Compound or salt thereof, and photosensitizer

Abstract

The compound of one aspect of the present invention is represented by formula (1). R1 represents an aryl group that has one or more alkoxy groups, when the aryl group has two or more alkoxy groups, it being possible for at least two of the two or more alkoxy groups to be bonded to each other, R2 and R4 each independently represent a substituted or unsubstituted aryl group, R3 and R5 each independently represent a substituted or unsubstituted chain hydrocarbon group, a substituted or unsubstituted styryl group, or a fluorine atom, R6 and R7 each independently represent a hydrogen atom or a substituted or unsubstituted chain hydrocarbon group, X1 and X2 each independently represent a fluorine atom or a group represented by -OR8, and R8 represents an alcohol residue or a sugar residue.

Description

[Technical Field]

[0001] The present invention relates to a compound or a salt thereof, and a photosensitizer. This application claims priority based on Japanese Patent Application No. 2021-097218, filed on June 10, 2021, the contents of which are incorporated herein by reference. [Background technology]

[0002] Photodynamic therapy (PDT) has attracted attention as a promising means of combating the challenges facing humanity, such as cancer and multidrug-resistant bacteria. Photosensitizers are essential for PDT. In PDT, photosensitizers are incorporated into target cells (e.g., cancer cells) and then irradiated with light, causing cell damage. Photosensitizers undergo photoexcitation to a short-lived excited singlet state, which transitions to a long-lived excited triplet state via intersystem crossing. It is believed that the photosensitizer in this excited triplet state either directly causes cell damage or transfers energy to triplet oxygen, generating excited singlet oxygen, which then causes cell damage.

[0003] Intersystem crossing from the singlet state to the triplet state is a forbidden transition. Conventionally, to efficiently induce intersystem crossing, heavy atoms such as transition metal atoms, iodine atoms, and bromine atoms have been introduced into molecules. However, many compounds containing heavy atoms are themselves cytotoxic. Furthermore, the reduced stability of the compounds makes their application to materials difficult. Therefore, photosensitizers based on molecules composed of light atoms up to the second row have been explored, and porphyrins and phthalocyanines have been discovered. However, porphyrins and phthalocyanines have large molecular weights, posing challenges to their intracellular distribution (Non-Patent Document 1).

[0004] On the other hand, boron dipyrromethene (BODIPY) dyes, which have a core structure of BODIPY, are known as low-molecular-weight fluorescent dyes. Because BODIPY has a stable molecular structure and a high fluorescence quantum yield, it is being considered as a basic skeleton for constructing low-molecular-weight sensitizers. Although the PDT activity of BODIPY derivatives containing halogen atoms has been reported, these BODIPY derivatives are also known to have cytotoxicity due to the halogen atoms (e.g., Br) in the molecules (Non-Patent Documents 2 and 3). To confer sensitization without using halogen atoms, methods such as constructing a BODIPY dimer (Non-Patent Document 4), introducing a twisted molecular skeleton (Non-Patent Document 5), and introducing an electron-donating molecule into a molecule (Non-Patent Document 6) have been reported. However, all of these methods require the construction of a large molecule. It has also been reported that photoelectron transfer (Pet) with a substituent at the 8th position (called the meso position) of BODIPY promotes intersystem crossing, but none of these methods have been applied to the development of cytotoxicity. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Chem. Rec.,2017,17,1-29 [Non-patent document 2] Journal of Photochemistry and Photobiology C:Photochemistry Reviews,2019,40,21-48 [Non-patent document 3] Coordination Chemistry Reviews,2019,379,47-64 [Non-patent document 4] Org. Lett.,2016,18,4821-4823 [Non-Patent Document 5] Org. Lett.,2020,22,5535-5539 [Non-patent document 6] Angew. Chem. Int. Ed.,2020,59,8957-8962 Summary of the Invention [Problem to be solved by the invention]

[0006] If we can construct a low-molecular-weight photosensitizer composed only of light atoms, it is expected that such a photosensitizer will be distributed to intracellular organelles and be able to control the functions of cells that turn on apoptosis, autophagy, etc. Treatment of lesions caused by apoptosis and autophagy may be an ideal therapy that is extremely minimally invasive. The present invention aims to provide a compound or a salt thereof that is capable of intersystem crossing from an excited singlet state to an excited triplet state even though it has a low molecular weight and is composed only of light atoms, and a photosensitizer for photodynamic therapy using the same. [Means for solving the problem]

[0007] As a result of extensive investigations, the present inventors have found that the above-mentioned problems can be solved by a BODIPY derivative with a tetrad molecular structure in which an aromatic structure having one or more electron-donating groups is introduced at the meso position (8th position) of BODIPY and aromatic structures are introduced at the 1st and 7th positions.

[0008] The present invention has the following aspects. [1] A compound represented by the following formula (1) or a salt thereof:

[0009] [ka]

[0010] However, R 1 represents an aryl group having one or more alkoxy groups, and when the aryl group has two or more alkoxy groups, at least two of the two or more alkoxy groups may be bonded to each other; R 2 and R 4 each independently represents a substituted or unsubstituted aryl group, R 3 and R 5 each independently represents a substituted or unsubstituted chain hydrocarbon group, a substituted or unsubstituted styryl group, or a fluorine atom, R 6 and R 7each independently represents a hydrogen atom or a substituted or unsubstituted chain hydrocarbon group, X 1 and X 2 each independently represents a fluorine atom or -OR 8 R represents a group represented by 8 indicates an alcohol residue or a sugar residue. [2] R in the formula (1) 2 and R 4 are each independently a substituted or unsubstituted phenyl group, or a salt thereof. [3] R in the formula (1) 1 represents a 2-alkoxyphenyl group, a 4-alkoxyphenyl group, a 2,3-dialkoxyphenyl group, a 2,4-dialkoxyphenyl group, a 2,5-dialkoxyphenyl group, a 2,6-dialkoxyphenyl group, a 3,4-dialkoxyphenyl group, a 3,5-dialkoxyphenyl group, a 2,3,4-trialkoxyphenyl group, a 2,4,5-trialkoxyphenyl group, or a 2,4,6-trialkoxyphenyl group, the compound or salt thereof according to [1] or [2] above. [4] A photosensitizer comprising any one of the compounds [1] to [3] above or a salt thereof. [5] The photosensitizer according to [4] above, which is used in photodynamic therapy. [Effects of the Invention]

[0011] According to the present invention, it is possible to provide a compound or a salt thereof that is capable of intersystem crossing from an excited singlet state to an excited triplet state even though it has a low molecular weight and is composed only of light atoms, and a photosensitizer using the same. [Brief explanation of the drawings]

[0012] [Figure 1] Fluorescence spectrum of 25DMP obtained in the example. [Figure 2] Fluorescence spectrum of 245TMP obtained in the example. [Figure 3] Fluorescence spectrum of 234TMP obtained in the example. [Figure 4] Fluorescence spectra of 246TMP and ST246TMP obtained in the examples. [Figure 5] FIG. 1 is a graph showing the change in absorption maximum due to the addition of an acid (TFA) for 2PY246TMP obtained in an example. [Figure 6] FIG. 1 shows changes in quantum yield and fluorescence spectrum before and after the addition of acid (TFA) to 2PY246TMP. [Figure 7] UV absorption spectrum showing the evaluation results of singlet oxygen generation for 25DMP. [Figure 8] Graph showing the evaluation results of singlet oxygen generation in 25DMP (horizontal axis: elapsed time, vertical axis: absorption intensity at a wavelength of 410 nm). [Figure 9] UV absorption spectrum showing the evaluation results of singlet oxygen generation in 245TMP. [Figure 10] Graph showing the evaluation results of singlet oxygen generation in 245TMP (horizontal axis: elapsed time, vertical axis: absorption intensity at a wavelength of 410 nm). [Figure 11] UV absorption spectrum showing the evaluation results of singlet oxygen generation in 234TMP. [Figure 12] Graph showing the evaluation results of singlet oxygen generation in 234TMP (horizontal axis: elapsed time, vertical axis: absorption intensity at a wavelength of 410 nm). [Figure 13] UV absorption spectrum showing the evaluation results of singlet oxygen generation in 246TMP. [Figure 14] Graph showing the evaluation results of singlet oxygen generation in 246TMP (horizontal axis: elapsed time, vertical axis: absorption intensity at a wavelength of 414 nm). [Figure 15] Graph showing the results of evaluating the effect of irradiation intensity on the generation of singlet oxygen in 25DMP. [Figure 16] The emission spectrum of a red LED with an absorption maximum at a wavelength of 660 nm. [Figure 17] 1 is a graph showing the evaluation results of singlet oxygen generation for ST246TMP, NP246TMP, 2PY246TMP, and 2PY246TMP+TFA. [Figure 18] 1 is a graph showing the results of toxicity evaluation (MTT assay) of 25DMP on HSC-2 cells in the dark or under green light irradiation. [Figure 19]1 is a graph showing the results of toxicity evaluation (MTT assay) of 245TMP on HSC-2 cells in the dark or under green light irradiation. [Figure 20] 1 is a graph showing the results of evaluating the toxicity (MTT assay) of 234TMP on HSC-2 cells in the dark or under green light irradiation. [Figure 21] 1 is a graph showing the results of toxicity evaluation (MTT assay) of 25DMP on HSC-2 cells when irradiated with green light. [Figure 22] 1 is a graph showing the results of toxicity evaluation (MTT assay) of 245TMP on HSC-2 cells when irradiated with green light. [Figure 23] 1 is a graph showing the results of toxicity evaluation (MTT assay) of 234TMP on HSC-2 cells when irradiated with green light. [Figure 24] 1 is a graph showing the results of toxicity evaluation (MTT assay) on HSC-2 cells cultured for 3 days in the presence of 25DMP, 245TMP, or 234TMP with green light irradiation. [Figure 25] 1 is a graph showing the results of toxicity evaluation (MTT assay) on HSC-2 cells cultured for 5 days in the presence of 25DMP, 245TMP, or 234TMP with green light irradiation. [Figure 26] 2 is a graph showing the results of toxicity evaluation (MTT assay) of HeLa cells cultured for 3 days in the presence of 234TMP and irradiated with green light for 0 or 10 minutes. [Figure 27] 2 is a graph showing the results of toxicity evaluation (MTT assay) of HeLa cells cultured for 3 days in the presence of 245TMP and irradiated with green light for 0 or 10 minutes. [Figure 28] 2 is a graph showing the results of toxicity evaluation (MTT assay) of HeLa cells cultured for 5 days in the presence of 234TMP and irradiated with green light for 0 or 10 minutes. [Figure 29] 2 is a graph showing the results of toxicity evaluation (MTT assay) of HeLa cells cultured for 5 days in the presence of 245TMP and irradiated with green light for 0 or 10 minutes. [Figure 30]2 is a graph showing the results of toxicity evaluation (MTT assay) of SAOS cells cultured for 3 days in the presence of 234TMP and irradiated with green light for 0 or 10 minutes. [Figure 31] 2 is a graph showing the results of toxicity evaluation (MTT assay) of SAOS cells cultured for 3 days in the presence of 245TMP and irradiated with green light for 0 or 10 minutes. [Figure 32] 2 is a graph showing the results of toxicity evaluation (MTT assay) of SAOS cells cultured for 5 days in the presence of 234TMP and irradiated with green light for 0 or 10 minutes. [Figure 33] 2 is a graph showing the results of toxicity assessment (MTT assay) of SAOS cells cultured for 5 days in the presence of 245TMP and irradiated with green light for 0 or 10 minutes. [Figure 34] Fluorescence microscopy image of the distribution of 25DMP after adding a 10 μM solution to HSC2 cells. [Figure 35] 1 is a graph showing the results of evaluating the triplet lifetime of I2BOD by transient absorption spectroscopy. [Figure 36] Graph showing the evaluation results of triplet lifetime for 246TMP by transient absorption spectrum. [Figure 37] Graph showing the results of a transient absorption measurement experiment for I2BOD. [Figure 38] Graph showing the results of transient absorption measurement experiments for 246TMP. [Figure 39] Molecular orbitals of 25DMP calculated using the time-dependent density functional theory (TD-CAMDFT) for excited states. [Figure 40] Graph showing the results of density functional calculations of the ground state (left), singlet transition state (center), and triplet excited state (right) of 25DMP. DETAILED DESCRIPTION OF THE INVENTION

[0013] A compound according to one aspect of the present invention is represented by the following formula (1). Hereinafter, the compound represented by formula (1) will also be referred to as "compound (1)." Compounds represented by other formulas will also be referred to in the same manner.

[0014] [ka]

[0015] However, R 1 represents an aryl group having one or more alkoxy groups, and when the aryl group has two or more alkoxy groups, at least two of the two or more alkoxy groups may be bonded to each other; R 2 and R 4 each independently represents a substituted or unsubstituted aryl group, R 3 and R 5 each independently represents a substituted or unsubstituted chain hydrocarbon group, a substituted or unsubstituted styryl group, or a fluorine atom, R 6 and R 7 each independently represents a hydrogen atom or a substituted or unsubstituted chain hydrocarbon group, X 1 and X 2 each independently represents a fluorine atom or -OR 8 A group represented by (hereinafter simply referred to as "OR 8 ") and R 8 indicates an alcohol residue or a sugar residue.

[0016] R 1 In the above, the aryl group may be monocyclic or polycyclic. The number of carbon atoms in the aryl group is, for example, 6 to 14. The number of carbon atoms in the aryl group does not include the number of carbon atoms in the substituent. Examples of the aryl group include a phenyl group, a naphthyl group, a phenanthryl group, and an anthryl group.

[0017] R 1 In the above, the aryl group has one or more alkoxy groups. The aryl group has an electron-donating alkoxy group, which enables intersystem crossing. Furthermore, the alkoxy group is less likely to cause dark toxicity than other electron-donating groups, such as amino groups. The alkoxy group may be linear or branched and may have, for example, 1 to 20 carbon atoms, or preferably 1 to 8 carbon atoms. When the aryl group has two or more alkoxy groups, the two or more alkoxy groups may be the same or different. When the aryl group has two or more alkoxy groups, at least two of the two or more alkoxy groups may be bonded to each other. For example, two alkoxy groups may be bonded to each other to form -OR 9 R may form a group represented by -O-. 9 represents an alkylene group. The alkylene group may be linear or branched. The alkylene group has, for example, 1 to 6 carbon atoms, or preferably 1 to 2 carbon atoms.

[0018] R 1 Specific examples of the alkoxyphenyl group include monoalkoxyphenyl groups such as a 2-, 3-, or 4-methoxyphenyl group, and a 2-, 3-, or 4-ethoxyphenyl group; dialkoxyphenyl groups such as a 2,5-dimethoxyphenyl group and a 3,4-dimethoxyphenyl group; trialkoxyphenyl groups such as a 2,3,4-trimethoxyphenyl group, a 2,4,5-trimethoxyphenyl group, and a 3,4,5-trimethoxyphenyl group; and a 1,4-benzodioxan-5-yl group and a 1,4-benzodioxan-6-yl group. R 1 is preferably a 2-alkoxyphenyl group, a 4-alkoxyphenyl group, a 2,3-dialkoxyphenyl group, a 2,4-dialkoxyphenyl group, a 2,5-dialkoxyphenyl group, a 2,6-dialkoxyphenyl group, a 3,4-dialkoxyphenyl group, a 3,5-dialkoxyphenyl group, a 2,3,4-trialkoxyphenyl group, a 2,4,5-trialkoxyphenyl group, or a 2,4,6-trialkoxyphenyl group, from the viewpoint of the ability to electronically interfere with the BODIPY basic structure upon excitation. R 1is more preferably a 2,5-dialkoxyphenyl group, a 2,3,4-trialkoxyphenyl group, a 2,4,5-trialkoxyphenyl group, a 2,4-dialkoxyphenyl group, or a 2,4,6-trialkoxyphenyl group from the viewpoint of occupied orbital energy. Among these, a 2,4-dialkoxyphenyl group or a 2,4,6-trialkoxyphenyl group is preferred from the viewpoint of singlet oxygen generating ability. On the other hand, a 2,5-dialkoxyphenyl group or a 2,4,5-trialkoxyphenyl group is preferred from the viewpoint of excellent compound stability against singlet oxygen.

[0019] R 2 and R 4 In the above formula, the unsubstituted aryl group may be monocyclic or polycyclic. The unsubstituted aryl group has, for example, 6 to 14 carbon atoms. Examples of the substituent in the substituted aryl group include a substituted or unsubstituted alkyl group, -NR 21 R 22 a group represented by -N + R 23 R 24 R 25 A group represented by -(OCH2CH2) n Examples of such groups include a group represented by OH (hereinafter also referred to as a "polyethylene glycol group"), a sulfone group, and a phosphate group. 21 and R 22 R each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group. 23 , R 24 and R 25 each independently represents a substituted or unsubstituted alkyl group, and n represents an integer of 2 or greater. The upper limit of n is 24, for example. The unsubstituted alkyl group may be linear or branched. The number of carbon atoms in the unsubstituted alkyl group is, for example, 1 to 3. Examples of the substituent in the substituted alkyl group include an alkoxy group. The substituted alkyl group may have one or more substituents. Specific examples of the substituted or unsubstituted alkyl group include a methyl group, an ethyl group, and a 2-propyl group. The substituted aryl group may have one or more substituents. The substituted aryl group is an aryl group in which at least some of the hydrogen atoms bonded to carbon atoms are substituted with a substituent. The same applies to groups other than aryl groups. Specific examples of the substituted or unsubstituted aryl group include a phenyl group, a naphthyl group, a trimethylammonium-substituted phenyl group, and a polyethylene glycol-substituted phenyl group. R 2 and R 4 is preferably a substituted or unsubstituted phenyl group from the viewpoint of solubility in aqueous solvent systems.

[0020] R 3 and R 5 In the formula (I), the unsubstituted chain hydrocarbon group may be linear or branched, and may be saturated or unsaturated. Examples of the unsubstituted chain hydrocarbon group include an unsubstituted alkyl group, an unsubstituted alkenyl group, and an unsubstituted alkynyl group. The number of carbon atoms in the unsubstituted alkyl group is, for example, 1 to 12. The number of carbon atoms in each of the unsubstituted alkenyl group and the unsubstituted alkynyl group is, for example, 2 to 12. Examples of the substituent in the substituted chain hydrocarbon group include substituted or unsubstituted aryl groups (phenyl, 1-naphthyl, 2-naphthyl, etc.), substituted or unsubstituted heteroaryl groups (pyridyl groups such as 2-pyridyl, imidazolyl groups such as 2-imidazolyl, and triazolyl groups such as 4-triazolyl), alkoxy groups, and hydroxyl groups. Examples of the substituent in the substituted aryl group and substituted heteroaryl group include amino groups such as dialkylamino, ammonio groups, alkyl groups, and phenyl groups. The number of carbon atoms in the alkoxy group is, for example, 1 to 3. The substituted chain hydrocarbon group may have one or more substituents. Specific examples of the substituted or unsubstituted chain hydrocarbon group include a methyl group, an ethyl group, a vinyl group, a 1-naphthyl vinyl group, a 2-pyridyl vinyl group, an ethynyl group, and a hydroxyethyl group. Examples of the substituent in the substituted styryl group include a substituted or unsubstituted alkyl group, and an amino group such as a dialkylamino group (e.g., a dimethylamino group). The substituted styryl group may have one or more substituents. R 3 and R 5 In terms of lowering the molecular weight and improving solubility in water, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, and a methyl group is particularly preferred. R 3 and R 5 is preferably a chain hydrocarbon group having a substituted or unsubstituted pyridyl group, and particularly preferably a chain hydrocarbon group having an unsubstituted pyridyl group, in terms of the ability to respond to electromagnetic waves on the longer wavelength side and to selectively respond to acidic conditions, etc.

[0021] R 6 and R 7 In the formula (I), examples of the substituted or unsubstituted chain hydrocarbon group include the same as those described above.

[0022] X 1 and X 2 In OR 8 R 8 indicates an alcohol residue or a sugar residue. The alcohol residue is a group obtained by removing one hydroxyl group from an alcohol. The alcohol may be a monohydric alcohol or a polyhydric alcohol. The alcohol may be linear or branched. The number of carbon atoms in the alcohol is, for example, 1 to 12. A sugar residue is a group in which one hydroxyl group has been removed from a sugar. The sugar has, for example, 5 to 18 carbon atoms. Specific examples of alcohols or sugars include methanol, ethanol, 2-propanol, ethylene glycol, glycerol, glucose, lactose, and the like. X 1 and X 2 In terms of chemical stability, a fluorine atom is preferred. X 1 and X 2 In terms of increasing water solubility and promoting biological metabolism, OR 8 is preferred.

[0023] In terms of cytotoxicity, it is preferable that the atoms directly bonded to the BODIPY skeleton of compound (1) are composed only of light atoms, although compound (1) may entirely be composed of light atoms. In the present invention, a light atom refers to an atom in the first two periods (atomic numbers up to 10) of the periodic table (long period type). A heavy atom refers to an atom in the third period or later (atomic numbers 11 or later) of the periodic table (long period type).

[0024] Specific examples of compound (1) (R 1 ~R 5 , X 1 and X 2 In the following, F represents a fluorine atom. Compound (1-1a):R 1 = 2,5-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-1b):R 1 = 2,5-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-1c):R 1 = 2,5-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-2a):R 1 = 3,4-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-2b):R 1= 3,4-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-2c):R 1 = 3,4-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-3a):R 1 = 2,4-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-3b):R 1 = 2,4-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-3c):R 1 = 2,4-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-4a):R 1 = 2,3,4-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4= phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-4b):R 1 = 2,3,4-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-4c):R 1 = 2,3,4-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-5a):R 1 = 2,4,5-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-5b):R 1 = 2,4,5-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-5c):R 1 = 2,4,5-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR8 . Compound (1-6a):R 1 = 2-methoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-6b):R 1 = 2-methoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-6c):R 1 = 2-methoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-7a):R 1 = 1,4-benzodioxan-5-yl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-7b):R 1 = 1,4-benzodioxan-5-yl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-7c):R 1 = 1,4-benzodioxan-5-yl group, R 2 = phenyl group, R3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-8a):R 1 = 2,3-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-8b):R 1 = 2,3-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-8c):R 1 = 2,3-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-9a):R 1 = 2,6-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-9b):R 1 = 2,6-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X2 =OR 8 . Compound (1-9c):R 1 = 2,6-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-10a):R 1 = 3,5-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-10b):R 1 = 3,5-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-10c):R 1 = 3,5-dimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-11a):R 1 = 2,4,6-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-11b):R 1= 2,4,6-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-11c):R 1 = 2,4,6-trimethoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . Compound (1-12a):R 1 = 4-methoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-12b):R 1 = 4-methoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =OR 8 . Compound (1-12c):R 1 = 4-methoxyphenyl group, R 2 = phenyl group, R 3 = methyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =OR 8 , X 2 =OR 8 . R in these compounds 3 Also included are compounds in which R is substituted with a styryl group, a 2-pyridylvinyl group, or a 1-naphthylvinyl group. For example, R in compound (1-11a)3 Examples include the following compounds in which the group is substituted with a styryl group, a 2-pyridylvinyl group, or a 1-naphthylvinyl group. Compound (1-13a):R 1 = 2,4,6-trimethoxyphenyl group, R 2 = phenyl group, R 3 = styryl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-14a): R 1 = 2,4,6-trimethoxyphenyl group, R 2 = phenyl group, R 3 = 2-pyridyl vinyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F. Compound (1-15a):R 1 = 2,4,6-trimethoxyphenyl group, R 2 = phenyl group, R 3 = 1-naphthyl vinyl group, R 4 = phenyl group, R 5 = methyl group, X 1 =F, X 2 =F.

[0025] The molecular weight of compound (1) is preferably less than 850. When the molecular weight is less than 850, the compound is easily distributed in cells and has excellent solubility. The molecular weight of compound (1) may further be 750 or less, 700 or less, or 550 or less. The lower limit of the molecular weight of compound (1) is not particularly limited as long as it is within the range that satisfies the above formula (1), but it may be 450 or 480, for example.

[0026] Compound (1) can be produced, for example, by reacting compound (3) and compound (6) with a Grignard reagent, reacting the reaction product of compound (3) and the Grignard reagent with compound (4), reacting the resulting compound (5) with the reaction product of compound (6) and the Grignard reagent in the presence of phosphoryl chloride (POCl3), and reacting the resulting compound (7) with boron trifluoride ether complex in the presence of a tertiary amine. 1 and X 2 In this case, compound (1) is obtained, in which R is a fluorine atom. When compound (3) and compound (6) are the same, the reaction product of compound (3) and a Grignard reagent may be divided into two parts, and one part may be reacted with compound (4) and the other part may be reacted with compound (5). 3 and R 5 When compound (1) is a substituted or unsubstituted styryl group, compound (3) is 3 is a methyl group, compound (6) is R 5 R is a compound where R is a methyl group. 3 and R 5 is a methyl group, and R 3 and R 5 The target compound may be obtained by converting the styryl group to a styryl group. The conversion of the styryl group can be carried out by a known method, for example, by the method described in the Examples below. Then, if necessary, the resulting compound and an alcohol or sugar (R 8 OH), which converts one or both of the two fluorine atoms to OR 8 is replaced by X 1 and X 2 One of the atoms is a fluorine atom and the other is OR 8 Compound (1), or X 1 and X 2 OR 8 A compound is obtained which is

[0027] [ka]

[0028] R1 ~R 7 has the same meaning as above.

[0029] Grignard reagents are R 10 It is expressed as MgX. 10 represents an organic group, and X represents a halogen atom. Examples of the organic group include alkyl groups such as methyl and ethyl groups, and allyl groups. Examples of the halogen atom include iodine, chlorine, and bromine atoms. When compound (3) is reacted with a Grignard reagent, a compound in which the hydrogen atom bonded to the nitrogen atom of the ring skeleton of compound (3) is substituted with MgX is produced. The same is true for compound (6).

[0030] The compounds (3) and (6) and the Grignard reagent may be commercially available products, or may be synthesized by known methods. The reaction of compound (3) with a Grignard reagent can be carried out, for example, by mixing a solution of compound (3) with a solution of a Grignard reagent and reacting for 0.5 to 3 hours at 0 to 40° C. After the reaction, the solvent is removed, if necessary. The reaction of compound (6) with a Grignard reagent can also be carried out in a similar manner.

[0031] Compound (4) may be a commercially available product, or may be synthesized by a known method. The reaction of compound (4) with the reaction product of compound (3) and a Grignard reagent can be carried out, for example, by adding the reaction product of compound (3) and a Grignard reagent to a solution of compound (4) and reacting at 0 to 110°C for 2 to 72 hours. After the reaction, quenching, extraction, etc. are carried out as necessary. An example of a quenching method is adding sodium bicarbonate to the reaction solution. Examples of the solvent include tetrahydrofuran (THF), dichloromethane, chloroform, and toluene.

[0032] The reaction of compound (5) with the reaction product of compound (6) and a Grignard reagent can be carried out, for example, by adding the reaction product of compound (6) and a Grignard reagent and phosphoryl chloride to a solution of compound (5), and reacting at 20 to 110°C for 3 to 72 hours. The amount of phosphoryl chloride used is, for example, 200 to 300 parts by mass per 100 parts by mass of compound (5). After the reaction, quenching, extraction, removal of the solvent, purification, etc. may be carried out as necessary.

[0033] An example of a boron trifluoride etherate is boron trifluoride diethyl etherate (BF3·OEt2), where Et is an ethyl group. Tertiary amines include, for example, triethylamine and diisopropylethylamine. The reaction of compound (7) with boron trifluoride etherate can be carried out, for example, by adding a tertiary amine and boron trifluoride etherate in that order to a solution of compound (7) dissolved in a solvent, and reacting the mixture at 15 to 30°C for 12 to 72 hours. The amount of the tertiary amine used is, for example, 500 to 1000 parts by mass per 100 parts by mass of the compound (7). After the reaction, purification or the like is carried out as necessary.

[0034] X 1 and X 2 The alcohol or sugar to be reacted with compound (1) in which is a fluorine atom is, 8 The one corresponding to is used. X 1 and X 2 Compound (1), in which is a fluorine atom, can be reacted with an alcohol or a sugar under relatively mild conditions (for example, at room temperature and atmospheric pressure). After the reaction, purification may be carried out as necessary.

[0035] However, the method for producing compound (1) is not limited to the above method, and appropriate modifications can be made by referring to known methods for synthesizing BODIPY derivatives and the like.

[0036] Compound (1) may be in the form of a salt. Examples of salts include chlorides, sodium salts, potassium salts, ammonium salts, phosphonates, sulfates, carboxylates, etc. When a salt of compound (1) is used for PDT, it is usually used in the form of a pharmaceutically acceptable salt (chloride, sodium salt, potassium salt, etc.).

[0037] The compound (1) described above has the above structure, and therefore, even though it has a low molecular weight and is composed only of light atoms, it is capable of intersystem crossing from an excited singlet state to an excited triplet state. Therefore, compound (1) can be used as a photosensitizer. For example, PDT can be performed using a photosensitizer containing compound (1). Because compound (1) has a low molecular weight, it can be easily combined with drug delivery technology to accumulate the photosensitizer in cells (e.g., cancer cells) in vivo. PDT can be applied not only to cells in vivo, but also to bacteria such as multidrug-resistant bacteria. Furthermore, when compound (1) is composed only of light elements, its safety and toughness can be utilized to incorporate it into plastics, etc., making it possible to obtain antibacterial plastics that exhibit antibacterial and deodorizing effects when irradiated with light in the visible light range. [Example]

[0038] The present invention will be described in detail below with reference to examples, but is not limited to these. Hereinafter, a phenyl group will also be referred to as "Ph," a methyl group will also be referred to as "Me," and an ethyl group will also be referred to as "Et." The equipment used for compound identification and evaluation is shown below. Fluorescence spectrum: Shimadzu RF-1500 spectrofluorometer. Absolute quantum yield: Hamamatsu Photonics "C9920-02G". UV-visible absorption spectrum: Shimadzu UV-3100PC UV-visible absorption spectrophotometer. Transient absorption spectrum: Andor "iStar" Emission spectrum: Hamamatsu Photonics "PMA-12" Infrared absorption spectrum (IR): "Nicolet Nexus 670NT FT-IR" manufactured by Thermo Fisher Scientific, "IR-4600ST" manufactured by JASCO Corporation. Nuclear magnetic resonance spectroscopy (NMR): Agilent Technologies "NMR System 500PS SN" and JEOL Ltd. "JNM-ECZ400R". High-resolution mass spectrometry (HRMS): "JMS-700N" manufactured by JEOL.

[0039] (Synthesis Example 1: Synthesis of 2-methyl-4-phenylpyrrole) 5 mL of aqueous NaNO3 (402 mg, 5.83 mmol in terms of NaNO3) was added to a solution of 1 mL (5.83 mmol) of ethyl benzoylacetate in 10 mL of acetic acid at 0 °C, and the mixture was stirred at room temperature for 2 h. Subsequently, the resulting solution was added to a mixture of 762 mg (11.65 mmol) of zinc and 0.736 mL (5.83 mmol) of ethyl acetoacetate in 4 mL of acetic acid, and the mixture was refluxed at 120 °C overnight. The resulting reaction mixture was then washed with water and extracted with ethyl acetate. The extracted organic phase was dried over MgSO4, and the residue was purified by column chromatography to give diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (1.11 g, 63% yield). Next, 714 mg (2.37 mmol) of diethyl 1H-pyrrole-2,4-dicarboxylate and 652 mg (11.62 mmol) of KOH were mixed with ethylene glycol, and the resulting mixture was stirred at 170 °C for 3 hours. It was then washed with water and extracted with dichloromethane. The extracted organic phase was dried over MgSO4, and the residue was purified by column chromatography to obtain 2-methyl-4-phenylpyrrole (297 mg, 80% yield).

[0040] [ka]

[0041] Examples 1 to 14 <Production of Compounds> Compounds represented by the following formula 1, in which R is 2,5-dimethoxyphenyl group (25DMP), 2,4,5-trimethoxyphenyl group (245TMP), 2,3,4-trimethoxyphenyl group (234TMP), 2,4,6-trimethoxyphenyl group (246TMP), 2,4-dimethoxyphenyl group (24DMP), 3,4-dimethoxyphenyl group (34DMP), 4-methoxyphenyl group (4MMP), 2,6-dimethoxyphenyl group (26DMP), 3,5-dimethoxyphenyl group (35DMP), 2,3-dimethoxyphenyl group (23DMP), or 2-methoxyphenyl group (2MMP), were produced according to the following scheme. Hereinafter, the compound in which R in formula 1 is 25DMP will also be referred to as "25DMP." Other compounds will be referred to in the same manner.

[0042] [ka]

[0043] [ka]

[0044] The details of the manufacturing method of 25DMP are shown below. Under a N2 atmosphere, magnesium ribbon (80 mg, 3.3 mmol) was added to 10 mL of dry diethyl ether, and ethyl iodide (266 μL, 3 mmol) was added thereto, followed by stirring for 2 hours. The resulting gray solution was transferred via syringe to a THF solution (5 mL) of 2-methyl-4-phenylpyrrole (472 mg, 3 mmol). The mixture was stirred for 1 hour, and the solvent was removed under reduced pressure. The resulting 960 mg solid (magnesium salt I) was divided equally into Part A (480 mg) and Part B (480 mg), which were used in subsequent processes. Next, 2,5-dimethoxybenzoic acid (274 mg, 1.5 mmol) was dissolved in dichloromethane, and oxalyl chloride (172 μL, 3 mmol) was added and stirred at room temperature for 3 hours. The resulting mixture was thoroughly dried and then dissolved in THF (5 mL). To this solution was added Part A (480 mg). The mixture was stirred at 50°C for 48 hours, then poured into aqueous NaHCO3 (100 mL) and stirred for 1 hour. The resulting mixture was placed in a separatory funnel and extracted three times with 50 mL of ethyl acetate. The extracted organic layers were combined, dried over magnesium sulfate, and filtered. The solvent of the filtrate was removed under reduced pressure. Next, the residue was dissolved in THF (5 mL) at room temperature, and to this solution were added Part B (480 mg) and phosphoryl chloride (273 μL, 3 mmol) successively. The mixture was stirred at 60°C for 48 hours. The resulting deep-red mixture was poured into aqueous NaHCO3 (100 mL), stirred for 1 hour, and then extracted three times with ethyl acetate (50 mL). The combined organic layers were dried over MgSO4 and filtered. The solvent from the filtrate was removed under reduced pressure. The resulting deep-red residue was dissolved in dichloromethane (5 mL), and trimethylamine (697 μL, 5 mmol) and boron trifluoride diethyl etherate (377 μL, 3 mmol) were added sequentially. The mixture was stirred at room temperature for 24 hours. The resulting mixture was poured into aqueous NaHCO3 (100 mL), stirred for 1 hour, and then extracted three times with ethyl acetate (50 mL). The combined organic layers were dried over MgSO4 and filtered. The solvent from the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 8:2) to give 25DMP (30 mg, 4% yield) as a dark red powder.

[0045] 245TMP was prepared in the same manner as 25DMP, except that 2,4,5-trimethoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 234TMP was prepared in the same manner as 25DMP, except that 2,3,4-trimethoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 246TMP was prepared in the same manner as 25DMP, except that 2,4,6-trimethoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 24DMP was prepared in the same manner as 25DMP, except that 2,4-dimethoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 34DMP was prepared in the same manner as 25DMP, except that 3,4-dimethoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 4MMP was prepared in the same manner as 25DMP, except that 4-methoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 26DMP was prepared in the same manner as 25DMP, except that 2,6-dimethoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 35DMP was prepared in the same manner as 25DMP, except that 3,5-dimethoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 23DMP was prepared in the same manner as 25DMP, except that 2,3-dimethoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. 2MMP was prepared in the same manner as 25DMP, except that 2-methoxybenzoic acid was used instead of 2,5-dimethoxybenzoic acid. The properties and identification data of the compound obtained are shown below.

[0046] "25DMP" Dark red powder; melting point 93-96°C; IR (ATR, cm -1 ):2923.6,1494.6,1203.4,1108.9,1043.3,1018.2; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.67(6H,s),3.36(3H,s),3.40(3H,s),5.75(1H,d,J=8.8Hz),6.15(3H,m),6.24(1H,d,J=2.7Hz),6.74-6.92(10H,m); 13 C-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) HRMS(EI+ ):calcd for C 31 H 27 BF2N2O2M + ,508.2134,found,508.2134.

[0047]

change

[0048] 245TMP Dark red powder; melting point 179-181℃; IR (ATR, cm -1 ):2935.1,2837.7,1495.5,1462.7,1202.4,1161.9,1071.3; 1 H-NMR (400MHz, CDCl3, TMS, rt) δ (ppm) 2.67(6H,s),3.39(3H,s),3.43(3H,s),3.59(3H,s),5.45(1H,d,J=8.8Hz),6.15(2H,s),6.17(1H,s),6.72-6.77(4H,m),6.85-6.95(6H,m); 13 C-NMR (400MHz, CDCl3, TMS, rt) δ (ppm) 14.7,54.6,56.0,56.2,95.3,112.6,116.1,121.2,126.3,126.7,128.3,128.4,131.2,135.7,140.7,141.9,147.2,150.3,151.8; + ):calcd for C 32 H 29 BF2N2O3M + ,538.2239,found,538.2238.

[0049]

change

[0050] "234TMP" Dark red powder; melting point 191-192℃; IR (ATR, cm -1):2938.0,2836.8,1491.7,1460.8,1407.8,1204.3,1066.4; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.67(6H,s),3.29(3H,s),3.58(3H,s),3.70(3H,s),5.78(1H,d,J=8.6Hz) ,6.16(2H,s),6.36(1H,d,J=8.3Hz),6.77-6.81(4H,m),6.88-6.95(6H,m); 13 C-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 55.9,60.2,60.5,105.3,118.5,117.8,121.7,126.2,126.8,127.8,131.3,135.6,140.0,140.6,147.3,150.8,154.6,155.1;HRMS(FAB + ):calcd for C 32 H 29 BF2N2O3M + ,538.2239,found,538.2237.

[0051]

change

[0052] 246TMP Dark red powder; melting point 211-212℃; IR (ATR, cm -1 ):2923.1,2852.2,1596.8,1542.8,1494.6,1202.9,1150.8; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.66(6H,s),3.40(6H,s),3.52(3H,s),5.17(1H,m),6.09(2H,s),6.74-6.75,(4H,m),6.86-6.93(6H,m); 13C-NMR (125MHz, CDCl3, TMS, rt) δ (ppm) 14.78,54.79,55.22,89.16,103.57,109.99,120.66,126.23,126.44,128 .11,131.61,135.71,138.01,146.73,154.32,158.41,162.31;HRMS:calcd for C 32 H 29 BF2N2O3[M],538.22393,Found 538.2239.

[0053]

change

[0054] "24DMP" Dark red powder; melting point 195-196℃; IR (ATR, cm -1 ):2921.6,2852.2,1607.4,1538.4,1495.0,1456.0,1203.8,1164.8; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.67(6H,s),3.35(3H,s),3.52(3H,s),5.39(1H,s),5.68(1H,m),6.14(2H, s),6.50(1H,d,J=8.3Hz),6.71(4H,d,J=7.3Hz),6.86(4H,m),6.91(2H,m); 13 C-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 14.8,54.4,55.2,96.9,103.4,114.5,121.1,128.1,128.7,128.5,131.4,133.1,135.6,141.1,147.3,154.8,158.0,161.6; + ):calcd for C 31 H 27 BF2N2O2M + ,508.2134;found,508.2112.

[0055]

change

[0056] "23DMP" Dark red powder; melting point 212-213℃; IR (ATR, cm -1 ):2921.6,1538.9,1488.8,1403.0,1361.5,1264.1,1202.9,1162.4; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.68(6H,s),3.46(3H,s),3.65(3H,s),6.13-6.16(3H,m),6.18-6.19(1H,m),6.28-6.28(1H,m),4.18(4H,m),6.83-6.92(6H,m); 13 C-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 14.8,55.8,60.3,113.9,121.7,121.8,125.0,125.6,126.1,126.6,128.6,131.0,135.4,140.6,146.6,147.4,150.9,155.2.HRMS (EI + ):calcd for C 31 H 27 BF2N2O2M + ,508.2134;found,508.2130.

[0057]

change

[0058] "26DMP" Dark red powder; melting point >300℃; IR(ATR,cm -1 ):2923.1,2851.7,1607.4,1540.4,1497.5,1458.4,1203.8,1164.8; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.67(6H,s),3.43(3H,s),5.6(2H,J=8.3Hz),6.08(2H,s),6.51(1H,t,J=8.4Hz),6.72(4H,d,J=7.1Hz),6.83(4H,t,J=7.5Hz),6.89(2H,m);13 C-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 14.8,54.9,102.0,110.0,120.9,126.4,126.5,128.0,130.8,131.2,135.5,138.0,148.8,154.5,157.8;HRMS(EI + ):calcd for C 31 H 27 BF2N2O2M + ,508.2134;found,508.2134.

[0059]

change

[0060] "35DMP" Dark red powder; melting point 188-189℃; IR (ATR, cm -1 ):2934.6,2835.8,1592.4,1538.4,1495.0,1295.4,1203.8,1150.3; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.68(6H,s),3.36(6H,s),5.74(1H,s),5.94(2H,s),6.20(2H,s),6.77(4H,d,J=7.1Hz),6.89(4H,m),6.94(2H,d,J=7.1Hz); 13 C-NMR (500MHz, CDCl3, TMS, rt) δ (ppm) 55.0, 101.5, 110.0, 121.8, 126.3, 126.9, 128.2, 130.5, 132.8, 135.9, 144.0, 147.6, 155.7, 159.3; HRMS (EI + ):calcd for C 31 H 27 BF2N2O2M + ,508.2134;found,508.2134.

[0061]

change

[0062] "34DMP" Dark red powder; melting point 210-211℃; IR (ATR, cm -1 ):2926.0,2832.9,1539.4,1495.0,1403.9,1205.3,1167.2,1062.1; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.68(6H,s),3.40(3H,s),3.59(3H,s),5.95(1H,d,J=8.1Hz),6.21(1H,s), 6.24(2H,m),6.33(1H,m),6.71(4H,d,J=7.3Hz),6.87(4H,m),6.91(2H,m); 13 C-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 14.8,55.3,55.8,110.0,114.4,121.7,124.1,125.3,125.3,126.2,127.0,128.5,130.8,136.0,144.3,147.5,149.3,155.4; + ):calcd for C 31 H 27 BF2N2O2M + ,508.2134;found,508.2134.

[0063]

change

[0064] "2MMP" Dark red powder; melting point 219-221℃; IR (ATR, cm -1 ):3050.8,2953.4,2833.4,1542.8,1500.8,1491.2,1203.4,1162.4,972.9; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.68(6H,s),3.39(3H,s),5.81(1H,d,J=8.6Hz),6.13(2H,s),6.16(1H,m),6.59(1H,m),6.64(1H,m),6.69(3H,m),6.81(3H,m),6.87(2H,m); 13C-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 14.8,54.3,108.7,119.0,121.2,121.4,126.2,126.7,128.3,130.4,131.0,132.3,135.4,141.2,147.4,155.0,157.0;HRMS (EI + ):calcd for C 30 H 25 BF2N2O M + ,478.20280;found,478.2027.

[0065]

change

[0066] "4MMP" オレンジ colored powder; melting point 225-227.0℃; IR (ATR, cm -1 ):2915.8,2835.8,1605.9,1535.1,1496.5,1245.8,1204.8,1166.2; 1 H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 2.68(6H,s),3.52(3H,s),5.94(2H,d,J=8.3Hz),6.20(2H,s),6.61(1H,d,J=8.3Hz),6.67(3H,7.8),6.85(4H,m),6.89(2H,m); 13 C-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 14.8,55.1,112.2,121.6,123.7,125.9,127.1,128.7,130.1,132.9,135.6,144.6,147.6,155.3,159.8;HRMS(EI + ):calcd for C 30 H 25 BF2N2O M + ,478.20280;found,478.2027.

[0067]

change

[0068] From these results, it was confirmed that the obtained compounds each had the above structure.

[0069] Using the 246TMP obtained above, a compound represented by the following formula ST246TMP (hereinafter also referred to as "ST246TMP") was produced according to the following scheme. Details of the production method for ST246TMP are shown below. In a reaction vessel, 246TMP (50 mg, 0.087 mmol) and benzaldehyde (37 mg, 0.35 mmol, 4 equiv.) were dissolved in 3 mL of dimethylformamide. Piperidine (112 mg, 1.3 mmol, 15 equiv.) and acetic acid (52 mg, 0.87 mmol, 10 equiv.) were added, stirred, and sealed. The mixture was irradiated with microwaves at 150 °C for 5 minutes under stirring using a microwave irradiation system for synthesis. After cooling, the contents of the reaction vessel were transferred to a flask, and the dimethylformamide was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 95:5 to 80:20). This afforded 32 mg (50% yield) of ST246TMP as a purple powder.

[0070] [ka]

[0071] [ka]

[0072] The properties and identification data of the compound obtained are shown below. "ST246TMP" Dark blue powder; melting point 253-256°C; IR (ATR, cm -1 ):3057.1,2933.7,2836.3,1609.8,1586.6,1535.5,1491.7,1470.5,1443.0,1171.1,1106.9; 1H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 3.41(6H,s),3.52(3H,s),5.18(1H,m),6.75(2H,s),6.80-6.81,(4H,m),6.89-6.97(6H,m),7.30(2H,d, J=16.1Hz),7.34(2H,d,J=7.6Hz),7.41(4H,t,J=7.6Hz),7.66(4H,d,J=7.6Hz),7.87(2H,d,J=16.4Hz); 13 C-NMR(125MHz,CDCl3,TMS,rt) δ(ppm) 54.8,55.2,89.1,103.6,117.5,119.6,126.3,126.5,127.5,128.1,128.7, 128.8,133.5,135.6,135.9,138.7,146.1,151.7,158.4,162.4;HRMS:calcd for C 46 H 37 BF2N2O3[M],714.28653,Found 714.2865. These results confirmed that the compound obtained had the above structure.

[0073] The compound represented by the following formula 2PY246TMP (hereinafter also referred to as "2PY246TMP") was obtained by the same procedure as in the synthesis of ST246TMP, except that 2-picolylcarboxaldehyde was used instead of benzaldehyde. The yield of 2PY246TMP was 19.5%.

[0074] [ka]

[0075] The properties and identification data of the compound obtained are shown below. "2PY246TMP" Dark blue powder; Melting point 187.5-189°C; IR (ATR, cm -1 ):2933.2,2835.8,1579.4,1534.1,1472.4,1368.2,1172.5,1105.0; 1H-NMR(400MHz,CDCl3,TMS,rt) δ(ppm) 3.42(6H,s),3.53(3H,s),5.18(2H,s),6.80-6.81,(6H,m),6.90-7.00(6H,m),7.16-7.2 0(2H,m),7.40(2H,d,J=16.2Hz),7.70-7.76(4H,m),8.20(2H,d,J=16.2Hz),8.67(2H,m); 13 C-NMR(100MHz,CDCl3,TMS,rt) δ(ppm) 54.8,55.2,89.2,103.5,118.2,122.0,122.7,123.2,128.5,126.6,128.2,134.1, 135.4,135.7,136.4,138.6,148.6,149.9,151.3,155.2,158.5,162.5;HRMS:calcd for C 44 H 35 BF2N4O3[M],716.27703,Found 716.2770. These results confirmed that the compound obtained had the above structure.

[0076] The compound represented by the following formula NP246TMP (hereinafter also referred to as "NP246TMP") was obtained by the same procedure as in the synthesis of ST246TMP, except that 1-naphthylaldehyde was used instead of benzaldehyde. The yield of NP246TMP was 23.5%.

[0077] [ka]

[0078] The properties and identification data of the compound obtained are shown below. "NP246TMP" Dark blue powder; decomposition point (Td.) 142°C; IR (ATR, cm -1 ):3051.8,2921.6,2849.3,1607.4,1490.7,1474.3,1205.3,1171.5,1109.8; 1H-NMR(500MHz,CDCl3,TMS,rt) δ(ppm) 3.49(6H,s),3.54(3H,s),5.21(2H,s),6.84-6.87,(4H,m),6.89-7.01(8H,m),7.45-7.59(6H,m),7.83-7 .89(4H,m),7.98(2H,d,J=16.2Hz),8.06(2H,d,J=7.1Hz),8.16(2H,d,J=16.1Hz),8.20(2H,d,J=8.1Hz); 13 C-NMR(125MHz,CDCl3,TMS,rt) δ(ppm) 54.8,55.2,89.2,103.8,117.8,121.9,123.2,123.4,124.7,125.2,125.8,125.9,126.4,126.4,126.5,126. 8,128.2,128.3,128.8,128.8,129.3,131.3,132.4,133.7,133.7,135.5,135.6,148.2,151.8,158.5,162.4. These results confirmed that the compound obtained had the above structure.

[0079] <Evaluation of Fluorescence Spectrum> The resulting compounds were each dissolved in dichloromethane and their fluorescence spectra were measured. The maximum fluorescence wavelengths in the fluorescence spectra are shown in Table 1. Fluorescence spectra of 25DMP, 245TMP, and 234TMP are shown in FIGS. 1 to 3, and fluorescence spectra of 246TMP and ST246TMP are shown in FIG.

[0080] <Photophysical properties> Each synthesized compound was dissolved in dichloromethane, and the resulting solution was placed in a quartz cell to measure the UV-visible absorption spectrum. The absorption maximum wavelength (λmax) in the UV-visible absorption spectrum is shown in Table 1. In addition, each compound was dissolved in dichloromethane, and the molar absorption coefficient (ε) and fluorescence quantum yield φ were measured. f The results are shown in Table 1.

[0081] Separately, the visible absorption spectrum of a 6.1 μM dichloromethane solution of 2PY246TMP was measured in the wavelength range of 800 nm to 550 nm, and an absorption maximum was observed at a wavelength of 638 nm, as shown in Figure 5 and Table 1. When 5 μL of trifluoroacetic acid (TFA) was added to this sample, the absorption maximum shifted to 681 nm, and the linewidth of the waveform expanded, reaching a region exceeding 700 nm, as shown in Figure 5 and Table 1. On the other hand, when TFA was added to ST246TMP, such a dramatic change was not observed. Therefore, this large wavelength shift is thought to be due to the protonation of the two pyridyl groups of 2PY246TMP. The region of high transmittance through living organisms, generally known as the biological window, is said to be between 650 and 900 nm. While the absorption maximum of 2PY246TMP is outside the biological window, it was shown that protonation shifts the absorption maximum to a wavelength region inside the biological window. Cancer cells are known to be more acidic than healthy cells. By combining a photosensitizer whose absorption wavelength shifts to longer wavelengths under acidic conditions with a monochromatic laser and optical filters, it is possible to activate the photosensitizer only in an acidic environment, enabling treatment that kills only cancer cells.

[0082] FIG. 6 shows the fluorescence spectra of 2PY246TMP and a sample in which TFA was added to 2PY246TMP (2PY246TMP+TFA). 2PY246TMP absorbed light at a wavelength of 635 nm and exhibited bright fluorescence with a quantum yield of 0.649. The fluorescence had a maximum at 638 nm and extended into the near-infrared region, reaching wavelengths of 750 nm. In contrast, the quantum yield of 2PY246TMP+TFA was 0.001, and no fluorescence was observed. This indicates that the distribution of 2PY246TMP within tissue can be confirmed by measuring fluorescence in the near-infrared region, which has high transparency. Furthermore, since fluorescence disappears in acidic regions, the depth of treatment can be monitored by observing this change. For example, acidic cancer cells can be selectively treated with a laser beam around 380 nm and a sharp-cut filter to block the shorter wavelength excitation light. To kill cancer cells, high irradiation intensity and excitation at the shorter wavelength side of the body are desirable. However, this increases the risk of damage to normal cells. By monitoring the near-infrared fluorescence, which has high tissue penetration, it is possible to estimate the degree of excitation of 2PY246TMP in the neutral state, making it possible to carry out treatment while checking the degree of damage to normal cells.

[0083] [Table 1]

[0084] <Evaluation of singlet oxygen generation> The generation of singlet oxygen in dichloromethane (DCM) was evaluated using 25DMP with 1,3-diphenylisobenzofuran (DPBF) according to the following procedure. A solution of 25DMP (15 nmol, 5 μM) and DPBF (150 nmol, 50 μM) in 3 mL of dichloromethane was used as the sample. The obtained sample was wrapped in aluminum foil and stored in a container protected from light until the next procedure. A portion of the sample was removed from the container and placed in a quartz cell. The ultraviolet-visible absorption spectrum was measured, revealing an absorption maximum for 25DMP at a wavelength of 521 nm and an absorption maximum for DPBF at a wavelength of around 410 nm. A green LED lamp with a maximum wavelength of 525 nm was placed at a position where the illuminance at the sample position was 3380 lux (lx), and green light from this green LED lamp was irradiated for varying periods of time. The illuminance was measured using a SEKONIC i-346. The reaction of the generated singlet oxygen with DPBF to produce 1,2-phenylenebis(phenylmethanone) was tracked over time by measuring the absorbance of DPBF at 410 nm. It was also confirmed that the absorbance at 521 nm derived from 25DMP did not change during this process. Figure 7 shows the UV absorption spectra for given irradiation times (0.5, 1, 1.5, 2, 2.5, and 3 minutes). Figure 8 shows a graph with elapsed time (minutes) on the horizontal axis and absorbance at 410 nm on the vertical axis. From Figure 8, the first-order rate constant k (mol / min) was calculated from the slope of the graph, using the portion where the decay of absorbance at 410 nm with respect to irradiation time had a correlation coefficient of 0.99 or greater. The first-order rate constant k was multiplied by minus 1 to obtain the singlet oxygen generation rate constant. DPBF is known to react with singlet oxygen, and the slope of this decay line indicates its ability to generate singlet oxygen. The same evaluations as above were also carried out for 245TMP, 234TMP, and 246TMP. The results for 245TMP are shown in Figures 9 and 10. The results for 234TMP are shown in Figures 11 and 12. The results for 246TMP are shown in Figures 13 and 14. In Figure 14, the vertical axis represents absorbance at a wavelength of 414 nm.

[0085] When singlet oxygen is generated, DPBF is decomposed by the singlet oxygen, and the absorption at a wavelength of 410 nm decreases. As shown in Figures 7, 9, 11, and 13, 25DMP, 245TMP, 234TMP, and 246TMP all had an absorption maximum (λ max While no change was observed in the absorption of 25DMP, the absorption at the absorption maximum of DPBF decreased inversely proportional to the irradiation time. Furthermore, graphs plotting the absorbance at 410 nm versus irradiation time (minutes) (Figures 8, 10, 12, and 14) showed a good linear relationship. These results confirmed that 25DMP, 245TMP, 234TMP, and 246TMP are capable of intersystem crossing from the excited singlet state to the excited triplet state and function as photosensitizers.

[0086] The singlet oxygen ( 1 The O2) formation rate constant (the negative value of the first-order rate constant for elimination of DPBF) is shown in Table 2.

[0087] [Table 2]

[0088] <Evaluation of the effect of irradiation intensity> The singlet oxygen generation rate constant was evaluated for a sample prepared by dissolving 25DMP and DPBF in dichloromethane to a concentration of 0.39 μM and 50 μM, respectively, using the same procedure as above, except that the illuminance at the sample position was varied from 4,800 to 42,800 lx. The results are shown in Figure 15 and Table 3. As shown in these results, it was observed that the rate of singlet oxygen generation increased in proportion to the illuminance.

[0089] [Table 3]

[0090] FIG. 16 shows the emission spectrum of a red LED having an absorption maximum at a wavelength of 660 nm. ST246TMP, NP246TMP, and 2PY246TMP have absorption maxima at wavelengths from 673 nm to 681 nm, but it can be seen that the red LED light source, which has an absorption maxima at a wavelength of 660 nm, sufficiently covers each wavelength. Singlet oxygen generation experiments using DPBF were performed using the same procedure as above for ST246TMP, NP246TMP, 2PY246TMP, and 2PY246TMP+TFA, except that this red LED was used as the light source. The same procedure was performed in the absence of a sensitizer as a background. The results are shown in Figure 17. The vertical axis of the graph on the right in Figure 17 represents the change in absorbance of DPBF at 414 nm, expressed as a percentage (%) of the value before irradiation, with the value taken as 100. As shown in FIG. 17, ST246TMP, NP246TMP, 2PY246TMP, and 2PY246TMP+TFA each exhibited significant singlet oxygen sensitization ability over the background.

[0091] <Comparison of initial DPBF decay rates for each compound (1)> As a reference photosensitizer, I2BOD, represented by the following formula, was synthesized according to ACS Appl. Mater. Interfaces 2018, 10, 18771-1877.

[0092] [ka]

[0093] A dichloromethane solution of 45 μM DPBF with absorbances of 0.023–0.016 for a photosensitizer with an absorption maximum between 518 nm and 533.5 nm was prepared in a 1 cm square quartz cell. The cell surface was illuminated with an LED lamp with a 518 nm maximum wavelength at 4800 lx for 15 seconds to 1 minute. Spectra were acquired over the wavelength range of 600 nm to 380 nm. The absorbance of DPBF at 414 nm was plotted against cumulative irradiation time. The initial linear section was fitted using the least-squares method. The slope was multiplied by minus 1 to obtain the initial slope (Abs / min) of the observed DPBF (414 nm) absorbance. This value was then divided by the absorbance of the photosensitizer to obtain the DPBF decay rate (Abs / min) per unit of photosensitizer absorbance. Furthermore, this value was multiplied by the extinction coefficient of each photosensitizer and divided by 100,000 to obtain the decay rate (Abs / min) of DPBF per 10 μM photosensitizer concentration. The results are shown in Table 4. These results demonstrate that each compound has oxygen-sensitizing ability, and that this ability varies depending on the position of the methoxy group on the mesophenyl group. In particular, 246TMP was shown to have oxygen-sensitizing ability equal to or greater than that of I2BOD, which contains an iodine atom.

[0094] [Table 4]

[0095] <Comparison of initial DPBF decay rates for each compound (2)> For ST246TMP, 2PY246TMP, 2PY246TMP+TFA, and NP246TMP, the same operations as in the above DPBF decay initial rate comparison (1) were performed except for the following conditions. · A photosensitizer having an absorption maximum wavelength from 673 nm to 681 nm was used. · The absorbance of the photosensitizer was adjusted to 0.112 - 0.024. · As the light source, an LED lamp with a maximum wavelength of 660 nm was used. · Irradiation was performed at a position where the illuminance on the cell surface was 10000 lx. The results are shown in Table 5. From these results, it was revealed that each compound has oxygen-sensitizing ability. Substituent R 3 , R 5 By changing the substituents of, the response wavelength (absorption wavelength) of the photosensitizer can be changed. In particular, from the results of 2PY246TMP+TFA, it was shown that the one with a long wavelength shift to 681 nm still has oxygen-sensitizing ability after protonation, indicating that a photosensitizer having a nitrogen-containing heterocyclic substituent can function effectively in an acidic environment.

[0096]

Table 5

[0097] <Evaluation of toxicity to HSC-2 cells (MTT assay)> For 25DMP, 245TMP, and 234TMP, the toxicity to HSC-2 cells (human squamous carcinoma cells) was evaluated by MTT assay using Cell Counting Kit (CCK)-8 manufactured by the same chemical research institute. The details of the evaluation method are shown below. A 10 mM dimethyl sulfoxide (DMSO) solution of the sample (25DMP, 245TMP, or 234TMP) was diluted with water so that the sample concentration in the culture solution was 0.001 μM, 0.01 μM, 0.1 μM, 1 μM, or 10 μM to prepare a sample solution. HSC-2 cells in the logarithmic growth phase were counted and seeded into each well of two 96-well microplates at 4000 cells / well (100 μL), followed by pre-culture for 24 hours in a CO2 incubator at 37°C. After pre-incubation, 1 μL of sample solution was added to each well of one 96-well microplate in the dark, and the 96-well microplate was wrapped in aluminum foil and cultured for 72 hours in a CO2 incubator at 37°C. 1 μL of sample solution was added to each well of the other 96-well microplate, and the plates were irradiated with green light (wavelength 512 nm) at 3800 lx for 10 minutes using a green LED with a UV-visible absorbance maximum of 525 nm. The 96-well microplate was then wrapped in aluminum foil and cultured for 72 hours in a CO2 incubator at 37°C. After incubation, 10 μL of CCK solution was added to each well of the 96-well microplate and incubated in a CO2 incubator at 37°C for 3 hours to allow color development. The absorbance at 450 nm was then measured using a microplate reader. The absorbance at 450 nm is proportional to the number of viable cells.

[0098] The results are shown in Figures 18 to 23. Figures 18 to 20 are graphs in which the horizontal axis represents the logarithm of the concentration of the sample (Figure 18: 25DMP, Figure 19: 245TMP, Figure 20: 234TMP) and the vertical axis represents the relative number of viable cells (absorbance at a wavelength of 450 nm). Figures 21 to 23 are graphs in which the horizontal axis represents the concentration of the sample (Figure 21: 25DMP, Figure 22: 245TMP, Figure 23: 234TMP) and the vertical axis represents the relative number of viable cells (absorbance at a wavelength of 450 nm). Figures 21 to 23 only show the results when green light was irradiated.

[0099] As shown in the results above, no toxicity was observed in any of the samples when they were protected from light. When cultured under green light, a rapid decrease was observed at concentrations of 1 μM or higher, and a slight proliferation effect was observed at concentrations lower than 1 μM. This is a typical response to oxidative stress, and it was observed that exceeding a threshold led to rapid cell death. From these results, it was confirmed that 25DMP, 245TMP, and 234TMP themselves do not have cytotoxicity, and cytotoxicity is expressed by light irradiation.

[0100] Separately, a 10 mM dimethyl sulfoxide (DMSO) solution of the sample (25DMP, 245TMP, or 234TMP) was used to prepare a sample solution diluted with sterile purified water so that the sample concentration in the culture solution was 1 μM. Except that the irradiation dose of green light (wavelength 512 nm) was changed to 9790 lx and the irradiation time was changed to 0 to 30 minutes, and the culture period was set to 3 days or 5 days, the toxicity to HSC-2 cells was evaluated in the same manner as above. Dimethyl sulfoxide (DMSO) was used as a control sample. The results are shown in FIGS. 24 to 25. FIG. 24 shows the results at the time of 3-day culture, and FIG. 25 shows the results at the time of 5-day culture. In each graph, the irradiation time of green light is taken on the horizontal axis, and the relative number of viable cells (absorbance at wavelength 450 nm) is taken on the vertical axis. From these results, it was confirmed that HSC-2 cells died by irradiating green light (wavelength 512 nm) at an intensity of 2.5 mW / cm 2 for 10 to 20 minutes in the presence of 25DMP, 245TMP, or 234TMP. This result is superior in terms of dosage, dose, and effect compared to conventional reported examples.

[0101] <Evaluation of toxicity to HeLa cells (MTT assay)> For 234TMP and 245TMP, the toxicity to HeLa cells was evaluated by an MTT assay using Cell Counting Kit (CCK)-8 manufactured by the same chemical research institute. The evaluation was carried out in the same procedure as the evaluation of toxicity to HSC-2 cells, except that HeLa cells were used. The results are shown in FIGS. 26 to 29. FIG. 26 shows the results at the time of 3-day culture in the presence of 234TMP. FIG. 27 shows the results at the time of 3-day culture in the presence of 245TMP. FIG. 28 shows the results at the time of 5-day culture in the presence of 234TMP. FIG. 29 shows the results at the time of 5-day culture in the presence of 245TMP. In each graph, the irradiation time of green light is taken on the horizontal axis, and the relative number of viable cells (absorbance at wavelength 450 nm) is taken on the vertical axis. As shown in the above results, no toxicity was observed in any of the samples under light shielding. When irradiated with green light, a sharp decrease was observed at a concentration of 1 μM or higher.

[0102] <Evaluation of Toxicity to SAOS Cells (with p53 Mutation in Sarcoma) (MTT Assay)> For 234TMP and 245TMP, the toxicity to SAOS cells (with p53 mutation in sarcoma) was evaluated by MTT assay using Cell Counting Kit (CCK)-8 manufactured by the same chemical research institute. The details of the evaluation method are shown below. The evaluation was carried out in the same procedure as the evaluation of toxicity to HSC-2 cells, except that SAOS cells (with p53 mutation in sarcoma) were used. The results are shown in Figures 30 to 33. Figure 30 shows the results at 3-day culture in the presence of 234TMP. Figure 31 shows the results at 3-day culture in the presence of 245TMP. Figure 32 shows the results at 5-day culture in the presence of 234TMP. Figure 33 shows the results at 5-day culture in the presence of 245TMP. In each graph, the irradiation time of green light is on the horizontal axis, and the relative number of viable cells (absorbance at wavelength 450 nm) is on the vertical axis. As shown in the above results, no toxicity was observed in any of the samples under light shielding. When irradiated with green light, a sharp decrease was observed at a concentration of 1 μM or higher.

[0103] <Observation of Fluorescence Microscope Images> A 10 μM solution of 25DMP was added to HSC2 cells, incubated for 15 minutes, then the excess reagent was removed and observed with a fluorescence microscope. The fluorescence microscope image is shown in Figure 34. As shown in Figure 34, 25DMP was localized in the cell membrane.

[0104] <Comparison of Triplet State Lifetimes by Transient Absorption Spectra: Absorption Spectrum Changes of YAG Laser 532 nm Pulse (10 Hz)> For I2BOD and 246TMP, the triplet state lifetimes were compared by transient absorption spectra according to the following procedure. Dichloromethane solutions of I2BOD and 246TMP were placed in 1 cm square quartz cells, and argon gas was passed through them for 20 minutes to remove oxygen from the solution, after which the cells were sealed with a septum. Spectra were acquired every 10 μs from 360 to 740 nm wavelengths, starting immediately before irradiation with a 532 nm YAG laser pulse (0 μs). The results are shown in Figures 35 and 36. The graph on the left in Figure 35 shows the spectrum of I2BOD in the wavelength range of 470–600 nm, recorded every 10 μs from just before (0 μs) to 40 μs after pulse irradiation, while the graph on the right shows the GSB decay curve of I2BOD at 534 nm, expressed as a ratio with the initial value set to 1. The graph on the left in Figure 36 shows the spectrum of 246TMP in the wavelength range of 470–600 nm, recorded every 10 μs from just before (0 μs) to 40 μs after pulse irradiation, while the graph on the right shows the GSB decay curve of 246TMP at a wavelength of 520.5 nm. As shown in Figure 36, the decay curves were in good agreement with a first-order reaction rate equation, and the lifetimes of the excited species of I2BOD and 246TMP (time to reach 1 / e) were 13 μs and 28 μs, respectively. When second-order reaction rate constants were taken into account, the lifetimes were 16.7 μs for I2BOD and 32.3 μs for 246TMP. The lifetime, taking into account reaction rate constants up to second order, was calculated using the following second-order reaction rate equation (reference paper: J.Phys.Chem.C2018,122,1,185-193).

[0105]

number

[0106] These results indicated that excitation of 246TMP at a wavelength of 532 nm generates a triplet state, and that its lifetime is significantly longer than that of I2BOD, a photosensitizer containing a heavy iodine atom.

[0107] <Transient absorption measurement experiment: Reaction of triplet excited species with oxygen> Transient absorption measurement experiments were carried out for I2BOD and 246TMP using the following procedure. Dichloromethane solutions of I2BOD and 246TMP were placed in 1 cm square quartz cells and used as samples without any deoxidation or other procedures. Transient absorption spectra were obtained by recording spectra in the wavelength range of 360 to 740 nm every 0.2 μs from just before to 1.8 μs after irradiation with a 532 nm YAG laser pulse. The results are shown in Figures 37 and 38. The graph on the left in Figure 37 shows the spectrum of I2BOD in the wavelength range of 470 to 600 nm, recorded every 0.2 μs, from just before the pulse irradiation until 1.8 μs after. The graph on the right shows the change in the GSB intensity at a wavelength of 534 nm for each I2BOD spectrum, recorded every 200 μs, from 1800 ns after pulse irradiation, with the vertical axis representing the decay rate and the horizontal axis representing time (ns). The graph on the left in Figure 38 shows the spectrum of 246TMP in the wavelength range of 470 to 600 nm, recorded every 0.2 μs, from just before the pulse irradiation until 1.8 μs after. The graph on the right shows the change in the GSB intensity at a wavelength of 520 nm for each 246TMP spectrum, recorded every 200 ns, with the vertical axis representing the decay rate and the horizontal axis representing time (ns). The decay curves were in good agreement with first-order kinetics, and the time constants of the excited species of I2BOD and 246TMP were both approximately 1 μs. These results, combined with the results of experiments under an argon atmosphere, indicate that the excited triplet state of 246TMP reacts rapidly with atmospheric oxygen, at a rate comparable to that of the triplet state of I2BOD, an iodine-containing compound known as an oxygen sensitizer.

[0108] <First principles calculation> First-principles calculations were performed on 25DMP in acetonitrile using Gaussian 16 with the density functional CAM-B3LYP and 6-31G(d) basis set. Figure 39 shows molecular orbitals for which chemical calculations of excited states were performed using the time-dependent density functional theory (TD-CAMDFT). S1 (left side) represents the singlet excited state, and T1 (right side) represents the triplet excited state. In the triplet state (T1), the total electron spin is biased, so the α spin and β spin have different energy levels. In the singlet excited state, the orbital was the 132nd (2nd HOMO) orbital, but in the excited triplet state (T1), it was elevated to just below the excited orbital. This suggests that by creating a state where the π orbital is twisted between the meso-substituent and the BODIPY body, allowing for partial conjugation, and by controlling the friction with the solvent, it becomes easier for intersystem crossing to occur between orbitals of similar rank, such as the n→π* to π-π* intersystem crossing. Figure 40 shows the results of density functional calculations of the ground state (left), singlet transition state (center), and triplet excited state (right) of 25DMP. It can be seen that the dihedral angle between the meso-substituent and BODIPY decreases as we move to the right. The introduction of aryl groups at the 1 and 7 positions creates a tetrad structure, which allows for protected, twisted π orbitals, enabling spin-orbit coupling through controlled conjugation, suggesting that it is possible to generate a triplet excited state without using heavy atoms. These results suggest that compound (1) can efficiently achieve intersystem crossing by using substituents at the 1,7 positions (R 2 ,R 4 It is assumed that the mechanism is not only the photoelectron transfer mechanism (PET mechanism) that has been accepted so far for BPDIPY derivatives in which n is a methyl group, but also a mechanism involving energy exchange between orbitals, such as that seen in n→π* to π→π*, following photoexcitation, and that this is more effectively realized by controlled conjugation and a molecular structure that prevents friction with solvent molecules.

[0109] The ground-state molecular orbital calculations were performed using density functional theory (DFT) with Gaussian software using the 6-31G basis for ST246TMP, the singly protonated 2PY246TMP (ST246TMP+), the doubly protonated 2PY246TMP (ST246TMP++), 246TMP, 26DMP, 35DMP, and 25DMP, and the LUMO, HOMO, and 2nd HOMO energy levels were calculated. The results are shown in Table 6.

[0110] [Table 6]

[0111] The energy results for the LUMO, HOMO, and 2nd HOMO are displayed in Hartree, and the difference ΔE is expressed in electron volts (eV) by multiplying the value obtained by subtracting the 2nd HOMO from the HOMO by 27.21162. The HOMO and LUMO are located on the BODIPY dye skeleton, while the 2nd HOMO is mostly located on the meso-positioned aromatic substituent. It has been reported that the smaller the energy difference between the HOMO and the 2nd HOMO, the easier the interaction between the 2nd HOMO of the interfering substituent and the BODIPY dye occurs, and that it must be less than 0.5 eV (J. Am. Chem. Soc. 2020, 142, 6777-6785). For example, the ΔE of 25DMP is 0.17, which explains well the fluorescence quantum yield of 0.008. The ΔE of 246TMP is 0.36, which suggests an interaction with the substituent, and the fluorescence quantum yield is a small value of 0.046. On the other hand, the ΔE of 26DMP was 0.66, which is consistent with the high fluorescence quantum yield of 0.635 observed as a result of the low interference between the meso-substituent and BODIPY. However, 35DMP exhibits a high fluorescence quantum yield of 0.635, despite its ΔE of 0.39, which suggests that the meso-substituent may interfere with BODIPY. This is because the nodal plane of the 2nd HOMO of 35DMP is located on the carbon atom connected to the BODIPY dye, significantly reducing the overlap of the molecular orbitals between the meso-substituent and the BODIPY dye structure. 2PY246TMP has a large ΔE of 0.79, which explains its high fluorescence quantum yield of 0.694. The calculated results for the singly protonated 2PY246TMP+ and doubly protonated 2PY246TMP++ show a large decrease in HOMO energy, resulting in ΔEs of 0.46 and 0.15, respectively, which explains the significant decrease in fluorescence quantum yield upon addition of trifluoroacetic acid. [Industrial Applicability]

[0112] The present invention provides a compound or salt thereof capable of intersystem crossing from an excited singlet state to an excited triplet state, even though it has a low molecular weight and is composed only of light atoms, and a photosensitizer using the compound. Because the lifetime of the excited triplet state is significantly longer than that of photosensitizers containing heavy atoms, the compound is expected to be effective not only in Type 2 photodynamic therapy for hypoxic cells, but also in Type 1 photodynamic therapy, which is oxygen-independent. Meanwhile, excited species that do not undergo intersystem crossing efficiently fluoresce, allowing the distribution location of the photosensitizer to be confirmed, making it useful for both diagnosis and treatment. Furthermore, photosensitizers with an absorbance maximum near 520 nm coincide with the emission wavelength of green fluorescent protein, etc., and can be applied to deep tissues when combined with existing chemiluminescence systems. In addition, the substituent R 3 ,R 5 By using a conjugable substituent, it is possible to adjust the operating wavelength. In particular, conjugating a nitrogen-containing aromatic heterocycle produces a specific wavelength shift in the acidic region, allowing it to act selectively on cancer cells. On the other hand, sensitizers in the neutral region have a high fluorescence quantum yield in the deep red to near-infrared region, making it possible to monitor the extent of damage to healthy cells caused by treatment. In this way, by controlling the wavelength and irradiation intensity, the photosensitizer can act only on cancer cells while checking the extent to which that intensity affects surrounding healthy cells, allowing it to be used for treatment tailored to the situation. In this way, by utilizing the present invention, it is possible to activate the photosensitizing ability only in specific cells, and therefore its range of applications extends beyond cancer cells to the selective elimination of specific cells such as bacteria, microorganisms, infected cells, and senescent cells.

Claims

1. A compound represented by the following formula (1) or a salt thereof: 【Chemistry 1】 However, R １ represents an aryl group having one or more alkoxy groups, and when the aryl group has two or more alkoxy groups, at least two of the two or more alkoxy groups may be bonded to each other; R ２ and R ４ each independently represents a substituted or unsubstituted aryl group, R ３ and R ５ each independently represents a substituted or unsubstituted chain hydrocarbon group, a substituted or unsubstituted styryl group, or a fluorine atom, R ６ and R ７ each independently represents a hydrogen atom or a substituted or unsubstituted chain hydrocarbon group, X １ and X ２ each independently represents a fluorine atom or —OR ８ R represents a group represented by ８ indicates an alcohol residue or a sugar residue.

2. R in the formula (1) ２ and R ４ and each independently represent a substituted or unsubstituted phenyl group, or a salt thereof, according to claim 1 .

3. R in the formula (1) １ represents a 2-alkoxyphenyl group, a 4-alkoxyphenyl group, a 2,3-dialkoxyphenyl group, a 2,4-dialkoxyphenyl group, a 2,5-dialkoxyphenyl group, a 2,6-dialkoxyphenyl group, a 3,4-dialkoxyphenyl group, a 3,5-dialkoxyphenyl group, a 2,3,4-trialkoxyphenyl group, a 2,4,5-trialkoxyphenyl group, or a 2,4,6-trialkoxyphenyl group, or a salt thereof.

4. A photosensitizer comprising the compound according to claim 1 or 2 or a salt thereof.

5. The photosensitizer according to claim 4, which is used in photodynamic therapy.

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