Phthalocyanine dye and its applications

Abstract

To provide a phthalocyanine dye that triggers a rapid photochemical reaction in photoimmunotherapy.SOLUTION: The present invention provides a phthalocyanine dye having the following formula (1) or its salt, stereoisomer, or tautomer.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a phthalocyanine dye and its use. [Background technology]

[0002] Currently, there are three main methods for treating cancer: surgery, chemotherapy, and radiation therapy. In addition to these therapies, minimally invasive cancer therapies that cause minimal damage to normal tissues, such as photodynamic therapy (PDT) using photosensitizers and photoimmunotherapy (PIT), have been developed in recent years.

[0003] In particular, photoimmunotherapy is a treatment in which a drug consisting of a photosensitizer phthalocyanine dye bound to an antibody is bound to cancer cells, and then light is applied to cause a photochemical change in the phthalocyanine dye, thereby killing the cancer cells.

[0004] In photoimmunotherapy, in order to improve cytotoxicity and therapeutic efficiency deep inside the body, it is necessary to speed up the photochemical reaction of the photosensitizer. However, currently, IRDye700DX, a phthalocyanine dye known as a photosensitizer, has an issue with the rapidity of the photochemical reaction (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] J.Photochem.And 375 Photobiol.:Chem.408,113094(2021). Summary of the Invention [Problem to be solved by the invention]

[0006] The problem to be solved by the present invention is to provide a phthalocyanine dye that induces a rapid photochemical reaction in photoimmunotherapy. [Means for solving the problem]

[0007] As a result of extensive investigations aimed at solving the above problems, the present inventors have found a phthalocyanine dye having excellent properties for solving the above problems, and have completed the present invention.

[0008] That is, the embodiments of the present invention relate to the following [1] to [7]. However, the present invention is not limited to the following embodiments and includes various embodiments.

[0009] [1] A phthalocyanine dye having the following formula (1), or a salt, stereoisomer, or tautomer thereof: Formula (1): [ka] In formula (1), R1 represents -(L)-(W) or (L)-(Q), where (L) represents a linker, (W) represents a reactive group for bonding the substance that recognizes a target substance to the phthalocyanine, and (Q) represents the substance that recognizes a target substance. n is 1 or 2. M1 represents Al, Ga, or In. R2 to R4 each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or -XN + -R 20 R 21 R 22 Represents. At least one of R2 to R4 is -XN + -R 20 R 21 R 22 Represents R 20 ~R 22 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbamoyl group, or a water-soluble group. 20 ~R 22When there is no anionic substituent, the counter anion Y - has. Each X is independently a direct bond or a linear or branched, cyclic or heterocyclic, saturated or unsaturated molecular chain having 1 to 60 atoms selected from C, N, P, O, and S. R8~R 19 are each independently hydrogen, CR 23 R 24 R 25 , N.R. 26 R 27 , -(A)-(B), or an electron-withdrawing group, where R 23 ~R 27 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. (A) represents an O, S, Se, or Te atom, and (B) represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. R8~R 19 At least one of is an electron-withdrawing group.

[0010] [2] A phthalocyanine dye having the following formula (2), or a salt, stereoisomer, or tautomer thereof: Formula (2): [ka] In formula (2), R1 represents -(L)-(W) or (L)-(Q), where (L) represents a linker, (W) represents a reactive group for bonding the substance that recognizes a target substance to the phthalocyanine, and (Q) represents the substance that recognizes a target substance. n is 1 or 2. M2 represents Si, Ge, or Sn. R2 to R4 and R5 to R7 each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or -XN + -R 20 R 21 R 22 Represents. At least one of R2 to R4 and R5 to R7 is -XN + -R 20 R 21 R 22 Represents R 20 ~R 22 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbamoyl group, or a water-soluble group. 20 ~R 22 When Y has no anionic substituent, the counter anion Y - has. Each X is independently a direct bond or a linear or branched, cyclic or heterocyclic, saturated or unsaturated molecular chain having 1 to 60 atoms selected from C, N, P, O, and S. R8~R 19 are each independently hydrogen, CR 23 R 24 R 25 , N.R. 26 R 27 , -(A)-(B), or an electron-withdrawing group, where R 23 ~R 27 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. (A) represents an O, S, Se, or Te atom, and (B) represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. R8~R 19At least one of is an electron-withdrawing group.

[0011] [3] R9, R 10 , R 13 , R 14 , R 17 , and R 18 The phthalocyanine dye, or a salt, stereoisomer, or tautomer thereof according to [1] or [2], wherein at least one of

[0012] [4] The phthalocyanine dye or a salt, stereoisomer, or tautomer thereof according to any one of [1] to [3], which is for use in photoimmunotherapy.

[0013] [5] The phthalocyanine colorant, or a salt, stereoisomer, or tautomer thereof according to any one of [1] to [4], having a HOMO value of −6.0 eV or less.

[0014] [6] The phthalocyanine dye or a salt, stereoisomer, or tautomer thereof according to any one of [1] to [5], wherein the substance that recognizes a target substance is an antibody, an antibody fragment, or a peptide.

[0015] [7] A pharmaceutical composition comprising the phthalocyanine dye or a salt, stereoisomer, or tautomer thereof according to any one of [1] to [6] and a pharma- ceutically acceptable carrier. Effect of the Invention

[0016] According to the present invention, it is possible to provide a phthalocyanine dye that induces a rapid photochemical reaction in photoimmunotherapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention will be described in detail below. In the present specification, an example of the structure of the isomer is shown.

[0018] The phthalocyanine colorant of the present invention is a phthalocyanine colorant represented by the following formula (1) or a salt, stereoisomer, or tautomer thereof. Formula (1): [ka] In formula (1), R1 represents -(L)-(W) or (L)-(Q), where (L) represents a linker, (W) represents a reactive group for bonding the substance that recognizes a target substance to the phthalocyanine, and (Q) represents the substance that recognizes a target substance. n is 1 or 2. M1 represents Al, Ga, or In. R2 to R4 each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or -XN + -R 20 R 21 R 22 Represents. At least one of R2 to R4 is -XN + -R 20 R 21 R 22 Represents R 20 ~R 22 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbamoyl group, or a water-soluble group. 20 ~R 22 When there is no anionic substituent, the counter anion Y - has. Each X is independently a direct bond or a linear or branched, cyclic or heterocyclic, saturated or unsaturated molecular chain having 1 to 60 atoms selected from C, N, P, O, and S. R8~R 19 are each independently hydrogen, CR 23 R 24 R 25 , N.R. 26 R 27 , -(A)-(B), or an electron-withdrawing group, where R 23 ~R 27represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. (A) represents an O, S, Se, or Te atom, and (B) represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. R8~R 19 At least one of is an electron-withdrawing group.

[0019] The phthalocyanine colorant of the present invention is a phthalocyanine colorant represented by the following formula (2) or a salt, stereoisomer, or tautomer thereof. Formula (2): [ka] In formula (2), R1 represents -(L)-(W) or (L)-(Q), where (L) represents a linker, (W) represents a reactive group for bonding the substance that recognizes a target substance to the phthalocyanine, and (Q) represents the substance that recognizes a target substance. n is 1 or 2. M2 represents Si, Ge, or Sn. R2 to R4 and R5 to R7 each independently represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or -XN + -R 20 R 21 R 22 Represents. At least one of R2 to R4 and R5 to R7 is -XN + -R 20 R 21 R 22 Represents R 20 ~R 22each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbamoyl group, or a water-soluble group. 20 ~R 22 When Y has no anionic substituent, the counter anion Y - has. Each X is independently a direct bond or a linear or branched, cyclic or heterocyclic, saturated or unsaturated molecular chain having 1 to 60 atoms selected from C, N, P, O, and S. R8~R 19 are each independently hydrogen, CR 23 R 24 R 25 , N.R. 26 R 27 , -(A)-(B), or an electron-withdrawing group, where R 23 ~R 27 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. (A) represents an O, S, Se, or Te atom, and (B) represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. R8~R 19 At least one of is an electron-withdrawing group.

[0020] In formula (1) and formula (2), the linker (L) represents a direct bond or a covalent bond. The covalent bond is linear or branched, cyclic or heterocyclic, saturated or unsaturated, and has 1 to 60 atoms selected from the group consisting of C, N, P, O, and S atoms, and includes, but is not limited to, a single bond, a double bond, a triple bond, an aromatic carbon-carbon bond, a phosphorus-oxygen bond, a phosphorus-sulfur bond, a nitrogen-carbon bond, a nitrogen-nitrogen bond, a nitrogen-oxygen bond, a sulfur-carbon bond, a sulfur-sulfur bond, an aromatic bond, and a heteroaromatic bond.

[0021] In formula (1) and formula (2), examples of the reactive group (W) for binding the substance that recognizes a target substance to the phthalocyanine include, but are not limited to, a reactive amino group, a reactive thiol group, an activated ester such as N-hydroxysuccinimide (NHS) ester, an acyl halide, an alkyl halide, a haloacetyl, a pyridyl disulfide, an aziridine, an acryloyl, an arylating agent, a vinyl sulfone, an anhydride, a carboxylic acid, a carbodiimide, a carbonate, a carbamate, a haloacetamide (e.g., iodoacetamide), an isocyanate, an isothiocyanate, a maleimide, a phosphoramidite, a platinum complex, a sulfonate ester, and a thiocyanate.

[0022] In formula (1) and formula (2), examples of the substance (Q) that recognizes the target substance (target biological substance) include antibodies (including cancer antibodies) that can specifically recognize proteins, antibody fragments, peptides, protein receptors, low molecular weight compounds that can bind to the proteins, etc. For example, when the target substance is a variety of proteins or peptides that are specifically expressed in disease sites such as cancer, or cells, examples of the substance that recognizes the target substance include antibodies against these (cancer antibodies such as cetuximab, panitumumab, zalutumumab, nimotuzumab, and trastuzumab, endothelial cell marker antibodies, tissue-specific antibodies, and phosphorylated protein antibodies, etc.) or their affinity substances, biotin, folic acid, transferrin, and transferrin-binding peptides, but are not limited thereto. Here, the antibody fragment refers to a molecule other than a whole antibody that contains a part of a whole antibody and binds to an antigen to which the whole antibody binds. Examples of antibody fragments include Fab, Fab', Fab'-SH, F(ab')2, Fv, single domain antibody (sdAb), single chain Fv (scFv), diabody, scFv dimer, tandem scFv (taFv), (scFv)2, single chain diabody (scDb), single chain Fab (scFab), tandem scDb (TandAb), triabody, tetrabody, hexabody, one-arm antibody, and multispecific antibodies formed from antibody fragments, such as Fab-scFv, scFv-Fc, Fab-scFv-Fc, scDb-Fc, and taFv-Fc. Among these, the substance that recognizes the target substance is preferably an antibody, an antibody fragment, or a peptide.

[0023] In formula (1) and formula (2), the number of bonds n of the linker (L) is 1 or 2, but n is preferably 1 from the viewpoint of suppressing denaturation associated with antibody aggregation.

[0024] In the formula (1), the central metal M1 is preferably Al, Ga, or In, more preferably Al, from the viewpoint of ease of synthesis. Also, in the formula (2), the central metal M2 is preferably Si, Ge, or Sn, more preferably Si, from the same viewpoint.

[0025] In formula (1) and formula (2), the substituted or unsubstituted alkyl group may be a straight-chain or branched-chain alkyl group. Specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a dodecyl group, an octadecyl group, an isopropyl group, an isobutyl group, an isopentyl group, a 2-ethylhexyl group, a sec-butyl group, a tert-butyl group, a sec-pentyl group, a tert-pentyl group, a tert-octyl group, and a neopentyl group. The number of carbon atoms in the alkyl group is preferably within the range of 1 to 30.

[0026] When a substituted or unsubstituted alkyl group has a substituent, examples of the substituent include halogen atoms such as fluorine, chlorine, and bromine, hydroxyl groups, amino groups, nitro groups, formyl groups, cyano groups, and carboxyl groups, as well as the above-mentioned alkyl groups, the below-mentioned aryl groups, cycloalkyl groups, and heterocyclic groups. In addition, when a part of the structure is substituted with an amide bond (-NHCO-), an ester bond (-COO-), and / or an ether bond (-O-), the substituted portion is also included as a "substituent".

[0027] The substituted alkyl group may be substituted with one or more substituents. Specific examples of the alkyl group substituted with a halogen atom include a trifluoromethyl group, a 2,2,2-trifluoroethyl group, -(CF2)4CF3, -(CF2)5CF3, -(CF2)6CF3, -(CF2)7CF3, -(CF2)8CF3, a trichloromethyl group, and a 2,2-dibromoethyl group.

[0028] Specific examples of the alkyl group substituted with an amide bond include -CH2-CH2-CH2-NHCO-CH2-CH2-, -CH2-CH(-CH3)-CH2-NHCO-CH2-CH2-, -CH2-CH2-CH2-NHCO-CH2-CH2-, -CH2-CH2-CH2-CH2-NHCO-CH2-CH2-, -CH2-CH2-CH2-CH2-NHCO-CH2-CH2-, -CH2-CH2-CH2-CH2-NHCO-CH2-CH(CH2-CH3)-CH2-CH2-CH2-CH2-CH2-CH2-, -(CH2)5-NHCO-(CH2) 11 Examples of the alkyl group substituted with an amide bond include -CH3, -CH2-CH2-CH2-C(-NHCO-CH2-CH3)2-, etc. The number of carbon atoms in the alkyl group substituted with an amide bond is preferably within the range of 2 to 30.

[0029] Specific examples of alkyl groups substituted with an ester bond include -CH2-CH2-CH2-COO-CH2-CH3, -CH2-CH(-CH3)-CH2-COO-CH2-CH3, -CH2-CH2-CH2-OCO-CH2-CH3, -CH2-CH2-CH2-CH2-COO-CH2-CH(CH2-CH3)-CH2-CH2-CH2-CH3, -(CH2)5-COO-(CH2) 11Examples include -CH3, -CH2-CH2-CH2-CH-(COO-CH2-CH3)2, etc. The number of carbon atoms in the alkyl group substituted with an ester bond is preferably within the range of 2 to 30.

[0030] Specific examples of alkyl groups substituted with an ether bond include -CH2-O-CH3, -CH2-CH2-O-CH2-CH3, -CH2-CH2-CH2-O-CH2-CH3, -(CH2-CH2-O) n -CH3 (wherein n is an integer from 1 to 8), -(CH2-CH2-CH2-O) m Examples of the alkyl group substituted with an ether bond include, but are not limited to, -CH3 (wherein m is an integer of 1 to 5), -CH2-CH(CH3)-O-CH2-CH3-, -CH2-CH-(OCH3)2, etc. The number of carbon atoms in the alkyl group substituted with an ether bond is preferably within the range of 2 to 30.

[0031] Specific examples of the alkyl group substituted with two or more substituents selected from an amide bond (-NHCO-), an ester bond (-COO-), and an ether bond (-O-) include -CH2-CH2-NHCO-CH2-CH2-O-CH2-CH(CH2-CH3)-CH2-CH2-CH2-CH3, -CH2-CH2-COO-CH2-CH2-O-CH2-CH2-NHCO-CH2-CH(CH2-CH3)-CH2-CH2-CH2-CH3, etc. The number of carbon atoms in the alkyl group substituted with two or more substituents selected from an amide bond (-NHCO-), an ester bond (-COO-), and an ether bond (-O-) is preferably within the range of 3 to 30.

[0032] In formula (1) and formula (2), the substituted or unsubstituted alkanoyl group may be a group of the form -(C=O)-(alkyl group). Here, the alkyl group is as defined in the present specification. Specific examples include methoyl group, ethoxyl group, etc. In the case where the alkanoyl group has a substituent, the substituent may be the same as the substituent in the alkyl group described above.

[0033] In formula (1) and formula (2), the substituted or unsubstituted alkoxycarbonyl group may be a group such as -(C=O)-O-(alkyl group) or -O-(C=O)-(alkyl group). Here, the alkyl group is as defined in the present specification. Specific examples include methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl groups. When the alkoxycarbonyl group has a substituent, the substituent may be the same as the substituent in the alkyl group described above.

[0034] In formula (1) and formula (2), the substituted or unsubstituted alkylcarbamoyl group may be a group such as -(C=O)-NH-(alkyl group) or -NH-(C=O)-(alkyl group). Here, the alkyl group is as defined in the present specification. Specific examples include a methylcarbamoyl group, an ethylcarbamoyl group, and a tert-butylcarbamoyl group. When the alkylcarbamoyl group has a substituent, the substituent may be the same as the substituent in the alkyl group described above.

[0035] In the formulas (1) and (2), the water-soluble group is a carboxy group having any counter ion (-COO - ), sulfo group (-SO2-O - ), phosphono group (phosphonic acid group, -PO-(O - )2), phosphonooxy group (phosphate group, -OPO-(O - )2), sulfamoyl group (-SO2NH2), hydroxyl (-O - ) group, amino group (-NH2), quaternary ammonium group (-N + Examples of the water-soluble group include, but are not limited to, a carboxy group, a sulfo group, a phosphonooxy group, an amino group, a quaternary ammonium group, and a poly(ethylene glycol) group, and among the above, the water-soluble group is preferably at least one selected from the group consisting of a carboxy group, a sulfo group, a phosphonooxy group, and a quaternary ammonium group, and more preferably at least one selected from the group consisting of a carboxy group, a sulfo group, a phosphonooxy group, and a quaternary ammonium group.

[0036] In formula (1) and formula (2), the counter anion Y - Examples of the ion include halide ions such as hydroxide ion, fluoride ion, chloride ion, bromide ion, and iodide ion, as well as nitrate ion, formate ion, acetate ion, trifluoroacetate ion, p-toluenesulfonate ion, trifluoromethanesulfonate, hexafluorophosphate, and tetrafluoroborate. Of these, chloride ion, bromide ion, formate ion, acetate ion, and trifluoroacetate ion are preferred, but the ion is not limited to these.

[0037] In formula (1) and formula (2), (X) represents a direct bond or a covalent bond. The covalent bond is linear or branched, cyclic or heterocyclic, saturated or unsaturated, and has 1 to 60 atoms selected from the group consisting of C, N, P, O, and S atoms, and includes, but is not limited to, a single bond, a double bond, a triple bond, an aromatic carbon-carbon bond, a phosphorus-oxygen bond, a phosphorus-sulfur bond, a nitrogen-carbon bond, a nitrogen-nitrogen bond, a nitrogen-oxygen bond, a sulfur-carbon bond, a sulfur-sulfur bond, an aromatic bond, and a heteroaromatic bond. In addition, from the viewpoint of reactivity, the number of atoms is preferably 30 or less.

[0038] In formula (1) and formula (2), the substituted or unsubstituted alkenyl group may be a linear or branched alkenyl group. An alkenyl group generally refers to one having one double bond in its structure, but in this specification, an alkenyl group having multiple double bonds is also included. Specific examples include a vinyl group, a 1-propenyl group, an allyl group, a 2-butenyl group, a 3-butenyl group, an isopropenyl group, an isobutenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, and a 1,3-butadienyl group. The number of carbon atoms in the alkenyl group is preferably within the range of 2 to 18. When the alkenyl group has a substituent, the substituent may be the same as the substituent in the alkyl group described above.

[0039] In formula (1) and formula (2), the substituted or unsubstituted alkynyl group may be a linear or branched alkenyl group. An alkynyl group generally refers to one having one triple bond in its structure, but in this specification, an alkenyl group having multiple triple bonds is also included. Specific examples include an ethynyl group, a 1-propynyl group, a 2-butynyl group, a 3-butynyl group, an isopropynyl group, an isobutynyl group, a 1-pentynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group, a 1-hexynyl group, a 2-hexynyl group, a 3-hexynyl group, and a 4-hexynyl group. The number of carbon atoms in the alkynyl group is preferably within the range of 2 to 18. When the alkynyl group has a substituent, the substituent may be the same as the substituent in the alkyl group described above.

[0040] In formula (1) and formula (2), the substituted or unsubstituted aryl group includes a monocyclic or condensed polycyclic aryl group. Examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a p-biphenyl group, a m-biphenyl group, a 2-anthryl group, a 9-anthryl group, a 2-phenanthryl group, a 3-phenanthryl group, a 9-phenanthryl group, a 2-fluorenyl group, a 3-fluorenyl group, a 9-fluorenyl group, a 1-pyrenyl group, a 2-pyrenyl group, a 3-perylenyl group, an o-tolyl group, a m-tolyl group, a p-tolyl group, a 4-methylbiphenyl group, a terphenyl group, a 4-methyl-1-naphthyl group, a 4-tert-butyl-1-naphthyl group, a 4-naphthyl-1-naphthyl group, a 6-phenyl-2-naphthyl group, a 10-phenyl-9-anthryl group, a spirofluorenyl group, and a 2-benzocyclobutenyl group. The number of carbon atoms in the aryl group is preferably within the range of 6 to 18. When the aryl group has a substituent, examples of the substituent include the same substituents as those in the alkyl group described above.

[0041] In formula (1) and formula (2), examples of the substituted or unsubstituted cycloalkyl group include a cyclopentyl group, a cyclohexyl group, a 2,5-dimethylcyclopentyl group, and a 4-tert-butylcyclohexyl group. The number of carbon atoms in the cycloalkyl group is preferably within a range of 5 to 12. When the cycloalkyl group has a substituent, examples of the substituent include the same substituents as those in the alkyl group described above.

[0042] In formula (1) and formula (2), the substituted or unsubstituted heterocyclic group may be an aliphatic heterocyclic group or an aromatic heterocyclic group. Specific examples include a pyridyl group, a pyrazyl group, a piperidino group, a pyranyl group, a morpholino group, and an acridinyl group. In addition, groups represented by the following structural formulas may also be included. The number of carbon atoms in the heterocyclic group is preferably 4 to 12. The number of ring members is preferably 5 to 13.

[0043] [ka]

[0044] When the heterocyclic group has a substituent, the substituent may be the same as the substituent in the alkyl group described above. Examples of the heterocyclic group having a substituent include a 3-methylpyridyl group, an N-methylpiperidyl group, and an N-methylpyrrolyl group.

[0045] In formula (1) and formula (2), (A) represents an O, S, Se, or Te atom. Among these, O and S are preferred from the viewpoints of ease of synthesis and safety, and Se and Te are preferred from the viewpoint of photochemical reaction rate.

[0046] In formula (1) and formula (2), examples of the electron-withdrawing group include a substituent having a positive Hammett substituent constant σpara value. As the electron-withdrawing group, a group having a σpara value of 0.05 or more is more preferable, a group having a σpara value of 0.20 or more is even more preferable, and a group having a σpara value of 0.30 or more is particularly preferable.

[0047] Examples of groups with a σpara value of 0.05 or more include halogen atoms such as fluorine atom (0.06), chlorine atom (0.23), bromine atom (0.23), and iodine atom (0.18); -CHO (0.42), -COCH3 (0.50), -COC6H5 (0.43), -CONH2 (0.36), -COOH (0.45), -COOCH3 (0.45), and -COOC Carbonyl substituents such as 2H5 (0.45); sulfonyl or sulfinyl substituents such as -SOCH3 (0.49), -SO2CH3 (0.72), -SO2C6H5 (0.68), -SO2CF3 (0.96), -OSO2CF3 (0.53), -SO2N(CH3)2 (0.65), -SO3- (0.35); -CN (0.66), -N(CH3) 3+ (0.82), -N(CF3)2 (0.53), and other nitrogen-containing substituents; -CCl3, -CH2Cl (0.26), -CHCl2 (0.12), -CF2CF3 (0.52), and other halogen atom-containing substituents. The numerical values ​​in parentheses above are the σpara values ​​of each compound.

[0048] In the formulas (1) and (2), R9, R 10 , R 13 , R 14 , R 17 , and R 18 The number of electron-withdrawing groups contained in is preferably one or more, more preferably three or more, and even more preferably six.

[0049] In formulas (1) and (2), R to R 19 The number of -(A)-(B) in the formula (I) is preferably 3 or more, and more preferably 6, in order to lengthen the maximum absorption wavelength of the near-infrared absorbing dye and improve the biological permeability.

[0050] In photoimmunotherapy, photoexcited IRDye700DX is converted into a radical anion through a one-electron transfer reaction from a reducing agent present around the cancer cells, followed by elimination of the water-soluble axial ligand, resulting in cytotoxicity.

[0051] Therefore, in order to improve the cytotoxicity in photoimmunotherapy, it is important to lower the HOMO and LUMO energy levels and promote the one-electron transfer reaction from the reducing agent. The lowering of the HOMO and LUMO energy levels can be achieved by reducing the electron density of the π-conjugated system by introducing an electron-withdrawing group.

[0052] From the above viewpoints, the phthalocyanine dye of the present invention preferably has 3 or more electron-withdrawing groups, and more preferably has 6. The HOMO value of the phthalocyanine dye of the present invention is preferably −6.0 eV or less, more preferably −6.2 eV or less, and even more preferably −6.5 eV or less.

[0053] Specific examples of the phthalocyanine dye according to one embodiment of the present invention include the following dyes. However, the phthalocyanine dye according to the present invention is not limited to these. In addition, in this specification, only one example of the phthalocyanine structure is shown, but isomers having different positions of the substituents are not excluded.

[0054] [Table 1-1]

[0055] [Table 1-2]

[0056] [Table 1-3]

[0057] [Table 1-4]

[0058] The phthalocyanine dye of the present invention can be used as a pharmaceutical composition together with a pharma- ceutically acceptable carrier. A pharma- ceutically acceptable carrier refers to an ingredient in a pharmaceutical formulation / composition other than the active ingredient that is non-toxic to a subject. Specific examples of pharma- ceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, preservatives, etc. EXAMPLES

[0059] The present invention will be described below based on examples, but the present invention is not limited thereto.

[0060] (mass spectrometry) The analysis was performed using a mass spectrometer (MALDI-TOF-MS: Bruker Daltonics microflex LRF).

[0061] [Production Example 1] <Method of producing compound A-1> In a 30 mL eggplant flask purged with nitrogen, 190 mg (0.5 mmol) of 4,5-diiodophthalonitrile, 810 mg (2.0 mmol) of Jagolovsky's reagent, and 190 mg (3.0 mmol) of copper were added and dissolved in 5 mL of dimethylformamide (DMF) and heated to 60°C. After stirring overnight, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried with sodium sulfate, and purified by silica gel column chromatography to obtain compound A-1 shown in Table 2 in a yield of 79%.

[0062] [Production Example 2] <Production method of compound A-2> 2.6g (15.0mmol) of 4-nitrophthalonitrile, 2.5g (22.5mmol) of thiophenol, and 3.1g (22.5mmol) of potassium carbonate were added to 50mL of DMF and stirred at 50℃. After cooling to room temperature, water was added and the precipitated solid was filtered. The obtained solid was dissolved in 100mL of dichloromethane, and then 25.9g (150.2mmol) of 3-chloroperbenzoic acid was added and stirred overnight at room temperature. After extraction with ethyl acetate, the organic layer was washed several times with a saturated aqueous solution of sodium bicarbonate. The product was purified by silica gel column chromatography to obtain compound A-2 shown in Table 2 in a yield of 53%.

[0063] [Production Example 3] <Production method of compound A-3> 504mg (3.5mmol) of 3-hydroxyphthalonitrile and 0.49mL (3.5mmol) of triethylamine were added to 50mL of dichloromethane, and the mixture was stirred for 30 minutes under a nitrogen atmosphere. The reaction solution was cooled to 0°C, and 0.37mL (3.5mmol) of trifluoromethanesulfonyl chloride was slowly added dropwise, and the mixture was stirred at room temperature for 16 hours. Then, 100mL of diethyl ether was added to the reaction solution, and the precipitate was filtered. The filtrate was washed with saturated saline, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain compound A-3 shown in Table 2 in a yield of 74%.

[0064] [Production Example 4] <Production method of compound A-4> To 20 mL of toluene, 414 mg (2.0 mmol) of 4-bromophthalonitrile, 567 mg (5.9 mmol) of sodium tert-butoxide, 11 mg (0.05 mmol) of palladium (II) acetate, 61 mg (0.15 mmol) of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and 904 mg (5.9 mmol) of 1,1,1-trifluoro-N-(trifluoromethyl)methanamine were added, and the mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, water was added, the mixture was extracted with chloroform, and purified by silica gel column chromatography to obtain compound A-4 shown in Table 2 in a yield of 46%.

[0065] [Production Example 5] <Production method of compound A-5> 270mg (1mmol) of 3-benzoylphthalic acid and 810mg (18mmol) of formamide were added and stirred at 120℃ for 90 minutes. The reaction solution was added to ice water, and the precipitated solid was filtered. The obtained solid was added to 2mL of 28% ammonia water and stirred for 4 hours, and the obtained solid was filtered, washed with water, filtered again, and dried. Separately, a solution was prepared by slowly dropping 240mg (2mmol) of thionyl chloride into 1mL of DMF, and the dried solid was added and stirred for 2 hours. The reaction solution was added to ice water, and the precipitated solid was filtered, washed with water, filtered again, and the obtained solid was dried, obtaining compound A-5 shown in Table 2 with a yield of 60%.

[0066] [Table 2]

[0067] [Production Example 6] <Method of producing compound B-1> 40.0 g (231 mmol) of 3-nitrophthalonitrile, 22.0 g (289 mmol) of 1,3-propanediol, and 63.8 g (462 mmol) of potassium carbonate were added to 200 mL of DMF, and the mixture was stirred at 70° C. for 3 hours. After cooling to room temperature, water was added, and the precipitated solid was filtered to obtain compound B-1 shown in Table 3 in a yield of 70%.

[0068] [Production Example 7] <Method of producing compound B-2> 400mg (2.6mmol) of 4-methoxybenzyl chloride and 1.15g (7.7mmol) of sodium iodide were added to 10mL of acetone. After stirring at room temperature for 12 hours in the dark, the mixture was extracted with diethyl ether. The organic layer was washed with 1mol / L sodium thiosulfate solution to remove excess iodine. The organic layer was then dried over anhydrous magnesium sulfate and concentrated with an evaporator to obtain compound B-2 shown in Table 3 in a yield of 89%.

[0069] [Production Example 8] <Method of producing compound B-3> Compound B-1 (506 mg, 2.5 mmol) was added to 10 mL of tetrahydrofuran (THF) and dissolved. 60% sodium hydride (148 mg, 3.7 mmol) was added thereto and stirred at -60°C for 15 minutes. Compound B-2 (918 mg, 3.7 mmol) was then added to the reaction mixture and stirred at -60°C for another 3 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and purified by silica gel column chromatography to obtain compound B-3 shown in Table 3 in a yield of 78%.

[0070] [Production Example 9] <Method of producing compound B-4> 40 g (231 mmol) of 4-nitrophthalonitrile, 26.6 g (289 mmol) of 3-mercapto-1-propanol, and 63.8 g (462 mmol) of potassium carbonate were added to 200 mL of DMF, and the mixture was stirred at 60° C. for 5 hours. After cooling to room temperature, water was added, and the precipitated solid was filtered and purified by silica gel column chromatography to obtain compound B-4 shown in Table 3 in a yield of 47%. [Production Example 10] <Production method of compound B-5> Compound B-4 (546 mg, 2.5 mmol) was added to 10 mL of THF and dissolved. 60% sodium hydride (148 mg, 3.7 mmol) was added thereto and stirred at -60°C for 15 minutes. Compound B-2 (918 mg, 3.7 mmol) was then added to the reaction mixture and stirred at -60°C for an additional 3 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and purified by silica gel column chromatography to obtain compound B-5 shown in Table 3 in a yield of 73%.

[0071] [Production Example 11] <Production method of compound B-6> 40.0 g (231 mmol) of 3-nitrophthalonitrile, 24.3 g (289 mmol) of 4-pentyn-1-ol, and 63.8 g (462 mmol) of potassium carbonate were added to 200 mL of DMF, and the mixture was stirred at 60° C. for 16 hours. After cooling to room temperature, water was added, and the precipitated solid was filtered and purified by silica gel column chromatography to obtain compound B-6 shown in Table 3 in a yield of 64%.

[0072] [Table 3]

[0073] [Production Example 12] <Method of producing compound C-1> 85 mg (3.7 mmol) of metallic sodium was dissolved in 25 mL of ethylene glycol, and 934 mg (2.9 mmol) of compound B-3 was added. After stirring at 115° C. for 2 hours while bubbling ammonia gas, the reaction mixture was added to ice water. The precipitated solid was filtered and washed with a large amount of ice water. The solid was dried under vacuum for 1 hour to obtain compound C shown in Table 4 in a yield of 86%.

[0074] [Examples 13-14] <Method of producing compound C-2 and compound C-3> Compounds C-2 and C-3 shown in Table 4 were produced in the same manner as in the production of compound C-1, except that compound B-3 used in the production of compound C-1 was changed to a phthalonitrile precursor shown in Table 4. Compounds B-5 and B-6, which are phthalonitrile precursors, were used in the same molar amount as compound B-3 in the production of compound C-1.

[0075] [Table 4]

[0076] [Production Example 15] <Method of producing compound D-1> 85 mg (3.7 mmol) of metallic sodium was dissolved in 25 mL of ethylene glycol, and 580 mg (2.9 mmol) of tetrafluorophthalonitrile was added. After stirring at 115°C for 2 hours while bubbling ammonia gas, the reaction mixture was added to ice water. The precipitated solid was filtered and washed with a large amount of ice water. The solid was dried under vacuum for 1 hour to obtain compound D-1 shown in Table 5 in a yield of 75%.

[0077] [Examples 16-21] <Method of producing compounds D-2 to D-7> Compounds D-2 to D-7 shown in Table 5 were produced in the same manner as in the production of compound D-1, except that the tetrafluorophthalonitrile used in the production of compound D-1 was changed to the phthalonitrile precursor shown in Table 5. The phthalonitrile precursors, compounds A-1 to A-5 and 4-iodophthalonitrile, were used in the same molar amount as tetrafluorophthalonitrile in the production of compound D-1.

[0078] [Table 5]

[0079] [Production Example 22] <Synthesis of compound E-1> 3.0g (12.6mmol) of 3-(tert-butoxycarbonylamino)propyl bromide was dissolved in 50mL of dehydrated THF and cooled to -78℃, then 8.0mL (12.8mmol) of 1.6mol / L n-butyllithium-hexane solution was slowly added dropwise and stirred for 30 minutes. 0.48mL (4.2mmol) of tetrachlorosilane was slowly added dropwise to the mixed solution and stirred for 2 hours. An aqueous solution of ammonium chloride was added dropwise to the reaction solution to terminate the reaction, and the solvent was removed by extraction with ethyl acetate. The compound was purified by silica gel column chromatography to obtain compound E-1 shown in Table 6 with a yield of 18%.

[0080] [Production Example 23] <Synthesis of compound E-2> 300 mg (0.58 mmol) of compound E-1 was dissolved in 3 mL of 4 mol / L hydrogen chloride-ethyl acetate solution and stirred for 3 hours. The resulting solution was concentrated under reduced pressure to obtain compound E-2 shown in Table 6 in a yield of 94%. [Table 6] Boc: tert-butoxycarbonyl group

[0081] [Production Example 24] <Method of producing compound F-1> To 5 mL of quinoline, 339 mg (1.0 mmol) of compound C-1, 652 mg (3.0 mmol) of compound D-1, and 2.6 g (20.0 mmol) of AlCl3 were added. The mixture was heated under reflux for 24 hours under an Ar atmosphere, and then methanol and a 10% aqueous hydrochloric acid solution were added. The precipitated solid was collected by filtration and washed with water. The obtained solid was dissolved in 20 mL of pyridine, and then 5 mL of n-butanol was added and the mixture was heated under reflux for 2 hours under an Ar atmosphere. Then, pyridine was distilled off, and the mixture was purified by silica gel column chromatography to obtain compound F-1 shown in Table 7 in a yield of 21%.

[0082] [Examples 25-37] <Method of producing compounds F-2 to F-14> Compounds F-2 to F-14 shown in Table 7 were produced in the same manner as in the production of compound F-1, except that compound C-1, compound D-1 and AlCl3 used in the production of compound F-1 were replaced with compound C, compound D and metal source shown in Table 7. Compounds C-2, compound C-3, compounds D-2 to 7 and metal source were used in the same molar amounts as compound C-1, compound D-1 and AlCl3 in the production of compound F-1. The structures of the obtained compounds F-2 to F-14 were identified by mass spectrometry and confirmed to have the structures shown in Table 7. Table 7 shows the results of mass spectrum analysis.

[0083] [Table 7-1]

[0084] [Table 7-2]

[0085] [Production Example 38] <Method of producing compound G-1> Compound F-1 (102 mg, 0.1 mmol) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (45 mg, 0.2 mmol) were added to a mixed solvent of chloroform (9 mL) and water (1 mL). The mixture was stirred at room temperature for 24 hours, and then methanol and water were added. The precipitated solid was collected by filtration and washed with water. The obtained solid was dissolved in pyridine (20 mL), and then 3-aminopropyldimethylethoxysilane (161 mg, 1.0 mmol) was added and refluxed for 2 hours under an Ar atmosphere. Then, pyridine was distilled off, and the precipitated solid was washed with a mixed solution of methanol:water = 2:1, to obtain compound G-1 shown in Table 7 in a yield of 41%.

[0086] [Examples 39-42] <Method of producing compounds G-2 to G-5> Compounds G-2 to G-5 shown in Table 7 were produced in the same manner as in the production of compound G-1, except that compound F-1 used in the production of compound G-1 was changed to compound F shown in Table 8. Compounds F-2 to F-5 were used in the same molar amount as compound F-1 in the production of compound G-1.

[0087] [Manufacture Example 43] <Method of producing compound G-6> Compound F-3 (121 mg, 0.1 mmol) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (45 mg, 0.2 mmol) were added to a mixed solvent of chloroform (9 mL) and water (1 mL). The mixture was stirred at room temperature for 24 hours, and then methanol and water were added. The precipitated solid was collected by filtration and washed with water. The obtained solid was dissolved in DMF (20 mL), and then compound E-2 (219 mg, 1.0 mmol) was added and reacted at 100° C. for 4 hours under an Ar atmosphere. Water was then added, and the precipitated solid was washed with a mixed solution of methanol:water=2:1, to obtain compound G-6 shown in Table 8 in a yield of 36%.

[0088] [Examples 44-50] <Method of producing compounds G-7 to G-13> Compounds G-7 to G-13 shown in Table 8 were produced in the same manner as in the production of compound G-1, except that compound F-1 used in the production of compound G-1 was changed to compound F shown in Table 7. Compounds F-6 to F-12 were used in the same molar amount as compound F-1 in the production of compound G-1, and 3-aminopropyldimethylethoxysilane was used in twice the molar amount.

[0089] [Example 51] <Method of producing compound G-14> Compound F-13 (119 mg, 0.1 mmol) was dissolved in pyridine (20 mL), 3-aminopropyldimethylethoxysilane (161 mg, 1.0 mmol) was added, and the mixture was refluxed under Ar atmosphere for 2 hours. Pyridine was then distilled off, and the precipitated solid was washed with a mixed solution of methanol:water = 2:1 to obtain compound G-14 shown in Table 8 with a yield of 47%.

[0090] [Example 52] <Method of producing compound G-15> Compound G-15 shown in Table 8 was produced in the same manner as in the production of compound G-14, except that compound F-13 used in the production of compound G-14 was changed to compound F shown in Table 8. Compound F-14 was used in the same molar amount as compound F-13 in the production of compound G-14. The structures of the obtained compounds G-1 to G-15 were identified by mass spectrometry and confirmed to have the structures shown in Table 8. Table 8 shows the results of mass spectrum analysis.

[0091] [Table 8-1]

[0092] [Table 8-2]

[0093] [Table 8-3]

[0094] [Example 53] <Method of producing compound H-1> Compound G-1 (48 mg, 0.05 mmol), 1,3-propane sultone (73 mg, 0.60 mmol), and N,N-diisopropylethylamine (85 mg, 0.66 mmol) were dissolved in 2 mL of DMF, and the mixture was stirred at 50° C. for 48 hours under an Ar atmosphere. The solvent was distilled off, and the crude was purified by reversed-phase HPLC. The purified product was desalted with a cation exchange resin, and compound H-1 shown in Table 9 was obtained in a yield of 41%.

[0095] [Examples 54-67] <Method of producing compounds H-2 to H-15> Compounds H-2 to 15 shown in Table 9 were produced in the same manner as in the production of compound G-1, except that compound G-1 used in the production of compound H-1 was changed to compound F or G shown in Table 9. Compounds G-2 to 5, 14 and 15 were used in the same molar amount as compound G-1 in the production of compound H-1, compounds G-7 to 13 were used in twice the molar amount, and compound G-6 was used in three times the molar amount. The structures of the obtained compounds H-2 to 15 were identified by mass spectrometry and were confirmed to have the structures shown in Table 9. Table 9 shows the results of mass spectrum analysis.

[0096] [Table 9-1]

[0097] [Table 9-2]

[0098] [Table 9-3]

[0099] [Example 68] <Method of producing compound I-1> Compound H-1 (69 mg, 0.05 mmol) and carbonyldiimidazole (122 mg, 0.75 mmol) were added to 10 mL of dehydrated THF and refluxed for 1 hour. The mixture was cooled to room temperature and ε-aminocaproic acid (13 mg, 0.10 mmol) was added. After stirring at room temperature for 24 hours, the solvent was removed and the crude was purified by reversed-phase HPLC to obtain compound H-1 shown in Table 10 in a yield of 67%.

[0100] [Examples 69-80] <Method of producing compounds I-2 to I-13> Compounds I-2 to I-13 shown in Table 10 were each produced in the same manner as in the production of compound I-1, except that compound H-1 used in the production method of compound I-1 was changed to compound H shown in Table 10.

[0101] [Example 81] <Method of producing compound I-14> Compound H-1 83mg (0.05mmol), 11-azido-3,6,9-trioxaundecanoic acid 175mg (0.75mmol) were dissolved in 4mL of a mixed solvent of water:acetonitrile = 1:1, and mixed with copper sulfate pentahydrate 12mg (0.05mmol), tris(3-hydroxypropyltriazolylmethyl)amine 43mg (0.1mmol), and sodium ascorbate 217mg (0.5mmol) dissolved in 6mL of water, and stirred at room temperature for 2 hours. The resulting solution was purified by reverse phase HPLC to obtain compound H-1 shown in Table 10 in a yield of 67%.

[0102] [Manufacturing Example 82] <Method of producing compound I-15> Compound I-15 shown in Table 10 was produced in the same manner as in the production of compound I-14, except that compound H-14 used in the production of compound I-14 was changed to compound H shown in Table 10. Compounds H-2 to 15 were used in the same molar amount as compound H-1 in the production of compound I-1. The structures of the obtained compounds I-2 to 15 were identified by mass spectrometry and confirmed to have the structures shown in Table 10. Table 10 shows the results of mass spectrum analysis.

[0103] [Table 10-1]

[0104] [Table 10-2]

[0105] [Table 10-3]

[0106] [Example 1] <Method of manufacturing dye 1> Compound I-1 (76 mg, 0.05 mmol), N,N'-disuccinimidyl carbonate (64 mg, 0.25 mmol), and diisopropylethylamine (32 mg, 0.25 mmol) were added to DMF (8 mL) and stirred at room temperature for 24 hours. The solvent was removed by distillation, and the crude was purified by reversed-phase HPLC to obtain dye 1 shown in Table 11 in a yield of 71%.

[0107] [Examples 2 to 15] <Method of producing dyes 2 to 15> Dyes 2 to 15 shown in Table 11 were each produced in the same manner as in the production of dye 1, except that compound I-1 used in the production of dye 1 was changed to compound I shown in Table 11. Compounds I-2 to 15 were used in the same molar amount as compound I-1 in the production of dye 1. The structures of the obtained dyes 2 to 15 were identified by mass spectrometry, and it was confirmed that they had the structures shown in Table 11. Table 11 shows the results of the mass spectrum analysis.

[0108]

Table 11-1

[0109]

Table 11-2

[0110]

Table 11-3

[0111] [Comparative Example 1] As the dye of Comparative Example 1, IRDye 700DX shown in Table 12 was used.

[0112]

Table 12

[0113] [Example 16] <Production of pan-dye 1: Conjugation of dye 1 to EGFR antibody> Panitumumab (1 mg, about 7 nmol) was dissolved in 0.1 mol / L aqueous Na2HPO4 solution (pH 8.5). After dissolving the dye 1 (57 μg, 35 nmol) obtained in Example 1 above in 150 μL of DMSO solution, it was added to the panitumumab aqueous solution prepared above and incubated at room temperature for 1 hour. After purifying the reaction mixture with a Sephadex G50 column (PD-10, Cytiva), the eluate was adjusted to pH 7.4 with PBS solution to obtain pan-dye 1.

[0114] [Examples 17 to 30, Comparative Example 2] <Production of pan-dyes 2 to 15, pan-IRDye 700DX: Conjugation of dyes 2 to 15, IRDye 700DX to EGFR antibody> Pan - pigment 2 to 15 and pan - IRDye 700DX were each produced in the same manner as the production of pan - pigment 1, except that the pigment 1 used in the production of the above pan - pigment 1 was changed to pigments 2 to 15 and IRDye 700DX. Note that pigments 2 to 15 and IRDye 700DX were used in the same molar amount as pigment 1 in the production of pan - pigment 1.

[0115] [Evaluation] <Measurement of photodegradation rate> The pigment 1 synthesized in Example 1 was dissolved in water containing 1 mM of L - cysteine to a concentration of 5 μM. After performing Ar bubbling on this solution for 1 h, laser light (690 nm, 25 mW / cm 2 ) was irradiated for 15 minutes in a four - sided cell. The absorption spectrum was measured every 5 minutes of irradiation time using a UV - vis spectrophotometer (UH5700, manufactured by Hitachi High - Tech), and the change in absorbance at the absorption maximum wavelength was plotted to measure the photodegradation rate of pigment 1.

[0116] The above measurement was also performed on the pigments of Examples 2 to 15 and Comparative Example 1, and the photodegradation rate was evaluated based on the following criteria. The evaluation results of the photodegradation rate are shown in Table 13. · The absorbance at the absorption maximum wavelength after 15 minutes of light irradiation is ◎: Less than 20% of that before irradiation (fast photodegradation rate) 〇: 20% or more and less than 60% of that before irradiation (moderate photodegradation rate) △: 60% or more of that before irradiation (slow photodegradation rate)

[0117] <In vitro PIT test> 100,000 A431 cells were seeded in a 24 - well plate, and the pigment - EGFR antibody conjugates (pan - pigments 1 to 15, pan - IRDye 700DX) of Examples 17 to 30 and Comparative Example 2 were added at a concentration of 10 μg / mL and incubated at 37 °C for 6 hours. After washing twice with PBS, PBS was added. Then, laser light (690 nm, 50 mW / cm 2) for 3 minutes. After washing twice with PBS, 10 μL of Cell Counting Kit-8 (Dojindo Chemical Industries, Ltd.) was added to each well and left to stand for 1 hour in an incubator (37°C, 5% CO2-containing air, humidified environment). Then, absorbance was measured at 450 nm using a plate reader (TECAN, SPARK), and phototoxicity to A431 cells was evaluated based on the following criteria. The results of phototoxicity evaluation are shown in Table 13. ◎: absorbance less than 0.5 (high phototoxicity) 〇: Absorbance 0.5 or more to less than 1.0 (moderate phototoxicity) △: Absorbance 1.0 or more (low phototoxicity)

[0118] <Calculation of HOMO and LUMO energy levels of dyes> For the dyes obtained in Examples 1 to 15 and Comparative Example 1, the HOMO and LUMO energy levels were calculated. The calculations were performed using Gaussian 16 software. For the structural optimization of the target molecule, the functional CAM-B3LYP and the basis set 6-31+G(d,p) were used. The results are shown in Table 13.

[0119] [Table 13]

[0120] From the results in Table 13, it was confirmed that the absorbance of all the dyes was reduced by light irradiation. This is believed to be because light irradiation causes decomposition of the axial ligand, which significantly reduces the solubility of the phthalocyanine and causes aggregation. In addition, it was confirmed that the dyes 1 to 15 of the examples, which have an electron-withdrawing group on the phthalocyanine ring, have a faster photochemical reaction rate than the comparative example IRDye 700DX, which does not have an electron-withdrawing group on the phthalocyanine ring, and can efficiently induce cell death in photoimmunotherapy.

[0121] Calculation results of the HOMO and LUMO energy levels of the dyes showed that the HOMO and LUMO energy levels of dyes 1 to 15 in the examples were lower than those of IRDye 700DX in the comparative example. In the examples, it is believed that the lowering of the HOMO and LUMO energy levels of the dyes promoted the one-electron transfer reaction from the reducing agent, and the subsequent elimination reaction rate of the water-soluble axial ligand was improved, allowing efficient induction of cell death in photoimmunotherapy.

Claims

1. A phthalocyanine dye having the following formula (1): Formula (1): 【Chemistry 1】 (In formula (1), R １ represents -(L)-(W) or (L)-(Q), in which (L) is a linker, (W) is a reactive group for bonding the substance that recognizes a target substance to the phthalocyanine, and (Q) is a substance that recognizes a target substance. n is 1 or 2. M １ represents Al, Ga, or In. R ２ ~R ４ each independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or -X-N ＋ -R ２０ R ２１ R ２２ Represents. R ２ ~R ４ At least one of the following is -X-N ＋ -R ２０ R ２１ R ２２ Represents R ２０ ~R ２２ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbamoyl group, or a water-soluble group. ２０ ~R ２２ When Y does not have an anionic substituent, the counter anion Y － has. Each X is independently a direct bond or a linear or branched, cyclic or heterocyclic, saturated or unsaturated chain having 1 to 60 atoms selected from C, N, P, O, and S. R ８ ~R １９ are each independently hydrogen, CR ２３ R ２４ R ２５ , N.R. ２６ R ２７ , -(A)-(B), or an electron-withdrawing group. ２３ ~R ２７ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. (A) represents an O, S, Se, or Te atom, and (B) represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. R ８ ~R １９ At least one of is an electron-withdrawing group.

2. A phthalocyanine dye having the following formula (2): Formula (2): 【Chemistry 2】 (In formula (2), R １ represents -(L)-(W) or (L)-(Q), in which (L) is a linker, (W) is a reactive group for bonding the substance that recognizes a target substance to the phthalocyanine, and (Q) is a substance that recognizes a target substance. n is 1 or 2. M ２ represents Si, Ge, and Sn. R ２ ~R ４ , R ５ ~R ７ each independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or -X-N ＋ -R ２０ R ２１ R ２２ Represents. R ２ ~R ４ , R ５ ~R ７ At least one of the following is -X-N ＋ -R ２０ R ２１ R ２２ Represents R ２０ ~R ２２ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbamoyl group, or a water-soluble group. ２０ ~R ２２ When Y has no anionic substituent, the counter anion Y － has. Each X is independently a direct bond or a linear or branched, cyclic or heterocyclic, saturated or unsaturated chain having 1 to 60 atoms selected from C, N, P, O, and S. R ８ ~R １９ are each independently hydrogen, CR ２３ R ２４ R ２５ , N.R. ２６ R ２７ , -(A)-(B), or an electron-withdrawing group. ２３ ~R ２７ represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. (A) represents an O, S, Se, or Te atom, and (B) represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. R ８ ~R １９ At least one of is an electron-withdrawing group.

3. R ９ , R １０ , R １３ , R １４ , R １７ , and R １８ 3. The phthalocyanine dye, or a salt, stereoisomer, or tautomer thereof according to claim 1 or 2, wherein at least one of the following is an electron-withdrawing group:

4. The phthalocyanine dye or a salt, stereoisomer or tautomer thereof according to claim 1 or 2, which is for use in photoimmunotherapy.

5. 3. The phthalocyanine dye, or a salt, stereoisomer, or tautomer thereof according to claim 1 or 2, wherein the HOMO value is −6.0 eV or less.

6. 3. The phthalocyanine dye, or a salt, stereoisomer, or tautomer thereof according to claim 1 or 2, wherein the substance that recognizes a target substance is an antibody, an antibody fragment, or a peptide.

7. A pharmaceutical composition comprising the phthalocyanine dye according to claim 1 or 2, or a salt, stereoisomer or tautomer thereof, and a pharma- ceutically acceptable carrier.

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