ³¹ P-NMR confirmed that this slightly yellow solid was the axial ligand precursor (b-2/PF ₆ ).

Production Example 9 Synthesis of axial ligand precursor (b-3/Cl) (1) Intermediate-6: N-(4-dimethylsulfonio)phenylmethyl-N-(2-bromoethyl)dimethylammonium dibromide Synthesis 2.2 g of 4-methylthio-α-bromotoluene and 20 mL of THF were added to a reaction vessel, and 1.5 g of 2-(dimethylamino)ethyl bromide was added dropwise in an ice bath. After dropping, the mixture was stirred at room temperature for 20 hours. After that, 15 mL of bromomethane (2MTHF solution) was added and further reacted at 40° C. for 6 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. The obtained crude crystal was used as intermediate-6 as it was. It was confirmed by ¹ H-NMR that the main component was Intermediate-6.
(2) Intermediate-7: Synthesis of 4-[{8-(ethoxydimethylsilyl)-2,2,5,5-tetramethylbisazonia}octyl]phenyldimethylsulfonium tribromide 6) 4.6 g was added to 50 mL of acetone and 1.9 g of 3-dimethylaminopropyldimethylethoxysilane, and reacted at room temperature for 18 hours. The reaction mixture was poured into 100 mL of water. After extracting the organic matter with 30 mL of ethyl acetate, the aqueous layer was concentrated to obtain 2.9 g of white solid (yield 45%). This slightly yellow solid was confirmed to be Intermediate-7 by ¹ H-NMR.
(3) Synthesis of Axial Ligand Precursor (b-3/Cl) 0.6 g of (Intermediate-7) and 10 mL of acetonitrile were added to an aqueous silver acetate solution prepared by dissolving 0.5 g of silver acetate in 100 mL of water. The dissolved solution was added portionwise and stirred for 1 hour. The resulting precipitate was removed by centrifugation, 0.5 g of potassium chloride was added to the solution portion, and the mixture was stirred at room temperature for 6 hours. 50 mL of dichloromethane was added for extraction, 50 mL of 1N hydrochloric acid was added, the mixture was stirred for 2 hours, and further washed with 50 mL of water five times. After that, the organic layer was concentrated under reduced pressure using an evaporator and recrystallized with ethyl acetate-methanol to obtain 0.28 g of a white solid (yield: 57%). It was confirmed by ¹ H-NMR that this slightly yellow solid was the axial ligand precursor (b-3/Cl).

Production Example 10 Synthesis of Axial Ligand Precursor (b-3/CF ₃ CO ₂ ) 0.5 g of axial ligand precursor (b-3/Cl) was dissolved in 10 mL of methanol in a reaction vessel. 0.66 g of silver fluoroacetate was added and stirred at room temperature for 24 hours. 10 mL of water was added, the resulting precipitate was removed by centrifugation, and the organic layer was concentrated. Recrystallization was performed with ethyl acetate-methanol to obtain 0.63 g of a white solid (yield 88%). ¹ H, ¹⁹ F-NMR confirmed that this white solid was an axial ligand precursor (b-3/CF ₃ CO ₂ ).

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 12 Synthesis of Axial Ligand Precursor (b-4/Cl) (1) Intermediate-8: Synthesis of 4-carboxyphenyldiphenylsulfonium chloride 10 g of 4-iodobenzoic acid was added to reaction vessel (A) and 150 mL of THF. dissolved in 1.8 g of sodium hydride was added thereto. It was stirred for 10 minutes and then cooled to -40°C. 30 mL of a 15% THF solution of diisopropylmagnesium bromide was added dropwise thereto. The mixture was stirred at -10°C for 3 hours. 16 g of diphenyl sulfoxide was added to another reaction vessel (B) and dissolved in 50 mL of THF. This was cooled to -40°C and 15 g of trimethylsilyl chloride was added dropwise. After stirring at -40°C for 30 minutes, the mixture was added to the reaction vessel (A) through a tube. Stir at -20°C for 3 hours and cool to -70°C. 100 mL of 20% hydrochloric acid aqueous solution was added thereto. The mixture was warmed to room temperature and 300 mL of diethyl ether and 200 mL of 20% aqueous hydrochloric acid were added. This was stirred for 1 hour and allowed to stand. By liquid separation, the aqueous layer was extracted with diethyl ether and dichloromethane, and the extract was combined with the organic layer and concentrated. Purification by silica gel column chromatography gave 15 g of a white solid. This white solid was confirmed to be Intermediate-8 by ¹ H-NMR.
(2) Intermediate-9: Synthesis of 4-(2-dimethylaminoethyloxycarbonyl)phenyldiphenylsulfonium chloride 3.4 g of (Intermediate-8) and 30 mL of DMF were added to a reaction vessel, and 1-ethyl-3- An additional 3.8 g of (3-dimethylaminopropyl)carbodiimide hydrochloride was added. This was stirred for 1 hour, and 1.0 g of dimethylaminoethanol was added dropwise thereto. After dropping, the mixture was stirred for 12 hours, and then poured into 100 mL of water. After extraction with 50 mL of dichloromethane, the organic layer was washed with 1N hydrochloric acid, further washed with an aqueous sodium hydrogencarbonate solution, washed with water five times, and concentrated. The obtained crude crystal was used as intermediate-9 as it was. It was confirmed by ¹ H-NMR that the main component was Intermediate-9.
(3) Synthesis of Axial Ligand Precursor (b-4/Cl) 4.1 g of (Intermediate-9) was added to a reaction vessel, and 50 mL of acetone and 1.9 g of 2-chloroethyldimethylethoxysilane were added, and the mixture was refluxed for 18 hours. reacted over time. After the reaction, concentration under reduced pressure was performed using an evaporator. 50 mL of dichloromethane was added to the residue for extraction, and the organic layer was washed with 1N hydrochloric acid, further washed with water five times, and concentrated. Recrystallization was performed with dichloromethane-hexane to obtain 2.7 g of pale yellow solid (yield 49%). ¹ H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-4/Cl).

Production Example 13 Synthesis of Axial Ligand Precursor (b-5/Br) (1) Intermediate-10: Synthesis of 4-{N-(2-bromoethyl)dimethylammonio}methylphenyldiphenylsulfonium dibromide Reactor 4.4 g of 4-(bromomethyl)phenyldiphenylsulfonium bromide and 50 mL of THF were added to the solution, and 1.5 g of 2-(dimethylamino)ethyl bromide was added dropwise at room temperature. After dropping, the mixture was stirred at room temperature for 20 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. The light brown solid obtained was washed with diethyl ether and dried to obtain 3.9 g of a light yellow solid (yield 67%). This pale yellow solid was confirmed to be Intermediate-10 by ¹ H-NMR.
(2) Synthesis of Axial Ligand Precursor (b-5/Br) 0.6 g of (Intermediate-10), 10 mL of acetone, and 0.2 g of 2-dimethylaminoethyldimethylethoxysilane were added to a reactor and refluxed. The reaction was allowed to proceed for 8 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. The residue was extracted with 50 mL of dichloromethane, 20 mL of 1N hydrochloric acid was added, and the mixture was stirred for 2 hours, washed with water 5 times, and concentrated. The obtained solid was washed with diethyl ether to obtain 0.45 g of pale yellow solid (61% yield). ¹ H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-5/Br).

Production Example 14 Synthesis of Axial Ligand Precursor (b-6/PF ₆ ) (1) Intermediate-11: Synthesis of (3-carboxypropyl-1-one-phenyl)diphenylsulfonium Chloride 9.0 g of chloride, 50 mL of dichloromethane, and 4.0 g of aluminum chloride were added and stirred. This was cooled in an ice bath, and 9.0 g of succinic anhydride was added dropwise. After stirring at room temperature for 8 hours, the reaction solution was poured into 100 mL of ice water. An additional 50 mL of dichloromethane was added, and the mixture was further stirred for 1 hour. After allowing to stand, the aqueous layer was removed, and the organic layer was washed with water five times and then concentrated. Purification by silica gel column chromatography gave 13.8 g of a white solid. This white solid was confirmed to be Intermediate-11 by ¹ H-NMR.
(2) Intermediate-12: Synthesis of 4-{3-(N-dimethylaminoethyl)carbamoylpropyl-1-one}phenyldiphenylsulfonium chloride In Production Example 12 (2), (Intermediate-8) 3.4 g Instead of (Intermediate-11) 4.0 g, N,N-dimethylethylenediamine 1.1 g instead of 1.0 g of dimethylaminoethanol was obtained according to the method described in Production Example 12 (2). The crude crystal was used as intermediate-12 as it is. It was confirmed by ¹ H-NMR that the main component was Intermediate-12.
(3) Synthesis of Axial Ligand Precursor (b-6/PF ₆ ) 4.7 g of (Intermediate-12), 50 mL of acetone, and 2.3 g of 3-bromopropyldimethylethoxysilane were added to a reactor and refluxed. The reaction was allowed to proceed for 18 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. 50 mL of dichloromethane was added to the residue for extraction, the organic layer was washed with 1N hydrochloric acid, and the aqueous layer was removed by liquid separation. 50 mL of an aqueous solution prepared by dissolving 4.0 g of KPF ₆ in 50 mL of water was added and stirred for 3 hours. The organic layer was further washed with water five times and concentrated. Recrystallization was performed with dichloromethane-hexane to obtain 2.7 g of pale yellow solid (yield 32%). ¹ H, ¹⁹ F and ³¹ P-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-6/PF ₆ ).

Production Example 15 Synthesis of Axial Ligand Precursor (b-7/CF ₃ CO ₂ ) 0.5 g of (Intermediate-5), 20 mL of methanol, 1.6 g of diisopropylethylamine, and 1,3-propanesultone were placed in a reaction vessel. .2 g was added and reacted under reflux for 20 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. It was dissolved again in 10 mL of methanol, 5 mL of 1N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 3 hours. Extracted with 10 mL of dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, washed with water five times, and concentrated. The resulting solid was dissolved in 10 mL of methanol, 0.66 g of silver trifluoroacetate was added, and the mixture was stirred at room temperature for 24 hours. 10 mL of water was added, the resulting precipitate was removed by centrifugation, and the organic layer was concentrated. Recrystallization was performed with dichloromethane-methanol to obtain 0.4 g of pale yellow solid (yield 53%). ¹ H, ¹⁹ F-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-7/CF ₃ CO ₂ ).

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).

Production Example 17 Synthesis of Axial Ligand Precursor (b-8/Br) (1) Intermediate-13: Synthesis of (2-methoxy-4-hydroxyphenyl)phenyliodonium bromide - 12.4 g of methoxyphenol, 700 g of glacial acetic acid and 70 g of acetic anhydride were dissolved and mixed, and cooled in an ice bath. 12 g of concentrated sulfuric acid was added dropwise so that the temperature did not exceed 5° C., and the mixture was allowed to react at room temperature for an additional 3 hours. The reaction solution was slowly added to 200 mL of a 20% potassium bromide aqueous solution with stirring while being cooled in an ice bath. An additional 100 mL of dichloromethane was added and stirred for 1 hour. After standing, the aqueous layer was removed by liquid separation, and the organic layer was washed with 50 mL of water five times and concentrated. Separation and purification were performed by silica gel column chromatography to obtain 23.2 g of a white solid (yield 57%). This white solid was confirmed to be (Intermediate-13) by ¹ H-NMR.
(2) Intermediate-14: Synthesis of 2-methoxy-4-(3-bromo-1-propoxy)phenylphenyliodonium bromide 20 g of 1,3-dibromopropane was added and reacted at room temperature for 18 hours. The reaction solution was concentrated by an evaporator, and the resulting oil was dissolved in 50 mL of dichloromethane. It was washed with 50 mL of water five times, and the organic layer was concentrated. Recrystallization was performed with dichloromethane-hexane to obtain 3.8 g of a white solid (yield 72%). This white solid was confirmed to be (Intermediate-14) by ¹ H-NMR.
(3) Synthesis of Axial Ligand Precursor (b-8/Br) Except for using 5.3 g of (Intermediate-14) instead of 4.1 g of (Intermediate-2) in Production Example 3(3). obtained 4.0 g of a slightly yellow solid (yield 65%) according to the method described in Production Example 3(3). It was confirmed by ¹ H-NMR that this slightly yellow solid was the axial ligand precursor (b-8/Br).

Production Example 18 Synthesis of Axial Ligand Precursor (b-9/Br) (1) Intermediate-15: {4-(2-bromoethyldimethylammoniomethyl)phenyl}(2,4,6-trimethoxy Phenyl)iodonium dibromide In Production Example 13 (1), {4-(bromomethyl)phenyl}(2,4,6-trimethoxyphenyl)iodonium bromide 5 instead of 4.4 g of 4-(bromomethyl)phenyldiphenylsulfonium bromide 4.9 g (yield 70%) of a slightly yellow solid was obtained according to the method described in Production Example 13(1) except that the amount was 4 g. This slightly yellow solid was confirmed to be Intermediate-15 by ¹ H-NMR.
(2) Synthesis of axial ligand precursor (b-9/Br) In Production Example 13(2), instead of 0.6 g of (Intermediate-10), 0.7 g of (Intermediate-15), 1N hydrochloric acid According to the method described in Production Example 13(2) except that 20 mL of 10% hydrobromic acid was used instead of 20 mL, 0.54 g of a pale yellow solid was obtained (yield 64%). It was confirmed by ¹ H-NMR that this slightly yellow solid was the axial ligand precursor (b-9/Br).

Production Example 19 Synthesis of Axial Ligand Precursor (b-10/TfO) (1) Intermediate-16: [4-{N-3-(ethoxydimethylsilyl)propyl-N-methylaminomethyl}phenyl] ( Synthesis of 2,4,6-trimethoxyphenyl)iodonium triflate In a reaction vessel {4-(bromomethyl)phenyl}(2,4,6-trimethoxyphenyl)iodonium bromide 5.4 g, acetone 50 mL, sodium carbonate 5 g, 3 -N-methylaminopropyldimethylethoxysilane (1.8 g) was added and reacted under reflux for 18 hours. The 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).
(2) Synthesis of Axial Ligand Precursor (b-10/TfO) A reaction vessel was charged with 0.7 g of (Intermediate-16), 20 mL of methanol, 0.8 g of diisopropylethylamine, and 0.6 g of 1,3-propanesultone. Then, the mixture was reacted under reflux for 20 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. It was dissolved again in 10 mL of methanol, 5 mL of 1N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 3 hours. Extracted with 10 mL of dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, washed with water five times, and concentrated. The obtained solid was washed with diethyl ether and dried to obtain 0.4 g of a pale yellow solid (yield 50%). ¹ H, ¹⁹ F-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-10/TfO).

Production Example 20 Synthesis of axial ligand precursor (b-11/Br) (1) Intermediate-17: Synthesis of (2,6-dimethoxy-4-hydroxyphenyl)phenyliodonium bromide In Production Example 17 (1) , 23.6 g of a white solid (yield 54%) was obtained according to the method described in Production Example 17 (1) except that 15.4 g of 3,5-dimethoxyphenol was used instead of 12.4 g of 3-methoxyphenol. . This white solid was confirmed to be (Intermediate-17) by ¹ H-NMR.
(2) Intermediate-18: Synthesis of {2,6-dimethoxy-4-(2-bromoethoxy)phenyl}phenyliodonium bromide In Production Example 17 (2), (Intermediate-13) instead of 4.1 g (Intermediate-17) 4.4 g, white solid 2.4 g (yield rate of 44%) was obtained. This white solid was confirmed to be (Intermediate-18) by ¹ H-NMR.
(3) Intermediate-19: Synthesis of (2,6-dimethoxy-4-[2-{N-(3-dimethylethoxysilylpropyl)amino}ethoxy]phenyl)phenyliodonium bromide In Production Example 7 (3), (Intermediate-4) Instead of 4.5g (Intermediate-18) 5.4g, according to the method described in Production Example 7 (3), 2.3g of slightly yellow solid (yield 37%) Obtained. It was confirmed by ¹ H-NMR that this slightly yellow solid was (Intermediate-19).
(4) Synthesis of Axial Ligand Precursor (b-11/Br) 0.6 g of (Intermediate-19), 20 mL of methanol, 1.6 g of diisopropylethylamine, and 1.2 g of 1,3-propanesultone were placed in a reaction vessel. Then, the mixture was reacted under reflux for 20 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. It was dissolved again in 10 mL of methanol, 5 mL of 10% hydrobromic acid aqueous solution was added thereto, and the mixture was stirred at room temperature for 3 hours. Extracted with 10 mL of dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, washed with water five times, and concentrated. Recrystallization was performed with dichloromethane-methanol to obtain 0.49 g of pale yellow solid (yield 57%). It was confirmed by ¹ H-NMR that this pale yellow solid was the axial ligand precursor (b-11/Br).

Production Example 21 Synthesis of axial ligand precursor (b-11/CF ₃ CO ₂ ) In Production Example 10, 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 ).

Production Example 22 Synthesis of axial ligand precursor (b-11/TfO) In Production Example 10, the axial ligand precursor (b -11/Br) 0.9 g, and 0.31 g of a pale yellow solid (yield 33 %) was obtained. ¹ H, ¹⁹ F-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-11/TfO).

Production Example 23 Synthesis of Axial Ligand Precursor (b-12/PF ₆ ) (1) Intermediate-20: Synthesis of 4-(2-bromoethoxy)-2,6-dimethoxyaniline 8.5 g of dimethoxy-4-hydroxyaniline, 100 mL of THF, 7.5 g of potassium carbonate and 50 g of 1,2-dibromoethane were added and reacted at 50° C. for 6 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. The residue was extracted with 50 mL of ethyl acetate, and the organic layer was washed with water and concentrated. Purification was performed by silica gel column chromatography to obtain 5.8 g of a yellow oil (yield 42%). This yellow oil was confirmed to be Intermediate-20 by ¹ H-NMR.
(2) Intermediate-21: Synthesis of 4-[2-{3-(ethoxydimethylsilyl)propyldimethylammonio}ethoxy]-2,6-dimethoxyaniline bromide (or N-(3-ethoxydimethylsilyl) Propyl-N-2-{(4-amino-3,5-dimethoxy)phenoxy}ethyl-dimethylammonium bromide)
In Production Example 9 (2), 3.1 g of a yellow solid ( Yield 67%) was obtained. This yellow solid was confirmed to be Intermediate-21 by ¹ H-NMR.
(3) Synthesis of Axial Ligand Precursor (b-12/PF ₆ ) 4.6 g of (Intermediate-21), 10 mL of water, and 2 mL of 35% hydrochloric acid are added to a reaction vessel and cooled in a salt ice bath while stirring. did. An aqueous solution prepared by previously dissolving 0.7 g of sodium nitrite in 5 mL of water at 0° C. was slowly added with stirring. The mixture was stirred at 0° C. for 1 hour. An aqueous solution prepared by previously dissolving 2.0 g of KPF ₆ in 50 mL of water was added while maintaining the temperature, and the mixture was further stirred for 6 hours. 50 mL of dichloromethane was added thereto for extraction, and the aqueous layer was removed by a liquid separation operation. It was washed with water five times and concentrated by an evaporator. Recrystallization was performed with methanol-diethyl ether to obtain 2.5 g of a slightly yellow solid (yield 38%). ¹ H, ¹⁹ F and ³¹ P-NMR confirmed that this slightly yellow solid was the axial ligand precursor (b-12/PF ₆ ).

Production Example 24 Synthesis of Axial Ligand Precursor (b-13/PF ₆ ) (1) Intermediate-22: 4-(2-[N-{3-(ethoxydimethylsilyl)propyl}amino]ethoxy)- Synthesis of 3,5-dimethoxyaniline In Production Example 7 (3), 2.8 g of (Intermediate-20) instead of 4.5 g of (Intermediate-4) and 1.6 g of 3-aminopropyldimethylethoxysilane 2.3 g of a yellow solid (yield 62%) was obtained according to the method described in Production Example 7(3) except that 1.8 g of 3-aminopropyldimethylisopropoxysilane was used. ¹ H-NMR confirmed that this yellow solid was (Intermediate-22).
(2) Synthesis of Axial Ligand Precursor (b-13/PF ₆ ) In a reaction vessel, 0.4 g of (Intermediate-22), 20 mL of methanol, 1.6 g of diisopropylethylamine, and 1.2 g of 1,3-propanesultone were placed. was added and reacted under reflux for 20 hours. After the reaction, concentration under reduced pressure was performed using an evaporator. The obtained solid was charged into another reaction vessel, and 10 mL of water and 2 mL of 35% hydrochloric acid were added and cooled in a salt ice bath while stirring. An aqueous solution prepared by previously dissolving 0.7 g of sodium nitrite in 5 mL of water at 0° C. was slowly added with stirring. The mixture was stirred at 0° C. for 1 hour. An aqueous solution prepared by previously dissolving 2.0 g of KPF ₆ in 50 mL of water was added while maintaining the temperature, and the mixture was further stirred for 6 hours. 50 mL of dichloromethane was added thereto for extraction, and the aqueous layer was removed by a liquid separation operation. It was washed with water five times and concentrated by an evaporator. Recrystallization was performed with methanol-diethyl ether to obtain 0.27 g of a slightly yellow solid (yield 36%). ¹ H, ¹⁹ F and ³¹ P-NMR confirmed that this slightly yellow solid was the axial ligand precursor (b-13/PF ₆ ).

<Examples 1 to 43> (Synthesis of the photosensitizer of the present invention)
Synthesis of the photosensitizer of the present invention was carried out based on the following synthesis methods (I to III). The structures of the photosensitizers (abbreviated as PS) synthesized in Examples 1 to 43 and the synthetic methods used are shown in Table 1.

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) was obtained.

Synthesis method (II) (where there are two axial ligands, a cationic metal complex, and a counter anion X ₂ ^- )
Examples 18-22
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. Then dissolved in dichloromethane. An aqueous solution of an alkali metal salt (lithium, sodium or potassium salt) of the anion X ₂ ^- was added thereto and stirred for 1 hour. After allowing to stand, the aqueous layer was removed, and the organic layer was washed with water five times and concentrated. Purification with dichloromethane-hexane gave 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.

(Evaluation-1: solubility test)
<Examples 44 to 86 and Comparative Examples 1 to 4>
Using the photosensitizers obtained in Examples 1 to 43 and the compounds for comparison, solubility was evaluated under the following conditions. Table 2 shows the results.
DMSO solution preparation:
(a) 10 mg of photosensitizer is dissolved in 1 mL of DMSO to make a 1% DMSO solution.
(b) 1 mg of photosensitizer is dissolved in 1 mL of DMSO to make a 0.1% DMSO solution.
Then, these were diluted with A: 10 mL of water and B: diluted with 10 mL of 0.1 M phosphate buffer, and the solubility was visually evaluated. The results are shown in Tables 2 and 3.
◎: Transparent 〇: Slightly misty △: Slightly misty, slight sedimentation ×: Immediate sedimentation (Evaluation-2: Photoresponsive test)
Using the photosensitizers obtained in Examples 1 to 43 and a compound for comparison, 1×10 ⁻⁶ M 0.1% DMSO-containing aqueous solutions were prepared, and an irradiation device LIGHTNINGCURE was used as a light source. Using a spot light source LC8 (manufactured by Hamamatsu Photonics), exposure was performed through an infrared transmission filter (manufactured by HOYA) R64 (620 nm or less cut), and changes in appearance were evaluated. This is shown in Tables 2 and 3 as results of photoresponsivity.
◎: Aggregates present, liquid phase transparent 〇: Aggregates present, liquid phase suspended ×: No aggregates [Raw materials used]
PS-1 to PS-43 (photosensitizers described in Table 1)
H-1: Comparative photosensitizer-1 (compound described in Japanese Patent Application Publication No. H09-504811)

H-2: Comparative photosensitizer-2 (compound described in JP-A-2014-522811)

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

*Cannot be evaluated because it does not show appropriate solubility in the photoresponse test.

From Tables 2 and 3, as shown in Examples 44 to 86, it can be seen that 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.

<Photosensitizer bound to probe>
(Synthesis of Metal Complex Precursor Having Reactive Group in Side Chain)

Production Example-25 Synthesis of Metal Complex Precursor (a-10) In a reaction vessel, 200 g of n-pentanol, 2.3 g of 4-{4-(methoxycarbonyl)butoxy}phthalonitrile, 23 g of 1,2-dicyanobenzene, tetra 10 g of chlorosilane was added, and 27 g of DBU (1,8-diazabicyclo[5.4.0]-7-undecene) was added and mixed. The mixture was heated to 140° C. and reacted under reflux for 12 hours. After cooling to room temperature, the reaction solution was gradually added dropwise to 1,500 g of methanol/water=1/2 (weight ratio) while stirring to obtain a slurry. This was filtered, and the filtrate was washed 5 times with 100 g of methanol/water=1/2 (weight ratio) and dried. It was separated and purified by column chromatography to obtain a bluish-green solid. It was confirmed by ¹ H-NMR that this solid was the metal complex precursor (a-10).

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).

(Synthesis example of a photosensitizer (PS-Ra) having a reactive group in the side chain)
Synthesis of the photosensitizer (PS-Ra) having a reactive group in the side chain of the present invention was performed based on the following flow. Table 4 shows the structures of the synthesized photosensitizers (PS-Ra1 to 5).

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.

Synthesis of Intermediate II:
(Intermediate I) and sodium 5-aminovalerate were mixed in a reaction vessel at a molar ratio of 1:1 in acetonitrile solvent and stirred at 40° C. for 48 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain the desired product (Intermediate II).

Synthesis of PS-Ra:
1 mmol of (Intermediate II) was added to a reaction vessel, dissolved in dimethylsulfoxide, 1 mmol of pyridine and 1 mmol of di(N-succinimidyl) carbonate were added, and the mixture was reacted at 50° C. for 6 hours. After the reaction, the mixture was concentrated and washed with IPA/water to obtain the desired product (PS-Ra).

(Synthesis of photosensitizer (PS-Rb) having reactive group in side chain)
Synthesis of the photosensitizer (PS-Rb) having a reactive group in the side chain of the present invention was performed based on the following flow, which is a known method. Table 4 shows the structures of the synthesized photosensitizers (PS-Rb1 to 5).

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.

Synthesis of Intermediate II:
(Intermediate I) and sodium 12-amino-4,7,10-trioxadodecanoate were mixed in a reaction vessel at a molar ratio of 1:1 in acetonitrile solvent and stirred at 40° C. for 48 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain the desired product (Intermediate II).

Synthesis of PS-Ra:
1 mmol of (Intermediate II) was added to a reaction vessel, dissolved in dimethylsulfoxide, 1 mmol of pyridine and 1 mmol of di(N-succinimidyl) carbonate were added, and the mixture was reacted at 50° C. for 10 hours. After the reaction, it was concentrated and washed with ethanol/water to obtain the desired product (PS-Rb).

(Example of photosensitizer bound to probe)
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).

(Evaluation-1: solubility test)
<Examples 107 to 116>
Using the photosensitizers bound to the probes obtained in Examples 97-106, solubility was evaluated under the following conditions. Table 6 shows the results.
DMSO solution preparation:
(a) 10 mg of photosensitizer is dissolved in 1 mL of DMSO to make a 1% DMSO solution.
(b) 1 mg of photosensitizer is dissolved in 1 mL of DMSO to make a 0.1% DMSO solution.
Then, these were diluted with A: 10 mL of water and B: diluted with 10 mL of 0.1 M phosphate buffer, and the solubility was visually evaluated. The results are shown in Tables 2 and 3.
◎: Transparent 〇: Slightly misty △: Slightly misty, slight sedimentation ×: Immediate sedimentation (Evaluation-2: Photoresponsive test)
Using the photosensitizers bound to the probes obtained in Examples 97 to 106, 1×10 ⁻⁶ M 0.1% DMSO-containing aqueous solutions were prepared, and a LIGHTNINGCURE spot light source was used as the light source for the irradiation device. Using LC8 (manufactured by Hamamatsu Photonics), exposure was performed through an infrared transmission filter (manufactured by HOYA) R64 (620 nm or less cut), and changes in appearance were evaluated. This is shown in Table 6 as a result of photoresponsivity.
◎: Aggregates present, liquid phase transparent 〇: Aggregates present, liquid phase suspended ×: No aggregates

From Table 6, it can be seen that the photosensitizers bound to the probes of the present invention, as shown in Examples 107-116, 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.

Claims

general formula (1) or general formula (2), which has a cyclic ligand forming a ring structure in which pyrrole rings are connected directly or by π-conjugation, and an axial ligand having an onium salt structure; Photosensitizer containing a metal complex represented by.

[In formula (1), R 1 to R 8 are substituents on a cyclic ligand, and R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 are may form a condensed polycyclic aromatic structure, Y is a nitrogen atom, CR 9 or may be directly bonded, and 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, and L 1 and L 2 are coordinated to the metal M and have an axial orientation represented by formula (3) L 1 only if 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 and Bi and X 2 - represents a monovalent counter anion corresponding to the central metal cation. ]

[In the formula (3), D represents an oxygen atom or a sulfur atom, E is an alkylene having 1 to 8 carbon atoms, an alkenylene having 2 to 8 carbon atoms, an alkynylene having 2 to 8 carbon atoms, or an arylene having 6 to 14 carbon atoms and contains at least one ammonio group represented by the following 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 groups, silyl groups or phenylene groups, A + is a monovalent onium cation and X 1 - represents a monovalent counter anion corresponding to the onium cation. ]

[In the formula (4), R 10 and R 11 are groups selected from the group represented by an alkyl group having 1 to 3 carbon atoms and 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. ]

[In formula (5), L 3 is methylene, ethylene or propylene, and X 4 - is an anion selected from the group represented by carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid and phosphonic acid. However, when both R 10 and R 11 have formula (5), either one of X 4 - has a hydrogen ion or a monovalent metal cation. ]
2. The photosensitizer according to claim 1, wherein A + in formula (3) is a sulfonium cation, a diazonium cation or an iodonium cation.
3. The photosensitizer according to claim 1, wherein the cyclic ligand is a porphyrin skeleton or a phthalocyanine skeleton.
The photosensitizer according to any one of claims 1 to 3, wherein M in formula (1) is Al, Si, Ge, Sn or P, and M in formula (2) is P.
The photosensitizer according to any one of claims 1 to 4, wherein at least one of the substituents on the cyclic ligand contains a group represented by the following formula (6).

[In formula (6), (G) represents a biomolecule (probe), and L4 represents a divalent group that bonds (G) to a photosensitizer molecule. ]
6. The photosensitizer according to claim 5, wherein at least one of the substituents on the cyclic ligand contains a group represented by the following formula (7).

[In formula (7), L4 is the same as in formula ( 6 ), and (G') represents a reactive group for binding the probe (G) in formula (6). ]
7. The photosensitizer according to claim 5 or 6, wherein (G) is an antibody.
An antibody conjugate to which the photosensitizer according to claim 7 is bound.
8. A method of using the photosensitizer according to any one of claims 1 to 7, wherein the release of the axial ligand is accelerated by irradiation with light of 500 to 1500 nm.
A method of using the photosensitizer according to any one of claims 1 to 7 for therapeutic purposes.