Photosensitizers

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

[Technical Field]

[0001] The present invention relates to a photosensitizer containing a metal complex having a specific structure that is sensitive to light in the visible to infrared region, a conjugate formed by binding the same to an antibody, and a therapeutic method involving light irradiation using the same. [Background technology]

[0002] Phthalocyanines, porphyrins, and their analogues are used in fields such as bioimaging due to their characteristic of emitting high fluorescence when irradiated with visible light. It is also known that light irradiation generates reactive species such as radicals and singlet oxygen from an excited state. This is used in a treatment called photodynamic therapy, in which these compounds are administered by ingestion or injection and then irradiated with light to destroy specific cells in the body. These compounds are called "photosensitizers," and when irradiated with light of a specific wavelength, they generate cytotoxic reactive oxygen species that induce apoptosis, necrosis, or autophagy in nearby cells (see Patent Documents 1 to 3).

[0003] Although near-infrared (NIR) excitation light itself is considered harmless to cells, the use of current non-targeted photosensitizers can result in serious side effects due to their uptake by normal cells. Therefore, conventional photodynamic therapy, which combines non-ionizing physical energy with the photosensitizers to kill cells, may be of limited use.

[0004] In order to avoid the above-mentioned side effects, molecular targeted therapy has attracted attention, particularly in the field of treatment. A compound having a medicinal effect is chemically bonded to a protein or the like for specifically binding to the surface of a specific cell, and the compound is accumulated in the target cell during use, thereby enabling more effective treatment. Based on the above idea, in recent years, photosensitizers used in light-based treatments have been introduced with a unit for specifically binding to the surface of a specific cell, such as an antibody or a fragment thereof, with the aim of localizing the photosensitizer in the target cell.

[0005] For example, Patent Document 4 discloses a method for killing cells, which comprises using an antibody bound to one or more IR-700 molecules, a photosensitizer, to bind specifically to cells containing a cell surface protein in a therapeutically effective amount, irradiating the cells with light having a wavelength of 660 to 740 nm, and then killing the cells with another drug after the irradiation. Patent Document 5 discloses a method for inducing cytotoxicity in a subject suffering from a pathological condition, which comprises administering a drug containing a photosensitizer unit of a phthalocyanine derivative bound to a probe that specifically binds to target cells, and irradiating the cells with appropriate excitation light in an amount suitable for inducing cell death.

[0006] Furthermore, Patent Document 6 discloses a method in which a complex formed by specifically binding a compound comprising an IR-700 photosensitizer molecule and an antibody or the like to a specific target cell is irradiated with near-infrared light, causing a portion of the IR-700 molecule to dissociate, thereby changing from a hydrophilic molecule to a hydrophobic molecule, causing the complex to aggregate and remove the specific target cell. According to this method, a portion of the IR-700 molecule is hydrolyzed and released by irradiation with near-infrared light, changing to a hydrophobic molecule, thereby causing the aggregation. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Special Publication No. 09-504811 [Patent Document 2] Patent No. 2532368 [Patent Document 3] Special Publication No. 2014-522881 [Patent Document 4] Patent No. 6127045 [Patent Document 5] Patent No. 6741599 [Patent Document 6] Special Publication No. 2017-524002 Summary of the Invention [Problem to be solved by the invention]

[0008] The problem to be solved by the present invention is to provide a photosensitizer having a specific structure, which has higher sensitivity than conventional photosensitizers when light irradiation brings about a rapid change from hydrophilic to hydrophobic properties as described above. For example, the present invention provides a photosensitizer with higher sensitivity than conventional photosensitizers, which can be used in a method in which a complex formed by specifically binding an antibody conjugate formed by binding the photosensitizer to a specific target cell is agglutinated by irradiation with visible light to infrared light. [Means for solving the problem]

[0009] As a result of extensive research aimed at solving the above problems, the present inventors have discovered that a photosensitizer having a specific structure has an excellent effect in solving the above problems. That is, the present invention provides a photosensitizer containing a metal complex represented by general formula (1) or general formula (2), which has a cyclic ligand in which pyrrole rings are connected directly or through π-conjugation to form a ring structure, and has an axial ligand having an onium salt structure.

[0010] [ka]

[0011] In formula (1), R 1 ~R 8 is a substituent 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 may be bonded to each other to form a condensed polycyclic aromatic structure, Y is a nitrogen atom, CR 9 or may be directly bonded, R 9is a hydrogen atom or an aromatic hydrocarbon having 6 to 14 carbon atoms, M is selected from the group consisting of Al, Ga, In, Si, Ge, Sn, Fe, Ti, Co and Mn, and L 1 and L 2 is an axial ligand represented by formula (3) coordinated to a metal M, and when M is Al, Ga, In, Fe, Co, or Mn, L 1 Only has.

[0012] [ka]

[0013] Formula (2) shows the case where the central metal M is cationic, and R 1 ~R 8 , Y., L. 1 and L 2 is the same as formula (1), M is selected from the group consisting of P, Sb and Bi, and X2 - represents the monovalent counter anion corresponding to the central metal cation.

[0014] [ka]

[0015] In formula (3), D represents an oxygen atom or a sulfur atom, E represents 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 these groups contain at least one ammonio group represented by the following formula (4) in the main chain, and 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, and A + is a monovalent onium cation, and X1 - represents the monovalent counter anion corresponding to the onium cation.

[0016] [ka]

[0017] R in formula (4)10 , R 11 is an alkyl group having 1 to 3 carbon atoms or a group selected from the group represented by the following formula (5), where R 10 , R 11 When both are alkyl groups having 1 to 3 carbon atoms, the monovalent counter anion X3 corresponding to the ammonio group - It has.

[0018] [ka]

[0019] L in formula (5) 3 is methylene, ethylene or propylene, and X4 - is an anion selected from the group consisting of carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid, and phosphonic acid, where R 10 , R 11 If both have the formula (5), then X4 - Either one of them has a hydrogen ion or a monovalent metal cation.

[0020] The present invention further relates to an antibody conjugate in which the photosensitizer containing an antibody is bound to at least one of the substituents on a cyclic ligand.

[0021] Furthermore, the present invention provides a method for using the photosensitizer, which comprises accelerating the elimination of the axial ligand by irradiation with light of 500 to 1500 nm. [Effects of the Invention]

[0022] The photosensitizer of the present invention is sensitive to light in the visible to infrared wavelength range of 500 nm to 1500 nm, thereby efficiently generating protons, and the action of the protons can promote the detachment of the axial ligand. As a result, when used in a method in which a complex that has specifically bound to a specific target cell is agglutinated by irradiation with visible to infrared light, the photosensitizer can bring about an agglutination effect more efficiently than conventional photosensitizers. DETAILED DESCRIPTION OF THE INVENTION

[0023] Hereinafter, embodiments of the present invention will be described in detail.

[0024] The photosensitizer of the present invention contains a metal complex represented by general formula (1) or (2), which has a cyclic ligand in which pyrrole rings are connected directly or through π-conjugation to form a ring structure, and has an axial ligand having an onium salt structure.

[0025] In formula (1), R 1 ~R 8 is a substituent 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 may be bonded to each other to 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 consisting of Al, Ga, In, Si, Ge, Sn, Fe, Ti, Co and Mn, and L 1 and L 2 is an axial ligand represented by formula (3) coordinated to a metal M, and when M is Al, Ga, In, Fe, Co, or Mn, L 1 Only has.

[0026] Formula (2) shows the case where the central metal M is cationic, and R 1 ~R 8 , Y., L. 1 and L 2 is the same as formula (1), M is selected from the group consisting of P, Sb and Bi, and X2 - represents the monovalent counter anion corresponding to the central metal cation.

[0027] In formula (3), D represents an oxygen atom or a sulfur atom, E represents 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 these groups contain at least one ammonio group represented by formula (4) in the main chain, and 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, and A + is a monovalent onium cation, and X1 - represents the monovalent counter anion corresponding to the onium cation.

[0028] R in formula (4) 10 , R 11 is a methyl group, an ethyl group, or a group selected from the group represented by the following formula (5): 10 , R 11 When both are methyl or ethyl groups, the monovalent counter anion X3 corresponding to the ammonio group - It has.

[0029] L in formula (5) 3 is methylene, ethylene or propylene, and X4 - is an anion selected from the group consisting of carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid, and phosphonic acid, where R 10 , R 11 If both have the formula (5), then X4 - Either one of them has a hydrogen ion or a monovalent metal cation.

[0030] A cyclic ligand in which pyrrole rings are connected directly or through π-conjugation to form a ring structure is a ligand moiety for a central metal element in a metal complex constituting the photosensitizer of the present invention, and is a compound in which four pyrrole rings are connected to form a ring structure by direct bonding or by bonding via one carbon atom or nitrogen atom while maintaining a π bond. From the viewpoints of availability of raw materials and ease of synthesis, specific examples of compounds useful as cyclic ligands include porphyrin, polyphyllazine, corrole, phthalocyanine, and chlorin. Porphyrin and phthalocyanine are preferred.

[0031] In the present invention, the axial ligand having an onium salt structure refers to a ligand that is coordinated to the central metal of the metal complex of the present invention, and that is coordinated in a direction perpendicular to the plane in which the cyclic ligand is coordinated, and the axial ligand has an onium salt structure.

[0032] In formula (1) and formula (2), Y is a nitrogen atom, CR 9 Alternatively, they may be directly bonded. Here, the term "direct bond" means that the pyrrole rings are directly bonded to each other and connected by π-conjugation to form a ring structure. 9 is a hydrogen atom or an aromatic hydrocarbon having 6 to 14 carbon atoms.

[0033] M in 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, with Al, Si, Ge, and Sn being preferred from the viewpoint of photoreactivity. M in formula (2) has a cyclic ligand and represents a central metal that forms a cationic metal complex, and is selected from the group consisting of P, Sb, and Bi, with P being preferred from the viewpoint of photoreactivity.

[0034] In formulas (1) and (2), R 1 ~R 8are substituents on the cyclic ligand, and each independently represents an aryl group having 6 to 30 carbon atoms, 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 1 ... Examples include an arylthiocarbonyl group, an acyloxy group having 2 to 19 carbon atoms, an arylthio group having 6 to 20 carbon atoms, an alkylthio group having 1 to 18 carbon atoms, an alkylsulfinyl group having 1 to 18 carbon atoms, an arylsulfinyl group having 6 to 10 carbon atoms, an alkylsulfonyl group having 1 to 18 carbon atoms, an arylsulfonyl group having 6 to 10 carbon atoms, an alkyleneoxy group, an amino group, a cyano group, a nitro group, and a halogen group, and R1 and R2, R3 and R4, R5 and R6, and R7 and R8 may be bonded to each other to form a condensed polycyclic aromatic structure.

[0035] Examples of the aryl group having 6 to 30 carbon atoms include monocyclic aryl groups such as a phenyl group and a biphenylyl group, and condensed polycyclic aryl groups such as naphthyl, anthracenyl, phenanthrenyl, pyrenyl, chrysenyl, naphthacenyl, benzanthracenyl, anthraquinolyl, fluorenyl, naphthoquinone, and anthraquinone.

[0036] 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. Specific examples include monocyclic heteroaryl groups such as thienyl, furanyl, pyranyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, and pyrazinyl, and fused polycyclic heteroaryl groups such as indolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, carbazolyl, acridinyl, phenothiazinyl, phenazinyl, xanthenyl, thianthrenyl, phenoxazinyl, phenoxathiinyl, chromanyl, isochromanyl, dibenzothienyl, xanthonyl, thioxanthonyl, and dibenzofuranyl.

[0037] Examples of the alkyl group having 1 to 30 carbon atoms include linear alkyl groups such as methyl, ethyl, propyl, butyl, hexadecyl, and octadecyl; branched alkyl groups such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, and isohexyl; and cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0038] Examples of the alkenyl group having 2 to 30 carbon atoms include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, and 1-methyl-1-propenyl.

[0039] Examples of the alkynyl group having 2 to 30 carbon atoms include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-1-propynyl, and 1-methyl-2-propynyl.

[0040] Examples of the alkoxy group having 1 to 18 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and dodecyloxy.

[0041] Examples of the aryloxy group having 6 to 10 carbon atoms include phenoxy and naphthyloxy.

[0042] Examples of the alkylcarbonyl group having 2 to 19 carbon atoms include acetyl, trifluoroacetyl, propionyl, butanoyl, 2-methylpropionyl, heptanoyl, 2-methylbutanoyl, 3-methylbutanoyl, and octanoyl.

[0043] Examples of the arylcarbonyl group having 7 to 11 carbon atoms include benzoyl, 4-tert-butylbenzoyl, and naphthoyl.

[0044] Examples of the alkoxycarbonyl group having 2 to 19 carbon atoms include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, and tert-butoxycarbonyl.

[0045] Examples of the aryloxycarbonyl group having 7 to 11 carbon atoms include phenoxycarbonyl and naphthoxycarbonyl.

[0046] Examples of the arylthiocarbonyl group having 7 to 11 carbon atoms include phenylthiocarbonyl and naphthoxythiocarbonyl.

[0047] Examples of the acyloxy group having 2 to 19 carbon atoms include acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy, and octadecylcarbonyloxy.

[0048] Examples of the arylthio group 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, and 4-(p-tert-butylbenzoyl)phenylthio.

[0049] Examples of the alkylthio group having 1 to 18 carbon atoms include methylthio, ethylthio, propylthio, tert-butylthio, neopentylthio, and dodecylthio.

[0050] Examples of the alkylsulfinyl group having 1 to 18 carbon atoms include methylsulfinyl, ethylsulfinyl, propylsulfinyl, tert-pentylsulfinyl, and octylsulfinyl.

[0051] Examples of the arylsulfinyl group having 6 to 10 carbon atoms include phenylsulfinyl, tolylsulfinyl, and naphthylsulfinyl.

[0052] Examples of the alkylsulfonyl group having 1 to 18 carbon atoms include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, and octylsulfonyl.

[0053] Examples of the arylsulfonyl group having 6 to 10 carbon atoms include phenylsulfonyl, tolylsulfonyl, and naphthylsulfonyl.

[0054] Halogen groups include fluoro, chloro, bromo, and iodo.

[0055] The substituents R on these cyclic ligands 1 ~R 8 Among these, preferred are alkyl groups having 1 to 6 carbon atoms, aryl groups having 6 to 14 carbon atoms, hydroxy groups, alkoxy groups having 1 to 6 carbon atoms, alkylcarbonyl groups having 2 to 6 carbon atoms, arylcarbonyl groups having 7 to 11 carbon atoms, alkylthio groups having 1 to 6 carbon atoms, arylthio groups having 6 to 14 carbon atoms, aryloxy groups having 6 to 10 carbon atoms, chloro groups, and fluoro groups, and more preferred are alkyl groups having 1 to 6 carbon atoms, aryl groups having 6 to 14 carbon atoms, heteroaryl groups having 4 to 14 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, alkylcarbonyl groups having 2 to 6 carbon atoms, benzoyl groups, aryloxy groups having 6 to 10 carbon atoms, and fluoro groups.

[0056] In equation (2), X2 - is the monovalent counter anion corresponding to the central metal cation. In formulas (1) and (2), L 1 and L 2 is an axial ligand represented by formula (3) that coordinates to a metal, and in formula (3), X1 - is a monovalent onium cation A + It is the monovalent counter anion to X1 - and X2 - is not limited except that it is a halogen anion and a monovalent polyatomic anion, for example, F - , Cl - , Br - , I - , BY a - , P.Y. a - , SbY a - , (Rf) b PF 6-b - , R 12 c BY 4-c - , R 12 c Gay 4-c - , R 13 SO3 - , (R 13 SO2)3C- and (R 13 SO2)2N - Examples include anions represented by the following formula:

[0057] P represents a phosphorus atom, B represents a boron atom, Sb represents an antimony atom, F represents a fluorine atom, and Ga represents 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.

[0058] Rf represents an alkyl group in which 80 mol % or more of the hydrogen atoms have been substituted with fluorine atoms (preferably an alkyl group having 1 to 8 carbon atoms). Examples of alkyl groups that are substituted with fluorine atoms to form Rf include linear alkyl groups (methyl, ethyl, propyl, butyl, pentyl, octyl, etc.), branched alkyl groups (isopropyl, isobutyl, sec-butyl, tert-butyl, etc.), and cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.). The ratio of hydrogen atoms in these alkyl groups substituted with fluorine atoms in Rf is preferably 80 mol % or more, more preferably 90 mol % or more, and particularly preferably 100 %, based on the number of moles of hydrogen atoms possessed by the original alkyl group. When the substitution ratio with fluorine atoms is within these preferred ranges, the photosensitivity of the sulfonium salt is further improved. Particularly preferred Rf is CF3 - , CF3CF2 - , (CF3)2CF - , CF3CF2CF2 - , CF3CF2CF2CF2 - , (CF3)2CFCF2 - , CF3CF2(CF3)CF - and (CF3)3C - The b Rfs are independent of each other and may be the same or different.

[0059] R 12represents a phenyl group in which a portion of the hydrogen atoms has been substituted with at least one element or electron-withdrawing group. Examples of such an element include a halogen atom, such as a fluorine atom, a chlorine atom, and a bromine atom. Examples of electron-withdrawing groups include a trifluoromethyl group, a nitro group, and a cyano group. Of these, a phenyl group in which one hydrogen atom has been substituted with a fluorine atom or a trifluoromethyl group is preferred. c R 12 are mutually independent and therefore may be the same or different from each other.

[0060] 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 may be linear, branched, or cyclic, and the aryl group may be unsubstituted or may have a substituent.

[0061] a represents an integer of 4 to 6. b is an integer of 1 to 5, preferably 2 to 4, and more preferably 2 or 3. c is an integer of 1 to 4, and is preferably 4.

[0062] (Rf) b PF 6-b - The anion represented by (CF3CF2)2PF4 - , (CF3CF2)3PF3 - , ((CF3)2CF)2PF4 - , ((CF3)2CF)3PF3 - , (CF3CF2CF2)2PF4 - , (CF3CF2CF2)3PF3 - , ((CF3)2CFCF2)2PF4 - , ((CF3)2CFCF2)3PF3 - , (CF3CF2CF2CF2)2PF4 - and (CF3CF2CF2CF2)3PF3 - Among these, anions represented by (CF3CF2)3PF3 - , (CF3CF2CF2)3PF3- , ((CF3)2CF)3PF3 - , ((CF3)2CF)2PF4 - , ((CF3)2CFCF2)3PF3 - and ((CF3)2CFCF2)2PF4 - Anions represented by the following formula are preferred.

[0063] R 12 c BY 4-c - As an anion represented by (C6F5)4B - , ((CF3)2C6H3)4B - , (CF3C6H4)4B - , (C6F5)2BF2 - , C6F5BF3 - and (C6H3F2)4B - Among these, anions represented by (C6F5)4B - and ((CF3)2C6H3)4B - Anions represented by the following formula are preferred.

[0064] R 12 c Gay 4-c - The anion represented by the formula is (C6F5)4Ga - , ((CF3)2C6H3)4Ga - , (CF3C6H4)4Ga - , (C6F5)2GaF2 - , C6F5GaF3 - and (C6H3F2)4Ga - Among these, (C6F5)4Ga - and ((CF3)2C6H3)4Ga - Anions represented by the following formula are preferred.

[0065] R 13 SO3 -Examples of the anion represented by the formula (I) include a trifluoromethanesulfonate anion, a pentafluoroethanesulfonate anion, a heptafluoropropanesulfonate anion, a nonafluorobutanesulfonate anion, a pentafluorophenylsulfonate anion, a p-toluenesulfonate anion, a benzenesulfonate anion, a camphorsulfonate anion, a methanesulfonate anion, an ethanesulfonate anion, a propanesulfonate anion, and a butanesulfonate anion. Among these, a trifluoromethanesulfonate anion, a nonafluorobutanesulfonate anion, a methanesulfonate anion, a butanesulfonate anion, a camphorsulfonate anion, a benzenesulfonate anion, and a p-toluenesulfonate anion are preferred.

[0066] (R 13 SO2)3C - The anion represented by (CF3SO2)3C - , (C2F5SO2)3C - , (C3F7SO2)3C - and (C4F9SO2)3C - Examples of the anion include anions represented by the following formula:

[0067] (R 13 SO2)2N - The anion represented by (CF3SO2)2N - , (C2F5SO2)2N - , (C3F7SO2)2N - and (C4F9SO2)2N - Examples of the anion include anions represented by the following formula:

[0068] As monovalent polyatomic anions, BY a - , P.Y. a - , SbY a - , (Rf) b PF 6-b - , R 12 c BY 4-c - , R12 c Gay 4-c - , R 13 SO3 - , (R 13 SO2)3C - or (R 13 SO2)2N - In addition to the anions represented by - , BrO4 - etc.), halogenated sulfonate anion (FSO3 - , ClSO3 - etc.), sulfate anion (CH3SO4 - , CF3SO4 - , HSO4 - etc.), carbonate anion (HCO3 - , CH3CO3 - etc.), aluminate anion (AlCl4 - , AlF4 - , ( t- C4F9O)4Al - etc.), hexafluorobismuthate anion (BiF6 - ), carboxylate anion (CH3COO - , CF3COO - , C6H5COO - , CH3C6H4COO - , C6F5COO - , CF3C6H4COO - etc.), aryl borate anion (B(C6H5)4 - , CH3CH2CH2CH2B(C6H5)3 - etc.), thiocyanate anion (SCN - ) and nitrate anion (NO3 - ) etc. can be used.

[0069] Among these anions, F - , Cl - , Br - , I - , BF4 - , SbF6 - , PF6 - , (Rf) b PF 6-b - , R12 c BY 4-c - , R 12 c Gay 4-c - , R 13 SO3 - , (R 13 SO2)3C - , (R 13 SO2)2N - and carboxylate ions (CH3COO - , CF3COO - , C6H5COO - , CH3C6H4COO - , C6F5COO - , CF3C6H4COO - Anions represented by the formula (e.g.), are preferred, and Cl - , Br - , I - , BF4 - , PF6 - , (CF3CF2)3PF3 - , ((CF3)2CF)3PF3 - , (CF3CF2CF2)3PF3 - , trifluoromethanesulfonate anion, nonafluorobutanesulfonate anion, CH3COO - , CF3COO - , (CF3SO2)3C - and (CF3SO2)2N - is more preferred from the viewpoint of solubility in water or polar solvents (dimethyl sulfoxide, etc.). When two or more anions are present in the same molecule, they may be the same or different.

[0070] L represented by formula (1) and formula (2) 1 and L 2 is an axial ligand represented by formula (3) that coordinates to the central metal M, and the number of axial ligands varies depending on the type of M. When M is Al, Ga, In, Fe, Co, or Mn, L 1 In the case of two axial ligands (L 1 and L 2 ) may be the same or different.

[0071] In formula (3), D is directly bonded to the central metal M and represents an oxygen atom or a sulfur atom.

[0072] In formula (3), E is a combination of D and an onium cation A + and represents 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 the main chain of these groups contains at least one ammonio group represented by formula (4), and 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. Here, the main chain is D and the onium cation A + It is the main skeleton that connects the above. Examples of alkylene having 1 to 8 carbon atoms include linear alkylene such as methylene, ethylene, trimethylene, tetramethylene, hexamethylene, and octamethylene; branched alkylene such as 1-methylethyl, 1-methylethylidene, 1,1-dimethylethylene, 1,2-dimethylethylene, and 1-methylpropylidene; and cyclic alkylene 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, and 2,4,6-octatrienylene. Examples of the alkynylene having 2 to 8 carbon atoms include ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene, 1,3-butadiynylene, and hexan-1-en-3-ynylene. Examples of the arylene having 6 to 14 carbon atoms include phenylene, naphthylene, anthracenylene, and biphenylene.

[0073] The main chain contains at least one ammonio group represented by formula (4), which improves the water solubility of the entire compound.

[0074] R in formula (4) 10 , R 11 is an alkyl group having 1 to 3 carbon atoms or a group selected from the group represented by formula (5), where R 10 , R 11 When both are alkyl groups having 1 to 3 carbon atoms, the monovalent counter anion X3 corresponding to the ammonio group - The anions X3 - As mentioned above, X1 - or X2 - This is the same as the example shown in

[0075] Specific examples of the ammonio group represented by formula (4) include the following. * indicates the bond position.

[0076] [ka]

[0077] Among these, those having carboxylic acid or sulfonic acid are preferred from the viewpoint of ease of synthesis, and sulfonic acid and its salts, which have a high degree of dissociation, are even more preferred from the viewpoint of improving water solubility.

[0078] 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, and specific examples of E include the following: * indicates a bonding position.

[0079] [ka]

[0080] In formula (3), A + is a monovalent onium cation that is bonded to the metal via D and E as an axial ligand. +is a compound in which the cyclic ligand receives energy through light absorption and decomposes it through a photochemical process (electron transfer, energy transfer, etc.) to generate a proton, and does not include the ammonio group represented by the above formula (4). A monovalent onium cation is a cation formed when a proton or a cationic atomic group (such as an alkyl group) coordinates with a compound containing an element with an unshared electron pair. Examples of monovalent onium cations include the following:

[0081] Pyrilinium cations (such as 4-methylpyrilinium cation and 2,6-diphenylpyrilinium cation); chromenium cations (e.g., 2,4-dimethylchromenium cation); Isochromenium cations (such as 1,3-dimethylisochromenium cation); Pyridinium cations (such as N-methylpyridinium cation, N-methoxypyridinium cation, N-butoxypyridinium cation, N-benzyloxypyridinium cation, and N-benzylpyridinium cation). imidazolium cations (such as N,N'-dimethylimidazolium cation and 1-ethyl-3-methylimidazolium cation); Quinolium cations (such as N-methylquinolium cations and N-benzylquinolium cations); isoquinolium cations (e.g., N-methylisoquinolium); Thiazonium cations (e.g., benzylbenzothiazonium cations); Acridium cations (such as benzyl acridium cation and phenacyl acridium cation); diazonium cations (such as phenyldiazonium cation, 2,4,6-trimethoxyphenyldiazonium cation, 2,4,6-triethoxyphenyldiazonium cation, and 4-anilinophenyldiazonium cation); Phosphonium cations [quaternary phosphonium cations (tetraphenylphosphonium cation, tetra-p-tolylphosphonium cation, triphenylbenzylphosphonium cation, triphenylbutyl cation, tetraethylphosphonium cation, tetrabutylphosphonium cation, etc.)]. sulfonium cations {triphenylsulfonium cation, diphenylmethylsulfonium cation, phenyldimethylsulfonium cation, 4-(phenylthio)phenyldiphenylsulfonium cation, 4-hydroxyphenylmethylbenzylsulfonium cation, etc.}; sulfoxonium cations (e.g., triphenylsulfoxonium); thianthrenium cations [such as 5-(4-methoxyphenyl)thianthrenium, 5-phenylthianthrenium, and 5-trilylthianthrenium cations]; Thiophenium cations (e.g., 2-naphthyltetrahydrothiophenium); Iodonium cations [diphenyliodonium cation, di-p-tolyliodonium cation, 4-isopropylphenyl(p-tolyl)iodonium cation, etc.].

[0082] Among the above onium cations, sulfonium cations, iodonium cations, and diazonium cations are preferred in terms of photoresponsiveness.

[0083] Preferred axial ligands L of formula (3) containing sulfonium cations 1 and L 2 Specific examples include the following:

[0084] [ka]

[0085] [ka]

[0086] Preferred axial ligands L of formula (3) containing an iodonium cation 1 and L 2 Specific examples include the following:

[0087] [ka]

[0088] Preferred axial ligands L containing a diazonium cation and represented by formula (3) 1 and L 2 Specific examples include the following:

[0089] [ka]

[0090] The photosensitizer (target product) represented by general formula (1) of the present invention can be produced by a known method. Specifically, the target compound can be obtained by synthesizing a metal complex precursor (a) having the target aromatic heterocyclic compound as a cyclic ligand, in which pyrrole rings are connected directly or via π-conjugation to form a ring structure, and an axial ligand precursor (b) containing an onium structure and the target anion, and then combining these. The following chemical formula shows an example of the production method. (Here, the aromatic heterocyclic compound is porphyrin.) The metal complex precursor (a) can be produced by various known methods. (Methods for synthesizing porphyrin and phthalocyanine compounds can be used, for example, the methods described in "The Porphyrin Handbook, Vols. 1-10, Academic Press (2000) and Vols. 11-20, (2003)" by Karl M. Kadis H, Kevin M. Smith, and Roger Guillard.)

[0091] [ka]

[0092] (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 represents a halogen atom or a hydroxy group. [Onium] is the same as A in formula (3), and X1 is the same as X1 in formula (3).

[0093] When the photosensitizer (target product) represented by general formula (2) of the present invention is a cationic metal complex, the target compound can be obtained by combining the cationic metal complex precursor (a') with the axial ligand precursor (b) containing an onium structure and having the target anion. In this case, to introduce the counter anion X2 of the central metal cation, the target metal complex is obtained by exchanging the X2 anion in the presence of an equivalent or greater amount of an alkali metal salt or alkaline earth metal salt, etc., that serves as the raw material.

[0094] [ka]

[0095] (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 represents a halogen atom or a hydroxy group; [Onium] is the same as A in formula (3); X1 is the same as X1 in formula (3); M' represents an alkali metal, an alkaline earth metal, or an alkyl group; and X2 is the same as X2 in formula (2).

[0096] The onium cation structure used in the axial ligand precursor (b) of the present invention can be prepared by a metathesis method. The metathesis method is described in, for example, Shin Jikken Kagaku Koza (New Experimental Chemistry Lectures), Vol. 14-I (1978, Maruzen), p. 448; Advance in Polymer Science, 62, 1-48 (1984); Shin Jikken Kagaku Koza (New Experimental Chemistry Lectures), Vol. 14-III (1978, Maruzen), pp. 1838-1846; Organic Sulfur Chemistry (Synthetic Reactions, 1982, Kagaku Dojin), Chapter 8, pp. 237-280; Japan Chemical Journal, 87, (5), 74 (1966); Japanese Patent Application Laid-Open Nos. 64-45357, 61-212554, 61-100557, 5-4996, 7-82244, 7-82245, 58-210904, and 6-184170. First, the F of the onium cation is reacted with the cation. - , Cl - , Br - , I - Halogen ion salts such as;OH - Salt; ClO4 - Salt; FSO3 - , ClSO3 - , CH3SO3 - , C6H5SO3 - , CF3SO3 - Salts with sulfonic acid ions such as HSO4 - , SO4 2- Salts with sulfate ions such as HCO3 - , CO3 2- , and salts with carbonate ions such as H2PO4 - , HPO4 2- , PO4 3-Salts with phosphate ions such as phosphate ions are prepared, and then metathesis is carried out by adding these to a solvent or aqueous solution containing a stoichiometric amount or more of an alkali metal salt, alkaline earth metal salt, or quaternary ammonium salt of the anion that constitutes the target onium salt, and, if necessary, other anion components such as KPF6, KBF4, or NaB(CF5)4. Water or an organic solvent can be used as the solvent. Organic solvents include hydrocarbons (e.g., hexane, heptane, toluene, xylene), cyclic ethers (e.g., tetrahydrofuran and dioxane), chlorinated solvents (e.g., chloroform and dichloromethane), alcohols (e.g., methanol, ethanol, and isopropyl alcohol), ketones (e.g., acetone, methyl ethyl ketone, and methyl isobutyl ketone), nitriles (e.g., acetonitrile), and polar organic solvents (e.g., dimethyl sulfoxide, dimethylformamide, and N-methylpyrrolidone). These solvents can be used alone or in combination.

[0097] The target photosensitizer thus obtained can be purified, if necessary, by column chromatography using silica gel or the like, recrystallization, or washing with water or a solvent. Purification by recrystallization can be achieved by dissolving the target photosensitizer in a small amount of water or organic solvent, and then separating the target photosensitizer from the water or organic solvent by adding another poor solvent directly (or after concentrating) to the water or organic solvent solution containing the target photosensitizer to precipitate the target photosensitizer. Poor solvents that can be used here include linear ethers (e.g., diethyl ether and dipropyl ether), esters (e.g., ethyl acetate and butyl acetate), aliphatic hydrocarbons (e.g., hexane and cyclohexane), and aromatic hydrocarbons (e.g., toluene and xylene). Purification can also be achieved by utilizing temperature-dependent differences in solubility. Purification can be achieved by recrystallization (using methods that utilize differences in solubility due to cooling, by adding a poor solvent to cause precipitation, or by a combination of these). If the photosensitizer is oily (i.e., does not crystallize), it can be purified by washing the oil with water or a poor solvent.

[0098] The structure of the photosensitizer thus obtained can be determined by a general analytical method, e.g., 1 H,13 C. 19 F, 31 Identification can be achieved by nuclear magnetic resonance spectroscopy such as P, infrared absorption spectroscopy, mass spectrometry, or elemental analysis.

[0099] The photosensitizer of the present invention is particularly adapted for use in a method for converting from a water-soluble form to a hydrophobic form by irradiation with light, thereby causing aggregation, and therefore, R 1 ~R 8 At least one of the above is preferably the following general formula (6).

[0100] [ka]

[0101] [In formula (6), (G) represents a biomolecule (probe), and L 4 represents a divalent group that bonds (G) to the photosensitizer molecule.

[0102] In formula (6), (G) represents a biomolecule (hereinafter referred to as a 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, and nucleotide triphosphates.

[0103] In formula (6), L 4 is a divalent group that bonds the probe (G) to the photosensitizer molecule of the present invention, and is composed of a straight, branched or cyclic chain having 1 to 60 atoms selected from, but not limited to, carbon, oxygen, nitrogen, sulfur and phosphorus atoms, and may contain a double bond, triple bond or a bonding group represented by the following chemical formula as part of the chain: * indicates the bonding position.

[0104] [ka]

[0105] For the introduction of the probe (G), R, which is a substituent of the cyclic ligand, 1 ~R 8 It is simple and preferable to introduce a group represented by the following general formula (7) into at least one of the above.

[0106] [ka]

[0107] [In formula (7), L 4 is the same as formula (6), and (G') represents a reactive group for binding the probe (G) in formula (6).

[0108] In formula (7), L 4 is the same as formula (6), and (G') is a reactive group for binding the above-mentioned probe (G) in formula (6). Specific examples of (G') include activated ester groups (here, carboxylic acid esters having a good leaving group, such as succinimidyloxy, sulfosuccinimidyloxy, 1-benzotriazolyl, 4-nitrophenyloxy, and pentafluorophenyloxy), acyl halides, alkyl halides, amino groups, acid anhydrides, carboxylic acids, carbodiimide groups, hydroxy groups, iodoacetamide groups, isocyanate groups, isothiocyanate groups, maleimide groups, phosphoramidite groups, sulfonate ester groups, and thiol groups.

[0109] To introduce the probe (G), a carboxyl group, amino group, thiol group, or the like contained in (G) may be reacted with the reactive group (G') to form a bond. For example, an amide bond is formed by the reaction of the amino group of (G) with the succinimidyloxyester group of (G'), and a sulfide bond is formed between the thiol group of (G) and the maleimide group of (G'). In this way, the probe (G) and the photosensitizer of the present invention are bonded.

[0110] When the photosensitizer of the present invention is irradiated with light, the decomposable onium salt bonded to the axial ligand decomposes, and the protons thus generated cause the detachment of the axial ligand. The wavelength of the irradiated light is not particularly limited as long as it is within the range of wavelengths that can be absorbed by the photosensitizer. Specifically, irradiation with light in the visible to infrared region of 500 to 1500 nm is preferred, and from the viewpoint of the effect on cells and photoresponsiveness, irradiation with light in the near-infrared region of 650 to 1200 nm is even more preferred.

[0111] The photosensitizer of the present invention undergoes aggregation due to a change from hydrophilic to hydrophobic properties caused by the detachment of the axial ligand upon irradiation with light. That is, when used in a therapeutic method for killing specific target cells (e.g., cancer cells) by irradiation with light, the photosensitizer of the present invention and a probe (preferably an antibody) for binding to the specific target cells are introduced and administered to form a complex that specifically binds to the target cells. When irradiated with, for example, near-infrared light, the complex undergoes a change in hydrophilicity to hydrophobicity due to the detachment of the axial ligand, causing aggregation and destroying the target cells. By conjugating the photosensitizer of the present invention to an antibody, it acts on proteins or the like that specifically bind to the surface of specific cells, allowing it to accumulate in target cells. Therefore, antibody conjugates conjugated with the photosensitizer of the present invention can be used in molecular targeted therapy, just like antibody conjugates conjugated with compounds that have other medicinal effects. When the photosensitizer of the present invention is used to target cancer cells, monoclonal antibodies are preferably used, such as cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, trastuzumab, pertuzumab, tositumomab, rituximab, daclizumab, gemtuzumab, alemtuzumab, J591, and basiliximab. Furthermore, the photosensitizer can also be suitably used in other analytical and purification methods that utilize specific antibody binding, such as affinity chromatography and photoinactivation of molecules by irradiation (CALI and FALI). [Example]

[0112] The present invention will be further explained below with reference to examples, but is not intended to be limited thereto. Unless otherwise specified, % means % by weight.

[0113] Production Example 1 Synthesis of Metal Complex Precursor (a-1) Synthesis of octaethylporphyrinatosilicon(IV) dichloride (a-1) The title compound (a-1) was synthesized from octaethylporphyrin and tetrachlorosilane according to JW Buchler, et al., Chem. Ber. 1973, 106, 2710.

[0114] Production Example 2 Synthesis of Metal Complex Precursor (a-4) Synthesis of phthalocyanatogermanium(IV) dichloride. A reaction vessel was charged with 150 g of n-pentanol, 23 g of 1,2-dicyanobenzene, and 10 g of germanium tetrachloride, and then 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 mixture was slowly added dropwise to 1500 g of methanol / water (1 / 2 by weight) while stirring to obtain a slurry. This was filtered, and the residue was washed five times with 100 g of methanol / water (1 / 2 by weight) 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).

[0115] The structure of the metal complex precursor (a) is shown below: All of the metal complex precursors used except for those in the above production examples were reagents purchased from Aldrich.

[0116] [ka]

[0117] Preparation Example 3: Synthesis of axial ligand precursor (b-1 / Cl) (1) Intermediate 1: Synthesis of 3,5-dimethyl-4-hydroxyphenyldiphenylsulfonium chloride salt 7.3 g of 2,6-dimethylphenol, 50 g of methanesulfonic acid, and 7 g of diphosphorus pentoxide were added to a reaction vessel and stirred. 10 g of diphenyl sulfoxide was added and the mixture was allowed to react at 45°C for 6 hours. The reaction mixture was gradually added to 100 mL of 20% brine while cooling in an ice bath and stirring. 100 mL of dichloromethane was then added and the mixture was stirred for 1 hour. After allowing to stand, the aqueous layer was removed by separation, and the organic layer was washed five times with 50 mL of water and concentrated. Recrystallization was carried out from acetone to obtain 15.2 g of a white solid. 1 This white solid was identified as (Intermediate-1) by 1 H-NMR. (2) Intermediate-2: Synthesis of 4-chloroethoxy-3,5-dimethylphenyldiphenylsulfonium chloride salt 3.4 g of (Intermediate-1), 20 mL of THF, 1.5 g of potassium carbonate, and 14 g of 1-bromo-2-chloroethane were added to a reaction vessel and reacted at 60°C for 6 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator, and 50 mL of dichloromethane was added to the residue for extraction, followed by washing five times with 50 mL of water. The organic layer was then concentrated under reduced pressure using an evaporator and recrystallized from dichloromethane-hexane to obtain 3.2 g of a white solid. 1 This white solid was identified as (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 reacted at 60°C for 12 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator, and 50 mL of dichloromethane was added to the residue for extraction, followed by washing five times with 50 mL of water. The organic layer was then concentrated under reduced pressure using an evaporator and recrystallized from dichloromethane-hexane to obtain 2.5 g of a pale yellow solid (yield 51%). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-1 / Cl).

[0118] Preparation Example 4 Synthesis of axial ligand precursor (b-1 / Br) To a silver acetate solution prepared by dissolving 0.5 g of silver acetate in 100 mL of water, 0.5 g of the axial ligand precursor (b-1 / Cl) and 10 mL of acetonitrile were added in small portions and stirred for 1 hour. The resulting precipitate was removed by centrifugation, and 0.5 g of potassium bromide was added to the solution, which was then stirred at room temperature for 6 hours. 50 mL of dichloromethane was added for extraction, and the mixture was washed five times with 50 mL of water. The organic layer was then concentrated under reduced pressure using an evaporator and recrystallized from dichloromethane-hexane to obtain 0.35 g of a pale yellow solid (60% yield). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-1 / Br).

[0119] Preparation Example 5 Synthesis of axial ligand precursor (b-1 / (C2F5)3PF3) 4.9 g of the axial ligand precursor (b-1 / Cl) was added to a reaction vessel and dissolved in 100 mL of dichloromethane. An aqueous solution of 10.6 g of K(C2F5)3PF3 dissolved in 100 mL of water was added and stirred for 6 hours. The aqueous layer was removed by separation. The organic layer was washed five times with 50 mL of water and concentrated. Recrystallization from dichloromethane-hexane yielded 5.7 g of a pale yellow solid (44% yield). 1 H, 19 F and 31 P-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-1 / (C2F5)3PF3).

[0120] Preparation Example 6 Synthesis of axial ligand precursor (b-1 / PF6) The same procedure as in Production Example 5 was followed, except that 64.0 g of KPF was used instead of 310.6 g of K(C2F5)3PF, to obtain 4.9 g of a pale yellow solid (yield: 58%). 1 H, 19 F and 31 P-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-1 / PF6).

[0121] Preparation Example 7 Synthesis of axial ligand precursor (b-2 / I) (1) Intermediate-3: Synthesis of 4-phenylthiophenyl-2-bromoethyl ether A reaction vessel was charged with 4.0 g of 4-phenylthiophenol, 50 mL of THF, 3.0 g of potassium carbonate, and 15 g of 1,2-dibromoethane, and the mixture was allowed to react at 60°C for 6 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. 50 mL of dichloromethane was added to the residue, which was then extracted and washed five times with 50 mL of water. The organic layer was then concentrated under reduced pressure using an evaporator and purified by silica gel column chromatography to obtain 5.2 g of a pale yellow oil (yield 84%). 1 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 reacted for 5 hours at 50° C. After the reaction, the mixture was washed five times with 30 mL of water, 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%). 1 This pale yellow solid was identified as (Intermediate-4) by 1 H-NMR. (3) Intermediate-5: Synthesis of 4-(2-[N-{3-(ethoxydimethylsilyl)propyl}amino]ethoxy)phenylphenylmethylsulfonium iodide 4.5 g of (Intermediate-4), 50 mL of acetone, 5 g of sodium carbonate, and 1.6 g of 3-aminopropyldimethylethoxysilane were added to a reaction vessel and reacted under reflux for 18 hours. The reaction mixture was poured into 100 mL of water. The mixture was extracted with 50 mL of dichloromethane, washed with water five times, and concentrated. The product was purified by silica gel column chromatography to obtain 2.7 g of a pale yellow solid (yield 51%). 1 This pale yellow solid was identified as (Intermediate-5) by 1 H-NMR. (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. After the reaction, the precipitated solid was filtered off, and the filtrate was added to 100 mL of 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 saturated aqueous sodium bicarbonate solution, washed five times with water, and then concentrated. Recrystallization from dichloromethane-hexane yielded 2.5 g of a pale yellow solid (yield 38%). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-2 / I).

[0122] Preparation Example 8 Synthesis of axial ligand precursor (b-2 / PF6) The same procedure as in Production Example 5 was followed, except that 4.9 g of the axial ligand precursor (b-1 / Cl) was replaced with 6.6 g of the axial ligand precursor (b-2 / I), and 64.0 g of KPF was used instead of 10.6 g of K(C2F5)3PF, to obtain 6.1 g of a pale yellow solid (yield 88%). 1 H, 19 F and 31 P-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-2 / PF6).

[0123] Preparation Example 9 Synthesis of axial ligand precursor (b-3 / Cl) (1) Intermediate-6: Synthesis of N-(4-dimethylsulfonio)phenylmethyl-N-(2-bromoethyl)dimethylammonium dibromide 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 the dropwise addition, the mixture was stirred at room temperature for 20 hours. Then, 15 mL of bromomethane (2M THF solution) was added, and the mixture was further reacted at 40°C for 6 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. The obtained crude crystals were used as they were as intermediate-6. 1 H-NMR confirmed that the main component was intermediate-6. (2) Intermediate-7: Synthesis of 4-[{8-(ethoxydimethylsilyl)-2,2,5,5-tetramethylbisazonia}octyl]phenyldimethylsulfonium tribromide 4.6 g of (Intermediate-6) was added to a reaction vessel, 50 mL of acetone, and 1.9 g of 3-dimethylaminopropyldimethylethoxysilane, and the mixture was allowed to react 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 a white solid (yield 45%). 1 This pale yellow solid was identified as Intermediate-7 by 1 H-NMR. (3) Synthesis of axial ligand precursor (b-3 / Cl) To a silver acetate solution prepared by dissolving 0.5 g of silver acetate in 100 mL of water, 0.6 g of (Intermediate-7) and 10 mL of acetonitrile were added in small portions and stirred for 1 hour. The resulting precipitate was removed by centrifugation, and 0.5 g of potassium chloride was added to the solution, followed by stirring at room temperature for 6 hours. 50 mL of dichloromethane was added for extraction, 50 mL of 1N hydrochloric acid was added, and the mixture was stirred for 2 hours. The mixture was then washed five times with 50 mL of water. The organic layer was then concentrated under reduced pressure using an evaporator and recrystallized from ethyl acetate-methanol to obtain 0.28 g of a white solid (yield 57%). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-3 / Cl).

[0124] Preparation Example 10: Synthesis of axial ligand precursor (b-3 / CF3CO2) 0.5 g of the axial ligand precursor (b-3 / Cl) was dissolved in 10 mL of methanol in a reaction vessel, and 0.66 g of silver trifluoroacetate was added and stirred at room temperature for 24 hours. 10 mL of water was added, and the resulting precipitate was removed by centrifugation. The organic layer was concentrated. Recrystallization from ethyl acetate-methanol yielded 0.63 g of a white solid (88% yield). 1 H, 19 F-NMR confirmed that this white solid was the axial ligand precursor (b-3 / CF3CO2).

[0125] Preparation Example 11 Synthesis of axial ligand precursor (b-3 / TfO) The same procedure as in Preparation Example 10 was followed, except that 0.77 g of silver trifluoromethanesulfonate was used instead of 0.66 g of silver trifluoroacetate, to give 0.49 g of a white solid (yield 59%).1 H, 19 F-NMR confirmed that this white solid was the axial ligand precursor (b-3 / TfO).

[0126] Preparation 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 a reaction vessel (A) and dissolved in 150 mL of THF. 1.8 g of sodium hydride was added to the mixture. The mixture was stirred for 10 minutes and then cooled to -40°C. 30 mL of a 15% THF solution of diisopropylmagnesium bromide was added dropwise to the mixture. Stirring was continued at -10°C for 3 hours. 16 g of diphenyl sulfoxide was added to a separate reaction vessel (B) and dissolved in 50 mL of THF. The mixture was cooled to -40°C, and 15 g of trimethylsilyl chloride was added dropwise to the mixture. Stirring was continued at -40°C for 30 minutes, and the mixture was then transferred to the reaction vessel (A) via a tube. The mixture was stirred at -20°C for 3 hours and then cooled to -70°C. 100 mL of 20% aqueous hydrochloric acid was added to the mixture. The mixture was warmed to room temperature, and 300 mL of diethyl ether and 200 mL of 20% aqueous hydrochloric acid were added. The mixture was stirred for 1 hour and allowed to stand. The aqueous layer was separated and extracted with diethyl ether and dichloromethane, and the combined organic layer was concentrated. The extract was purified by silica gel column chromatography to obtain 15 g of a white solid. 1 This white solid was identified as 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 3.8 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was further added thereto. This was stirred for 1 hour, and 1.0 g of dimethylaminoethanol was added dropwise thereto. After the dropwise addition, the mixture was stirred for 12 hours, and then poured into 100 mL of water. Extraction was performed with 50 mL of dichloromethane, and the organic layer was washed with 1N hydrochloric acid, further washed with aqueous sodium bicarbonate solution, and then washed with water five times and concentrated. The obtained crude crystals were used as they were as Intermediate-9. Note that, 1H-NMR confirmed 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, 50 mL of acetone, and 1.9 g of 2-chloroethyldimethylethoxysilane were added, and the mixture was allowed to react under reflux for 18 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. 50 mL of dichloromethane was added to the residue and extracted, and the organic layer was washed with 1N hydrochloric acid and then washed five times with water before being concentrated. Recrystallization from dichloromethane-hexane yielded 2.7 g of a pale yellow solid (49% yield). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-4 / Cl).

[0127] Preparation Example 13 Synthesis of axial ligand precursor (b-5 / Br) (1) Intermediate-10: Synthesis of 4-{N-(2-bromoethyl)dimethylammonio}methylphenyldiphenylsulfonium dibromide A reaction vessel was charged with 4.4 g of 4-(bromomethyl)phenyldiphenylsulfonium bromide and 50 mL of THF, and 1.5 g of 2-(dimethylamino)ethyl bromide was added dropwise at room temperature. After the dropwise addition, the mixture was stirred at room temperature for 20 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. The resulting light brown solid was washed with diethyl ether and dried to obtain 3.9 g of a light yellow solid (yield 67%). 1 This pale yellow solid was identified as Intermediate-10 by 1 H-NMR. (2) Synthesis of axial ligand precursor (b-5 / Br) 0.6 g of (Intermediate-10) was added to a reaction vessel, 10 mL of acetone, and 0.2 g of 2-dimethylaminoethyldimethylethoxysilane were added, and the mixture was allowed to react under reflux for 8 hours. After the reaction, the mixture was concentrated under reduced pressure 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. The mixture was then washed with water five times and concentrated. The resulting solid was washed with diethyl ether, yielding 0.45 g of a pale yellow solid (61% yield). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-5 / Br).

[0128] Preparation Example 14 Synthesis of axial ligand precursor (b-6 / PF6) (1) Intermediate-11: Synthesis of (3-carboxypropyl-1-one-phenyl)diphenylsulfonium chloride A reaction vessel was charged with 9.0 g of triphenylsulfonium chloride, 50 mL of dichloromethane, and 4.0 g of aluminum chloride and stirred. This was cooled in an ice bath, and 9.0 g of succinic anhydride was added dropwise. The mixture was then stirred at room temperature for 8 hours, and the reaction solution was poured into 100 mL of ice water. An additional 50 mL of dichloromethane was added, and the mixture was stirred for another hour. After allowing to stand, the aqueous layer was removed, and the organic layer was washed five times with water and then concentrated. The mixture was purified by silica gel column chromatography, yielding 13.8 g of a white solid. 1 H-NMR confirmed that this white solid was Intermediate-11. (2) Intermediate-12: Synthesis of 4-{3-(N-dimethylaminoethyl)carbamoylpropyl-1-one}phenyldiphenylsulfonium chloride The same procedure as in Production Example 12(2) was followed, except that 4.0 g of (Intermediate-11) was used instead of 3.4 g of (Intermediate-8) and 1.1 g of N,N-dimethylethylenediamine was used instead of 1.0 g of dimethylaminoethanol, and the obtained crude crystals were used as they were as Intermediate-12. 1 H-NMR confirmed that the main component was intermediate-12. (3) Synthesis of axial ligand precursor (b-6 / PF6) 4.7 g of (Intermediate-12) was added to a reaction vessel with 50 mL of acetone and 2.3 g of 3-bromopropyldimethylethoxysilane, and the mixture was allowed to react under reflux for 18 hours. After the reaction, the mixture was concentrated under reduced pressure 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 separation. 50 mL of an aqueous solution prepared by dissolving 64.0 g of KPF in 50 mL of water was added, and the mixture was stirred for 3 hours. The organic layer was washed five times with water and then concentrated. Recrystallization from dichloromethane-hexane yielded 2.7 g of a 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 / PF6).

[0129] Preparation Example 15 Synthesis of axial ligand precursor (b-7 / CF3CO2) A reaction vessel was charged with 0.5 g of (Intermediate-5), 20 mL of methanol, 1.6 g of diisopropylethylamine, and 1.2 g of 1,3-propane sultone, and the mixture was allowed to react under reflux for 20 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. The mixture was again dissolved in 10 mL of methanol, and 5 mL of 1N hydrochloric acid was added thereto and stirred at room temperature for 3 hours. The mixture was extracted with 10 mL of dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, washed five times with water, and then concentrated. The resulting solid was dissolved in 10 mL of methanol, and 0.66 g of silver trifluoroacetate was added thereto and stirred at room temperature for 24 hours. 10 mL of water was added, and the resulting precipitate was removed by centrifugation, and the organic layer was concentrated. Recrystallization from dichloromethane-methanol yielded 0.4 g of a pale yellow solid (yield: 53%). 1 H, 19 F-NMR analysis confirmed that this pale yellow solid was the axial ligand precursor (b-7 / CF3CO2).

[0130] Preparation Example 16: Synthesis of axial ligand precursor (b-7 / TfO) The same procedure as in Production Example 15 was followed, except that 0.77 g of silver trifluoromethanesulfonate was used instead of 0.66 g of silver trifluoroacetate, to give 0.22 g of a pale yellow solid (yield 28%). 1 H, 19 F-NMR confirmed that this white solid was the axial ligand precursor (b-7 / TfO).

[0131] Preparation Example 17 Synthesis of axial ligand precursor (b-8 / Br) (1) Intermediate-13: Synthesis of (2-methoxy-4-hydroxyphenyl)phenyliodonium bromide 22 g of iodosylbenzene, 12.4 g of 3-methoxyphenol, 700 g of glacial acetic acid, and 70 g of acetic anhydride were dissolved and mixed in a reaction vessel 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 reaction was continued at room temperature for an additional 3 hours. The reaction mixture was gradually added to 200 mL of 20% aqueous potassium bromide solution while cooling in an ice bath and stirring. 100 mL of dichloromethane was added and the mixture was stirred for 1 hour. After allowing to stand, the aqueous layer was removed by separation, and the organic layer was washed five times with 50 mL of water and concentrated. The product was separated and purified by silica gel column chromatography to obtain 23.2 g of a white solid (yield 57%). 1 This white solid was identified as (Intermediate-13) by H-NMR. (2) Intermediate-14: Synthesis of 2-methoxy-4-(3-bromo-1-propoxy)phenylphenyliodonium bromide A reaction vessel was charged with 4.1 g of (Intermediate-13), 20 mL of THF, 1.5 g of potassium carbonate, and 20 g of 1,3-dibromopropane, and the mixture was allowed to react at room temperature for 18 hours. The reaction mixture was concentrated using an evaporator, and the resulting oil was dissolved in 50 mL of dichloromethane. The mixture was washed five times with 50 mL of water, and the organic layer was concentrated. Recrystallization from dichloromethane-hexane yielded 3.8 g of a white solid (72% yield). 1 This white solid was identified as (Intermediate-14) by 1 H-NMR. (3) Synthesis of axial ligand precursor (b-8 / Br) The same procedure as in Production Example 3(3) was followed, except that 5.3 g of (Intermediate-14) was used instead of 4.1 g of (Intermediate-2), to obtain 4.0 g of a pale yellow solid (yield 65%). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-8 / Br).

[0132] Preparation Example 18 Synthesis of axial ligand precursor (b-9 / Br) (1) Intermediate-15: {4-(2-bromoethyldimethylammoniomethyl)phenyl}(2,4,6-trimethoxyphenyl)iodonium dibromide The procedure of Production Example 13(1) was followed, except that 5.4 g of {4-(bromomethyl)phenyl}(2,4,6-trimethoxyphenyl)iodonium bromide was used instead of 4.4 g of 4-(bromomethyl)phenyldiphenylsulfonium bromide, to obtain 4.9 g of a pale yellow solid (yield 70%). 1 This pale yellow solid was identified as Intermediate-15 by 1 H-NMR. (2) Synthesis of axial ligand precursor (b-9 / Br) The same procedure as in Production Example 13(2) was followed, except that 0.7 g of (Intermediate-15) was used instead of 0.6 g of (Intermediate-10) and 20 mL of 10% hydrobromic acid was used instead of 20 mL of 1N hydrochloric acid, to obtain 0.54 g of a pale yellow solid (yield 64%). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-9 / Br).

[0133] Preparation Example 19: Synthesis of axial ligand precursor (b-10 / TfO) (1) Intermediate-16: Synthesis of [4-{N-3-(ethoxydimethylsilyl)propyl-N-methylaminomethyl}phenyl](2,4,6-trimethoxyphenyl)iodonium triflate A reaction vessel was charged with 5.4 g of {4-(bromomethyl)phenyl}(2,4,6-trimethoxyphenyl)iodonium bromide, 50 mL of acetone, 5 g of sodium carbonate, and 1.8 g of 3-N-methylaminopropyldimethylethoxysilane, and the mixture was allowed to react under reflux for 18 hours. The reaction mixture was poured into 100 mL of 10% aqueous sodium trifluoromethanesulfonate solution. After stirring at room temperature for 2 hours, the mixture was extracted with 50 mL of dichloromethane, washed with water five times, and concentrated. Recrystallization from dichloromethane-hexane yielded 6.1 g of a pale yellow solid (86% yield). 1 H, 19 F-NMR confirmed that this pale yellow solid was (Intermediate-16). (2) Synthesis of axial ligand precursor (b-10 / TfO) 0.7 g of (Intermediate-16), 20 mL of methanol, 0.8 g of diisopropylethylamine, and 0.6 g of 1,3-propane sultone were added to a reaction vessel and reacted under reflux for 20 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. The mixture was again dissolved in 10 mL of methanol, to which 5 mL of 1N hydrochloric acid was added and stirred at room temperature for 3 hours. The mixture was extracted with 10 mL of dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, washed five times with water, and then concentrated. The resulting 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 analysis confirmed that this pale yellow solid was the axial ligand precursor (b-10 / TfO).

[0134] Preparation Example 20: Synthesis of axial ligand precursor (b-11 / Br) (1) Intermediate-17: Synthesis of (2,6-dimethoxy-4-hydroxyphenyl)phenyliodonium bromide The same procedure as in Production Example 17(1) was followed, except that 15.4 g of 3,5-dimethoxyphenol was used instead of 12.4 g of 3-methoxyphenol, to give 23.6 g of a white solid (yield 54%). 1 This white solid was identified as (Intermediate-17) by H-NMR. (2) Intermediate-18: Synthesis of {2,6-dimethoxy-4-(2-bromoethoxy)phenyl}phenyliodonium bromide The same procedure as in Production Example 17(2) was followed, except that 4.4 g of (Intermediate-17) was used instead of 4.1 g of (Intermediate-13) and 18 g of 1,2-dibromoethane was used instead of 20 g of 1,3-dibromopropane, to obtain 2.4 g of a white solid (yield 44%). 1 H-NMR confirmed that this white solid was (Intermediate-18). (3) Intermediate-19: Synthesis of (2,6-dimethoxy-4-[2-{N-(3-dimethylethoxysilylpropyl)amino}ethoxy]phenyl)phenyliodonium bromide The same procedure as in Production Example 7(3) was followed, except that 5.4 g of (Intermediate-18) was used instead of 4.5 g of (Intermediate-4), to obtain 2.3 g of a pale yellow solid (yield 37%). 1 This pale yellow solid was identified as (Intermediate-19) by H-NMR. (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-propane sultone were added to a reaction vessel and reacted under reflux for 20 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. The mixture was again dissolved in 10 mL of methanol, and 5 mL of 10% aqueous hydrobromic acid was added thereto and stirred at room temperature for 3 hours. The mixture was extracted with 10 mL of dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate and then washed five times with water before being concentrated. Recrystallization from dichloromethane-methanol yielded 0.49 g of a pale yellow solid (yield 57%). 1 H-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-11 / Br).

[0135] Preparation Example 21 Synthesis of axial ligand precursor (b-11 / CF3CO2) The same procedure as in Production Example 10 was followed, except that 0.9 g of the axial ligand precursor (b-11 / Br) was used instead of 0.5 g of the axial ligand precursor (b-3 / Cl), to obtain 0.39 g of a pale yellow solid (yield 44%). 1 H, 19 F-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-11 / CF3CO2).

[0136] Preparation Example 22: Synthesis of axial ligand precursor (b-11 / TfO) The same procedure as in Production Example 10 was followed, except that 0.9 g of the axial ligand precursor (b-11 / Br) was used instead of 0.5 g of the axial ligand precursor (b-3 / Cl) and 0.77 g of silver trifluoromethanesulfonate was used instead of 0.66 g of silver trifluoroacetate, to obtain 0.31 g of a pale yellow solid (yield 33%). 1 H, 19F-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-11 / TfO).

[0137] Preparation Example 23: Synthesis of axial ligand precursor (b-12 / PF6) (1) Intermediate-20: Synthesis of 4-(2-bromoethoxy)-2,6-dimethoxyaniline A reaction vessel was charged with 8.5 g of 2,6-dimethoxy-4-hydroxyaniline, 100 mL of THF, 7.5 g of potassium carbonate, and 50 g of 1,2-dibromoethane, and the mixture was allowed to react at 50°C for 6 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. The residue was extracted with 50 mL of ethyl acetate, and the organic layer was washed with water and then concentrated. Purification was carried out using silica gel column chromatography to obtain 5.8 g of a yellow oil (yield 42%). 1 H-NMR confirmed that this yellow oil was Intermediate-20. (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) According to the method described in Production Example 9(2), except that 2.8 g of (Intermediate-20) was used instead of 4.6 g of (Intermediate-6), 3.1 g of a yellow solid was obtained (yield 67%). 1 This yellow solid was identified as Intermediate-21 by 1 H-NMR. (3) Synthesis of axial ligand precursor (b-12 / PF6) A reaction vessel was charged with 4.6 g of (Intermediate-21), 10 mL of water, and 2 mL of 35% hydrochloric acid, and the mixture was cooled in a salt-ice bath while stirring. At 0°C, an aqueous solution prepared by dissolving 0.7 g of sodium nitrite in 5 mL of water was slowly added with stirring. The mixture was stirred at 0°C for 1 hour. While maintaining the temperature, an aqueous solution prepared by dissolving 62.0 g of KPF in 50 mL of water was added, and the mixture was stirred for an additional 6 hours. 50 mL of dichloromethane was added to the mixture for extraction, and the aqueous layer was removed by separation. The mixture was washed five times with water and concentrated using an evaporator. Recrystallization from methanol-diethyl ether yielded 2.5 g of a pale yellow solid (yield 38%). 1 H, 19 F and 31 P-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-12 / PF6).

[0138] Preparation Example 24 Synthesis of axial ligand precursor (b-13 / PF6) (1) Intermediate 22: Synthesis of 4-(2-[N-{3-(ethoxydimethylsilyl)propyl}amino]ethoxy)-3,5-dimethoxyaniline The same procedure as in Production Example 7(3) was followed, except that 2.8 g of (Intermediate-20) was used instead of 4.5 g of (Intermediate-4) and 1.8 g of 3-aminopropyldimethylisopropoxysilane was used instead of 1.6 g of 3-aminopropyldimethylethoxysilane, to obtain 2.3 g of a yellow solid (yield 62%). 1 This yellow solid was identified as (Intermediate-22) by 1 H-NMR. (2) Synthesis of axial ligand precursor (b-13 / PF6) A reaction vessel was charged with 0.4 g of (Intermediate-22), 20 mL of methanol, 1.6 g of diisopropylethylamine, and 1.2 g of 1,3-propane sultone, and the mixture was refluxed for 20 hours. After the reaction, the mixture was concentrated under reduced pressure using an evaporator. The resulting solid was placed in a separate reaction vessel, and 10 mL of water and 2 mL of 35% hydrochloric acid were added. The mixture was then cooled in a salt-ice bath while stirring. At 0°C, an aqueous solution prepared by dissolving 0.7 g of sodium nitrite in 5 mL of water was slowly added with stirring. The mixture was stirred at 0°C for 1 hour. While maintaining the temperature, an aqueous solution prepared by dissolving 2.0 g of KPF6 in 50 mL of water was added, and the mixture was stirred for an additional 6 hours. 50 mL of dichloromethane was added to the mixture for extraction, and the aqueous layer was removed by separation. The mixture was washed five times with water and then concentrated using an evaporator. Recrystallization from methanol-diethyl ether yielded 0.27 g of a pale yellow solid (36% yield). 1 H, 19 F and 31 P-NMR confirmed that this pale yellow solid was the axial ligand precursor (b-13 / PF6).

[0139] <Examples 1 to 43> (Synthesis of photosensitizers of the present invention) The photosensitizers of the present invention were synthesized 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 synthesis methods used are shown in Table 1.

[0140] Synthesis method (I) (metal complexes with two axial ligands) Examples 1 to 17, 23 to 32, 38 to 43 The metal complex precursor (a) and the axial ligand precursor (b) were mixed in a reaction vessel at room temperature in a molar ratio of 1:2 in acetonitrile solvent, and the mixture was reacted for 6 hours while blowing in nitrogen. The acetonitrile was then distilled off under reduced pressure to obtain the target product (photosensitizer).

[0141] Synthesis method (II) (Cationic metal complex with two axial ligands and counter anion X2 - (if you have) Examples 18 to 22 In a reaction vessel, a metal complex precursor (a) and an axial ligand precursor (b) were mixed in a molar ratio of 1:2 in acetonitrile solvent at room temperature, and the mixture was reacted for 6 hours while blowing in nitrogen. After the acetonitrile was distilled off under reduced pressure, the mixture was dissolved in dichloromethane. - An aqueous solution of an alkali metal salt (lithium, sodium, or potassium salt) of the above was added and stirred for 1 hour. After standing, the aqueous layer was removed, and the organic layer was washed with water five times and concentrated. The target product (photosensitizer) was obtained by purifying with dichloromethane-hexane.

[0142] Synthesis method (III) (Metal complexes with one axial ligand) Examples 33 to 37 The metal complex precursor (a) and the axial ligand precursor (b) were mixed in a 1:1 molar ratio in acetonitrile solvent in a reaction vessel at room temperature, and the mixture was reacted for 6 hours while blowing in nitrogen. The acetonitrile was then distilled off under reduced pressure to obtain the target product (photosensitizer).

[0143] [Table 1]

[0144] (Evaluation-1: Solubility test) <Examples 44 to 86 and Comparative Examples 1 to 4> The photosensitizers obtained in Examples 1 to 43 and the comparative compounds were evaluated for solubility under the following conditions. The results are shown in Table 2. DMSO solution preparation: (a) Dissolve 10 mg of photosensitizer in 1 mL of DMSO to make a 1% DMSO solution. (b) Dissolve 1 mg of photosensitizer in 1 mL of DMSO to make a 0.1% DMSO solution. Next, these were diluted with 10 mL of water (A) and with 10 mL of 0.1 M phosphate buffer (B), and the solubility was evaluated visually. The results are shown in Tables 2 and 3. ◎:Transparent 〇: Slight haze △: There is haze and slight sedimentation ×: Immediately settles (Evaluation-2: Photoresponsiveness test) The photosensitizers obtained in Examples 1 to 43 and the comparative compounds were used, and 1×10 -6 A 0.1% DMSO-containing aqueous solution of M was prepared, and this was exposed to light using a LIGHTNINGCURE spot light source LC8 (manufactured by Hamamatsu Photonics) as the light source through an infrared transmission filter (manufactured by HOYA) R64 (cutting off wavelengths below 620 nm), and the changes in appearance were evaluated. The results are shown in Tables 2 and 3 as the results of photoresponsiveness. ◎: Aggregates present, liquid phase is transparent ○: Aggregates present, liquid phase is suspended ×: No aggregates [Ingredients used] PS-1 to PS-43 (photosensitizers listed in Table 1) H-1: Comparative photosensitizer-1 (compound described in JP-A-H09-504811)

[0145] [ka]

[0146] H-2: Comparative photosensitizer-2 (compound described in JP-A-2014-522811)

[0147] [ka]

[0148] H-3: A 1:1 (molar ratio) mixture of H-1 and triphenylsulfonium bromide H-4: 1:1 (molar ratio) mixture of H-2 and diphenyliodonium chloride

[0149] [Table 2]

[0150] [Table 3]

[0151] *Did not show adequate solubility in the photoresponsive test, so evaluation was not possible.

[0152] Tables 2 and 3 show that the photosensitizers of the present invention exhibit good solubility even in hydrophilic solvents, particularly buffer solvents used in the biotechnology field, as shown in Examples 44 to 86. Furthermore, as shown in Examples 44 to 86, the photosensitizers of the present invention undergo hydrophobicity upon irradiation with light, allowing them to effectively aggregate. The photosensitizers of Comparative Examples 1 and 2 exhibit excellent solubility, but have almost no aggregation effect due to hydrophobicity. Furthermore, when the photosensitizer and the onium salt structure are formulated separately, as in Comparative Examples 3 and 4, they lack solubility and are not suitable for hydrophobicity by irradiation with light.

[0153] <Photosensitizer bound to probe> (Synthesis of metal complex precursors with reactive groups in the side chains)

[0154] [ka]

[0155] Production Example 25 Synthesis of metal complex precursor (a-10) A reaction vessel was charged with 200 g of n-pentanol, 2.3 g of 4-{4-(methoxycarbonyl)butoxy}phthalonitrile, 23 g of 1,2-dicyanobenzene, and 10 g of tetrachlorosilane, and then 27 g of DBU (1,8-diazabicyclo[5.4.0]-7-undecene) was added and mixed. The mixture was heated to 140°C and refluxed for 12 hours. After cooling to room temperature, the reaction mixture was slowly added dropwise to 1500 g of a 1 / 2 weight ratio of methanol and water while stirring to obtain a slurry. This was filtered, and the residue was washed five times with 100 g of a 1 / 2 weight ratio of methanol and water and then dried. The product was separated and purified by column chromatography to obtain a blue-green solid. 1 H-NMR confirmed that this solid was the metal complex precursor (a-10).

[0156] Production Example 26 Synthesis of metal complex precursor (a-11) The title compound (a-11) was synthesized according to Production Example 1 using 5-(4-methoxycarbonylphenyl)-10,15,20-triphenylporphyrin (manufactured by Tokyo Chemical Industry Co., Ltd.) instead of octaethylporphyrin and tetrachlorosilane.

[0157] (Synthesis example of a photosensitizer (PS-Ra) with a reactive group in the side chain) The synthesis of the photosensitizers (PS-Ra) of the present invention having a reactive group in the side chain was carried out according to the following flow. The structures of the synthesized photosensitizers (PS-Ra1 to 5) are shown in Table 4.

[0158] [ka]

[0159] Examples 87 to 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 a molar ratio of 1:2 in acetonitrile solvent in a reaction vessel at room temperature, and the mixture was reacted for 6 hours while blowing in nitrogen. The acetonitrile was then distilled off under reduced pressure to obtain the desired intermediate I.

[0160] Synthesis of intermediate II: In a reaction vessel, (Intermediate I) and sodium 5-aminovalerate were mixed in a molar ratio of 1:1 in acetonitrile solvent, and the mixture was stirred for 48 hours at 40° C. After the reaction, the solvent was distilled off under reduced pressure to obtain the target product (Intermediate II).

[0161] Synthesis of PS-Ra: 1 mmol of (Intermediate II) was added to a reaction vessel and dissolved in dimethyl sulfoxide, and 1 mmol of pyridine and 1 mmol of di(N-succinimidyl)carbonate were added, followed by reaction for 6 hours at 50°C. After the reaction, the mixture was concentrated and washed with IPA / water to obtain the target product (PS-Ra).

[0162] (Synthesis of photosensitizer (PS-Rb) with reactive groups in the side chain) The photosensitizers (PS-Rb) of the present invention having a reactive group in the side chain were synthesized according to the following known method. The structures of the synthesized photosensitizers (PS-Rb1 to 5) are shown in Table 4.

[0163] [ka]

[0164] Examples 92 to 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 a molar ratio of 1:2 in acetonitrile solvent in a reaction vessel at room temperature, and the mixture was reacted for 6 hours while blowing in nitrogen. The acetonitrile was then distilled off under reduced pressure to obtain the desired intermediate I.

[0165] Synthesis of intermediate II: In a reaction vessel, (Intermediate I) and sodium 12-amino-4,7,10-trioxadodecanoate were mixed in a molar ratio of 1:1 in acetonitrile solvent, and the mixture was stirred for 48 hours at 40° C. After the reaction, the solvent was distilled off under reduced pressure to obtain the target product (Intermediate II).

[0166] Synthesis of PS-Ra: 1 mmol of (Intermediate II) was added to a reaction vessel and dissolved in dimethyl sulfoxide, and 1 mmol of pyridine and 1 mmol of di(N-succinimidyl) carbonate were added, followed by a reaction at 50°C for 10 hours. After the reaction, the mixture was concentrated and washed with ethanol / water to obtain the target product (PS-Rb).

[0167] [Table 4]

[0168] (Example of a photosensitizer bound to a probe) Using the photosensitizers (PS-Ra and PS-Rb) with reactive groups in the side chains obtained in Examples 87 to 96, biotin-labeled photosensitizers (PS-Ba) and (PS-Bb) were synthesized as probes according to the known method described below. The structures of the synthesized photosensitizers (PS-Ba1 to 5 and PS-Bb1 to 5) are shown in Table 5.

[0169] [ka]

[0170] Examples 97 to 101 0.1 mmol of (PS-Ra) was dissolved in 10 mL of dimethyl sulfoxide in a reaction vessel, and 0.1 mmol of N-biotinyl-3,6-dioxaoctane-1,8-diamine (Tokyo Chemical Industry Co., Ltd.) and 10 mL of disodium phosphate buffer (pH 8.4) were added and stirred at room temperature for 24 hours. The reaction solution was concentrated and washed with acetonitrile and methanol to obtain the target product (PS-Ba).

[0171] [ka]

[0172] Examples 102 to 106 0.1 mmol of (PS-Rb) was dissolved in 10 mL of dimethyl sulfoxide in a reaction vessel, and 0.1 mmol of N-biotinyl-3,6-dioxaoctane-1,8-diamine (Tokyo Chemical Industry Co., Ltd.) and 10 mL of disodium phosphate buffer (pH 8.4) were added and stirred at room temperature for 24 hours. The reaction solution was concentrated and washed with acetonitrile and methanol to obtain the target product (PS-Bb).

[0173] [Table 5]

[0174] (Evaluation-1: Solubility test) <Examples 107 to 116> The photosensitizers bound to the probes obtained in Examples 97 to 106 were evaluated for solubility under the following conditions. The results are shown in Table 6. DMSO solution preparation: (a) Dissolve 10 mg of photosensitizer in 1 mL of DMSO to make a 1% DMSO solution. (b) Dissolve 1 mg of photosensitizer in 1 mL of DMSO to make a 0.1% DMSO solution. Next, these were diluted with 10 mL of water (A) and with 10 mL of 0.1 M phosphate buffer (B), and the solubility was evaluated visually. The results are shown in Tables 2 and 3. ◎:Transparent 〇: Slight haze △: There is haze and slight sedimentation ×: Immediately settles (Evaluation-2: Photoresponsiveness test) Using the photosensitizers bound to the probes obtained in Examples 97 to 106, 1 × 10 -6 A 0.1% DMSO-containing aqueous solution of M was prepared, and this was exposed to light using a LIGHTNINGCURE spot light source LC8 (manufactured by Hamamatsu Photonics) as the light source through an infrared transmission filter (manufactured by HOYA) R64 (cutting off wavelengths below 620 nm), and the change in appearance was evaluated. The results are shown in Table 6 as the photoresponsiveness results. ◎: Aggregates present, liquid phase is transparent ○: Aggregates present, liquid phase is suspended ×: No aggregates

[0175] [Table 6]

[0176] Table 6 shows that, as shown in Examples 107 to 116, photosensitizers bound to the probes of the present invention exhibit good solubility even in hydrophilic solvents, particularly buffer solvents used in the biotechnology field. Furthermore, as shown in Examples 107 to 116, photosensitizers bound to the probes of the present invention undergo hydrophobicity upon light irradiation, allowing for effective aggregation. That is, even in the form in which various probes are bound, the photosensitizers of the present invention can be aggregated by changing their hydrophilicity and hydrophobicity upon light irradiation without losing their effectiveness. Furthermore, the photosensitizers (PS-Ra) and (PS-Rb), which are precursors of the photosensitizers and have reactive groups in their side chains, can also achieve the aggregation effect upon light irradiation. [Industrial Applicability]

[0177] The photosensitizer of the present invention is suitable for use in methods that utilize light (particularly in the visible to infrared region) to aggregate complexes that specifically bind to specific target cells by light irradiation, and for use as a pharmaceutical for therapeutic purposes (photodynamic therapy, photoimmunotherapy, etc.). It can also be suitable for use in analytical and purification methods that utilize the specific binding of antibodies, such as affinity chromatography and photoirradiation molecular inactivation (CALI and FALI).

Claims

1. A photosensitizer containing a metal complex represented by general formula (1) or general formula (2), which has a cyclic ligand in which pyrrole rings are connected directly or through π-conjugation to form a ring structure, and has an axial ligand having an onium salt structure. 【Chemistry 1】 [In formula (1), R １ ~R ８ is a substituent 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 may be bonded to each other to form a condensed polycyclic aromatic structure, Y is a nitrogen atom, CR ９ Alternatively, R ９ is a hydrogen atom or an aromatic hydrocarbon having 6 to 14 carbon atoms, M is selected from the group consisting of Al, Ga, In, Si, Ge, Sn, Fe, Ti, Co and Mn, and L １ and L ２ is an axial ligand represented by formula (3) coordinated to a metal M, and when M is Al, Ga, In, Fe, Co, or Mn, L １ Only has 【Chemistry 2】 [Formula (2) represents the case where the central metal M is cationic, and R １ ~R ８ , Y., L. １ and L ２ is the same as formula (1), M is selected from the group consisting of P, Sb and Bi, and X ２ － represents a monovalent counter anion corresponding to the central metal cation. 【Transformation 3】 [In formula (3), D represents an oxygen atom or a sulfur atom, E represents 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 the main chain of these groups contains at least one ammonio group represented by the following formula (4), and 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; A ＋ is a monovalent onium cation, and X １ － represents a monovalent counter anion corresponding to the onium cation. 【Chemistry 4】 [R in formula (4) １０ , R １１ is a group selected from the group consisting of alkyl groups having 1 to 3 carbon atoms and groups represented by the following formula (5): １０ , R １１ When both are alkyl groups having 1 to 3 carbon atoms, a monovalent counter anion X corresponding to the ammonio group ３ － It has the following characteristics. 【Transformation 5】 [L in formula (5) ３ is methylene, ethylene or propylene, and X ４ － is an anion selected from the group consisting of carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid and phosphonic acid, １０ , R １１ are both formula (5), X ４ － Either one of them has a hydrogen ion or a monovalent metal cation.

2. A in formula (3) ＋ 2. The photosensitizer according to claim 1, wherein is a sulfonium cation, a diazonium cation, or an iodonium cation.

3. 3. The photosensitizer according to claim 1, wherein the cyclic ligand has a porphyrin skeleton or a phthalocyanine skeleton.

4. 4. The photosensitizer according to claim 1, wherein M in formula (1) is Al, Si, Ge, Sn, or P, and M in formula (2) is P.

5. 5. The photosensitizer according to claim 1, wherein at least one of the substituents on the cyclic ligand contains a group represented by the following formula (6): 【Transformation 6】 [In formula (6), (G) represents a biomolecule (probe), and L ４ represents a divalent group that bonds (G) to the photosensitizer molecule.

6. 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): 【Transformation 7】 [In formula (7), L ４ 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.

8. An antibody conjugate to which the photosensitizer according to claim 7 is bound.

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